Development and characterization of CyA-loaded poly(lactic acid)–poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with conventional PLA particulate carriers (original) (raw)
Related papers
Journal of Controlled Release, 2004
Homogeneous PLA/insulin solutions containing different amounts of 350, 750 or 1900 Da PEG (0-75 wt.% PEG) were processed by semi-continuous compressed CO 2 anti-solvent precipitation to fabricate protein-loaded polymeric nano-particles. Proper operative conditions (temperature, pressure, CO 2 flow rate and washing time) yielded more than 70% product recovery. Scanning electron microscopy, transmission electron microscopy and light scattering demonstrated that spherical, smooth surfaced particles with size below 1 Am could be obtained. X-ray diffraction analysis showed that the gas anti-solvent process modifies the polylactide crystalline state. PEG concentration and molecular weight were found to affect both optimal operative conditions and morphological and biopharmaceutical properties of the final product. Insulin loading yield dropped from 95% to 65% by increasing the 1900 Da PEG content from 0 to 75 wt.% or the PEG molecular weight from 350 to 1900 Da. The release rate increased significantly as the PEG content in the formulation increases. After 3-month incubation the drug released raised from 10% to 100% by increasing the 1900 Da PEG content from 23 to 7 wt.%. Formulations containing the same 350, 750 or 1900 Da PEG amount (67 wt.% PEG) displayed similar release profiles. Insulin release was found to take place by diffusion mechanism, despite the observation of matrix degradation.
Journal of Biomedical Materials Research, 1999
The development of injectable nanoparticulate "stealth" carriers for protein delivery is a major challenge. The aim of this work was to investigate the possibility of achieving the controlled release of a model protein, human serum albumin (HSA), from poly(ethylene glycol) (PEG)coated biodegradable nanospheres (mean diameter of about 200 nm) prepared from amphiphilic diblock PEG-poly(lactic acid) (PLA) copolymers. HSA was efficiently incorporated into the nanospheres, reaching loadings as high as 9% (w/ w). Results of the in vitro release studies showed that it is possible to control the HSA release by choosing the appropriate nanosphere size, loading, and composition. These results also revealed that, following their release, HSA molecules readsorbed onto the nanospheres surfaces when they were not protected by a PEG coating. We were surprised to observe that in spite of the water uptake of the PLA-PEG nanospheres [11-29% (w/w)], the copolymer did not significantly degrade after a 15-day incubation period. Therefore, we concluded that during this time HSA release from PLA-PEG nanospheres followed a diffusion mechanism where bulk erosion and surface desorption were negligible.
2004
The treatments for which proteins and peptides are prescribed as therapeutic agents require stable levels of active components over prolonged periods. One way to meet these requirements are sustained release systems, generally based on biodegradable polymers, of which polylactide (PLA) and its copolymers (PLGA) with glycolide (GA) are commonly used. An advantage of the lactide/glycolide copolymers is the well documented versatility in polymer properties (via manipulation of the comonomer ratio, molar mass, polymer crystallinity) and the corresponding performance characteristics (e.g., predictable in vivo degradation rates) (1, 2). In addition to the polymer chemistry, drug Poly(DL-lactide-co-glycolide) (PDLLGA) and poly(L-lactide-co-glycolide) (PLLGA) copolymers were prepared by bulk ring opening polymerization of lactide and glycolide and characterized by GPC, FTIR, 1 H NMR and DSC. Copolymers with different molar masses at a constant lactide/glycolide ratio were used for preparation of bovine serum albumin (BSA)-loaded microparticles by the double emulsion w/o/w method. The influence of the copolymer molar mass and composition on the microparticle morphology, size, yield, degradation rate, BSA-loading efficiency and BSA release profile were studied. For microparticles prepared from PDLLGA copolymers, a biphasic profile for BSA release was found and for those made from PLLGA copolymers the release profile was typically triphasic; both of them were characterized by high initial burst release. Possible reasons for such behavior are discussed.
