Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

Department of Pharmaceutical Technology Faculty of Pharmacy Charles University Akademika Heyrovskeho 1203 8 500 05 Hradec Kralove Czech Republic

Department of Pharmaceutics Institute of Pharmacy University of Bonn Gerhard Domagk Straße 3 53121 Bonn Germany

Zobrazit více v PubMed

Martinez MN, Rathbone MJ, Burgess D, Huynh M. Breakout session summary from AAPS/CRS joint workshop on critical variables in the in vitro and in vivo performance of parenteral sustained release products. J Control Release. 2010;142(1):2–7. 10.1016/j.jconrel.2009.09.028. PubMed

Martinez M, Rathbone M, Burgess D, Huynh M. In vitro and in vivo considerations associated with parenteral sustained release products: A review based upon information presented and points expressed at the 2007 Controlled Release Society Annual Meeting. J Control Release. 2008;129(2):79–87. 10.1016/j.jconrel.2008.04.004. PubMed

D’Souza SS, De Luca PP. Methods to assess in vitro drug release from injectable polymeric particulate systems. Pharm Res. 2006;23:460–474. PubMed

Seidlitz A, Weitschies W. In-vitro dissolution methods for controlled release parenterals and their applicability to drug-eluting stent testing. J Pharm Pharmacol. 2012;64:969–985. PubMed

Pestieau A, Evrard B. In vitro biphasic dissolution tests and their suitability for establishing in vitro-in vivo correlations: A historical review. Eur J Pharm Sci. 2017;102:203–19. 10.1016/j.ejps.2017.03.019. PubMed

Fotaki N, Vertzoni M. Biorelevant dissolution methods and their applications in in vitro-in vivo correlations for oral formulations. Open Drug Deliv J. 2010;4:2–13.

Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010 [cited 2020 Aug 10]. p. 397–406. Available from: /pmc/articles/PMC2895438/?report=abstract PubMed PMC

Iyer SS, Barr WH, Karnes HT. Characterization of a potential medium for “biorelevant” in vitro release testing of a naltrexone implant, employing a validated stability-indicating HPLC method. J Pharm Biomed Anal. 2007;43:845–853. PubMed

Kinnunen HM, Sharma V, Contreras-Rojas LR, Yu Y, Alleman C, Sreedhara A, et al. A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components. J Control Release. 2015;214:94–102. PubMed

Magri G, Selmin F, Cilurzo F, Fotaki N. Biorelevant release testing of biodegradable microspheres intended for intra-articular administration. Eur J Pharm Biopharm. 2019;139:115–122. PubMed

Sterner B, Harms M, Weigandt M, Windbergs M, Lehr CM. Crystal suspensions of poorly soluble peptides for intra-articular application: A novel approach for biorelevant assessment of their in vitro release. Int J Pharm. 2014;461:46–53. PubMed

Smith AM, Fleming L, Wudebwe U, Bowen J, Grover LM. Development of a synovial fluid analogue with bio-relevant rheology for wear testing of orthopaedic implants. J Mech Behav Biomed Mater. 2014;32:177–184. PubMed

Sun Y, Jensen H, Petersen NJ, Larsen SW, Østergaard J. Concomitant monitoring of implant formation and drug release of in situ forming poly (lactide-co-glycolide acid) implants in a hydrogel matrix mimicking the subcutis using UV–vis imaging. J Pharm Biomed Anal. 2018;150:95–106. PubMed

Ye F, Larsen SW, Yaghmur A, Jensen H, Larsen C, Østergaard J. Drug release into hydrogel-based subcutaneous surrogates studied by UV imaging. J Pharm Biomed Anal. 2012;71:27–34. PubMed

Klose D, Azaroual N, Siepmann F, Vermeersch G, Siepmann J. Towards more realistic in vitro release measurement techniques for biodegradable microparticles. Pharm Res. 2009;26:691–699. PubMed

Brandl F, Kastner F, Gschwind RM, Blunk T, Teßmar J, Göpferich A. Hydrogel-based drug delivery systems: Comparison of drug diffusivity and release kinetics. J Control Release. 2010;142:221–228. PubMed

Jensen SS, Jensen H, Møller EH, Cornett C, Siepmann F, Siepmann J, et al. In vitro release studies of insulin from lipid implants in solution and in a hydrogel matrix mimicking the subcutis. Eur J Pharm Sci. 2016;81:103–112. PubMed

Allababidi S, Shah JC. Kinetics and Mechanism of Release from Glyceryl Monostearate-Based Implants: Evaluation of Release in a Gel Simulating in Vivo Implantation. J Pharm Sci. 1998;87:738–744. PubMed

Kozak J, Rabiskova M, Lamprecht A. In-vitro drug release testing of parenteral formulations via an agarose gel envelope to closer mimic tissue firmness. Int J Pharm. 2020;594:120142. PubMed

