Review Article

Concise Review: Considerations for the Formulation, Delivery and Administration Routes of Biopharmaceuticals

Amir Mohammed Alsharabasy*

Published: 28 June, 2017 | Volume 1 - Issue 1 | Pages: 033-053

The drugs of biological origins have attracted the attention of many pharmaceutical companies where it is essential to protect the heterogeneous nature and the optimal three dimensional structures of the different macromolecules. These molecules are used in both the investigation and therapy purposes, so their maximum activities should be maintained. This requires the designing of certain delivery formulations that suits the macromolecule nature, its target organ, the required dose and delivery route, and that’s why the biotech companies invest millions of dollars towards achieving that. The first main focal point of this article includes the recent developments in the formulation technologies for several biomacromolecule classes. The second focal point concentrates on the current considerations for optimizing their delivery for a maximum performance in the body.

Read Full Article HTML DOI: 10.29328/journal.hjb.1001004 Cite this Article Read Full Article PDF


Biopharmaceutical; Drug formulation; Delivery; Administration routes


  1. Rader RA. BioExecutive Intl. 2005; 60-65.
  2. Rader RA. Biopharmaceutical Products in the US and European Markets. 6th ed., 2007; 2. Ref.: https://goo.gl/f9P2o9
  3. Rader RA. (Re) defining biopharmaceutical. Nature Biotechnol. 2008; 26: 743-751. Ref.: https://goo.gl/Ej6u1w
  4. Walsh G. Biopharmaceuticals biochemistry and biotechnology, 2nd Edition. John Wiley & Sons, Ltd, Chichester, U.K. 2003.
  5. Ho RJ, Gibaldi M. Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs. 2nd Edition. John Wiley & Sons, Ltd, Chichester, U.K. 2013.
  6. Pharmaceutical Research and Manufacturers of America. Medicines in Development -Biologics (2013 report). PhRMA [online]. 2016.
  7. Pharmaceutical Research and Manufacturers of America. Medicines in Development-Biologics (2015 report). PhRMA [online]. 2016.
  8. Biotech products in big pharma clinical pipelines have grown dramatically. Tufts CSDD Impact Report. 2013; 15: 1-4.
  9. PhRMA ChartPack (2015). Biopharmaceuticals in Prospective. 2016.
  10. Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. 2013.
  11. Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND. 2013.
  12. National Patient Safety Agency: National Reporting and Learning Service (2010) Vaccine cold storage. 2016.
  13. Lokesh B, et al. Excipients: Background/Introduction". In: Ashok K and Mahesh C (eds). Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. Informa Healthcare, New York. 2006.
  14. Hassan BA. Overview on Pharmaceutical Formulation and Drug Design. Pharmaceut Anal Acta. 3:10. 2012.
  15. Venkatesh S, Lipper RA. Role of the development scientist in compound lead selection and optimization. J Pharm Sci. 2000; 89: 145-154. Ref.: https://goo.gl/zBxer4
  16. Simler R, Walsh G, Mattaliano RJ, N Guziewicz, Perez-Ramirez B. Maximizing data collection and analysis during preformulation of biotherapeutic proteins. BioProcess Int. 2008; 4: 38-45.
  17. Li AP. A comprehensive approach for drug safety assessment. Chem Biol Interact. 2004; 150: 27-33. Ref.: https://goo.gl/VeqWjw
  18. Steele G, Austin T. Chapter (3): Preformulation Investigations using Small Amounts of Compound as an Aid to Candidate Drug Selection and Early Development. In: Gibson M. Pharmaceutical Preformulation and Formulation. Informa Healthcare. 2009; New York. 17-128.
  19. Wei Z, Emily Shacter, Mark Schenerman, John Dougherty, Lorna McLeod D. CMC Strategy Forum Report: The Role of Higher-Order Structure in Defining Biopharmaceutical Quality. BioProcess Int. 2011; 6: 54-65. Ref.: https://goo.gl/b9rkh1
  20. Shintani H. Development of test method for pharmaceutical and biopharmaceutical products. Pharm Anal Acta. 2013; 4: 1-14. Ref.: https://goo.gl/5RKrNA
  21. ICH Topic Q6B. Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products. CPMP/ICH/365/96. 1999.
  22. ICH Topic Q6A. Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. CPMP/ICH/367/96. 2000.
  23. ICH papers: ICH topic Q5E. Harmonised tripartite guideline: comparability of biotechnological/ biological products subject to changes in their manufacturing process. 2004.
  24. Berkowitz SA, Engen JR, Jeffrey RM, Graham BJ. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov. 2012; 11: 527-40. Ref.: https://goo.gl/3gMuzv
  25. Wishart DS. Characterization of biopharmaceuticals by NMR spectroscopy. Trends Anal Chem. 2013; 48: 96-111. Ref.: https://goo.gl/FVUbJT
  26. Zuperl S, P Pristovšek, V Menart, Porekar GV, Novic M. Chemometric approach in quantification of structural identity/similarity of proteins in biopharmaceuticals. J Chem Inf Model. 2007; 47: 737-743. Ref.: https://goo.gl/tKyYNy
  27. Aubin Y, G Gingras, S Sauvé. Assessment of the three-dimensional structure of recombinant protein therapeutics by NMR fingerprinting: demonstration on recombinant human granulocyte macrophagecolony stimulation factor. Anal Chem. 2008; 80: 2623-2627. Ref.: https://goo.gl/G6bGfB
  28. Lin Y, Schiavo S, Orjala J, Vouros P, Kautz R. Microscale LC-MS-NMR platform applied to the identification of active cyanobacterial metabolites. Anal Chem. 2008; 80: 8045-8054. Ref.: https://goo.gl/xf2kqW
  29. Nikolin B, Belma I, Medanhodzić-Vuk S, Soberet M.High perfomance liquid chromatography in pharmaceutical analyses. Bosn J Basic Med Sci. 2004; 4: 5-9. Ref.: https://goo.gl/55pxzd
  30. Lim A, Barnes CS. Chapter 11: Utilization of Mass Spectrometry for the Structural Characterization of Biopharmaceutical Protein Products. In: Gross ML. et al (eds). Protein and peptide mass spectrometry in drug discovery. John Wiley & Sons, Inc.: New Jersy. 2012; 304.
