Síntese e caracterização do poli(ácido láctico) para potencial uso em sistemas de liberação controlada de fármacos

With the advances in medicine, life expectancy of the world population has grown considerably in recent decades. Studies have been performed in order to maintain the quality of life through the development of new drugs and new surgical procedures. Biomaterials is an example of the researches to improve quality of life, and its use goes from the reconstruction of tissues and organs affected by diseases or other types of failure, to use in drug delivery system able to prolong the drug in the body and increase its bioavailability. Biopolymers are a class of biomaterials widely targeted by researchers since they have ideal properties for biomedical applications, such as high biocompatibility and biodegradability. Poly (lactic acid) (PLA) is a biopolymer used as a biomaterial and its monomer, lactic acid, is eliminated by the Krebs Cycle (citric acid cycle). It is possible to synthesize PLA through various synthesis routes, however, the direct polycondensation is cheaper due the use of few steps of polymerization. In this work we used experimental design (DOE) to produce PLAs with different molecular weight from the direct polycondensation of lactic acid, with characteristics suitable for use in drug delivery system (DDS). Through the experimental design it was noted that the time of esterification, in the direct polycondensation, is the most important stage to obtain a higher molecular weight. The Fourier Transform Infrared (FTIR) spectrograms obtained were equivalent to the PLAs available in the literature. Results of Differential Scanning Calorimetry (DSC) showed that all PLAs produced are semicrystalline with glass transition temperatures (Tgs) ranging between 36 - 48 °C, and melting temperatures (Tm) ranging from 117 to 130 °C. The PLAs molecular weight characterized from Size Exclusion Chromatography (SEC), varied from 1000 to 11,000 g/mol. PLAs obtained showed a fibrous morphology characterized by Scanning Electron Microscopy (SEM)

Síntese e caracterização do poli(ácido láctico) para potencial uso em sistemas de liberação controlada de fármacos

With the advances in medicine, life expectancy of the world population has grown considerably in recent decades. Studies have been performed in order to maintain the quality of life through the development of new drugs and new surgical procedures. Biomaterials is an example of the researches to improve quality of life, and its use goes from the reconstruction of tissues and organs affected by diseases or other types of failure, to use in drug delivery system able to prolong the drug in the body and increase its bioavailability. Biopolymers are a class of biomaterials widely targeted by researchers since they have ideal properties for biomedical applications, such as high biocompatibility and biodegradability. Poly (lactic acid) (PLA) is a biopolymer used as a biomaterial and its monomer, lactic acid, is eliminated by the Krebs Cycle (citric acid cycle). It is possible to synthesize PLA through various synthesis routes, however, the direct polycondensation is cheaper due the use of few steps of polymerization. In this work we used experimental design (DOE) to produce PLAs with different molecular weight from the direct polycondensation of lactic acid, with characteristics suitable for use in drug delivery system (DDS). Through the experimental design it was noted that the time of esterification, in the direct polycondensation, is the most important stage to obtain a higher molecular weight. The Fourier Transform Infrared (FTIR) spectrograms obtained were equivalent to the PLAs available in the literature. Results of Differential Scanning Calorimetry (DSC) showed that all PLAs produced are semicrystalline with glass transition temperatures (Tgs) ranging between 36 - 48 °C, and melting temperatures (Tm) ranging from 117 to 130 °C. The PLAs molecular weight characterized from Size Exclusion Chromatography (SEC), varied from 1000 to 11,000 g/mol. PLAs obtained showed a fibrous morphology characterized by Scanning Electron Microscopy (SEM)

Poly(ethylene-co-methyl acrylate)/poly(caprolactone) triol blends for drug delivery systems: characterization and drug release

Poly(ethylene-co-methyl acrylate) (EMA) and poly (caprolactone) triol (PCL-T) blends, a biodegradable aliphatic polyester with low molecular weight and moderate water solubility containing diltiazem hydrochloride (DZ) were studied in terms of the thermal and morphological properties, and drug release mechanism. An increase in the PCL-T content in the EMA/PCL-T/DZ films decreased the degree of DZ crystallinity. Drug release from these films is temperature-dependent, and it is possible to modify the drug release rate by adjusting the EMA/PCL-T composition of the blends. The mechanism of drug release is governed by PCL-T melting and PCL-T leaching from EMA matrix.

