10,991
Views
2
CrossRef citations to date
0
Altmetric
Review

Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules

Pages 927-944 | Received 04 May 2022, Accepted 20 Jul 2022, Published online: 28 Jul 2022

References

  • Lagassé HAD, Alexaki A, Simhadri VL, et al. Recent advances in (therapeutic protein) drug development. F1000Res. 2017;6:113.
  • What Are “Biologics” Questions and Answers | FDA [Internet]. cited 2021 Sep 9. Available from: https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers
  • Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov. 2019;18(1):19–40.
  • D’Aloisio V, Dognini P, Hutcheon GA, et al. PepTherDia: database and structural composition analysis of approved peptide therapeutics and diagnostics. Drug Discov Today. 2021;26(6):1409–1419.
  • Makurvet FD. Biologics vs. small molecules: drug costs and patient access. Med Drug Discov. 2021;9:100075.
  • Wang L, Wang N, Zhang W, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7(1):48.
  • Reynolds T, de Zafra C, Kim A, et al. Overview of biopharmaceuticals and comparison with small-molecule drug development. Nonclinical dev nov biol biosimilars vaccines spec biol [Internet]. Elsevier; 2013 [cited 2022 Jun 3]. p. 3–33. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780123948106000010
  • Dimitrov DS. Therapeutic Proteins. In: Voynov V, Caravella JA, editors. Ther Proteins Internet]. Totowa (NJ): Humana Press; 2012, 1–26. [cited 2022 Jun 3]. Available from: http://link.springer.com/10.1007/978-1-61779-921-1_1
  • Strohl WR. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs. 2015;29(4):215–239.
  • Vaishya R, Khurana V, Patel S, et al. Long-term delivery of protein therapeutics. Expert Opin Drug Deliv. 2015;12(3):415–440.
  • SANDOZ. Leuprolide Acetate Injection [Internet]. p. 4. cited 2021 Dec 7]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/074728s011lbl.pdf
  • ELIGARD® (leuprolide acetate for injectable suspension) | tolmar [Internet]. cited 2021 Dec 7]. Available from: https://www.tolmar.com/products/eligard
  • Genovese S, Mannucci E, Ceriello A. A review of the long-term efficacy, tolerability, and safety of exenatide once weekly for type 2 diabetes. Adv Ther. 2017;34(8):1791–1814.
  • Li T, Chandrashekar A, Beig A, et al. Characterization of attributes and in vitro performance of exenatide-loaded PLGA long-acting release microspheres. Eur J Pharm Biopharm. 2021;158:401–409.
  • Blasi P. Poly(lactic acid)/poly(lactic-co-glycolic acid)-based microparticles: an overview. J Pharm Investig. 2019;49(4):337–346.
  • Zhong H, Chan G, Hu Y, et al. A comprehensive map of FDA-approved pharmaceutical products. Pharmaceutics. 2018;10(4):263.
  • Moncalvo F, Martinez Espinoza MI, Cellesi F. Nanosized delivery systems for therapeutic proteins: clinically validated technologies and advanced development strategies. Front Bioeng Biotechnol. 2020;8:89.
  • Lee WY, Asadujjaman M, Jee J-P. Long acting injectable formulations: the state of the arts and challenges of poly(lactic-co-glycolic acid) microsphere, hydrogel, organogel and liquid crystal. J Pharm Investig. 2019;49(4):459–476.
  • Almeida M, Magalhães M, Veiga F, et al. Poloxamers, poloxamines and polymeric micelles: definition, structure and therapeutic applications in cancer. J Polym Res. 2018;25(1):31.
  • Lupron Depot (leuprolide acetate for depot suspension) [Internet]. cited 2021 Nov 10]. Available from: https://www.lupron.com
  • SANDOSTATIN® LAR Depot (octreotide acetate) for acromegaly and carcinoid syndrome [Internet]. cited 2021 Nov 10]. Available from: https://www.us.sandostatin.com
  • Kempe S, Mäder K. In situ forming implants — an attractive formulation principle for parenteral depot formulations. J Control Release. 2012;161(2):668–679.
  • Kanwar N, Sinha VR. In situ forming depot as sustained-release drug delivery systems. Crit Rev Ther Drug Carr Syst. 2019;36(2):93–136.
