Biodegradable microspheres for parenteral delivery.
ABSTRACT Nowadays, emphasis is being laid to development of controlled release dosage forms. Interest in this technology has increased steadily over the past few years. Although oral administration of drugs is a widely accepted route of drug delivery, bioavailability of drug often varies as a result of gastrointestinal absorption, degradation by first-pass effect, and hostile environment of gastrointestinal tract. Transdermal administration for percutaneous absorption of drug is limited by the impermeable nature of the stratum corneum. Ocular and nasal delivery is also unfavorable because of degradation by enzymes present in eye tissues and nasal mucosa. Hence, the parenteral route is the most viable approach in such cases. Of the various ways of achieving long-term parenteral drug delivery, biodegradable microspheres are one of the better means of controlling the release of drug over a long time. Because of the lipidic nature of liposomes, problems such as limited physical stability and difficulty of freeze-drying are encountered. Similarly, for emulsions, stability on long-term basis and in suspensions, rheological changes during filling, injecting, and storage poses limitation. Also, in all these systems, the release rate cannot be tailored to the needs of the patient. Parenteral controlled-release formulations based on biodegradable microspheres can overcome these problems and can control the release of drug over a predetermined time span, usually in the order of days to weeks to months. Various FDA-approved controlled-release parenteral formulations based on these biodegradable microspheres are available on the market, including Lupron Depot Nutropin Depot and Zoladex. This review covers various molecules encapsulated in biodegradable microspheres for parenteral delivery.
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ABSTRACT: Polymer microspheres for controlled release of therapeutic protein from within an implantable scaffold were produced and analysed using complimentary techniques to probe the surface and bulk chemistry of the microspheres. Time of Flight - Secondary Ion Mass Spectrometry (ToF-SIMS) surface analysis revealed a thin discontinuous film of polyvinyl alcohol (PVA) surfactant (circa 4.5nm thick) at the surface which was readily removed under sputtering with C(60). Atomic Force Microscopy (AFM) imaging of microspheres before and after sputtering confirmed that the PVA layer was removed after sputtering revealing poly(lactic-co-glycolic) acid(PLGA). Scanning electron microscopy showed the spheres to be smooth with some shallow and generally circular depressions, often with pores in their central region. The occurrence of the protein at the surface was limited to areas surrounding these surface pores. This surface protein distribution is believed to be related to a burst release of the protein on dissolution. Analysis of the bulk properties of the microspheres by confocal Raman mapping revealed the 3D distribution of the protein showing large voids within the pores. Protein was found to be adsorbed at the interface with the PLGA oil phase following deposition on evaporation of the solvent. Protein was also observed concentrated within pores measuring approximately 2μm across. The presence of protein in large voids and concentrated pores was further scrutinised by ToF-SIMS of sectioned microspheres. This paper demonstrates that important information for optimisation of such complex bioformulations, including an understanding of the release profile can be revealed by complementary surface and bulk analysis allowing optimisation of the therapeutic effect of such formulations.Journal of Controlled Release 05/2012; 162(2):321-9. DOI:10.1016/j.jconrel.2012.05.008 · 7.26 Impact Factor
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ABSTRACT: In this thesis, the development and characterization of biodegradable and/or enzymetriggered destabilizable polymersomes (Ps) for controlled and targeted drug delivery are presented. In Chapter 1, a general introduction, the aim of the study and structure of the thesis are given. Scientific background information on the criteria for the formation of Ps and methods for their characterization are discussed in Chapter 2. In this chapter, also the recent progress on and challenges for the design of biodegradable and/or stimulisensitive Ps in the field of drug delivery are reviewed. In Chapter 3, the preparation and characterizations of Oregon Green® 488 Labeled Paclitaxel (Flutax) loaded biodegradable Ps based on methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEGPDLLA), methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) or a mixture of the block copolymers is described. Hydrogel-containing Ps (Hs, hydrosomes) are reported in Chapter 4. Results of time-resolved fluorescence as well as the timeresolved fluorescence anisotropy of fluorescein isothicyanate labeled poly(Nisopropylacrylamide) FITC-N in Ps as a function of temperature are given in Chapter 5. Novel peptide-containing Ps (Ps (pep)) have been developed and characterized in Chapter 6. A peptide sequence, Phe-Gly-Leu-Phe-Gly (FGLFG) was introduced in between mPEG and PDLLA (mPEG-pep-PDLLA) and the Ps can be destabilized by the presence of lysosomal enzyme cathepsin B (Cath B) as a result of the enzymatic hydrolysis of the peptide linker. The surface of Ps (pep) was further modified by coupling with anti-epidermal growth factor receptor antibody (abEGFR) to enhance their interaction with cells. In Chapter 7, the results of in vivo studies of Ps prepared from PEG-PDLLA in tumor-bearing mice are compared with those of stealth liposomes. The effects of the surface charge of the Ps on circulation kinetics, organ distribution and tumor accumulation were evaluated.
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ABSTRACT: Oregon Green® 488 labeled paclitaxel (Flutax) loaded biodegradable polymersomes (Flutax-Ps) based on methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-PDLLA), methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) or a mixture of the block copolymers (50:50, w/w) were prepared (abbreviated as Flutax-Ps (L), Flutax-Ps (C) and Flutax-Ps (LC), respectively). For the formation of the Ps, the corresponding block copolymers and Flutax were dissolved in THF and the THF solution was injected into an aqueous phase. Flutax-Ps with a size less than 150nm were obtained, which had Flutax entrapment efficiencies higher than 55% (polymer concentration: 1mg/ml; Flutax concentration up to 100μg/ml). A sustained and complete release of Flutax was observed for Flutax-Ps (L) over one month with no initial burst. Flutax was released much slower from Ps (C) than from Ps (L) (49.9% after one month), which is probably due to differences in the crystallinity and rate of degradation of the consisting copolymers. The release rate of Flutax from Ps (LC) was in between those of Ps (L) and Ps (C). The in vitro cytotoxicity of Flutax-Ps (L) using cultured SKBR3 breast cancer cells was compared with that of empty Ps (L) and a Cremophor® EL/ethanol formulation (50:50, v/v) with Flutax (FCE) or without Flutax (CE). At a Flutax concentration of 5μg/ml, about 67% reduction in the viability of SKBR3 cells was observed for Flutax-Ps (L) after 3days exposure, while the FCE formulation reduced the cell viability for more than 90% under the same conditions. Empty Ps (L) showed a low toxicity of about 10% and the CE formulation exhibited a cytotoxicity higher than 54% without Flutax, indicating that the high reduction in SKBR3 cell viability for FCE is associated with the toxicity of the Cremophor® EL formulation.Journal of Controlled Release 10/2011; 158(2):312-8. DOI:10.1016/j.jconrel.2011.10.025 · 7.26 Impact Factor