Introduction: Biologics (biopharmaceuticals) present new promising therapies for many diseases such as cancers, chronical inflammatory diseases and today's biggest challenge - COVID-19. Research: Today, most biologics have been synthetized using modern methods of biotechnology, in particular DNA recombinant technology. Current pharmaceutical forms of protein/peptide biopharmaceuticals are intended for parenteral route of administration due to their instability and large size of molecules. In order to improve patient compliance, many companies are working on developing adequate forms of biopharmaceuticals for alternative, non-invasive routes of administration. The aim of this work is to review current aspirations and problems in formulation of biopharmaceuticals for alternative (non-parenteral) routes of administration and to review the attempts to overcome them. These alternative routes of administration could be promising in prevention and treatment of COVID-19, among other serious diseases. Conclusion: The emphasis is on stabilizing monoclonal antibodies into special formulations and delivery systems; their application should be safer, more comfortable and reliable. When it comes to hormones, vaccines and smaller peptides, some companies have already registered drugs intended for nasal and oral delivery.
References
1.
Hoyer H, Perera G, Bernkop-Schnürch A. Noninvasive delivery systems for peptides and proteins in osteoporosis therapy: a retroperspective. Drug Development and Industrial Pharmacy. 2010;36(1):31–44.
2.
Pharma I. Enabling Technologies for Precision Drug Delivery in the GI Tract.
3.
Annabestani Z, Sharghi S, Shahbazi S, Karimi F, Taheri E, Heshmat R, et al. Insulin buccal spray (Oral-Lyn) efficacy in type 1 diabetes. J Diab Metabolic Dis. 2010;9(18).
4.
Corp GB. Active Comparator Study of Generex Oral-lynTM Spray and Injected Human Insulin. 2008;
5.
Bajracharya R, Song JG, Back SY, Han HK. Recent Advancements in Non-Invasive Formulations for Protein Drug Delivery. Computational and Structural Biotechnology Journal. 2019;17:1290–308.
6.
Science TL. Tiziana Reports Positive Data from the Clinical Study of Nasal Administration with Foralumab, its proprietary fully human anti-CD3 monoclonal antibody. In: COVID-19 Patients in Brazil GlobeNewswire: Tiziana Life Science:cited 2021 Feb 02.
7.
Zhang H, Yang Z, Xiang J, Cui Z, Liu J, Liu C. Intranasal administration of SARS-CoV-2 neutralizing human antibody prevents infection in mice.
8.
Diomics Corporation US. Diomics aims to nose out coronavirus ahead of vaccines with nasal spray that delivers monoclonal antibody protection. 2020;
Esparza TJ, Martin NP, Anderson GP, Goldman ER, Brody DL. High affinity nanobodies block SARS-CoV-2 spike receptor binding domain interaction with human angiotensin converting enzyme. Scientific Reports. 10(1).
11.
Liang W, Pan HW, Vllasaliu D, Lam JKW. Pulmonary Delivery of Biological Drugs. Pharmaceutics. 12(11):1025.
12.
Nambulli S, Xiang Y, Tilston-Lunel NL, Rennick LJ, Sang Z, Klimstra WB, et al. Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses. Science Advances. 2021;7(22).
13.
Ghadiri M, Young PM, Traini D. Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes. Pharmaceutics. 11(3):113.
14.
Pharma I. Intract Pharma Enters into Research Collaboration with Ferring Pharmaceuticals to Evaluate Oral delivery of Monoclonal Antibodies for Treatment of Chronic Gastrointestinal Diseases-Intract Pharma: cited 2021 Apr 01.
15.
Zheng J, Zhang G, Lu Y, Fang F, He J, Li N, et al. Effect of Pulmonary Surfactant and Phospholipid Hexadecanol Tyloxapol on Recombinant Human-Insulin Absorption from Intratracheally Administered Dry Powders in Diabetic Rats. Chemical and Pharmaceutical Bulletin. 2010;58(12):1612–6.
16.
Rendell, M. Technosphere inhaled insulin (Afrezza). Drugs of Today. 50(12):813.
17.
Ma H, Zeng W, Meng X, Huang X, Yang Y, Zhao D, et al. Potent Neutralization of SARS-CoV-2 by Hetero-Bivalent Alpaca Nanobodies Targeting the Spike Receptor-Binding Domain. Journal of Virology. 2021;95(10).
18.
Martinez-Delgado G. Inhaled nanobodies against COVID-19. Nature Reviews Immunology. 2020;20(10):593–593.
19.
Hasan M, Khatun A, Fukuta T, Kogure K. Noninvasive transdermal delivery of liposomes by weak electric current. Advanced Drug Delivery Reviews. 2020;154–155:227–35.
20.
An Y, Park MJ, Lee J, Ko J, Kim S, Kang DH, et al. Recent Advances in the Transdermal Delivery of Protein Therapeutics with a Combinatorial System of Chemical Adjuvants and Physical Penetration Enhancements. Advanced Therapeutics. 2020;3(2).
21.
Kirkby M, Hutton ARJ, Donnelly RF. Microneedle Mediated Transdermal Delivery of Protein, Peptide and Antibody Based Therapeutics: Current Status and Future Considerations. Pharmaceutical Research. 2020;37(6).
22.
Yu J, Zhang Y, Ye Y, DiSanto R, Sun W, Ranson D, et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proceedings of the National Academy of Sciences. 2015;112(27):8260–5.