  31. Higel F, Demelbauer U, Andreas S, Wolfgang F, Fritz S. Reversed-phase liquid-chromatographic mass spectrometric N-glycan analysis of biopharmaceuticals. Anal Bioanal Chem. 2013; 405: 2481-2493. Ref.: https://goo.gl/K3onwc
  32. Rosenberg AS. Effects of Protein Aggregates: An Immunologic Perspective. AAPS J. 2006; 8: 501-507. Ref.: https://goo.gl/L69suP
  33. Lloyd L. Size-exclusion chromatography of protein aggregation in biopharmaceutical development and production. 2014; 32: 30-35.
  34. Engelsman J, Garidel P, Smulders R, Koll H, Smith B, et al. Strategies for the assessment of protein aggregates in pharmaceutical biotech product development. Pharm Res. 2011; 28: 920-33. Ref.: https://goo.gl/oJKcye
  35. McGrath BM. Chapter (11): Factor IX (Protease Zymogen). In: McGrath BM, Walsh G. Directory of therapeutic enzymes. CRC Press Taylor & Francis Group: New York. 2006; 225.
  36. Popovici ST, Kok WT, Schoenmakers PJ. Band broadening in size-exclusion chromatography of polydisperse samples. J Chromatogr A. 2004; 1060: 237-252. Ref.: https://goo.gl/2yYvUv
  37. Ziegler A, Zaia J. Size-exclusion chromatography of heparin oligosaccharides at high and low pressure. J Chromatogr B Analyt Technol Biomed Life Sci. 2006; 837: 76-86. Ref.: https://goo.gl/G9aUmb
  38. Gritti F, Farkas T, Heng J, Guiochon G. On the relationship between band broadening and the particle-size distribution of the packing material in liquid chromatography: theory and practice. J Chromatogr A. 2011; 1218: 8209-8221. Ref.: https://goo.gl/KCwXGh
  39. Hong P, Koza S, Bouvier ES. Size-exclusion chromatography for the analysis of protein biotherapeutics and their aggregates. J Liq Chromatogr Rel Technol. 2012; 35: 2923-2950. Ref.: https://goo.gl/sifx5d
  40. Aitken A, Learmonth M. Protein Determination by uv Absorption. In: Walker JM (ed). The Protein Protocols Handbook. Humana Press: New Jersy. 1996; 3-6.
  41. Bond MD, Mark EP, Zhang Z, Wang D, Mehndiratta, et al. Evaluation of a dual-wavelength size exclusion HPLC method with improved sensitivity to detect protein aggregates and its use to better characterize degradation pathways of an IgG1 monoclonal antibody. J Pharm Sci. 2010; 99: 2582-2597. Ref.: https://goo.gl/AeFJCR
  42. Kipouros K, Kachrimanis K, Nikolakakis I, Tserki V, Malamataris S. Simultaneous quantification of carbamazepine crystal forms in ternary mixtures (I, III, and IV) by diffuse reflectance FTIR spectroscopy (DRIFTS) and multivariate calibration. J Pharm Sci. 2006; 95: 2419-2431. Ref.: https://goo.gl/JSHGfV
  43. Li CH, Xichdao N, Linda N, Chemmalil L, Edward T. Applications of circular dichroism (CD) for structural analysis of proteins: qualification of near-and far-UV CD for protein higher order structural analysis. J Pharm Sci. 2011; 100: 4642-4654. Ref.: https://goo.gl/Rkrszu
  44. Dalal S, Balasubramanian S, Lynne Regan. Transmuting α-helices and β-sheets. Folding Design. 1997; 2: 71-79. Ref.: https://goo.gl/H74oG3
  45. Dong A, James M, Mark CM, John FC. Intermolecular beta-sheet results from trifluoroethanol-induced nonnative alpha-helical structure in beta-sheet predominant proteins: infrared and circular dichroism spectroscopic study. Arch Biochem Biophys. 1998; 355: 275-281. Ref.: https://goo.gl/59Y6aF
  46. Li G, Gianni T, Wendy J, Zai-qing W. Applications of FTIR in identification of foreign materials for biopharmaceutical clinical manufacturing. Vibrational Spectroscopy. 2009; 50: 152-159. Ref.: https://goo.gl/xKtE71
  47. Yazdanian M. Overview of determination of biopharmaceutical properties for development candidate selection. Curr Protoc Pharmacol. 2013. Ref.: https://goo.gl/Pa4x2V
  48. Lechuga-Ballesteros D. Chapter (7): Thermal Analysis of Lyophilized Pharmaceutical Peptide and Protein Formulations. In: Costantino HR, Pikal MJ (eds). Lyophilization of Biopharmaceuticals. Springer Science & Business Media: Arlington. 2005; 283.