Tropical Journal of Pharmaceutical Research, 2014
Biodegradable poly(D, L-lactide-co-glycolide) (PLGA) and PLGA-based polymeric nanoparticles are widely used for sustained release of protein and peptide drugs. These formulations are usually prepared by water/oil/water (W/O/W) and solid/oil/water (S/O/W) double emulsion solvent evaporation method. Other methods of preparation are nanoprecipitation, emulsion solvent diffusion and salting-out. This review attempts to address the effects of PLGA molecular weight, lactide to glycolide ratio, crystallinity, hydrophilicity as well as nanoparticles preparation variables (e.g., homogenizer speed, surfactants nature and concentration) on the size, morphology, drug encapsulation efficiency and release profile of PLGA mico/nanoparticles. The current knowledge of protein instability during preparation, storage and release from PLGA micro/nanoparticles and protein stabilization approaches has also been discussed in this review.
Poly(lactic acid)/poly(lactic-co-glycolic acid)-based microparticles: an overview
Journal of Pharmaceutical Investigation
Background Poly(glycolic acid), poly(lactic acid) and poly(lactic-co-glycolic acid) were approved by the United States Food and Drug Administration (FDA) in the 1970s as materials for the manufacturing of bioresorbable surgical sutures, but soon became the reference materials for the preparation of sustained release formulations, especially injectable microparticles. Since the 1986 approval of Decapeptyl ® SR, the first product based on PLGA microspheres, more than 15 such products have been approved for clinical use. Area covered This article highlights the key steps that brought to the development of injectable poly(lactic acid)/poly(lacticco-glycolic acid) microparticles for the sustained release of active pharmaceutical ingredients. After a brief history of some pioneering works that opened the field of controlled drug delivery, the key steps that led to the development of these polymers and the approval of the first microparticle-based medicinal products are reviewed. Finally, the general characteristics of these polymers are described and the classical preparation method is explained. Expert opinion Poly(lactic acid)/poly(lactic-co-glycolic acid) microparticles are among the most successful drug delivery systems. The recent approval of new medicinal products based on PLGA microspheres is the proof that pharmaceutical companies have continued to exploit this drug delivery technology. The possible development of generics and the continuous discovery of therapeutic peptides will hopefully further the success of microsphere technology.
European Journal of Pharmaceutics and Biopharmaceutics, 2010
The aim of the present study is to evaluate the effect of polyethylene glycol (PEG) chain organization on various physicochemical aspects of drug delivery from poly(D, L-lactide) (PLA) based nanoparticles (NPs). To reach that goal, two different pegylated polymers of poly(D, L-lactide) (PLA) were synthesized. Polymers used in this study are grafted ones in which PEG was grafted on PLA backbone at 7% (mol/mol of lactic acid monomer), PEG7%-g-PLA, and multiblock copolymer of both PLA and PEG, (PLA-PEG-PLA)n with nearly similar PEG insertion ratio and the same PEG chain length. Blank and ibuprofen-loaded NPs were prepared from both polymers and their properties were compared to PLA homopolymer NPs as a control. Encapsulation efficiency of ibuprofen was found to be approximately 25% for (PLA-PEG-PLA)n NPs and approximately 80% for PEG7%-g-PLA NPs. (PLA-PEG-PLA)n NPs either blank or loaded showed larger hydrodynamic diameter (approximately 200 nm) than PEG7%-g-PLA NPs (approximately 135 nm). A significant difference was observed in the amount of PVA associated with the surface of both NPs where 3.6% and 0.4% (wt/wt) were found on the surface of PEG7%-g-PLA and (PLA-PEG-PLA)n NPs, respectively. No observed difference in zeta potential values for both NPs formulations was found. DSC showed the existence of the drug in a crystalline state inside NPs matrix irrespective of the type of polymer used with either shifting or/and broadening of the drug melting endotherm. Both AFM phase imaging and XPS studies revealed the possibility of existence of more PEG chains at the surface of grafted polymer NPs than (PLA-PEG-PLA)n during NPs formation. The in vitro release behavior showed that (PLA-PEG-PLA)n NPs exhibited faster release rates than PEG7%-g-PLA NPs. The physicochemical differences obtained between both polymers were probably due to different chain organization during NPs formulation. Such pegylated NPs made from these two different polymers might find many applications, being able to convert poorly soluble, poorly absorbed substances into promising drugs, improving their therapeutic performance, and helping them reach adequately their target area. Our results suggest that the properties of pegylated PLA-based NPs can be tuned by proper selection of both polymer composition and polymer architecture.
