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Controlled Drug Release



ANISSA Permatadietha Ardiellaputri, 1006661203 Chemical Engineering Department, Universitas Indonesia

Biodegradable materials are natural or synthetic in origin and are degraded in vivo, either enzymatically or nonenzymatically or both, to produce biocompatible, toxicologically safe by-products which are further eliminated by the normal metabolic pathways. The number of such materials that are used in or as adjuncts in controlled drug delivery has increased dramatically over the past decade. The basic category of biomaterials used in drug delivery can be broadly classified as (1) synthetic biodegradable polymers, which includes relatively The number of such materials that are used in or as adjuncts in controlled drug delivery has increased dramatically over the past decade. The basic category of biomaterials used in drug delivery can be broadly classified as (1) synthetic biodegradable polymers, which includes relatively. PLGA is hydrolytically unstable, they degrade by hydrolytic attack of their ester bonds (Griffith, 2000) resulting in the formation of lactic and glycolic acids. An important attribute of these polymers is the possibility to modulate the degradation rate of a delivery system by changing, e. g. chemical composition (homo-or copolymers of lactic and glycolic acid) or the physical properties (molecular weight, glass-transition temperature) and consequently to control the drug release (Wu and Ding, 2004). PHYSIOCHEMICAL PROPERTIES OF PLGA Poly(lactic acid) (PLA) is a linear aliphatic thermoplastic polyester, produced by polymerization of lactide a cyclic dimer derived from lactic acid. It is a chiral molecule and can be produced as poly (L-lactide). PLA is soluble in common organic solvent. Poly(glycolic acid) (PGA) is the simple linear, aliphatic polyester. Since PGA is highly crystalline, it has a high melting point and low solubility in organic solvents. PGAs high crystallinity is because of its chemical structure lacking the methyl side groups of the PLA (Nieddu et al., 2009). PLGA is a copolymer of lactide and glycolide, which is synthesized by means of random ring-opening copolymerization of two different monomers, the cyclic dimers (1, 4-dioxane-2, 5-diones) of glycolic acid and lactic acid (Figure 1). When PGA randomly copolymerized (30-50 %) with PLA, successive monomeric units (of glycolic or lactic acid) are linked together in PLGA by ester linkages, thus yielding a linear, amorphous aliphatic polyester product . It also make PLGA retains physical properties more readily amenable to processing (those of low-melting thermoplastic with good solubility in common solvents). The degradation rate of PLGA is much faster than that of PLA due to the component glycolic acid in the backbone (Baldwin et al., 1998).

Figure 1 Structure of poly lactic-co-glycolic acid (x is the number of lactic acid units and y is number of glycolic acid units) (Source. Gadad A.P et al., 2012)

Physical properties such as the molecular weight affect the mechanical strength of the polymer and its ability to be formulated as a drug delivery device. Also, these properties may control the polymer biodegradation rate and hydrolysis. The mechanical strength, swelling behavior, capacity to undergo hydrolysis and subsequently, the biodegradation rate are directly influenced by the crystallinity of the PLGA polymer. The resultant crystallinity of the PLGA copolymer is dependent on the type and the molar ratio of the individual monomer components (lactide and glycolide) in the copolymer chain. PLGA polymers containing a 50:50 ratio of lactic and glycolic acids are hydrolyzed much faster than those containing a higher proportion of either of the two monomers. It has a glass transition temperature (Tg) of 45C and an inherent viscosity of 0.5-0.8 mPa. The Tgs of the PLGA co-polymers are above the physiological temperature of 37C and hence they are normally glassy in nature.

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Controlled Drug Release

Thus, they have a fairly rigid chain structure, which gives them significant mechanical strength to be formulated as a degradable device. It has been reported that the Tgs of PLGA decrease with the decrease of lactide content in the co-polymer composition with decreasing M.W (Gilding and Reed, 1979). BIOLOGICAL PROPERTIES AND BIODEGRADATION OF PLGA The PLGA co-polymer undergoes degradation in an aqueous environment (hydrolytic degradation or biodegradation) through cleavage of its backbone ester linkages. It has been recorded that the PLGA biodegradation occurs through random hydrolytic chain scissions of the swollen polymer. A three-phase mechanism for PLGA biodegradation has been proposed: 1. Random chain scission process. The M.W. of the polymer decreases significantly, but no appreciable weight loss and no soluble monomer products are formed. 2. In the middle phase, a decrease in M.W. accompanied by a rapid loss of mass and soluble oligomeric and monomer products are formed. 3. Soluble monomer products formed from soluble oligomeric fragments. This phase is that of complete polymer solubilization. PLGA NPs are biodegradable in the body because they undergo hydrolysis of their ester linkages in the presence of water to produce the original monomers, lactic acid and glycolic acid, which are also byproducts of various metabolic pathways in the body under normal physiological conditions (Figure 2).