  49. Chu B. Laser Light Scattering. Annu Rev Phys Chem. 1970; 21: 145-174.
  50. Niazi SK. Handbook of Preformulation: Chemical, Biological, and Botanical Informa Healthcare: USA. 2007.
  51. Sosic Z, Damian H, Blum A, Carlage T, Lyubarskaya Y. Application of Imaging Capillary IEF for Characterization and Quantitative Analysis of Recombinant Protein Charge Heterogeneity. Electrophor. 2008; 29: 4368-4376. Ref.: https://goo.gl/A2STiS
  52. Michels DA, Oscar Salas-Solano, Chantal Felten. Imaged Capillary Isoelectric Focusing for Charge-Variant Analysis of Biopharmaceuticals. BioProcess Int. 2011; 9: 48-54. Ref.: https://goo.gl/pxayRq
  53. Parkins DA, Lashmar UT. The formulation of biopharmaceutical products. PSTT. 2000; 3: 129-137. Ref.: https://goo.gl/nFrpWQ
  54. Ohtake S, Yoshiko Kita, Tsutomu Arakawa. Interactions of formulation excipients with proteins in solution and in the dried state. Adv Drug Deliv Rev. 2011; 63: 1053-1073. Ref.: https://goo.gl/3dXjrb
  55. Kleinman MH, Lee B. Chapter (14): challenges in early formulation: turning drug substance into drug product. In: Abdel-Magid AF, Caron S (eds). Fundamentals of early clinical drug development. Wiley: New Jersey. 2006; 272.
  56. Mills S. Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations. Archived from the original WHO. 2012.
  57. Hsu T, Mitragotri S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc Natl Acad Sci. 2011; 108: 15816-15821. Ref.: https://goo.gl/f86PXV
  58. Fairand BP, Razem D. Chapter (12): Radiation sterilization. In: Nema S, Ludwig JD (eds). Pharmaceutical dosage forms: parenteral medications (3rd edition, vol. 2)-facility design, sterilization and processing. Informa: London. 2010; 292.
  59. Excipients in pharmaceutical dosage forms: The challenge of the 21st century. IPEC, Nice. 1998.
  60. Nema S, Brendel RJ. Chapter (7): Excipients for parenteral dosage forms: regulatory considerations and controls. In: Nema S, Ludwig JD (eds). Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 3: Regulations, Validation and the Future. Informa Healthcare, London. 2010; 123.
  61. De Jong HJ. The safety of pharmaceutical excipients. Therapie. 1999; 54: 11-14. Ref.: https://goo.gl/yc2Nhc
  62. Steinberg M, Borzelleca JF, Enters EK, Kinoshita FK, Loper A, et al. A new approach to the safety assessment of pharmaceutical excipiens. The safety committee of the international pharmaceutical excipient council. Regul Toxicol Pharmacol. 1996; 24: 149-154. Ref.: https://goo.gl/AAPVeY
  63. Elder DP, Kuentz M, Holm R. Pharmaceutical excipients -quality, regulatory and biopharmaceutical considerations. Eur J Pharm Sci. 2016. 87: 88-99. Ref.: https://goo.gl/4suJ2t
  64. USP-NF General Chapter (1074) Excipient Biological Safety Evaluation Guidelines. 2016.
  65. Gokarn YR. Chapter (17): Excipients for Protein Drugs. In: Ashok K, Mahesh C. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. Informa Healthcare, New York. 2006.
  66. Cacace MG, Landau EM, Ramsden JJ. The Hofmeister series: salt and solvent effects on interfacial phenomena. Q Rev Biophys. 1997; 30: 241-277. Ref.: https://goo.gl/ivDsTa
  67. Kamerzell TJ, Esfandiary R, Joshi SB, Middaugh CR, Volkin, DB. Protein-excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev. 2011; 63: 1118-1159. Ref.: https://goo.gl/Mn1qYG
  68. : https://goo.gl/HEp7u2
  69. Aalto TR, Firman MC, Rigler NE. p-hydroxybenzoic acid esters as preservatives. I. Uses, antibacterial and antifungal studies, properties and determination. J Am Pharm Assoc Sci Ed. 1953; 42: 449-457. Ref.: https://goo.gl/QjMwQa
  70. Gerbino PP. Remington: The Science and practice of pharmacy, 21st edition. Lippincott Williams & Wilkins, Philadelphia.
  71. Roy S, Jung R, Kerwin BA, Randolphn TW. Effects of benzyl alcohol on aggregation of recombinant human interleukin-1receptor antagonist in reconstituted lyophilized formulations. J Pharm Sci. 2005; 94: 382-396. Ref.: https://goo.gl/vJrLx7
  72. Christensen PA. The stability of refined antivenin. Toxicon. 1975; 13: 75-77. Ref.: https://goo.gl/6eg2FX
  73. Rojas G, Jimenez JM, Gutiérrez JM. Caprylic acid fractionation of hyperimmune horse plasma: description of a simple procedure for antivenom production. Toxicon. 1994; 32: 351-363. Ref.: https://goo.gl/tYXPag
  74. Abd-Elsalam MA, Abdoon N, Al-Ahaidib MS. What is the optimum concentration of mcresol in antivenoms? J Venom Anim Toxins incl Trop Dis. 2011; 17: 12-22. Ref.: https://goo.gl/AAD3D6
  75. Izzat IN, Bennett EO. Effect of varying concentrations of EDTA on the antimicrobial properties of cutting fluid preservatives. Microbios. 1979; 26: 37-44. Ref.: https://goo.gl/JfF5it
