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Physico-chemical properties of poly(lactic-co-glycolic) acid
PLGA is a hetero-copolymer of lactic and glycolic acid obtained by the reaction of copolymerization. The monomers are linked by ester linkages and the result is a linear aliphatic polyester (Figure I.3) [29]. Lactic acid contains an asymmetric carbon making chiral molecule with two enantiomers: D- and L-lactic acid. PLGA typically contains the L and D in equal proportion; it is thus poly D, L-lactic-co-glycolic. Depending on the ratio of lactide : glycolide used for the polymerization, different forms of PLGA can be obtained (eg, PLGA (75:25), PLGA (50:50)…). The physical properties of the polymer such as molecular weight have an influence on the mechanical strength of the polymer and its ability to be designed for the formulation of controlled drug release systems. The presence of the methyl group in lactic acid (Figure I.3) makes it less hydrophilic than glycolic acid. Therefore, a PLGA rich in lactic acid is more hydrophobic, which leads to less water uptake then glycolic acid and have a slower degradation [9]. PLGA is degraded through hydrolysis of ester bonds in the presence of water. The time required for the degradation was related to the proportion of the monomers used in copolymerization reaction. More the glycolic acid content was increased, a faster degradation of the polymer was observed. PLGA with 50:50 ratio of PLA:PGA degraded, approximately, in 50 to 60 days [30]. PLGA can be dissolved in a wide range of organic solvents, including chlorinated solvents, tetrahydrofuran, acetone or ethyl acetate [31]. Its solubility in organic solvents is an important factor for its formulation as controlled drug release system. PLGA is amorphous and characterized by a glass transition temperature (Tg). The latter corresponds to the transition of the polymer from a glassy state to a rubbery state [32]. It is generally higher than the physiological temperature of 37 °C. The polymer viscoelastic properties dependent of the temperature (T):
– If T < Tg: the polymer is in a glassy state
– If T > Tg: the polymer is in the rubbery state
The rubbery state is characterized by a high molecular mobility and therefore, it can undergo more physical and chemical changes than the glassy state. The Tg of the polymer may be decreased when it is mixed with plasticizers which lead to an increase of the elasticity due to the higher flexibility of the polymer, influencing the release kinetics of encapsulated drug from systems based on PLGA [32]. Water is known to was a plasticizer for PLGA [33]. However, when the Tg is increased by the addition of some substances, the phenomenon is considered as an anti-plasticizing effect [34]. It has been reported in the literature that the Tg of the PLGA decreased with a decrease of the lactic acid content in the copolymer, and also with decreasing the molecular weight [33]. The mechanical strength of PLGA is affected, for example, by the molecular weight and the polydispersity index [9].
Biodegradation and biocompatibility of poly (lactic-co-glycolic) acid
The development of biodegradable drug delivery systems requires a good understanding of biodegradation processes as well as cellular and tissue responses that determine their biocompatibility [8]. PLGA is one of the most common biodegradable polymers. It undergoes hydrolysis in the human body, producing lactic acid and glycolic acid that are soluble in water [35] (Figure I.4): Lactic acid is a product of the anaerobic metabolism of the human body which is subsequently incorporated in the tricarboxylic acid cycle, metabolized and eliminated as carbon dioxide and water [36]. Glycolic acid is either eliminated unchanged by the kidney, or it penetrates into the tricarboxylic acid cycle and is eventually excreted as carbon dioxide and water [37]. The degradation products are formed at a very slow rate and therefore they do not affect cellular function because the body metabolizes effectively these two monomers. Thus, they represent minimal systemic toxicity associated with the use of PLGA microparticles as drug release system [38]. Drug entrapped in the PLGA matrix system are released at a sustained manner via diffusion and degradation of the polymer matrix [39]. The role of enzymes in the biodegradation of PLGA is controversial. It has been reported in the literature that spontaneous hydrolysis was the only degradation mechanism [40-41]. Other studies concluded that only a small involvement of enzymes is expected in the early stages of degradation with polymers in the glassy state, while the enzymes may play an important role in the degradation of polymers in the rubbery state. This is based on the differences between the rate of degradation in vivo and in vitro [42- 44].
The evaluation of biocompatibility of PLGA-based drug delivery systems requires an understanding of the acute and chronic inflammatory reactions after implantation of the dosage form [8]. The size, shape and physical-chemical properties of the biomaterial used can influence the intensity and duration of the inflammation and the healing process of the wound. Shive et al. showed that tissue response to injected biodegradable microparticles is characterized by three phases:
Phase I: takes place during the first two weeks following the injection of microparticles, and includes the development of acute and chronic inflammatory responses.