  • About Zoladex® | zoladex® (goserelin acetate implant) [Internet]. cited 2021 Nov 15]. Available from: https://www.zoladex.com/what-is-zoladex
  • [Internet]. cited 2021 Nov 5]. Available from: https://scenesse.com
  • Mezzenga R, Seddon JM, Drummond CJ, et al. Nature‐inspired design and application of lipidic lyotropic liquid crystals. Adv Mater. 2019;31(35):1900818.
  • Pipeline | Camurus [Internet]. cited 2021 Nov 8]. Available from: https://www.camurus.com/pipeline
  • Forsback A-P, Noppari P, Viljanen J, et al. Sustained In-Vivo release of triptorelin acetate from a biodegradable silica depot: comparison to pamorelin® LA. Nanomaterials. 2021;11(6):1578.
  • TNF-Bound colloidal gold in treating patients with advanced solid tumors - ClinicalTrials.gov [Internet]. cited 2021 Nov 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT00356980.
  • Pasut G. Grand challenges in nano-based drug delivery. Front Med Technol. 2019;1:1.
  • Yu M, Wu J, Shi J, et al. Nanotechnology for protein delivery: overview and perspectives. J Control Release. 2016;240:24–37.
  • Freitas S, Merkle HP, Gander B. Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology. J Control Release. 2005;102(2):313–332.
  • Sawant A, Kamath S, Kg H, et al. Solid-in-oil-in-water emulsion: an innovative paradigm to improve drug stability and biological activity. AAPS PharmSciTech. 2021;22(5):199.
  • Butreddy A, Gaddam RP, Kommineni N, et al. PLGA/PLA-based long-acting injectable depot microspheres in clinical use: production and characterization overview for protein/peptide delivery. Int J Mol Sci. 2021;22(16):8884.
  • Cai Y, Wei L, and Ma L, et al. Long-acting preparations of exenatide. Drug Des Devel Ther. 2013;7:963–970.
  • Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharm. 2008;364(2):298–327.
  • Stanković M, Frijlink HW, Hinrichs WLJ. Polymeric formulations for drug release prepared by hot melt extrusion: application and characterization. Drug Discov Today. 2015;20(7):812–823.
  • Schwendeman SP, Shah RB, Bailey BA, et al. Injectable controlled release depots for large molecules. J Control Release. 2014;190:240–253.
  • Zhou J, Walker J, Ackermann R, et al. Effect of manufacturing variables and raw materials on the composition-equivalent PLGA microspheres for 1-Month controlled release of leuprolide. Mol Pharm. 2020;17(5):1502–1515.
  • Shi N-Q, Zhou J, Walker J, et al. Microencapsulation of luteinizing hormone-releasing hormone agonist in poly (lactic-co-glycolic acid) microspheres by spray-drying. J Control Release. 2020;321:756–772.
  • Ogawa Y, Yamamoto M, Okada H, et al. A new technique to efficiently entrap leuprolide acetate into microcapsules of polylactic acid or copoly(Lactic/Glycolic) acid. Chem Pharm Bull (Tokyo). 1988;36(3):1095–1103.
  • Ogawa Y, Yamamoto M, Takada S, et al. Controlled-Release of leuprolide acetate from polylactic acid or copoly(Lactic/Glycolic) acid microcapsules: influence of molecular weight and copolymer ratio of polymer. Chem Pharm Bull (Tokyo). 1988;36(4):1502–1507.
  • Ogawa Y, Okada H, Yamamoto Y, et al. In vivo release profiles of leuprolide acetate from microcapsules prepared with polylactic acids or copoly(Lactic/Glycolic) acids and in vivo degradation of these polymers. Chem Pharm Bull (Tokyo). 1988;36(7):2576–2581.
  • Beig A, Feng L, Walker J, et al. Physical–chemical characterization of octreotide encapsulated in commercial glucose-star PLGA microspheres. Mol Pharm. 2020;17(11):4141–4151.
  • Zhou J, Hirota K, Ackermann R, et al. Reverse engineering the 1-Month Lupron Depot®. AAPS J. 2018;20(6):105.
  • Ochi M, Wan B, Bao Q, et al. Influence of PLGA molecular weight distribution on leuprolide release from microspheres. Int J Pharm. 2021;599:120450.
  • Wan B, Andhariya JV, Bao Q, et al. Effect of polymer source on in vitro drug release from PLGA microspheres. Int J Pharm. 2021;607:120907.
  • Hadar J, Skidmore S, Garner J, et al. Characterization of branched poly(lactide-co-glycolide) polymers used in injectable, long-acting formulations. J Control Release. 2019;304:75–89.
