Microparticules à base de copolymère d’acides lactique et glycolique 

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In vitro drug release from PLGA microparticles

The term drug release refers to a complex phenomenon involved on the transport and the release of drugs from a dosage form (41,149). It is impossible de list all potentially involved phenomenon, but Siepmann et al., (38,45) cited a few of them:
• Wetting of the system’s surface with water.
• Water penetration into the device (e.g., via pores and/or through continuous polymeric networks).
• Phase transitions of (polymeric) excipients (e.g., glassy-to rubbery-phase transitions).
• Drug and excipient dissolution.
• Drug and/or excipient degradation.
• Creation of water-filled pores.
• Pore closing due to polymer swelling.
• Creation of cracks within release rate limiting membranes.
• Creation of acidic or basic microenvironments within the dosage forms due to degradation products.
• Physical drug-excipient interactions.
• Diffusion of drugs and/or excipients out of the dosage form with potentially time- and/or position-dependent diffusion coefficients.
• Penetration of acids, bases or salts from the surrounding bulk fluid into the drug delivery system.
• Changes in the device geometry and/or dimensions.
• Creation if significant hydrostatic pressure within the delivery system.
Fredenberg et al. identified three possible ways for drug to be released from PLGA-based systems: (i) diffusion through water-filled pores, (ii) diffusion through the polymeric matrix and (iii) degradation or erosion of polymer matrix. However, The mass transport mechanisms controlling drug release from PLGA microparticles can be rather complex, including other types of Physico-chemical phenomena, such as water penetration into the system, drug dissolution (149), drug – PLGA interactions (90,101), the creation of water-soluble monomers and oligomers and the latter’s diffusion into the surrounding bulk fluid, PLGA swelling, pore closure effects (150) and osmotic effects due to the presence of water-soluble compounds within the systems (151). Due to the complexity of the system, it is not always clear to know which of the process is dominating.

In vitro drug release mechanisms

Diffusion through water filled pores

The diffusion through water filled pores is very depends on the porous structure of the polymer and the processes that promote pore formation and closure (41). These pores must be continuous from the drug molecules to the surface of the system and sufficiently large to allow the solute to pass through (41). In many studies, the diffusion through water filled pores has been used to describe the first stage of the release period, before the onset of polymer erosion (152–154). However, other studies, mentioned that the pores are formed by erosion. Indeed, these pores are created as polymer degrades and generates small monomers and oligomers which diffuse out of the particles generating interconnected pores that provide a route of escape for drug (155,156) (Figure 17 b).

Diffusion through the polymer

The diffusion through the polymer is possible for hydrophobic drugs of low molecular weight (64,157). However, the drug must be dissolved in water before being released, and this process could decrease the overall release rate (43,149). The diffusion is not dependent on the porous structure of the system but the physical state of the polymer is the most important parameter. Indeed, the diffusion coefficient increases at the transition from the glassy to the rubbery state (71,158,159). It can be explained by the fact that the Tg of the original polymer is above 37°C but upon exposure to water, the plasticizing effect of water transfers the polymer into the rubbery state (57,79). The diffusivity is often higher in polymers with low Mw, because of the high flexibility of the polymer chains (29,32,79) (Figure 17 a).

Degradation/Erosion of polymeric matrix

The erosion is the chain scission process by which polymer chains are cleaved into oligomers and monomers (58). It is a rate controlling release mechanism during the final period of drug release and the main release mechanism for low Mw PLGA formulations (114,160,161). It has been reported that during the first time of degradation, the Mw of the polymer decreased rapidly without a significant weight loss of the observed PLGA microparticles. The Significant weight loss started only after the critical Mw of 15 KDa was reached (162–164). This critical Mw was found to be identical for all polymer investigated. However, the time-period to reach the critical Mw is dependent on the polymer composition and initial Mw (162) (Figure 17 d).

Swelling of polymeric matrix

The swelling is the mechanism that controlled the drug release at the end of the second phase. Indeed, Gasmi et al., have shown that substential microparticles swelling coicided the begening of the third drug release phase (rapid) from PLGA microparticles (69,71,165). This swelling might result from the osmotic pressure created within the system and generated by the accumulation of the shorter chain degradation products which are dissolved. The swelling starts as soon as the polymeric structure becomes sufficiently weak (69,71,165,166) (Figure 17 c).
According to Siepmann et al., there are two most important consequences of polymer swelling in a controlled release matrix system (43):
• The length of the diffusion pathways increases, resulting in dacreasing drug concentration and , thus potentially decreasing drug release rates.
• The mobility of the macromolecules significantly increases, resulting in increased drug mobility and, thus potentielly increasing drug release rates.
Depending on the type of polymer and type of drug delivery system, one of these effects potentieally dominates, resulting in decreasing or increasing drug release (43).