Figure 2 PLGA undergoes hydrolysis in the body to produce lactic acid and glycolic acid (Source. Kerimoglu and Alarcin., 2012)

Lactic acid, a normal byproduct of anaerobic metabolism in the human body, which is incorporated into the tricarboxylic acid (TCA) cycle and is metabolized and subsequently eliminated from the body as carbon dioxide and water. Glycolic acid is either excreted unchanged in the kidney or it enters the tri-carboxylic acid cycle and eventually eliminated as carbon dioxide and water. The degradation time of PLGA can be controlled from weeks to over a year by varying both the ratio of monomers and the processing condition. The polymer containing a 50:50 ratio of lactic and glycolic acids is hydrolyzed much faster than those containing higher proportions of either of the two monomer (Atala and Robert, 2002). Hydrolytic degradation of members of the polylactide/ glycolide family proceeds through four stages(Figure 3). First stage of water diffusion followed by second stage, in which oligomers with acidic end-groups autocatalyze the hydrolysis reaction. A critical molecular weight is reached at the beginning of third stage, and oligomers start to diffuse out from the polymer. Water molecules diffuse into the void created by the removal of the oligomers, which in turn encourages oligomers diffusion. Marked decrease in polymer mass and a sharp increase in the drug release rate occur during third stage as the drug diffuses from the porous regions. In fourth stage, polymeric matrix become highly porous and degradation proceeds homogeneously and more slowly.

Figure 3 Schematic representation of hydrolytic degradation of polymer (Source. Engineer C. et al., 2011)

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Controlled Drug Release

The role of enzymes in biodegradation of PLGA is still unclear, early literature concluding that spontaneous hydrolysis was the only mechanism. Further work indicates the conclusion that the PLGA biodegradation does not involve any enzymatic activity and is purely through hydrolysis. However, enzymes could potentially play a role in degradation for polymers in the rubbery state and enzymatic role in PLGA breakdown based upon the difference in the in vitro and in vivo degradation rates. FACTORS AFFECTING BIODEGRADATION OF PLGA Effect of composition (Shieve and Anderson, 1997; Lu L., et al., 2000); Alexis F, 2005) Polymer composition is the most important factor to determine the rate of degradation of a delivery matrix, which influence the rate of degradation. A systematic study of polymer composition with its degradation has been shown by many groups. These results show that increase in glycolic acid percentage in the oligomers accelerates the weight loss of polymer. 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. Subsequently PLGA 65:35 shows faster degradation than PLGA 75:25 and PLGA 75:25 than PLGA 85:15. Thus, absolute value of the degradation rate increases with the glycolic acid proportion. Effect of Crystallinity (Tsuji H et al., 2000) The crystallinity of the homopolymer or copolymer comprising the microcapsule may play a significant role in modulating the degradation rate. For semicrystalline polyesters, degradation first occurs in the amorphous domains and later in the crystalline regions. During the degradation process, the crystallinity gradually increases resulting in a high crystalline material which is much more resistant to hydrolysis than the starting polymer. Effect of average molecular weight (Tsuji H et al., 2000) Molecular weight and molecular weight distribution may play a role in the degradation behaviour. A large molecular weight distribution would indicate relatively large numbers of carboxylic end groups which can facilitate the autocatalytic degradation of the polymer chains. Large or wide molecular weight distributions thus would be expected to accelerate the rate of degradation whereas a narrow molecular weight distribution would have fewer carboxylic end groups available for catalysis. Tsuji H and coworkers carried out a study in which two molecular weights of the copolymer were used: 10000 and 20000. It was demonstrated that the 10 000 molecular weight polymer degraded approximately twice as fast as the 20 000 molecular weight polymer. Effect of drug type and effect of drug load (Eniola and Hammer, 2005) Amount of drug loading in the drug delivery matrix plays a significant role on the rate and duration of drug release. Matrices having higher drug content possess a larger initial burst release than those having lower content because of their smaller polymer to drug ratio. However, this drug content effect is attenuated when the drug content reaches a certain level depending upon drug type. Effect of size and shape of the matrix (Eniola and Hammer, 2005) 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. It has also been reported that bulk degradation is faster than pure surface degradation for PLGA, which makes the release of the drug faster from the devices with higher surface area to volume. Effect of pH (Eniola and Hammer, 2005) The in vitro biodegradation/hydrolysis of PLGA showed that both alkaline and strongly acidic media accelerate polymer degradation. However, the difference between the slightly acidic and neutral media is less pronounced due to autocatalysis by the carboxylic end groups. CONCLUSION PLGA polymers have been shown to be excellent delivery carriers for controlled administration of drugs, peptides and proteins due to their biocompatibility and biodegradability. In general, the PLGA degradation and the drug release rate can be accelerated by greater hydrophilicity, increase in chemical interactions among the

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Controlled Drug Release

hydrolytic groups, less crystallinity and larger volume to surface ratio of the device. All of these factors should be taken into consideration in order to tune the degradation and drug release mechanism for desired application.

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