  • Na DH, Youn YS, Lee SD, et al. Monitoring of peptide acylation inside degrading PLGA microspheres by capillary electrophoresis and MALDI-TOF mass spectrometry. J Control Release. 2003;92(3):291–299.
  • Shirangi M, Hennink WE, Somsen GW, et al. Identification and assessment of octreotide acylation in polyester microspheres by LC–MS/MS. Pharm Res. 2015;32(9):3044–3054.
  • Molinier C, Picot-Groz M, Malval O, et al. Impact of octreotide counterion nature on the long-term stability and release kinetics from an in situ forming depot technology. J Control Release. 2021;336:457–468.
  • Zhang Y, Sophocleous AM, Schwendeman SP. Inhibition of peptide acylation in PLGA microspheres with water-soluble divalent cationic salts. Pharm Res. 2009;26(8):1986–1994.
  • Sophocleous AM, Zhang Y, Schwendeman SP. A new class of inhibitors of peptide sorption and acylation in PLGA. J Control Release. 2009;137(3):179–184.
  • O’Brien MN, Jiang W, Wang Y, et al. Challenges and opportunities in the development of complex generic long-acting injectable drug products. J Control Release. 2021;336:144–158.
  • Hua Y, Su Y, Zhang H, et al. Poly(lactic-co-glycolic acid) microsphere production based on quality by design: a review. Drug Deliv. 2021;28(1):1342–1355.
  • Carrascosa C, Espejo L, Torrado S, et al. Effect of c-Sterilization Process on PLGA Microspheres Loaded with Insulin-Like Growth Factor - I (IGF-I). J Biomater Appl. 2003;18(2):95–108.
  • Fineman M, Flanagan S, Taylor K, et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet. 2011;50(1):65–74.
  • Nauck MA, Meier JJ. MANAGEMENT OF ENDOCRINE DISEASE: are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181(6):R211–R234.
  • Buss N, Ryan P, Baughman T, et al. Nonclinical safety and pharmacokinetics of Miglyol 812: a medium chain triglyceride in exenatide once weekly suspension: PK and safety of MCTs. J Appl Toxicol. 2018;38(10):1293–1301.
  • Stewart S, Domínguez-Robles J, Donnelly R, et al. Implantable polymeric drug delivery devices: classification, manufacture, materials, and clinical applications. Polymers. 2018;10(12):1379.
  • Sequeira JAD, Santos AC, Serra J, et al. Poly(lactic- co -glycolic acid) (PLGA) matrix implants. Nanostructures Eng Cells Tissues Organs [Internet]. Elsevier; 2018 [cited 2021 Nov 29]. p. 375–402. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128136652000107
  • Jain A, Kunduru KR, Basu A, et al. Injectable formulations of poly(lactic acid) and its copolymers in clinical use. Adv Drug Deliv Rev. 2016;107:213–227.
  • Kim ES, Garnock-Jones KP. Afamelanotide: a review in erythropoietic protoporphyria. Am J Clin Dermatol. 2016;17(2):179–185.
  • Montgomery BSI, Borwell JP, Higgins DM. Does needle size matter? Patient experience of luteinising hormone-releasing hormone analogue injection. Prostate Cancer Prostatic Dis. 2005;8(1):66–68.
  • Southard G, Dunn R, Garrett S. The drug delivery and biomaterial attributes of the ATRIGEL®technology in the treatment of periodontal disease. Expert Opin Investig Drugs. 1998;7(9):1483–1491.
  • Shore N, Mincik I, DeGuenther M, et al. A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. World J Urol. 2020;38(1):111–119.
  • Zhou H, Hernandez C, Goss M, et al. Biomedical imaging in implantable drug delivery systems. Curr Drug Targets. 2015;16(6):672–682.
  • Roberge C, Cros J-M, Serindoux J, et al. BEPO®: bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation. J Control Release. 2020;319:416–427.
  • Saltzstein D, Shore ND, Moul JW, et al. Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects. Ther Adv Urol. 2018;10(2):43–50.
  • Mostafa NM, Chwalisz K, Larsen L, et al. Evaluation of the pharmacokinetics and pharmacodynamics of two leuprolide acetate 45 mg 6-month depot formulations in patients with prostate cancer: clinical pharmacology in drug development. Clin Pharmacol Drug Dev. 2014;3(4):270–275.