  76. Whalley G. Preservative Properties of EDTA, Manuf. Chem. 1991; 62: 22-23.
  77. Lam XM, Yang JY, Cleland JL. Antioxidants for prevention of methionine oxidation in recombinant monoclonal antibody HER2. J Pharm Sci. 1997; 86: 1250-1255. Ref.: https://goo.gl/FJR9Wy
  78. Liu J, Nguyen MD, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J Pharm Sci. 2005; 94: 1928-1940. Ref.: https://goo.gl/s2coMw
  79. Zhu G, Mallery SR, Schwendeman SP. Stabilization of proteins encapsulated in injectable poly(lactide-co-glycolide). Nat Biotechnol. 2000; 18: 52-57. Ref.: https://goo.gl/Ao2iXY
  80. Kang J, Schwendeman SP. Comparison of the effects of Mg(OH)2 and sucrose on the stability of bovine serum albumin encapsulated in injectable poly(D,L-lactide-co-glycolide) implants. Biomaterials. 2002; 23: 239-245. Ref.: https://goo.gl/2KUHtG
  81. Gualandi-Signorini AM, Giorgi G. Insulin formulations--a review. Eur Rev Med Pharmacol Sci. 2001; 5: 73-83. Ref.: https://goo.gl/1WTYoQ
  82. Chen B, Costantino HR, Liu J, Hsu CC, Shire SJ. Influence of calcium ions on the structure and stability of recombinant human deoxyribonuclease I in the aqueous and lyophilized states. J PharmSci. 1999; 88: 477-482. Ref.: https://goo.gl/AxQVt7
  83. Angelica Fatouros, Thomas Österberg, Marianne Mikaelsson. Recombinant factor VIII SQ-influence of oxygen, metal ions, pH and ionic strength on its stability in aqueous solution. Int J Pharm. 1997; 155: 121-131. Ref.: https://goo.gl/LTQKfG
  84. Treuheit MJ, Kosky AA, Brems DN. Inverse relationship of protein concentration and aggregation. Pharm Res. 2002; 19: 511-516. Ref.: https://goo.gl/XxFKuS
  85. Shah NH, Stiel D, Weiss M, Infeld MH, Malick AW. Evaluation of two new tablet lubricants-sodium stearyl fumarate and glyceryl behenate. Measurement of physical parameters (compaction, ejection and residual forces) in the tabletting process and effect of the dissolution rate. Drug Dev Ind Pharm. 1986; 12: 1329-1346. Ref.: https://goo.gl/3QPptK
  86. Fassihi RA, Mcphillips AM, Uraizee SA, Sakr AM. Potential use of magnesium stearate and talc as dissolution retardants in the development of controlled drug delivery systems. Pharm Ind. 1994; 56: 579-583. Ref.: https://goo.gl/x7yaBD
  87. Maejima T, McGinity JW. Influence of film additives on stabilizing drug release rates from pellets coated with acrylic polymers. Pharm Dev Technol. 2001; 6: 211-221. Ref.: https://goo.gl/vfvYEC
  88. Sugimoto M, Matsubara K, Koida Y, Kobayashi M. The preparation of rapidly disintegrating tablets in the mouth. Pharm Dev Technol. 2001; 6: 487-493. Ref.: https://goo.gl/Xk8vKx
  89. Shamblin S. Chapter(9): Controlled release using bilayer osmotic tablet technology: reducing theory to practice. In: Wen H, Park K (eds) Oral controlled release formulation design and drug delivery. Wiley & Sons, Inc.: New Jersey. 2010; 138.
  90. Siepmann J. Process and formulation factors affecting drug release from pellets coated with ethylcellulose pseudolatex aquacoat. In: McGinity JW, Felton LA (eds). Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, 3rd edition, New York: Informa Healthcare. 2008; 203-236.
  91. Chen S, Cao Y, Ferguson LR, Shu Q, Garg S. Evaluation of mucoadhesive coatings of chitosan and thiolated chitosan for the colonic delivery of microencapsulated probiotic bacteria. J Microencapsul. 2013; 30: 103-115. Ref.: https://goo.gl/AK3Vhb
  92. Dulin W. Oral targeted drug delivery systems: enteric coating. Oral controlled release formulation design and drug delivery. 2010; 213.
  93. Felton LA, McGinity JW. Influence of insoluble excipients on film coating systems. Drug Dev Ind Pharm. 2002; 28: 225-243. Ref.: https://goo.gl/vFzS7g
  94. Rowe RC, Paul Sheskey J, Owen SC. Handbook of Pharmaceutical Excipients. 5th edition, Pharmaceutical Press. 2006.
  95. Felton LA, McGinity JW. Influence of pigment concentration and particle size on adhesion of an acrylic resin copolymer to tablet compacts. Drug Dev Ind Pharm. 1999; 25: 599-606. Ref.: https://goo.gl/5qpTxx
  96. Shanraw R, Mitrevej A, Shah M. A new era of tablet disintegrants. Pham Technol. 1980; 4: 48-57.
  97. Chang RK, Xiaodi Guo, Burnside BA, Couch RA. Fast-dissolving tablets. Pharm Technol. 2000; 24: 52-58. Ref.: https://goo.gl/9kVxCq
  98. Elshattawy HH, Dane Kildsig O, Garnet Peck E. Aspartame-mannitol resolidified fused mixture: characterization studies by differential scanning calorimetry, thermomicroscopy, photomicrography and X-ray diffractometry. Drug Dev Ind Pharm. 1984: 10: 1-17. Ref.: https://goo.gl/S8WbaC
  99. Lin YA. Enteric-coated pellet formulation and process scale-up improvement using mono- and diglycerides as a glidant. Poster Presentation. AAPS Annual Meeting, San Diego, CA. 2007.
  100. Abhijit Sonje, Arun Yadav, Chandra A, Jain DA. Formulation and evaluation of immediate release tablet of antihypertensive drugs according to BCS system. Int J Therap Appl. 2012; 7: 18-24. Ref.: https://goo.gl/bm23bc
  101. Jones TM. Symposium on Powders. Dublin: Society of Cosmetic Chemists of Great Britain. 1969.
  102. Peleg M, Mannheim CH. Effect of conditioners on the flow properties of powdered sucrose. Powder Technol. 1973; 7: 45-50. Ref.: https://goo.gl/BRvPeb
  103. Tiwary AK. Dissolution. In: Gad SC. Preclinical Development handbook ADME and Biopharmaceutical Properties. John Wiley & Sons. Inc: New Jersey. 2008; 494.