Kinnunen HM, Mrsny RJ. Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site. J Control Release. 2014;182:22–32. PubMed

Zolnik BS, Burgess DJ. Evaluation of in vivo-in vitro release of dexamethasone from PLGA microspheres. J Control Release. 2008;127:137–145. PubMed

Fredenberg S, Wahlgren M, Reslow M, Axelsson A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems - a review. Int J Pharm. 2011;415:34–52. PubMed

Anderson JM, Shive MS. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev. 2012;64:72–82. 10.1016/j.addr.2012.09.004. PubMed

Fang Y, Zhang N, Li Q, Chen J, Xiong S, Pan W. Characterizing the release mechanism of donepezil-loaded PLGA microspheres in vitro and in vivo. J Drug Deliv Sci Technol. 2019;51:430–437.

Doty AC, Weinstein DG, Hirota K, Olsen KF, Ackermann R, Wang Y, et al. Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres. J Control Release. 2017;256:19–25. PubMed

Rawat A, Bhardwaj U, Burgess DJ. Comparison of in vitro–in vivo release of Risperdal® Consta® microspheres. Int J Pharm. 2012;434:115–121. PubMed

Alexis F. Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)] Polym Int. 2005;54:36–46.

Sharma CP, Williams DF. The effects of lipids on the mechanical properties of polyglycolic acid sutures. Eng Med. 1981;10(1):8–10. 10.1243/EMED_JOUR_1981_010_005_02.

Cuddihy EF, Moacanin J, Roschke EJ, Harrison EC. In vivo degradation of silicone rubber poppets in prosthetic heart valves. J Biomed Mater Res. 1976;10(3):471–81. 10.1002/jbm.820100314. PubMed

Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, et al. Skin models for the testing of transdermal drugs. Clin Pharmacol Adv Appl. 2016;8:163–76. 10.2147/CPAA.S64788. PubMed PMC

Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N, et al. Porcine ear skin: An in vitro model for human skin. Skin Res Technol. 2007;13:19–24. PubMed

Chung B, Lee H, Choi M, Seo KY, Kim EK, Kim TI. Preloaded and non-preloaded intraocular lens delivery system and characteristics: Human and porcine eyes trial. Int J Ophthalmol. 2018;11:6–11. PubMed PMC

Shelley H, Rodriguez-Galarza RM, Duran SH, Abarca EM, Babu RJ. In Situ Gel Formulation for Enhanced Ocular Delivery of Nepafenac. J Pharm Sci. 2018;107:3089–3097. PubMed

Loch C, Zakelj S, Kristl A, Nagel S, Guthoff R, Weitschies W, Seidlitz A. Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes. Eur J Pharm Sci. 2012;47:131–138. PubMed

Shen J, Choi S, Qu W, Wang Y, Burgess DJ. In vitro-in vivo correlation of parenteral risperidone polymeric microspheres. J Control Release. 2015;218:2–12. PubMed PMC

Semmling B, Nagel S, Sternberg K, Weitschies W, Seidlitz A. Long-term stable hydrogels for biorelevant dissolution testing of drug-eluting stents. J Pharm Technol Drug Res. 2013;2:19. PubMed

Liang S, Xu J, Weng L, Dai H, Zhang X, Zhang L. Protein diffusion in agarose hydrogel in situ measured by improved refractive index method. J Control Release. 2006;115:189–196. PubMed

Sirianni RW, Kremer J, Guler I, Chen Y-L, Keeley FW, Saltzman WM. Effect of extracellular matrix elements on the transport of paclitaxel through an arterial wall tissue mimic. Biomacromolecules. 2008;9:2792–2798. PubMed

Leung DH, Kapoor Y, Alleyne C, Walsh E, Leithead A, Habulihaz B, et al. Development of a convenient in vitro gel diffusion model for predicting the in vivo performance of subcutaneous parenteral formulations of large and small molecules. AAPS PharmSciTech. 2017;18:2203–2213. PubMed

Kurtz A, Pape H-C, Silbernagl S, Bondke Persson A, Brenner B, Burckhardt G, et al. 13 Wärmehaushalt und Temperaturregulation. Physiologie. 2018. 10.1055/b-006-149284.

Routledge PA, Barchowsky A, Blornsson TD, Kitchell BB, Shand DG. Lidocaine plasma protein binding. Clin Pharmacol Ther. 1980;27:347–351. PubMed

Szpunar GJ, Albert KS, Wagner JG. Pharmacokinetics of flurbiprofen in man II. Plasma protein binding. Res Commun Chem Pathol Pharmacol. 1989;64:17–30. PubMed

Aarons L, Khan AZ, Grennan DM, Alam-Siddiqi M. The binding of flurbiprofen to plasma proteins. J Pharm Pharmacol. 1985;37:644–646. PubMed

Gasmi H, Willart JF, Danede F, Hamoudi MC, Siepmann J, Siepmann F. Importance of PLGA microparticle swelling for the control of prilocaine release. J Drug Deliv Sci Technol. 2015;30:123–32. 10.1016/j.jddst.2015.10.009.