In vitro drug release profiles

Different types of drug release patterns can be observed from PLGA-based microparticles. Figure 18 shows the characteristics of three typical release profiles described in the literature: The monophasic profile, the biphasic profile that is characterized by the initial burst followed by a saturation, and the triphasic release profile which is composed of three phases. Phase I is often described as a burst release phase, phase II is commonly known as a period of a slower release and phase III is described as a rapid release period (41,61).
The monophasic profile is rare. Usually, drug release from PLGA microparticles is bi-phasic, but tri-phasic profile is the most common (41). The release of drug from PLGA microparticles obtained by extraction/evaporation solvent method is typically tri-phasic with a period of burst release, dormancy, and finally a rapid drug release (second burst) (65).
• The 1st Phase (Burst release):
In many formulations, upon placement in the release medium, an initial rapid drug release is observed before the release rate reaching the plateau. This phenomenon is typically referred as “burst release” (63). It can be defined as the amount of drug that releases from microparticles prior the polymer-erosion starts (64). The burst release is mainly attributed to the diffusion of the dissolved drug which is adsorbed to the surface of the particle or the diffusion of the drug molecules through water-filled pores in direct contact with the surface of the particle (65,69,167–173). Previous works suggested that the burst period ends once the material near the exterior of the microparticles is removed (65,69).
Recent researches have focused on the development of strategies to control the burst effect. For example, by altering the preparation method, Fu et al., obtained a homogeneous distribution of drug within the polymeric matrix due to the dissolution of both polymer and drug within the single-phase solution (174). Drug solubility in the mixed solvent system was further improved by increasing its hydrophobicity upon complexation with ionic surfactants. This modification leads to eliminate the initial burst of the drug (174). Some publications review other existing approaches, among those strategies (63,64,175–179):
▪ Modification of the drug (salt form of drugs may be changed, covalent modification of drugs with appropriate compounds…).
▪ Co-solvent system.
▪ Complex formation.
▪ The use of other excipient to modify the release of drug.
▪ Polymer modification.
▪ Surface modification.
▪ Surface extraction.
▪ Coated surfaces.
• The 2nd Phase:
Also called lag-phase. It is characterized by a slow diffusion of the drug through the relatively dense polymeric matrix or the few existing water-filled pores (66). This phase may be caused by pore closure (150,180), polymer-drug interactions or drug-drug interactions (181). Many factors have been found to induce pore closure. Some of these factors are: polymer degradation, the addition of plasticizing agents or increased temperature (67,68,182). The duration of this phase is dependent mainly on polymer characteristics (e.g. Mw, lactic acid: glycolic acid ratio, etc.) and formulation size/geometry (42). In some systems, the lag-phase is negligible, due to a fast degradation of PLGA (85).
In a study on the release of octreotide acetate from PLGA-based microparticles, a slow release was observed over the first 24 h of drug release (62). This phase was correlated with the formation of a non-porous film at the surface of the microparticles following a polymer rearrangement. This polymer rearrangement was the origin of the reduction in surface porosity, the closing of pores at the surface, and the formation of a skin layer (62,77,183).
In another study, Berkland et al. hypothesized that the formation of a dense polymer skin and the closing of pores may be a result of the high concentration of rhodamine distributed toward the surface of the microparticles (184). Indeed, the hydrophilic rhodamine localized in the surface causes a rapid water uptake which leads to a rapid polymer degradation forming a porous structure near the surface. Continued polymer degradation produces a rubbery PLGA at or near the surface due to a decrease in polymer glass transition temperature, producing a dense skin covering the eroding interior (184). In an another study on the release of leuprolide acetate from PLGA-based microparticles, SEM pictures showed that the interior of the microparticles is porous while the surface remained non-porous during the second release phase (66). It is logical to assume that the low porosity at the surface was the raison of the slow release.
The co-polymer composition was also shown to be important in controlling the release rate from PLGA-based microparticles. It has been suggested that the length of the lag phase during the release profile of macromolecules from PLGA-based microparticles is dependent on the rate of polymer degradation (185). Consequently, the release profiles of macromolecules from microparticles depend on the co-polymer composition and the Mw of PLGA (42,185). Indeed, published works reported that the length of the lag phase and the duration of protein release increased with higher Mw of PLGA and with lower glycolide content. This can be explained by the fact that this polymer takes up water easier and degrades slower (157). It has been also proved that, blending a low MW-PLGA with a high Mw-PLGA could be used in order to reduce the lag phase. Indeed, the lag-phase was reduced from 1 month to approximatively 15 days by blending 25 KDa PLGA with 75 KDa PLGA (158).
Gasmi et al. provided evidence that the second drug release phase depends mainly on the initial drug loading (69). They explained the release of dexamethasone from PLGA-based microparticles prepared by an oil-in-water solvent extraction/evaporation method as follows: at very high drug loadings, a part of the drug which does not have a direct access to the surface of microparticles is effectively trapped by the PLGA and takes time to diffuse through the polymeric barrier. Importantly, a saturated drug solution is most probably provided within the system. This could be explained by the very limited amounts of water available for drug dissolution in the PLGA-based microparticles at this phase (69). These saturated drug solutions combined with sink conditions provided outside the microparticles lead to about constant drug concentration gradients (69,186,187). Consequently, a constant drug release rates (“Zero order phase”) is observed (43).
• The 3rd phase:
This phase is characterized by a faster release of the drug. It is sometimes called the second burst. The release during this phase is caused mainly by a massive erosion of the polymer and the swelling /deformation of the microparticles (41,188). However, the beginning of the second burst was attributed to the point at which a fully continuous porous network had formed within the particle (65,189). In other studies, it has been confirmed that, the third phase starts when the autocatalytic degradation occurs because of limited diffusion of soluble degradation products during the lag-phase. In fact, a sufficiently, acidic environment can be created in the interior of the particle to cause essentially the complete degradation of polymer in the core (91,128,156,190). Another study confirms the role of pore closing/opening in PLGA-based microspheres on drug release. Indeed, the dissolved drug and polymer degradation products cause increased osmotic pressure (90,151). This phenomenon may lead to a polymer rupture. Consequently, previous isolated pores become open and drug molecules are released (150).