Journal of Pharmacy and Pharmacology, 2005
Poly(ethylene glycol) (PEG) was used as emulsifier to prepare α-chymotrypsin-loaded poly(lactic-coglycolic) acid (PLGA) microspheres by a solid-in-oil-in-water (s/o/w) technique. The effect of the molecular weight of PEG on protein stability was assessed by the determination of the amount of insoluble aggregates, the activity loss and the magnitude of structural perturbations. In addition, the effect of the molecular weight of PEG on the encapsulation efficiency, microsphere characteristics and release kinetics was investigated. X-ray photoelectron spectroscopy (XPS) was employed to characterize the surface chemistry of the microspheres. Microspheres were prepared using PEG with molecular weight of 6000, 8000, 10000, 12000 and 20000. The results indicate that PEG 20000 was the most effective emulsifier when producing α-chymotrypsin-loaded microspheres with respect to protein stability. The aggregate formation was decreased from 18% to 3%; the protein inactivation and the encapsulation-induced structural perturbations were largely prevented. XPS confirmed that PEG was largely located on the surface of microspheres. The molecular weight of PEG affected the microspheres' characteristics and release kinetics. Microspheres prepared with PEG 20000 showed improved encapsulation efficiency (80%) and a continuous release (for 50 days) with the lowest amount of initial release. It is demonstrated that the selection of the optimum molecular weight of PEG when used as emulsifier in the preparation of microspheres is a critical factor in the development of sustained-release formulations for the delivery of proteins.
Pharmaceutical Research, 2017
Purpose The present study aims to prepare poly(D,L-lactic acid) (PLA) nanofibers loaded by the immunosuppressant cyclosporine A (CsA, 10 wt%). Amphiphilic poly(ethylene glycol)s (PEG) additives were used to modify the hydrophobic drug release kinetics. Methods Four types of CsA-loaded PLA nanofibrous carriers varying in the presence and molecular weight (MW) of PEG (6, 20 and 35 kDa) were prepared by needleless electrospinning. The samples were extracted for 144 h in phosphate buffer saline or tissue culture medium. A newly developed and validated LC-MS/MS method was utilized to quantify the amount of released CsA from the carriers. In vitro cell experiments were used to evaluate biological activity. Results Nanofibers containing 15 wt% of PEG showed improved drug release characteristics; significantly higher release rates were achieved in initial part of experiment (24 h). The highest released doses of CsA were obtained from the nanofibers with PEG of the lowest MW (6 kDa). In vitro experiments on ConA-stimulated spleen cells revealed the biological activity of the released CsA for the whole study period of 144 h and nanofibers containing PEG with the lowest MW exhibited the highest impact (inhibition). Conclusions The addition of PEG of a particular MW enables to control CsA release from PLA nanofibrous carriers. The biological activity of CsA-loaded PLA nanofibers with PEG persists even after 144 h of previous extraction. Prepared materials are promising for l o c a l i m m u n o s u p p r e s s i o n i n v a r i o u s m e d i c a l applications. KEY WORDS cyclosporine A. drug release kinetics. LC-MS/MS. poly(D,L-lactic acid) nanofibers. poly(ethylene glycol) ABBREVIATIONS ConA Concanavalin CsA Cyclosporine A HPLC High-performance liquid chromatography IL-2 Interleukin-2 LC-MS/MS Liquid chromatography tandem mass spectrometry MW Molecular weight PBS Phosphate buffer saline PEG Poly(ethylene glycol) PLA Poly(D,L-lactic acid) PLGA Poly(lactide-co-glycolide) SEM Scanning electron microscopy Jakub Sirc and Zuzana Hampejsova have contributed equally to this work.