  • Park K, Skidmore S, Hadar J, et al. Injectable, long-acting PLGA formulations: analyzing PLGA and understanding microparticle formation. J Control Release. 2019;304:125–134.
  • Klein KO, Freire A, Gryngarten MG, et al. Phase 3 trial of a small-volume subcutaneous 6-Month duration leuprolide acetate treatment for central precocious puberty. J Clin Endocrinol Metab. 2020;105(10):e3660–e3671.
  • Tiberg F, Roberts J, Cervin C, et al. Octreotide s.c. depot provides sustained octreotide bioavailability and similar IGF‐1 suppression to octreotide LAR in healthy volunteers. Br J Clin Pharmacol. 2015;80(3):460–472.
  • Richard J, Prang N. The formulation and immunogenicity of therapeutic proteins: product quality is a key factor. Thomson Reuters. 2010;13:550–558.
  • Lee PW, Pokorski JK. PLGA devices: production and applications for sustained protein delivery. 2019;38.
  • Estey T, Kang J, Schwendeman SP, et al. BSA degradation under acidic conditions: a model for protein instability during release from PLGA delivery systems. J Pharm Sci. 2006;95(7):1626–1639.
  • Mohammadi-Samani S, Taghipour B. PLGA micro and nanoparticles in delivery of peptides and proteins; problems and approaches. Pharm Dev Technol. 2015;20(4):385–393.
  • Wang W, Nema S, Teagarden D. Protein aggregation—Pathways and influencing factors. Int J Pharm. 2010;390(2):89–99.
  • Wang W, Ohtake S. Science and art of protein formulation development. Int J Pharm. 2019;568:118505.
  • Sah H. Stabilization of proteins against methylene chloride/water interface-induced denaturation and aggregation. J Control Release. 1999;58(2):143–151.
  • Kamerzell TJ, Esfandiary R, Joshi SB, et al. Protein–excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 2011;63(13):1118–1159.
  • Moreno MR, Tabitha TS, Nirmal J, et al. Study of stability and biophysical characterization of ranibizumab and aflibercept. Eur J Pharm Biopharm. 2016;108:156–167.
  • Lee PW, Pokorski JK. Poly(lactic‐co‐glycolic acid) devices: production and applications for sustained protein delivery. WIREs Nanomed Nanobiotechnol. 2018;10(5). 10.1002/wnan.1516
  • Arakawa T, Kita Y, Timasheff SN. Protein precipitation and denaturation by dimethyl sulfoxide. Biophys Chem. 2007;131(1–3):62–70.
  • Leconet W, Liu H, Guo M, et al. Anti-PSMA/CD3 bispecific antibody delivery and antitumor activity using a polymeric depot formulation. Mol Cancer Ther. 2018;17(9):1927–1940.
  • Chang DP, Garripelli VK, Rea J, et al. Investigation of fragment antibody stability and its release mechanism from poly(Lactide-co-Glycolide)-triacetin depots for sustained-release applications. J Pharm Sci. 2015;104(10):3404–3417.
  • Nejadnik MR, Randolph TW, Volkin DB, et al. Postproduction handling and administration of protein pharmaceuticals and potential instability issues. J Pharm Sci. 2018;107(8):2013–2019.
  • Bee JS, Stevenson JL, Mehta B, et al. Response of a concentrated monoclonal antibody formulation to high shear. Biotechnol Bioeng. 2009;103(5):936–943.
  • Zhang C, Yang L, Wan F, et al. Quality by design thinking in the development of long-acting injectable PLGA/PLA-based microspheres for peptide and protein drug delivery. Int J Pharm. 2020;585:119441.
  • Le M-Q, Violet F, Paniagua C, et al. Penta-block copolymer microspheres: impact of polymer characteristics and process parameters on protein release. Int J Pharm. 2018;535(1–2):428–437.
  • Zhu G, Schwendeman SP Stabilization of Proteins Encapsulated in Cylindrical Poly(lactide-co-glycolide) Implants: mechanism of Stabilization by Basic Additives.:7.
  • Aubert-Pouëssel A, Bibby DC, Venier-Julienne M-C, et al. A novel in vitro delivery system for assessing the biological integrity of protein upon release from PLGA microspheres. Pharm Res. 2002;19(7):1046–1051.
  • Duralliu A, Matejtschuk P, Stickings P, et al. The influence of moisture content and temperature on the long-term storage stability of freeze-dried high concentration immunoglobulin G (IgG). Pharmaceutics. 2020;12(4):303.