Peña-Juárez MaC, Guadarrama-Escobar OR, Escobar-Chávez JJ. Transdermal Delivery Systems for Biomolecules. Journal of Pharmaceutical Innovation. 2022;17(2):319–32.
25.
Bialik M, Kuras M, Sobczak M, Oledzka E. Achievements in Thermosensitive Gelling Systems for Rectal Administration. International Journal of Molecular Sciences. 22(11):5500.
26.
Aprodu A, Mantaj J, Raimi-Abraham B, Vllasaliu D. Evaluation of a Methylcellulose and Hyaluronic Acid Hydrogel as a Vehicle for Rectal Delivery of Biologics. Pharmaceutics. 11(3):127.
27.
Viswanathan P, Muralidaran Y, Ragavan G. Challenges in oral drug delivery: a nano-based strategy to overcome. Nanostructures for Oral Medicine. 2017. p. 173–201.
28.
Crommelin D, Bermejo T. Bisssig M et al.Pharmaceutical evaluation of biosimilars: important differenceas from generic low molekulweight pharmaceuticals. Eur J Hosp; Pharm. 2005;11:11–7.
29.
Savić S, Pantelić I, Savić M. Farmaceutski oblici bioloških i drugih lekova u terapiji multiple skleroze. Arh Farm. 2015;65:237–55.
30.
Savić S, Vuleta G, Savić M. Hormoni kao biotehnološki lekovi: humani insulin i analozi. Arhiv Farm. 2010;60(2):207–25.
31.
Alten R, Cronstein BN. Clinical trial development for biosimilars. Seminars in Arthritis and Rheumatism. 2015;44(6):S2–8.
32.
International alliance of patients organizations. Biologics Introduction. 2017;1.
33.
Nagel KM. Therapeutic Proteins. AAPS Introductions in the Pharmaceutical Sciences. 2018. p. 31–54.
34.
Emami F, Vatanara A, Park EJ, Na DH. Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals. Pharmaceutics. 10(3):131.
35.
Awwad S, Angkawinitwong U. Overview of Antibody Drug Delivery. Pharmaceutics. 10(3):83.
36.
Madani F, Hsein H, Busignies V, Tchoreloff P. An overview on dosage forms and formulation strategies for vaccines and antibodies oral delivery. Pharmaceutical Development and Technology. 2020;25(2):133–48.
37.
Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nature Reviews Drug Discovery. 2019;18(1):19–40.
38.
Knowles SP, Printz MA, Kang DW, LaBarre MJ, Tannenbaum RP. Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery. Expert Opinion on Drug Delivery. 2021;18(11):1673–85.
39.
Dan N, Samanta K, Almoazen H. An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins in Adults and Pediatrics. Children. 7(12):307.
Morçöl T, Nagappan P, Nerenbaum L, Mitchell A, Bell SJD. Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. International Journal of Pharmaceutics. 2004;277(1–2):91–7.
42.
Eldor R, Neutel J, Homer K, Kidron M. Efficacy and safety of 28‐day treatment with oral insulin ( <scp>ORMD</scp> ‐0801) in patients with type 2 diabetes: A randomized, placebo‐controlled trial. Diabetes, Obesity and Metabolism. 2021;23(11):2529–38.
43.
Pharmaceuticals O. Oramed Initiates Second Phase 3 Oral Insulin Study Under the FDA’s Approved Dual Concurrent Protocol. PRNewswire: Oramed Pharmaceuticals-press releases. 2021;
44.
NAGARAJU R, MADAN S, ARORA K, ARORA NM, KUNDU PK, GREENBERG-SHUSHLAV Y, et al. Recombinant Protease Inhibitor Enhances Oral Insulin Pharmacodynamics in Pigs. Diabetes. 2018;67(Supplement_1).
45.
Traverso G, Schoellhammer CM, Schroeder A, Maa R, Lauwers GY, Polat BE, et al. Microneedles for Drug Delivery via the Gastrointestinal Tract. Journal of Pharmaceutical Sciences. 2015;104(2):362–7.
46.
Science TL. Tiziana Reports Phase 1 Clinical Data Demonstrating Oral Treatment with Foralumab, a Fully Human Anti-CD3 Monoclonal Antibody, is Well-tolerated in Healthy Volunteers.
47.
Science TL. Corporate Presentation.Tiziana Life Sience:published 2021 Jan.
48.
Ilan Y, Shailubhai K, Sanyal A. Immunotherapy with oral administration of humanized anti-CD3 monoclonal antibody: a novel gut-immune system-based therapy for metaflammation and NASH. Clinical and Experimental Immunology. 2018;193(3):275–83.
49.
Vass P, Démuth B, Hirsch E, Nagy B, Andersen SK, Vigh T, et al. Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals. Journal of Controlled Release. 2019;296:162–78.
50.
Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci. 2003;6(1):33–66.
51.
Maurer JM, Hofman S, Schellekens RCA, Tonnis WF, Dubois AOT, Woerdenbag HJ, et al. Development and potential application of an oral ColoPulse infliximab tablet with colon specific release: A feasibility study. International Journal of Pharmaceutics. 2016;505(1–2):175–86.
52.
Pharma I. Intract Pharma Limited and Celltrion Group announce collaboration for development of oral Infliximab. :0001.
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