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Table of contents :

I. Introduction générale 
II. Contexte bibliographique
II.1. Généralités
II.2. Copolymère d’acides lactique et glycolique
II.2.1. Formules chimiques et synthèse
II.2.2. Propriétés physico-chimiques
II.2.3. Biodégradation
II.3. Microparticules à base de copolymère d’acides lactique et glycolique
II.3.1. Caractéristiques générales
II.3.2. Techniques de préparation
II.3.2.1. Emulsion-évaporation et/ou extraction de solvant
II.3.2.2. Séparation de phase/coacervation
II.3.2.3. Atomisation-séchage
II.3.2.4. Autres méthodes
II.4. Mécanismes et profils de libération in vitro de substance active
II.4.1. Mécanismes de libération de substance active
II.4.1.1. Diffusion à travers des pores remplis d’eau
II.4.1.2. Diffusion à travers la matrice polymérique
II.4.1.3. Dégradation et érosion de la matrice polymérique
II.4.2. Profils de libération in vitro
II.4.2.1. Profil monophasique
II.4.2.2. Profil biphasique
II.4.2.3. Profil triphasique
III. Objectifs de recherche
CHAPTER I:INTRODUCTION
I. State of the art
II. Poly(lactic-co-glycolic) acid (PLGA)
II.1. Physicochemical properties of PLGA
II.2. Biodegradation of PLGA
II.3. Factors affecting the biodegradation of PLGA
I.3.1. Effect of polymer composition
I.3.2. Effect of molecular weight (Mw)
I.3.3. Effect of drug type
I.3.4. Effect of pH
I.3.5. Effect of size and shape of the matrix
I.3.6. Effect of enzymes
II.4. Biocompatibility of PLGA
II. PLGA microparticles
II.1. Microparticles characteristics
II.2. Microparticles preparation techniques
II.3.1. Conventional preparation techniques
II.3.1.1. Solvent extraction/evaporation techniques
II.3.1.2. Coacervation technique
II.3.1.3. Spray-drying technique
II.3.2. Novel preparation techniques
II.3.2.1. Microfluidic platforms
II.3. Process parameters influencing the microparticles characteristic
II.3.1. Process parameters affecting microparticle size
II.3.2. Process parameters affecting microparticle porosity
II.3.3. Parameters affecting encapsulation efficiency
III. In vitro drug release from PLGA microparticles
III.1. In vitro drug release mechanisms
III.3.1. Diffusion through water filled pores
III.3.2. Diffusion through the polymer
III.3.3. Degradation/Erosion of polymeric matrix
III.3.4. Swelling of polymeric matrix
III.2. In vitro drug release profiles
III.3. Factors influencing the in vitro drug release
III.3.1. Polymer properties
III.3.1.1. Influence of the copolymer composition
III.3.1.2. Influence of the polymer molecular weight
III.3.2. Formulation parameters
III.3.2.1. Influence of microparticle size
III.3.2.2. Influence of microparticle porosity
III.3.2.3. Influence of drug loading
III.3.2.4. Influence of the nature and the distribution of the encapsulated drug
III.3.3. Experimental conditions
III.3.3.1. Influence of medium composition
III.3.3.2. Influence of incubation temperature
III.3.3.3. Influence of agitation
IV. Research objectives
CHAPTER II:MATERIALS AND METHODS
I. Materials
II. Methods
II.1. Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Drug dispersions
II.1.1. Microparticle preparation
II.1.2. Microparticle characterization
II.1.2.1. Microparticle size
II.1.2.2. Practical drug loading
II.1.2.3. X ray powder diffraction
II.1.2.4. Differential scanning calorimetry (DSC)
II.1.2.5. Drug release measurements from ensembles of microparticle
II.1.2.6. Drug release measurements from single microparticles
II.1.2.7. Swelling of single microparticles