  104. James KC. Solubility and Related Phenomena. Mercel Dekker Inc. 1986.
  105. Bai JPF, Guo JH, Mahesh VC. Use of nonactive pharmaceutical excipients in oral drug formulations: Biopharmaceutical classification system considerations. In: Katdare A, Chaubal MV. (eds) Excipient development for pharmaceutical, biotechnology, and drug delivery. Informa Healthcare USA, Inc.: New York. 182. 2006.
  106. Ungell A, Abrahamsson B. Chapter(4): Biopharmaceutical support in candidate drug selection. 2nd edition. In: Gibson M. Pharmaceutical Preformulation and Formulation. Informa Healthcare. 2009.
  107. Alsenz J, Kansy M. High throughput solubility measurement in drug discovery and development. Adv Drug Deliv Rev. 2007; 59: 546-567. Ref.: https://goo.gl/GGPNDQ
  108. Valvani SC. Chapter (2): The Pharmaceutical Background. In: Lee C, et al. (eds) Clinical Trials of Drugs and Biopharmaceuticals. CRC Press Taylor & Francis Group: Boca Raton. 2006; 17.
  109. Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990; 62: 87-95. Ref.: https://goo.gl/V8ZX4V
  110. USP, The United States Pharmacopeia. XXIII Revision, United States Pharmacopeial Convention, Rockville, Md. 1995.
  111. Hancock BC, Dalton CR. The effect of temperature on water vapor sorption by some amorphous pharmaceutical sugars. Pharm Dev Techn. 1999; 4: 125-131. Ref.: https://goo.gl/Ut46Zo
  112. Callahan J, Cleary GW, Elefant M, Kaplan G, Kensler T, et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm; 1982; 8: 355-369. Ref.: https://goo.gl/tTP5XE
  113. Kumar L, Amin A, Bansal AK. An overview of automated systems relevant in pharmaceutical salt screening. Drug Discov Today. 2007; 12: 1046-1053. Ref.: https://goo.gl/M61VjW
  114. Murikipudi V, Gupta P, Sihorkar V. Efficient throughput method for hygroscopicity classification of active and inactive pharmaceutical ingredients by water vapor sorption analysis. Pharm Dev Technol. 2013; 18: 348-358. Ref.: https://goo.gl/rhBXHv
  115. Jaenicke R. Protein folding: local structures, domains, subunits, and assemblies. Biochemistry. 1991; 30: 3147-3161. Ref.: https://goo.gl/n8DdE8
  116. Pace CN, Shirley BA, McNutt M, Gajiwala K. Forces contributing to the conformational stability of proteins. FASEB J. 1996; 10: 75-83. Ref.: https://goo.gl/3n6HV4
  117. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999; 185: 129-188. Ref.: https://goo.gl/nQyt1q
  118. Cromwell ME, Hilario E, Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006; 8: 572-579. Ref.: https://goo.gl/Q1k1Da
  119. Brorson K, Phillips J. Defining your product profile and maintaining control over it, Part 4. Product-Related Impurities: Tackling Aggregates. Bioprocess Int. 2005; 3: 50-54. Ref.: https://goo.gl/CH6J7r
  120. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006; 8: 501-507. Ref.: https://goo.gl/qFtqqv
  121. Smales CM, Pepper DS, James DC. Protein modification during anti-viral heat-treatment bioprocessing of factor VIII concentrates, factor IX concentrates, and model proteins in the presence of sucrose. Biotechnol Bioeng. 2002; 77: 37-48. Ref.: https://goo.gl/fDPdCv
  122. McEntire J. Biotechnology Product Validation Part 5: Selection and Validation of Analytical Techniques. BioPharm. 1994; 7: 68-79.
  123. USP Guideline for Submitting Requests for Revision to USP-NF: V3.1 EXCIPIENTS. U S. PHARMACOPEIA. 2007. Ref.: https://goo.gl/8vDcph
  124. Qualification of excipients for use in pharmaceuticals. IPEC. 2008. Ref.: https://goo.gl/nN6KzX
  125. International Conference on Harmonisation- Quality of biotechnological products: ICH Q5C: Stability testing of biotechnological/biological products. 1995.
  126. "FDA Guidance for Industry PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance," September. 2004.
  127. WHO Annex 2. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. WHO Technical Report Series. No. 953. 2009.
  128. Patel J, Nadine Ritter M, Ruchi Kothari, Rashbehari Tunga, Binita Tunga S. Stability Considerations for Biopharmaceuticals: Overview of Protein and Peptide Degradation Pathways. BioProcess International. 2011; 9: 2-11. Ref.: https://goo.gl/bNSsrx
  129. Yu J. Intentionally Degrading Protein Pharmaceuticals to Validate Stability-Indicating Analytical Methods. BioPharm. 2000; 13: 46-52.
  130. Waterman KC, Adami RC. Accelerated ageing: prediction of chemical stability of pharmaceuticals. Int J Pharm. 2005; 293: 101-125. Ref.: https://goo.gl/rNzzoj
  131. Nieminen O, Kurki P, Nordström K. Differences in product information of biopharmaceuticals in the EU and the USA: implications for product development. Eur J Pharm Biopharm. 2005; 60: 319-326. Ref.: https://goo.gl/KxU8D6
  132. Kelly T. Accelerated Stability During Formulation Development of Early Stage Protein Therapeutics - Pros and Cons of Contrasting Approaches. KBI Biopharma. IBC Formulation Strategies for Protein Therapeutics. 2008.