Poly(lactic acid-glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis

Background and purpose: The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis. Experimental approach: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund`s adjuvant or entrapped in poly(lactic acid-glycolic acid) (PLGA) nanoparticles at different concentrations (1 mu g, 5 mu g, 10 mu g, 20 mu g or 40 mu g center dot 50 mu L-1). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines. Key results: Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non-treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 mu g center dot 50 mu L-1) was more effective than `free` P10 emulsified in Freund`s adjuvant (20 mu g center dot 50 mu L-1), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 mu g center dot 50 mu L-1) were most effective. Treatment with P10 emulsified in Freund`s adjuvant (20 mu g center dot 50 mu L-1) or P10 entrapped within PLGA (1 mu g center dot 50 mu L-1) were accompanied by high levels of interferon-gamma in lung. Conclusions and implications: Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.

Effect Of Confined Impinging Jet Mixing Processing Parameters On Poly (Lactic Acid) Nanoparticle Morphology

Biodegradable nanoparticles are at the forefront of drug delivery research as they provide numerous advantages over traditional drug delivery methods. An important factor affecting the ability of nanoparticles to circulate within the blood stream and interact with cells is their morphology. In this study a novel processing method, confined impinging jet mixing, was used to form poly (lactic acid) nanoparticles through a solvent-diffusion process with Pluronic F-127 being used as a stabilizing agent. This study focused on the effects of Reynolds number (flow rate), surfactant presence in mixing, and polymer concentration on the morphology of poly (lactic acid) nanoparticles. In addition to looking at the parameters affecting poly (lactic acid) morphology, this study attempted to improve nanoparticle isolation and purification methods to increase nanoparticle yield and ensure specific morphologies were not being excluded during isolation and purification. The isolation and purification methods used in this study were centrifugation and a stir cell. This study successfully produced particles having pyramidal and cubic morphologies. Despite successful production of these morphologies the yield of non-spherical particles was very low, additionally great variability existed between redundant trails. Surfactant was determined to be very important for the stabilization of nanoparticles in solution but appears to be unnecessary for the formation of nanoparticles. Isolation and purification methods that produce a high yield of surfactant free particles have still not been perfected and additional testing will be necessary for improvement.¿

Synthesis and Characterization of Lactic Acid Oligomers: Evaluation of Performance as Poly(Lactic Acid) Plasticizers

The use of fully bio-based and biodegradable materials for massive applications, such as food packaging, is an emerging tendency in polymer research. But the formulations proposed in this way should preserve or even increase the functional properties of conventional polymers, such as transparency, homogeneity, mechanical properties and low migration of their components to foodstuff. This is not always trivial, in particular when brittle biopolymers, such as poly(lactic acid) (PLA), are considered. In this work the formulation of innovative materials based on PLA modified with highly compatible plasticizers, i.e. oligomers of lactic acid (OLAs) is proposed. Three different synthesis conditions for OLAs were tested and the resulting additives were further blended with commercial PLA obtaining transparent and ductile materials, able for films manufacturing. These materials were tested in their structural, thermal and tensile properties and the best formulation among the three materials was selected. OLA with molar mass (Mn) around 1,000 Da is proposed as an innovative and fully compatible and biodegradable plasticizer for PLA, able to replace conventional plasticizers (phthalates, adipates or citrates) currently used for films manufacturing in food packaging applications.