  • Ohori R, Akita T, Yamashita C. Effect of temperature ramp rate during the primary drying process on the properties of amorphous-based lyophilized cake, Part 2: successful lyophilization by adopting a fast ramp rate during primary drying in protein formulations. Eur J Pharm Biopharm. 2018;130:83–95.
  • Ferber S, Behrens AM, McHugh KJ, et al. Evaporative cooling hydrogel packaging for storing biologics outside of the Cold Chain. Adv Healthc Mater. 2018;7(14):1800220.
  • Brader ML, Estey T, Bai S, et al. Examination of thermal unfolding and aggregation profiles of a series of developable therapeutic monoclonal antibodies. Mol Pharm. 2015;12(4):1005–1017.
  • Bommana R, Chai Q, Schöneich C, et al. Understanding the increased aggregation propensity of a light-exposed IgG1 monoclonal antibody using hydrogen exchange mass spectrometry, biophysical characterization, and structural analysis. J Pharm Sci. 2018;107(6):1498–1511.
  • Wang W, Ignatius AA, Thakkar SV. Impact of residual impurities and contaminants on protein stability. J Pharm Sci. 2014;103(5):1315–1330.
  • Qi F, Wu J, Li H, et al. Recent research and development of PLGA/PLA microspheres/nanoparticles: a review in scientific and industrial aspects. Front Chem Sci Eng. 2019;13(1):14–27.
  • Vehring R, Snyder H, and Lechuga‐Ballesteros D. Spray Drying. In: Ohtake S, Izutsu K, Lechuga‐Ballesteros D, editors. Drying Technologies for Biotechnoly and Pharmaceutical Applications. 1st ed. NJ, USA: Wiley; 2020. p. 179–216.
  • Pinto JT, Faulhammer E, Dieplinger J, et al. Progress in spray-drying of protein pharmaceuticals: literature analysis of trends in formulation and process attributes. Dry Technol. 2021;39(11):1415–1446.
  • Pham NB, Meng WS. Protein aggregation and immunogenicity of biotherapeutics. Int J Pharm. 2020;585:119523.
  • Kozma GT, Shimizu T, Ishida T, et al. Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv Drug Deliv Rev. 2020;154–155:163–175.
  • Immunogenicity Assessment for Therapeutic Protein Products | FDA [Internet]. cited 2021 Dec 17]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/immunogenicity-assessment-therapeutic-protein-products
  • Yu L, Sun Q, Hui Y, et al. Microfluidic formation of core-shell alginate microparticles for protein encapsulation and controlled release. J Colloid Interface Sci. 2019;539:497–503.
  • Kirchhof S, Gregoritza M, Messmann V, et al. Diels–Alder hydrogels with enhanced stability: first step toward controlled release of bevacizumab. Eur J Pharm Biopharm. 2015;96:217–225.
  • Fayd’herbe, De Maudave A, Leconet W, Toupet K, et al. Intra-articular delivery of full-length antibodies through the use of an in situ forming depot. J Control Release. 2022;341:578–590.
  • Brinks V, Jiskoot W, Schellekens H. Immunogenicity of therapeutic proteins: the use of animal models. Pharm Res. 2011;28(10):2379–2385.
  • Rombach-Riegraf V, Karle AC, and Wolf B, et al. Aggregation of human recombinant monoclonal antibodies influences the capacity of dendritic cells to stimulate adaptive T-cell responses in vitro. In: PLoS ONE. Vol. 9. 2014. pp. e86322.
  • Joubert MK, Deshpande M, and Yang J, et al. Use of in vitro assays to assess immunogenicity risk of antibody-based biotherapeutics. In: PLOS ONE. Vol. 11. 2016. e0159328.
  • Morgan H, Tseng S-Y, Gallais Y, et al. Evaluation of in vitro assays to assess the modulation of dendritic cells functions by therapeutic antibodies and aggregates. Front Immunol. 2019;10:601.
  • Lu Y, Kim S, Park K. In vitro–in vivo correlation: perspectives on model development. Int J Pharm. 2011;418(1):142–148.
  • Olthof MGL, Tryfonidou MA, Dadsetan M, et al. In vitro and in vivo correlation of bone morphogenetic protein-2 release profiles from complex delivery vehicles. Tissue Eng Part C Methods. 2018;24(7):379–390.