Phase II: was initiated by the prevalence of monocytes and macrophages. The duration of their persistence in the site of injection is determined by the microparticles degradation rate. It is associated with the formation of fibrous granulation tissue and new blood capillaries. It was shown that the PLGA-based microparticles (50:50) induce phase II response of 50 to 60 days [45].
Phase III: the molecular weight of the polymer decreases to the point that the integrity of microparticles cannot be maintained. These latter are divided into small particles which undergo phagocytosis by macrophages and thus lead to complete degradation. The fibrous capsule formed during the second phase is increased during phase III with fibroblasts and neovascularization caused by the loss of volume of the microparticles [8].
Microparticles preparation techniques
Although a number of microencapsulation techniques have developed and reported up today, the choice of technique depends on the nature of the polymer, the drug, the intended use and the duration of treatment. The method of microencapsulation used must meet the following requirements [12]:
The biological activity of the drug should not be affected during the encapsulation process or in the microparticles (final product).
The manufacturing yield of microparticles in the desired size range and encapsulation efficiency should be high.
Table of contents :
RÉSUMÉ DÉTAILLÉ
CHAPTER I. INTRODUCTION
I. State of the art
II. Physico-chemical properties of poly(lactic-co-glycolic) acid
III. Biodegradation and biocompatibility of poly (lactic-co-glycolic) acid
IV. Microparticles preparation techniques
IV.1. Solvent extraction/evaporation technique
IV.2. Coacervation technique
IV.3. Spray-drying technique
V. Factors influencing the production of PLGA-microparticles
V.1. Factors influencing the size of microparticles
V.2. Factors influencing the drug encapsulation efficiency
VI. In vitro drug release
VII. Factors influencing the drug release and degradation of the polymer
– Co-polymer composition
– Polymer molecular weight
– Crystallinity and glass transition temperature
– Nature of the drug
– Size and porosity of microparticles
– pH
– Enzyme
– In vitro drug release conditions (gel versus tubes)
VIII. Degradation mechanisms of poly(lactic-co-glycolic) acid
IX. Research objectives
CHAPTER II: Materials and methods
I.MATERIALS
II.METHODS
II.1. Acid drug: ketoprofen-loaded PLGA Microparticles
II.1.1 Microparticle preparation
II.1.2 Microparticles characterization
II.1.2.1 Microparticle size analysis
II.1.2.2 Practical drug loading
II.1.2.3 X-ray powder diffraction
II.1.2.4 In vitro drug release studies
II.1.2.5 Differential scanning calorimetry
II.1.2.6 Gel permeation chromatography
II.1.2.7 Swelling behavior of individual microparticles
II.1.3. Drug solubility measurements
II.2. Basic drug: Prilocaine-loaded PLGA Microparticles and films
II.2.1. Preparation of PLGA microparticles
II.2.2. Microparticles characterization
II.2.2.1 Particle size
II.2.2.2 Practical drug loading
II.2.2.3 X-ray powder diffraction
II.2.2.4 In vitro drug release measurements
II.2.2.5 Differential scanning calorimetry
II.2.2.6 Gel permeation chromatography
II.2.2.7 Scanning electron microscopy
II.2.2.8 Swelling behavior of individual microparticles
II.2.3. Preparation of thin PLGA films
II.2.4. Film characterization
II.3. Neutral drug: Dexamethasone-loaded PLGA microparticles
II.3.1. Microparticles preparation
II.3.2 Microparticles characterization
II.2.3.1 Particle size analysis
II.2.3.2 Determination of practical drug loading
II.2.3.3 In vitro drug release studies .
II.2.3.4 Determination of PLGA molecular weight
II.2.3.5 Differential scanning calorimetry
II.2.3.6 X-ray powder diffraction
II.2.3.7 Scanning electron microscopy
II.2.3.8 Swelling behavior of individual microparticles
CHAPTER III: RESULTS AND DISCUSSION
Part 1: Acid drug «Does PLGA microparticle swelling control ketoprofen release? »
III.1.1 Key properties of microparticles
III.1.2 Swelling kinetics of individual microparticles and correlation with drug release
III.1.3 Conclusion
Part 2: Basic drug «Importance of microparticle swelling for the control of prilocaine release».
III.2.1. In vitro drug release
III.2.2 Physico-chemical characterization of microparticles and films
III.2.3 Individual microparticle swelling
III.2.4 Conclusion
Part 3: Neutral Drug «Impact of swelling on dexamethasone release from PLGA-based microparticles».
III.3.1 Microparticle morphology, size, encapsulation efficiency and drug loading
III.3.2 Physico-chemical characterization of PLGA-loaded microparticles
III.3.3 In vitro drug release studies
III.3.4 Swelling behavior of Individual microparticles
III.3.5 Conclusion
GENERAL CONCLUSION AND PERSPECTIVES
REFERENCES
RÉSUMÉ
SUMMARY