II.1.2.8. Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectrometry (EDS)
II.2. Towards a better understanding of the release mechanisms of caffeine from PLGA microparticles
II.2.1. Microparticle preparation
II.2.2. Microparticle characterization
II.2.2.1. Microparticle size
II.2.2.2. Practical drug loading
II.2.2.3. X ray powder diffraction
II.2.2.4. Differential scanning calorimetry (DSC)
II.2.2.5. Drug release measurements from ensembles of microparticles
II.2.2.7. Swelling of single microparticles
II.2.2.8. Polymer degradation
II.2.2.9. Scanning Electron Microscopy (SEM)
II.3. Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Impact of the temperature.
II.3.1. Microparticle preparation
II.3.2. Microparticle characterization
II.3.2.1. Microparticle morphology and size
II.3.2.2. Practical drug loading
II.3.2.3. Drug release measurements from ensembles of microparticles
II.3.2.4. Drug release measurements from single microparticles
II.3.2.5. Swelling of single microparticles
II.3.2.6. Differential scanning calorimetry (DSC)
II.3.2.7. Scanning Electron Microscopy (SEM)
II.3.2.8. Gel Permeation Chromatography (GPC)
II.3.2.9. Drug solubility measurements
CHAPTER III:RESULTS AND DISCUSSION
Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Drug dispersions
I. Introduction
II. Materials and methods
II.1. Materials
II.2. Microparticle preparation
II.3. Microparticle characterization
II.3.1. Microparticle size
II.3.2. Practical drug loading
II.3.3. X ray powder diffraction
II.3.4. Differential scanning calorimetry (DSC)
II.3.5. Drug release measurements from ensembles of microparticle
II.3.6. Drug release measurements from single microparticles
II.3.7. Swelling of single microparticles
II.3.8. Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray Spectrometry (EDS)
III. Results and Discussion
III.1. Ensembles of microparticles
III.2. Single microparticles
III.3. Drug release mechanisms
IV. Conclusion
Towards a better understanding of the release mechanisms of caffeine from PLGA microparticles
I. Introduction
II. Materials and methods
II.1. Materials
II.2. Microparticle preparation
II.3. Microparticle characterization
II.3.1. Microparticle size
II.3.2. Practical drug loading
II.3.4. Differential scanning calorimetry (DSC)
II.3.5. Drug release measurements from ensembles of microparticles
II.3.6. Drug release measurements from single microparticles
II.3.7. Swelling of single microparticles
II.3.8. Polymer degradation
III. Results and Discussion
III.1. Ensembles of microparticles
III.2. Drug release mechanisms
IV. Conclusion
Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles:
Impact of the temperature
I. Introduction
II. Materials and methods
II.1. Materials
II.2. Microparticle preparation
II.3. Microparticle characterization
II.3.1. Microparticle morphology and size
II.3.3. Drug release measurements from ensembles of microparticles
II.3.4. Drug release measurements from single microparticles
II.3.5. Swelling of single microparticles
II.3.6. Differential scanning calorimetry (DSC)
II.3.7. Scanning Electron Microscopy (SEM)
II.3.8. Gel Permeation Chromatography (GPC)
II.3.9. Drug solubility measurements
III.1. Drug release from ensembles of microparticles
III.2. Polymer degradation, bulk fluid pH and outer microparticle morphology
III.3. Drug release from and swelling of single microparticles
III.4. Hypothesized drug release mechanisms
IV. Conclusion
GENERAL CONCLUSION

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