  • Jain P, Pawar RS, Pandey RS, et al. In-vitro in-vivo correlation (IVIVC) in nanomedicine: is protein Corona the missing link? Biotechnol Adv. 2017;35(7):889–904.
  • Zolnik BS, Burgess DJ. In vitro–in vivo correlation on parenteral dosage forms. In Krishna R, Yu L, editors. Biopharm appl drug dev Internet]. Boston (MA): Springer US; 2008, 336–358. [cited 2021 Nov 23]. Available from: http://link.springer.com/10.1007/978-0-387-72379-2_11
  • Lal RA, Hoffman AR. Long-acting growth hormone preparations in the treatment of children. 2019;9.
  • Teekamp N, Van Dijk F, Broesder A, et al. Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney. Int J Pharm. 2017;534(1–2):229–236.
  • Polymer technologies - Innocore Pharma [Internet]. cited 2021 Nov 29]. Available from: https://www.innocorepharma.com/nl/Technologies/Polymer%20technologies/SynBiosys%C2%AE
  • Stanković M, Tomar J, Hiemstra C, et al. Tailored protein release from biodegradable poly(ε-caprolactone-PEG)-b-poly(ε-caprolactone) multiblock-copolymer implants. Eur J Pharm Biopharm. 2014;87(2):329–337.
  • Tyagi P, Koskinen M, Mikkola J, et al. Silica microparticles for sustained zero-order release of an anti-CD40L antibody. Drug Deliv Transl Res. 2018;8(2):368–374.
  • Libutti SK, Paciotti GF, Byrnes AA, et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res. 2010;16(24):6139–6149.
  • [Internet]. cited 2022 Apr 12]. Available from: https://www.cytimmune.com/pipelilne
  • Chan Y-P, Meyrueix R, Kravtzoff R, et al. Review on Medusa ®:a polymer-based sustained release technology for protein and peptide drugs. Expert Opin Drug Deliv. 2007;4(4):441–451.
  • OctoPlus. PolyActiveTM A biodegradable polymer-based drug delivery system [Internet]. 2006 cited 2021 Dec 2]. Available from: http://www.afinitica.com/arnews/sites/default/files/techdocs/PolyActive_Nov20061%5B1%5D.pdf
  • Biolex Therapeutics, Inc. An Open-Label, 3-Panel, Dose-Escalation Study to Assess the Safety and Tolerability, Pharmacokinetics, and Viral Kinetics of Two Doses of LocteronTM (Poly ActiveTM - Interferon Alpha 2b) Given Every 2 Weeks for 4-12 Weeks in Comparison With PEG-Intron Given Weekly for 4-12 Weeks in Patients With Chronic Hepatitis C [Internet]. clinicaltrials.gov; 2012 [cited 2021 Dec 1]. Report No.: NCT00593151. Available from: https://clinicaltrials.gov/ct2/show/NCT00593151.
  • Biolex therapeutics researchers present Locteron® U.S. Phase 2a Hepatitis C Trial Results at EASL Conference | proteins and Peptides | news Channels [Internet]. cited 2021 Dec 1]. Available from: https://pipelinereview.com/index.php/2009042426544/Proteins-and-Peptides/Biolex-Therapeutics-Researchers-Present-Locteron-U.S.-Phase-2a-Hepatitis-C-Trial-Results-at-EASL-Conference.html
  • Ramos TI, Villacis-Aguirre CA, Santiago Vispo N, et al. Forms and methods for interferon’s encapsulation. Pharmaceutics. 2021;13(10):1533.
  • Technology – bioChaperone® – ADOCIA a biotechnology company dedicated to protein delivery [Internet]. cited 2021 Nov 29]. Available from: https://www.adocia.com/technology/biochaperone-technology-2
  • Products – bioChaperone® ultra-rapid insulin – ADOCIA a biotechnology company dedicated to protein delivery [Internet]. cited 2021 Dec 1]. Available from: https://www.adocia.com/products/biochaperone-ultra-fast-analog-insulin
  • Adocia ends BioChaperone PDGF development after phase III Failure [Internet]. cited 2021 Dec 1]. Available from: https://www.genengnews.com/news/adocia-ends-biochaperone-pdgf-development-after-phase-iii-failure
  • Serwer L, Hashizume R, and Ozawa T, et al. Systemic and local drug delivery for treating diseases of the central nervous system in rodent models. J Vis Exp. 2010;e1992.
  • Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010;26(3):355–369.
  • Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol. 2014;10(1):11–22.
