PLGA/PLA-Based Long-Acting Injectable Depot Microspheres in Clinical Use: Production and Characterization Overview for Protein/Peptide Delivery (original) (raw)
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Indian Journal of Pharmaceutical Education and Research, 2021
Objectives: Polylactic acid (PLA) and copolymer polylactic-co-glycolic acid (PLGA) are the most versatile drug carriers for long acting release injectable (LAI) formulations for small molecules, peptides and macromolecules such as proteins and nucleic acids. The present research work consists of a PLGA based one-month release microsphere formulation of GnRH agonist leuprolide acetate, using double emulsion (W1/O/W2) technique. Materials and Methods: Microparticles were prepared by double emulsion solvent evaporation technique and critical quality attributes of finished products such as drug loading, entrapment efficiency, particle size distribution (PSD), surface porosity, drug distribution within microparticles were analysed. Results and Conclusion: The microspheres have shown the mean particle size of 15.2 μm and suitable particle size distribution pattern ideal for syringe ability. The microparticles were spherical in shape with uniform pore distribution and uniform distribution ...
Development of polylactide microspheres for protein encapsulation and delivery
Journal of Applied Polymer Science, 2002
The development of injectable microparticles for protein delivery is a major challenge. We demonstrated the possibility of entrapping human serum albumin (HSA) and thrombin (Thr) in poly(ethylene glycol) (PEG)-coated, monodisperse, biodegradable microspheres with a mean diameter of about 10 m. In our earlier studies, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis was used to characterize the surface of PEG-coated, taxol-loaded poly(lactic acid) (PLA) microspheres. An analysis by DRIFTS revealed that PEG was incorporated well on the PLA microsphere surface. An emulsion of protein (in water) and PLA dissolved in an acetone-dichloromethane (or acetone-chloroform) mixture were poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA)] with stirring with a high-speed homogenizer for the formation of microparticles. HSA recovery in microspheres ranged from 13 to 40%, depending on the solvent and emulsification systems used for the preparation. PLA dissolved in a dichloromethane/acetone system and albumin loaded via a PEG emulsification solution (PLA-PEG-HSA) showed maximum drug recovery (39.5%) and drug content (9.9%). Scanning electron microscopy revealed that PEG-coated microspheres had less surface micropores than PVA-based preparations. The drug-release behavior of microspheres suspended in phosphate-buffered saline exhibited a biphasic pattern. An initial burst release (30%) followed by a constant slow release for 20 days was observed for HSA and Thr from PLA-PEG microspheres. PEG-coated PLA microspheres show great potential for protein-based drug delivery.
Journal of controlled …, 1993
Biodegradable polymers are used in diffusion controlled, swelling controlled and chemically controlled delivery systems. In this study, PLGA copolymers were used in a formulation which forms a gel matrix immediately on contact with aqueous fluids. This property of the formulation can circumvent the need for making a surgical incision to implant the matrix. The gel matrix thus formed will release the drug slowly (over a period of weeks to months) and ultimately biodegrade depending on the composition of the polymer used. In vitro release studies using small molecules and macromolecules, such as proteins, indicate that the drug release is influenced by the concentration of the polymer, physicochemical properties of the drug, method of incorporation of the drug in the formulation and the presence of other excipients. The drug release can therefore be modified to suit the desired release characteristics. This novel formulation design for a biodegradable injectable implant can provide prolonged release while avoiding the necessity for surgical procedures.
The AAPS Journal, 2009
The reduced injection frequency and more nearly constant serum concentrations afforded by sustained release devices have been exploited for the chronic delivery of several therapeutic peptides via poly(lactide-co-glycolide) (PLG) microspheres. The clinical success of these formulations has motivated the exploration of similar depot systems for chronic protein delivery; however, this application has not been fully realized in practice. Problems with the delivery of unmodified proteins in PLG depot systems include high initial "burst" release and irreversible adsorption of protein to the biodegradable polymer. Further, protein activity may be lost due to the damaging effects of protein-interface and protein-surface interactions that occur during both microsphere formation and release. Several techniques are discussed in this review that may improve the performance of PLG depot delivery systems for proteins. One promising approach is the covalent attachment of poly(ethylene glycol) (PEG) to the protein prior to encapsulation in the PLG microspheres. The combination of the extended circulation time of PEGylated proteins and the shielding and potential stabilizing effects of the attached PEG may lead to improved release kinetics from PLG microsphere system and more complete release of the active conjugate.
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.
Journal of pharmaceutical sciences, 2017
Drug-loaded polymeric microparticles have been used as long-acting injectable (LAI) depot formulations. To obtain FDA approval, a generic LAI depot product needs to be qualitatively (Q1) and quantitatively (Q2) the same in terms of inactive ingredients as its reference listed drug (RLD). However, Q1/Q2 sameness as the RLD does not guarantee the same in vitro drug release profile and in vivo performance, especially when the manufacturing methods are different. There is little consensus on how the in vitro testing needs to be done to examine the release profiles of LAI depot formulations. This study examined the manufacturing differences in making risperidone-loaded poly(lactide-co-glycolide) (PLGA) microparticles and their impact on the release kinetics. It also examined the impacts of in vitro testing methods on the drug release profiles. Two in-house manufactured risperidone PLGA microparticles and Risperdal Consta(®) were used in the study. Of the in vitro release methods tested, ...