Bode C, Kranz H, Fivez A, Siepmann F, Siepmann J. Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants. J Control Release. 2019;306:97–107. PubMed

Gasmi H, Danede F, Siepmann J, Siepmann F. Does PLGA microparticle swelling control drug release? New insight based on single particle swelling studies. J Control Release. 2015;213:120–127. PubMed

Samadi N, Abbadessa A, Di Stefano A, Van Nostrum CF, Vermonden T, Rahimian S, et al. The effect of lauryl capping group on protein release and degradation of poly(d,l-lactic-co-glycolic acid) particles. J Control Release. 2013;172(2):436–43. 10.1016/j.jconrel.2013.05.034. PubMed

Holgado MA, Arias JL, Cózar MJ, Alvarez-Fuentes J, Gañán-Calvo AM, Fernández-Arévalo M. Synthesis of lidocaine-loaded PLGA microparticles by flow focusing. Effects on drug loading and release properties. Int J Pharm. 2008;358:27–35. PubMed

Andhariya JV, Jog R, Shen J, Choi S, Wang Y, Zou Y, et al. Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres. J Control Release. 2019;308:1–13. PubMed

Bhusal P, Rahiri JL, Sua B, McDonald JE, Bansal M, Hanning S, et al. Comparing human peritoneal fluid and phosphate-buffered saline for drug delivery: do we need bio-relevant media? Drug Deliv Transl Res. 2018;8:708–718. doi: 10.1007/s13346-018-0513-9. PubMed DOI

Fröhlich SM, Eilenberg M, Svirkova A, Grasl C, Liska R, Bergmeister H, et al. Mass spectrometric imaging of in vivo protein and lipid adsorption on biodegradable vascular replacement systems. Analyst. 2015;140:6089–6099. PubMed

Choi J, Lee BS, Park K, Han DK, Park KD, Kim YH. Beneficial effect of sulfonated peografted polyurethanes on calcification and lipid adsorption of vascular implants. Macromol Res. 2010;18:1133–6. 10.1007/s13233-010-1112-x.

Fröhlich SM, Archodoulaki V-M, Allmaier G, Marchetti-Deschmann M. MALDI-TOF Mass Spectrometry Imaging Reveals Molecular Level Changes in Ultrahigh Molecular Weight Polyethylene Joint Implants in Correlation with Lipid Adsorption. Anal Chem. 2014;86:9723–9732. PubMed

Menei P, Daniel V, Montero-Menei C, Brouillard M, Pouplard-Barthelaix A, Benoit JP. Biodegradation and brain tissue reaction to poly(D,L-lactide-co-glycolide) microspheres. Biomaterials. 1993;14(6):470–8. 10.1016/0142-9612(93)90151-Q. PubMed

Carmen R, Mutha SC. Lipid absorption by silicone heart valve poppets—in-vivo and in-vitro results. J Biomed Mater Res. 1972;6:327–346. PubMed

Carmen R, Kahn P. In vitro testing of silicone rubber heart-valve poppets for lipid absorption. J Biomed Mater Res. 1968;2:457–464. PubMed

Swanson JW, Lebeau JE. The effect of implantation on the physical properties of silicone rubber. J Biomed Mater Res. 1974;8:357–367. PubMed

Janich C, Friedmann A, Martins de Souza e Silva J, Santos de Oliveira C, de Souza LE, Rujescu D, et al. Risperidone-Loaded PLGA–Lipid Particles with Improved Release Kinetics: Manufacturing and Detailed Characterization by Electron Microscopy and Nano-CT. Pharmaceutics. 2019;11:665. PubMed PMC

Siepmann F, Karrout Y, Gehrke M, Penz FK, Siepmann J. Limited drug solubility can be decisive even for freely soluble drugs in highly swollen matrix tablets. Int J Pharm. 2017;526(1–2):280–90. 10.1016/j.ijpharm.2017.05.001. PubMed

Siepmann J, Siepmann F. Sink conditions do not guarantee the absence of saturation effects. Int J Pharm. 2020;577 [cited 2020 Sep 9]. Available from: https://pubmed.ncbi.nlm.nih.gov/31917299/. PubMed

van der Vusse GJ. Albumin as fatty acid transporter. Drug Metab Pharmacokinet. 2009;24(4):300–7. 10.2133/dmpk.24.300. PubMed

Eriksson U, Falkevall A. Visualizing Fatty Acid Flux. 2018;27:1161–2. 10.1016/j.cmet.2018.05.017. PubMed