  133. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov. 2014; 13: 655-672. Ref.: https://goo.gl/g1EzCw
  134. Silva AC, Lopes CM, Lobo JM, Amaral MH. Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles. Curr Pharm Biotechnol. 2015; 16: 940-954. Ref.: https://goo.gl/GG3oQa
  135. Vilos C, Velasquez LA. Therapeutic Strategies Based on Polymeric Microparticles. J Biomed Biotechnol. 2012; 2012: 1-9. Ref.: https://goo.gl/vrpTgz
  136. Reis CP, Damgé C. Nanotechnology as a promising strategy for alternative routes of insulin delivery. Methods Enzymol. 2012; 508: 271-294. Ref.: https://goo.gl/8mztFS
  137. Umer H, H Nigam, AM Tamboli, MSM Nainar. Microencapsulation: Process, Techniques and Applications. International Journal of Research in Pharmaceutical and Biomedical Sciences. 2011; 2: 474-481.
  138. Bock N, Dargaville TR, Woodruff MA. Controlling microencapsulation and release of micronized proteins using poly(ethylene glycol) and electrospraying. Eur J Pharm Biopharm. 2014; 87: 366-377. Ref.: https://goo.gl/zLAQ4d
  139. Shi J, Xiao Z, Votruba AR, Vilos C, Farokhzad OC. Differentially charged hollow core/shell lipid-polymer-lipid hybrid nanoparticles for small interfering RNA delivery. Angew Chem Int Ed Engl. 2011; 50: 7027-7031. Ref.: https://goo.gl/2AR7kY
  140. Rahman MA, Amin AR, Wang X, Zuckerman JE, Choi CH, et al. Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth. J Control Release. 2012; 159: 384-392. Ref.: https://goo.gl/yx5PYD
  141. Silva AC, Amaral MH, Lobo JM, Lopes CM. Lipid nanoparticles for the delivery of biopharmaceuticals. Curr Pharm Biotechnol. 2015; 16: 291-302. Ref.: https://goo.gl/btimzW
  142. Ravi S, Peh KK, Darwis Y, Murthy BK, Singh TR, et al. Development and Characterization of Polymeric Microspheres for Controlled Release Protein Loaded Drug Delivery System. Indian J Pharm Sci. 2008; 70: 303-309. Ref.: https://goo.gl/BuxNDy
  143. Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA. 2006; 103: 4930-4934. Ref.: https://goo.gl/uQGih6
  144. Radomsky ML, Whaley KJ, Cone RA, Saltzman WM. Macromolecules released from polymers: diffusion into unstirred fluids. Biomaterials. 1990; 11: 619-624. Ref.: https://goo.gl/C5jehN
  145. Sandor M, Enscore D, Weston P, Mathiowitz E. Effect of protein molecular weight on release from micron-sized PLGA microspheres. J Control Release. 2001; 76: 297-311. Ref.: https://goo.gl/MNgRDU
  146. Liggins RT, Burt HM. Paclitaxel loaded poly(L-lactic acid) microspheres: properties of microspheres made with low molecular weight polymers. Int J Pharm. 2001; 222: 19-33. Ref.: https://goo.gl/SqiiMc
  147. Malyala P,Singh M.Micro/nanoparticle adjuvants: preparation and formulation with antigens. Methods Mol Biol. 2010; 626: 91-101. Ref.: https://goo.gl/pw45cr
  148. Leleux J, Roy K. Micro and nanoparticle-based delivery systems for vaccine immunotherapy: an immunological and materials perspective. Adv Healthc Mater. 2013; 2: 72-94. Ref.: https://goo.gl/yqAd8Z
  149. Zhao L, Arjun Seth, Nani Wibowo, Chun-Xia Zhao, Neena Mitter, et al. Nanoparticle vaccines. Vaccine. 2014; 32: 327-337. Ref.: https://goo.gl/8dh7mX
  150. Kirby DJ, Rosenkrands I, Agger EM, Andersen P, Coombes AG, et al. PLGA microspheres for the delivery of a novel subunit TB vaccine. J Drug Target. 2008; 16: 282-293. Ref.: https://goo.gl/K1xKsL
  151. Lin CY, Lin SJ, Yang YC, Wang DY, Cheng HF, et al. Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases. Hum Vaccin Immunother. 2015; 11: 650-656. Ref.: https://goo.gl/Hw86LA
  152. Chaudhari KR, Ukawala M, Manjappa AS, Kumar A, Mundada PK, et al. Opsonization, biodistribution, cellular uptake and apoptosis study of PEGylated PBCA nanoparticle as potential drug delivery carrier. Pharm Res. 2012; 29: 53-68. Ref.: https://goo.gl/sxQ5ya
  153. Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q, et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med. 2012; 4: 149-119. Ref.: https://goo.gl/7B26gE
  154. Sykes EA, Chen J, Zheng G, Chan WC. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano. 2014; 8: 5696-5706. Ref.: https://goo.gl/4hEZk5