Effect of drug loading and plasticizer on drug release from poly lactic acid film

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Effect of drug loading and plasticizer on drug release from poly lactic acid film

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Biodegradable polyanhydrides as drug delivery systems

Polyanhydrides are useful biodegradable vehicles for controlled drug delivery. In aqueous media the breaking of the anhydride bonds resulting in gradually polymer fragments collapse and release drugs in a controlled manner. In this study, two new biodegradable polyanhydrides copolymers were synthesised using a melt-polycondensation method. The first is poly (bis (p-carboxyphenoxy)-2-butene-co-sebacic acid) (CP2B: SA), which has double bonds along the polymer backbone. The second is crosslinked poly (glutamic acid-sebacic acid-co-sebacic acid) (GluSA: SA), where the conjugated unit of glutamic acid with sebacic acid (glutamic acid-SA) acted as a crosslinking fragment in producing the crosslinking polymer. The two polymers were applied to preparation of microspheres with bovine serum albumin (BSA) as a model protein, using both double emulsion solvent evaporation and spray drying methods. The characterisation of the microspheres, morphology, particle size, and drug loading, was studied. The in vitro hydrolytic degradation of polymers and blank microspheres was monitored using IR, GPC, and DSC. In vitro drug release behaviour was also studied. Though the studies showed cleavages of anhydride bonds occurred rapidly (<5 days), bulks of the polymer microspheres could be observed after a few weeks to a month; and only around 10-35% of the protein was detectable in a four-week period in vitro. We found the pH of the medium exerts a large impact on the release of the protein from the microspheres. The higher the pH, the faster the release. Therefore the release of the protein from the polyanhydride microspheres was pH-sensitive due mainly to the dissolution of monomers from the microspheres.

Synthesis, characterization, and preliminary application of new biocompatible nanogels useful as anticancer drug delivery systems

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Compatible Ternary Blends of Chitosan/poly(vinyl alcohol)/poly(lactic acid) Produced by Oil-in-Water Emulsion Processing

Ternary compatible blends of chitosan, poly(vinyl alcohol), and poly(lactic acid) were prepared by an oil-in-water (O/W) emulsion process. Solutions of chitosan in aqueous acetic acid, poly(vinyl alcohol) (PVA) in water, and poly(lactic acid) (PLA) in chloroform were blended with a high shear mixer. PVA was used as an emulsifier to stabilize the emulsion and to reduce the interfacial tension between the solid polymers in the blends-produced. It proved to work very well because the emulsions were stable for periods of days or weeks and compatible blends were obtained When PVA was added. This effect was attributed to a synergistic effect of PVA and chitosan because the binary blends PVA/PLA and chitosan/PLA were completely incompatible; The blends were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal mechanical analysis (TMA), stress strain tests, and Fourier transform infrared spectroscopy (FTIR). The results indicated that despite the fact that the system contained distinct phases some degree of molecular miscibility occurred when the three components were present in the blend.

Rheological, mechanical and mucoadhesive properties of thermoresponsive, bioadhesive binary mixtures composed of poloxamer 407 and carbopol 974P designed as platforms for implantable drug delivery systems for use in the oral cavity