Journal of Controlled Release, 1991
Poly(o~-lactide/glycolide, 50: 50) microspheres containing bovine serum albumin (RSA) were prepared with and without Carbopol" 95 I (a potential adjuvant agent) by o/o, o/w and (w/o)lw emulsion methods. The protein loading of the microspheres reached 50-700/o of the theoretical amount of protein put into the formulation medium. The microsphere particle size was approximately 500 pm, 2%IOOpm, IO-20pm usingojo, o/w, or (w/o)/ w emulsion techniques. respectively. The release of BSA was dependent on the preparation method. The greatest burst of release was found for vacuumdried microspheres formulated using the (w/0)/w method. This burst effect could be eliminated by lyophilizing the microspheres following their preparation. BSA was released at a higher initial rate from microspheres prepared by the o/w emulsion method that contained Carbopol" 95 I than from microspheres not containing CarbopolO 951. Release studies also suggested that the release of SSA could be sustained for 54, 36, or 34 days pa! microspheres prepared by o/o. o/w, or (w/o)@ methods, respectively. I 2 3 4 5 6 7 8 9 10 efemnces R.J. Linhardt, Bvadegradable polymers for the controlled release ofdrugs. In: M. Roroff (Ed. ), Controlled Releaseof Drugs: Po,ymersand Aggrcgatc Systems. VCH Publishers, New York, 1989, pp. 53-95. K. Junl and M. Nakano, Poly(hydroxy acids) in drug delivery. Crit. Rev. Ther. Drug Carrier Syst., 3 (1987) X9-232. J.P. Kilchell and D.L. Wise, Poly(lactide/glycolide) biodegradable drug-polymer matrix system. In: K.J. Widderand R. Green (Eds.), Methods in Enzymology, Vol. 112. Academic Press, Orlando, FL, 1985, pp. 436-448. J. Hcller. Zero order drug release from biocrodibk polp men. In: J.M. Anderson and S.W. Kim (Eds.), Recent Advancer in Drug Dclivcv Systems, Plenum Press New York. 1984,~~. 101-121. T.R. Tice and D.R. Cowsar. Biodegradable mntrolledrclcasc parenteral systems, Pharm. Tech., 8( I I ) ( ,984, 26-35. R.S. Langcr and N.A. Pcppas. Prcscnt and future applicauons of biomatcrials in controlled drug delivery systems. Biomalerials, 2 (1981 ) 201-214. D.A. Wood, Biodegmdable drug d&very systems, Jnt. J. Phsrm..7 (1980, l-18. S. Yolbs and M.F. Sanon, Dcgradablc polymers for sustained drug release. In: R.L. Juliano (Ed. ). Drug DP livery Systems, Oxford University Press, New York, ,980, pp. 84-1 IO. A. Schindler, R. Jeffcoat,G.L. Kimmel. C.G. Pit1.M.E. Wall and R. Zweldmger. Biodegradable polymers for sustained drug delivery. In: E.M. Pearce and J.R. Schaeffgrn (Eds ). Conrcmporary Topics in Polymer scwnce. "cd. 2. Acnum Press, New York, 1977, pp. 25 I-286. N. Marcotlc, A. Polk and M.F.A. Gooaen. Kinetics of protcm release from a poly(w-lactide) reservoir systcm.J.Pharm.Sci.. 79(5) (1990) 407-410. 26 R.J Llnhaidt, DR. Fhagim. E. SEhrnl,, and H.T. Wang. Blodcgradable poly(eners, and [he debvwy of bloacwc Bg",s. Pobm. Prcpr., 31(,) (1990, x9-259. ConwAled release of prowm and vatcmes from poly(e9er) microsphcrcs in vitro. In: G. 00. b&in (Ed 1. Polymers for Cosmeuc and Pharmaceuucal Appbcauons. Plenum, New York, I991 ~ in press. 29 J Kreuler and E. Liehl. Long-term studies of nucroenprolidc accLatc into microcapwles of polylactlc or copoly(lacuc,Slycol,c, acid. Cbem. Pbarm. Bull.. 36( 3, (1988) 1095-1103 35 M. Bradford, A raped and scnsilw method for the quanl~tation of microgram qu3nIilies of protein utiliring the principle of pmlem-dye bindtng. Anal. Biochem.. 72 (1976) 248-254. 36 G.L. Gualandi. NM Losio. C. Muratori and E. Font. The ab~bty by dxfferem preparations of porcine parve-+I~P to enhance humoral immunity m swine and guinea p,gs, MIcroblolag,ca. I I t 1988) 363-369.