  155. Baker R. Controlled release of biologically active agents. Wiley Interscience Publications. 1987.
  156. Baxter J, Mitragotri S. Needle-free liquid jet injections: mechanisms and applications. Expert Rev Med Devices. 2006; 3: 565-574. Ref.: https://goo.gl/gmktFa
  157. Engwerda EE, Abbink EJ, Tack CJ, de Galan BE. Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care. 2011; 34: 1804-1808. Ref.: https://goo.gl/ic1qG2
  158. Jackson LA, Austin G, Chen RT, Stout R, DeStefano F, et al. Safety and immunogenicity of varying dosages of trivalent inactivated influenza vaccine administered by needle-free jet injectors. Vaccine. 2001; 19: 4703-4709. Ref.: https://goo.gl/D9XVqd
  159. Daniels CS. Needle-Free Injection: Pros and Cons. High Plains Dairy Conference. 2010; 25-36. Ref.: https://goo.gl/x5WHqs
  160. Stachowiak JC, Li TH, Arora A, Mitragotri S, Fletcher DA. Dynamic control of needle-free jet injection. J Control Release. 2009; 135: 104-112. Ref.: https://goo.gl/vb3Tkh
  161. Taberner A, Hogan NC, Hunter IW. Needle-free jet injection using real-time controlled linear Lorentz-force actuators. Med Eng Phys. 2012; 34: 1228-1235. Ref.: https://goo.gl/VCFrd1
  162. Kontermann R. Therapeutic Proteins: Strategies to Modulate Their Plasma HalfLives. Wiley-VCH: Verlag GmbH. 2012.
  163. Mero A, Pasqualin M, Campisi M, Renier D, Pasut G. Conjugation of hyaluronan to proteins. Carbohydr Polym. 2013; 92: 2163-2170. Ref.: https://goo.gl/KiiPdd
  164. Zhao H, Yang K, Martinez A, Basu A, Chintala R, et al. Linear and branched bicin linkers for releasable PEGylation of macromolecules: controlled release in vivo and in vitro from mono- and multi-PEGylated proteins. Bioconjug Chem. 2006; 17: 341-351. Ref.: https://goo.gl/vsuY1J
  165. Riggs-Sauthier J, Riley T. The Benefits and Challenges of PEGylating Small Molecules. Pharmaceutical Technology. 2008.
  166. Peters T. All about albumin. Academic Press. 1995.
  167. Kermode M. Unsafe injections in low-income country health settings: need for injection safety promotion to prevent the spread of blood-borne viruses. Health Promot Int. 2004; 19: 95-103. Ref.: https://goo.gl/n1HP3d
  168. Schaepelynck P, Darmon P, Molines L, Jannot-Lamotte MF, Treglia C, et al. Advances in pump technology: insulin patch pumps, combined pumps and glucose sensors, and implanted pumps. Diabetes Metab. 2011; 37: 85-93. Ref.: https://goo.gl/puzJ4o
  169. Ricotti L, Assaf T, Dario P, Menciassi A. Wearable and implantable pancreas substitutes. J Artif Organs. 2013; 16: 9-22. Ref.: https://goo.gl/iHMNLA
  170. Erasmo Lopez A, Atif Yardimci. Designing and Manufacturing Biopharma Delivery Devices. MDDI. 2015. Ref.: https://goo.gl/m6LNfm
  171. Lopez I, Rodríguez-Ortiz ME, Almadén Y, Guerrero F, de Oca AM, et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int. 2011; 80: 475-482. Ref.: https://goo.gl/Mg7Wvc
  172. Farra R, Sheppard NF Jr, McCabe L, Neer RM, Anderson JM, et al. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci Transl Med. 2012; 4: 122ra21. Ref.: https://goo.gl/L7yEk2
  173. Zisser H, Palerm CC, Bevier WC, Doyle FJ 3rd, Jovanovic L. Clinical update on optimal prandial insulin dosing using a refined run-to-run control algorithm. J Diabetes Sci Technol. 2009; 3: 487-491. Ref.: https://goo.gl/JNi9x3
  174. Andrade F, Catarina M, Bruno S. Pulmonary Delivery of Biopharmaceuticals. Mucosal Delivery of Biopharmaceuticals. Springer. 2014. Ref.: https://goo.gl/d9Abw6
  175. Roth Y, Chapnik JS, Cole P. Feasibility of aerosol vaccination in humans. Ann Otol Rhinol Laryngol. 2003; 112: 264-270. Ref.: https://goo.gl/oyUSWY
  176. Lu D, Hickey AJ. Pulmonary vaccine delivery. Expert Rev Vaccines. 2007; 6: 213-226. Ref.: https://goo.gl/HkPkh5
  177. Arora P, Sharma S, Garg S. Permeability issues in nasal drug delivery. Drug Discov Today. 2002; 7: 967-975. Ref.: https://goo.gl/6AFGGE
  178. Illum L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems. J Pharm Sci. 2007; 96: 473-483. Ref.: https://goo.gl/Q3fkvt
  179. Dae-Duk K. In vitro Cellular Models for Nasal Drug Absorption Studies. Drug absorption studies. 2007; 216-234. Ref.: https://goo.gl/tRDXrJ
  180. Kao HD, Traboulsi A, Itoh S, Dittert L, Hussain A. Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs. Pharm Res. 2000; 17: 978-984. Ref.: https://goo.gl/pfQgz2
  181. Yuba E, Kono K. Nasal Delivery of Biopharmaceuticals. Mucosal Delivery of Biopharmaceuticals. Springer. 2014; 197-220. Ref.: https://goo.gl/97LY9x
  182. Dahl AR, Lewis JL. Respiratory tract uptake of inhalants and metabolism of xenobiotics. Annu Rev Pharmacol Toxicol. 1993; 33: 383-407. Ref.: https://goo.gl/EtYPbp
  183. Mitra AK, Krishnamoorthy R. Prodrugs for nasal drug delivery. Adv Drug Deliv Rev. 1998; 29: 135-146. Ref.: https://goo.gl/3MW4mR
  184. Nema T, Jain A, Hurkat P, Shilpi S, Gulbake A, et al. Insulin delivery through nasal route using thiolated microspheres. Drug Deliv. 2013; 20: 210-215. Ref.: https://goo.gl/R66UHj