This study described the formulation and characterisation of the viscoelastic, mechanical and mucoadhesive properties of thermoresponsive, binary polymeric systems composed of poloxamer (P407) and poly(acrylic acid, C974P) that were designed for use as a drug delivery platform within the oral cavity. Monopolymeric and binary polymeric formulations were prepared containing 10, 15 and 20% (w/w) poloxamer (407) and 0.10-0.25% (w/w) poly(acrylic acid, 934P). The flow theological and viscoelastic properties of the formulations were determined using controlled stress and oscillatory rheometry, respectively, the latter as a function of temperature. The mechanical and mucoadhesive properties (namely the force required to break the bond between the formulation and a pre-hydrated mucin disc) were determined using compression and tensile analysis, respectively. Binary systems composed of 10% (w/w) P407 and C934P were elastoviscous, were easily deformed under stress and did not exhibit mucoadhesion. Formulations containing 15 or 20% (w/w) Pluronic P407 and C934P exhibited a sol-gel temperature T(sol/gel), were viscoelastic and offered high elasticity and resistance to deformation at 37 degrees C. Conversely these formulations were elastoviscous and easily deformed at temperatures below the sol-gel transition temperature. The sol-gel transition temperatures of systems containing 15% (w/w) P407 were unaffected by the presence of C934P; however, increasing the concentration of C934P decreased the T(sol/gel) in formulations containing 20%(w/w) P407. Rheological synergy between P407 and C934P at 37 degrees C was observed and was accredited to secondary interactions between these polymers, in addition to hydrophobic interactions between P407 micelles. Importantly, formulations composed of 20% (w/w) P407 and C934P exhibited pronounced mucoadhesive properties. The ease of administration (below the T(sol/gel)) in conjunction with the viscoelastic (notably high elasticity) and mucoadhesive properties (at body temperature) render the formulations composed of 20% (w/w) P407 and C934P as potentially useful platforms for mucoadhesive, controlled topical drug delivery within the oral cavity. (c) 2009 Published by Elsevier B.V.

Volatile products and new polymer structures formed on Co-60 gamma-radiolysis of poly(lactic acid) and poly(glycolic acid)

A gas product analysis has been conducted on gamma-irradiated samples of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA) by means of gas chromatography. The major volatile products have been identified to be CO, CO2, CH4 and C2H6 for PLA, and CO and CO2 for PGA. In addition, the yield of evolved gases for PLA has been found to be 1.81 for CO2, 0.98 for CO, 0.026 for CH4 and 0.012 for C2H6; and that for PGA to be 1.70 for CO2 and 0.42 for CO. The new chain ends formed due to gamma-induced bond cleavage in PLA have been assigned to CH3-CH2-CO-O- and CH3-CH2-O-CO-, and the G values for formation of these chain ends were found to be 1.9 and 0.6, respectively. The G value for chain scission reported previously of 2.3 is comparable with that for the formation of the propanoic acid end group. (C) 1997 Elsevier Science Limited.

Mechanical characterization of polyhydroxyalkanoate and poly (lactic acid) blends

In this work, the mechanical behavior of polyhyroxyalkanoate (PHA)/poly(lactic acid) (PLA) blends is investigated in a wide range of compositions. The mechanical properties can be optimized by varying the PHA contents of the blend. The flexural and tensile properties were estimated by different models: the rule of mixtures, Kerner–Uemura–Takayanagi (KUT) model, Nicolai–Narkis model and Béla–Pukánsky model. This study was aimed at investigating the adhesion between the two material phases. The results anticipate a good adhesion between both phases. Nevertheless, for low levels of incorporation of PHA (up to 30%), where PLA is expectantly the matrix, the experimental data seem to deviate from the perfect adhesion models, suggesting a decrease in the adhesion between both polymeric phases when PHA is the disperse phase. For the tensile modulus, a linear relationship is found, following the rules of mixtures (or a KUT model with perfect adhesion between phases) denoting a good adhesion between the phases over the composition range. The incorporation of PHA in the blend leads to a decrease in the flexural modulus but, at the same time, increases the tensile modulus. The impact energy of the blends varies more than 157% over the entire composition. For blends with PHA weight fraction lower than 50%, the impact strength of the blend is higher than the pure base polymers. The highest synergetic effect is found when the PLA is the matrix and the PHA is the disperse phase for the blend PHA/PLA of 30/70. The second maximum is found for the inverse composition of 70/30. PLA has a heat-deflection temperature (HDT) substantially lower than PHA. For the blends, the HDT increases with the increment in the percentage of the incorporation of PHA. With up to 50% PHA (PLA as matrix), the HDT is practically constant and equal to PLA value. Above this point (PHA matrix), the HDT of the polymer blends increases linearly with the percentage of addition of PHA.