  • Fayd’herbe De Maudave A, Leconet W, Toupet K, et al. Intra-articular delivery of full-length antibodies through the use of an in situ forming depot. J Control Release. 2022;341:578–590
  • Shi WJ, Tjoumakaris FP, Lendner M, et al. Biologic injections for osteoarthritis and articular cartilage damage: can we modify disease? Phys Sportsmed. 2017;45(3):203–223.
  • Intra-tumoral ipilimumab plus intravenous nivolumab following the resection of recurrent glioblastoma - ClinicalTrials.gov [Internet]. cited 2021 Apr 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT03233152
  • Intratumoral Tilsotolimod, a TLR-9 agonist, together with intratumoral ipilimumab and intravenous nivolumab in patients with advanced cancers - ClinicalTrials.gov [Internet]. cited 2021 Apr 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT04270864
  • A trial evaluating the safety & efficacy of intra-tumoral ipilimumab in combination with intra-venous nivolumab in patients with metastatic melanoma - clinicalTrials.gov [Internet]. cited 2021 Apr 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT02857569
  • Heldin C-H, Rubin K, Pietras K, et al. High interstitial fluid pressure — an obstacle in cancer therapy. Nat Rev Cancer. 2004;4(10):806–813.
  • Nam J, Son S, Park KS, et al. Cancer nanomedicine for combination cancer immunotherapy. Nat Rev Mater. 2019;4(6):398–414.
  • Bhatia S, Miller NJ, Lu H, et al. Intratumoral G100, a TLR4 agonist, induces antitumor immune responses and tumor regression in patients with Merkel cell carcinoma. Clin Cancer Res. 2019;25(4):1185–1195.
  • Marabelle A, Andtbacka R, Harrington K, et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018;29(11):2163–2174.
  • Muñoz NM, Williams M, Dixon K, et al. Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy. J Immunother Cancer. 2021;9(2):e001800.
  • Peyman GA, Lad EM, Moshfeghi DM. Intravitreal injection of therapeutic agents. Retina. 2009;29(7):875–912.
  • Otero-Espinar FJ, Fernández-Ferreiro A, González-Barcia M, et al. Stimuli sensitive ocular drug delivery systems. Drug target stimuli sensitive drug deliv syst [Internet]. Elsevier; 2018 [cited 2021 Nov 26]. p. 211–270. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128136898000069.
  • Chandrasekaran PR, Madanagopalan VG. KSI-301: antibody biopolymer conjugate in retinal disorders. Ther Adv Ophthalmol. 2021;13:251584142110277.
  • Brown TD, Whitehead KA, Mitragotri S. Materials for oral delivery of proteins and peptides. Nat Rev Mater. 2020;5:127–148.
  • Brayden DJ, Hill TA, Fairlie DP, et al. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv Drug Deliv Rev. 2020;157:2–36.
  • Karsdal MA, Byrjalsen I, Riis BJ, et al. Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: the effect of water and timing of meal intake on oral delivery of salmon calcitonin. BMC Clin Pharmacol. 2008;8(1):5.
  • Richard J. Formulation Strategies based on Supercritical Fluid Technology for the Delivery of Biopharmaceuticals. Chem Today. 2008;26:48–51.
  • Lewis AL, Richard J. Challenges in the delivery of peptide drugs: an industry perspective. Ther Deliv. 2015;6(2):149–163.
  • Cherif-Cheikh R, Delgado De Sousa A-P, Lacombe F, et al. Sustained release formulations comprising very low molecular weight polymers.
  • Richard J. Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects. Ther Deliv. 2017;8(8):663–684.
  • Jamaledin R, Di Natale C, Onesto V, et al. Progress in microneedle-mediated protein delivery. J Clin Med. 2020;9(2):542.
  • Vora LK, Moffatt K, Tekko IA, et al. Microneedle array systems for long-acting drug delivery. Eur J Pharm Biopharm. 2021;159:44–76.
  • Daddona PE, Matriano James A, Mandema J, et al. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharm Res. 2011;28(1):159–165.
  • Kochba E, Levin Y, Raz I, et al. Improved insulin pharmacokinetics using a novel microneedle device for intradermal delivery in patients with type 2 diabetes. Diabetes Technol Ther. 2016;18(9):525–531.
  • Jacobse J, Voorde W, Tandon A, et al. Comprehensive evaluation of microneedle-based intradermal Adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial. Br J Clin Pharmacol. 2021;87(8):3162–3176.