  185. Coucke D, Schotsaert M, Libert C, Pringels E, Vervaet C, et al. Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine. Vaccine. 2009; 27: 1279-1286. Ref.: https://goo.gl/wJszFr
  186. Jabbal-Gill I. Nasal vaccine innovation. J Drug Target. 2010; 18: 771-786. Ref.: https://goo.gl/KEMrXm
  187. de Boer AG, Moolenaar F, de Leede LG, Breimer DD. Rectal drug administration: clinical pharmacokinetic considerations. Clin Pharmacokinet. 1982; 7: 285-311. Ref.: https://goo.gl/ceXzJv
  188. Kozlowski PA, Williams SB, Lynch RM, Flanigan TP, Patterson RR, et al. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: influence of the menstrual cycle. J Immunol. 2002; 169: 566-574. Ref.: https://goo.gl/fFYfyq
  189. Pechine S, Denève C, Le Monnier A, Hoys S, Janoir C, et al. Immunization of hamsters against Clostridium difficile infection using the Cwp84 protease as an antigen. FEMS Immunol Med Microbiol. 2011; 63: 73-81. Ref.: https://goo.gl/g19EuJ
  190. Czerkinsky C, Holmgren J. Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues. Curr Top Microbiol Immunol. 2012; 354: 1-18. Ref.: https://goo.gl/stkkJ2
  191. Rothbard JB, Garlington S, Lin Q, Kirschberg T, Kreider E, et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat Med. 2000; 6: 1253-1257. Ref.: https://goo.gl/osPdjf
  192. Medi BM, Singh J. Electronically facilitated transdermal delivery of human parathyroid hormone (1-34). Int J Pharm. 2003; 263: 25-33. Ref.: https://goo.gl/2Pqk4d
  193. Rastogi R, Anand S, Dinda AK, Koul V. Investigation on the synergistic effect of a combination of chemical enhancers and modulated iontophoresis for transdermal delivery of insulin. Drug Dev Ind Pharm. 2010; 36: 993-1004. Ref.: https://goo.gl/UhSyyJ
  194. Alba N, Naik A, Guy RH, Kalia YN. Effect of charge and molecular weight on transdermal peptide delivery by iontophoresis. Pharm Res. 2005; 22: 2069-2078. Ref.: https://goo.gl/7Nhmbd
  195. Abrego G, Alvarado H, Souto EB, Guevara B, Bellowa LH, et al. Biopharmaceutical profile of hydrogels containing pranoprofen-loaded PLGA nanoparticles for skin administration: In vitro, ex vivo and in vivo characterization. Int J Pharm. 2016; 501: 350-361. Ref.: https://goo.gl/JXBsZv
  196. Morishita M, Peppas NA. Is the oral route possible for peptide and protein drug delivery? Drug Discov Today. 2006; 11: 905-910. Ref.: https://goo.gl/Uq5CsC
  197. Whitehead K, Shen Z, Mitragotri S. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J Control Release. 2004; 98: 37-45. Ref.: https://goo.gl/SgaEoQ
  198. Gupta V, Hwang BH, Lee J, Anselmo AC, Doshi N, et al. Mucoadhesive intestinal devices for oral delivery of salmon calcitonin. J Control Release. 2013; 172: 753-762. Ref.: https://goo.gl/YGt9St
  199. Collnot EM, Ali H, Lehr CM. Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. J Control Release. 2012; 161: 235-246. Ref.: https://goo.gl/heTvs9
  200. Pridgen EM, Alexis F, Kuo TT, Levy-Nissenbaum E, Karnik R, et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal Fc receptor for oral delivery. Sci Transl Med. 2013; 5: 213ra167. Ref.: https://goo.gl/tQe99r
  201. McGinity JW, Stavchansky SA, Martin A. Bioavailability in Tablet Technology. Marcel Dekker: New York. 1981.
  202. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010; 12: 348-360. Ref.: https://goo.gl/R7yzU1
  203. Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006; 3: 275-287. Ref.: https://goo.gl/wZqzSE
  204. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007; 5: 93-107. Ref.: https://goo.gl/BKwcfc
  205. Abrego G, Alvarado H, Souto EB, Guevara B, Bellowa LH, et al. Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration. Eur J Pharm Biopharm. 2015; 95: 261-270. Ref.: https://goo.gl/nUJyDB
  206. Peng L, Cheng X, Zhuo R, Lan J, Wang Y, et al. Novel gene-activated matrix with embedded chitosan/plasmid DNA nanoparticles encoding PDGF for periodontal tissue engineering. J Biomed Mater Res A. 2009; 90: 564-576. Ref.: https://goo.gl/dDBoU4
  207. Elangovan S, Jain S, Tsai PC, Margolis HC, Amiji M. Nano-sized calcium phosphate particles for periodontal gene therapy. J Periodontol. 2013; 84: 117-125. Ref.: https://goo.gl/M7LX6N
  208. Torchilin V. Intracellular delivery of protein and peptide therapeutics. Drug Discov Today Technol. 2008; 5: 95-103. Ref.: https://goo.gl/wFPAkj
  209. Fu J, Yu C, Li L, Yao SQ. Intracellular Delivery of Functional Proteins and Native Drugs by Cell-Penetrating Poly(disulfide)s. J Am Chem Soc. 2015; 137: 12153-12160. Ref.: https://goo.gl/33R2zX
  210. Zolot RS, Satarupa B, Ryan Million P. Antibody-drug conjugates. Nature Reviews Drug Discovery. 2013; 12: 259-260. Ref.: https://goo.gl/JfS5Cd
  211. He C, Yin L, Tang C, Yin C. Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. Biomaterials. 2012; 33: 8569-8578. Ref.: https://goo.gl/p7zViN
  212. Wu SY, Lopez-Berestein G, Calin GA, Sood AK. RNAi therapies: drugging the undruggable. Sci Transl Med. 2014; 6: 240-247. Ref.: https://goo.gl/qqMdDN


Figure 1

Figure 1

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More