Novel Formulation Approaches for Peptide and Protein Injectables

Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines

Volumn , Issue , 2009, Pages 9-28

  Yang, Mingshi ^a,b   Frokjaer, Sven ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b NOVO NORDISK A S   (Denmark)

Author keywords

Biomacromolecular drug transport barriers; Biopharmaceuticals delivery; Chemical modification using synthetic and or molecular engineering techniques; Formulation challenges; Fusion of proteins through genetic engineering of fusion gene; Glycoengineering of protein molecular engineering approach linking saccharides to proteins of therapeutic interest; Novel formulation approaches for peptide and protein injectables; Parenteral drug delivery and invasive nature major drawbacks; Protein and peptide drugs important therapeutic agents; Protein and peptides drugs becoming important class of therapeutic agents

Indexed keywords

EID: 84889084605     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470688397.ch2     Document Type: Chapter

References (115)

1. Brange, J. (2000) Physical stability of proteins, in Pharmaceutical Formulation Development of Peptides and Proteins (eds S. Frokajer and L. Hovgaar), Taylor & Francis Limited, London, pp. 89-112.
2. Jorgensen, L., Kim, D.H., Vermehren, C. et al. (2004) Micropipette manipulation-a technique to evaluate the stability of water-in-oil emulsions containing proteins. J. Pharm. Sci., 93, 2994-3003.
3. Caliceti, P. and Veronese, F.M. (2003) Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv. Drug Del. Rev., 55, 1261-1277.
4. Chakravarti, V.S., Borns, P., Lobell, J. and Douglas, S.D. (1991) Chondroosseous dysplasia in severe combined immunodeficiency due to adenosine deaminase deficiency (chondroosseous dysplasia in ADA deficiency SCID). Pediatr. Radiol., 21, 447-448.
5. Graham, M.L. (2003) Pegaspargase: a review of clinical studies. Adv. Drug Deliv. Rev., 55, 1293-1302.
6. Bukowski, R.M., Tendler, C., Cutler, D. et al. (2002) Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation. Cancer, 95, 389-396.
7. Goffin V. and Touraine, P. (2004) Pegvisomant Pfizer/Sensus. Curr. Opin. Invest. Drugs, 5, 463-468.
8. Reddy, K.R. (2004) Development and pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a (40 kD). Semin. Liver Dis., 24, 33-38.
9. Molineux, G. (2004) The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr. Pharm. Des., 10, 1235-1244.
10. Moshfegh, A.A. and Puliafito, C.A. (2005) Pegaptanib sodium for the treatment of neovascular age-related macular degeneration. Expert Opin. Invest. Drugs, 14, 671-682.
11. Ryan, S.M., Mantovani, G., Wang, X. et al. (2008) Advances in PEGylation of important biotech molecules: delivery aspects. Expert Opin. Drug Deliv., 5, 371-383.
12. Pasut, G. and Veronese, F.M. (2007) Polymer drug conjugation, recent achievements and general strategies. Porg. Olym. Sci., 32, 933-961.
13. Roberts, M.J., Bentley, M.D. and Harris, J.M. (2002) Chemistry for peptides and protein PEGylation. Adv. Drug Deliv. Rev., 54, 459-476.
14. Herman, S., Hooftman, G. and Schacht, E. (1995) Poly(ethylene glycol) with reactive end groups: I modification of proteins. J. Bioact. Biocomp. Polym., 10, 145-187.
15. Veronese, F.M. (2001) Peptide and protein PEGylation: a review of problems and solutions. Biomaterials, 22, 405-417.
16. Greenwald, R.B. (2001) PEGdrugs an overview. J. Control. Release, 74, 159-171.
17. Coodson, R.J. and Katre, N.V. (1990) Site-directed PEGylation of recombinant interleukin-2 at its glycosylation site. Biotechnology, 8, 343-346.
18. Zalipsky, S. and Menon-Rudolph, S. (1997) Hydrazide derivatives of poly (ethylene glycol) and their bioconjugates, in Poly(ethylene glycol) Chemistry and Biological Applications, ACS Symposium Series, vol. 680 (eds J.M. Harris and S. Zalipsky), ACS Books, Washington, DC, pp. 318-340.
19. Gaertner, H.F. and Offord, R.E. (1996) Site-specific attachement of functionalized poly(ethylene glycol) to the amino termimus of proteins. Bioconjug. Chem., 7, 38-44.
20. Greenwald, R.B., Pendri, A. and Bolikal, D. (1995) Highly soluble taxal derivatives: 7-polyethylene glycol carbomates and carbonates. J. Org. Chem., 60, 331-336.
21. Yankeelov, J.A. (1972) Modification of arginines by diketones. Methods Enzymol., 25, 566-579.
22. Akihito, S., Maeda, H., Kai, Y. and Ono, K. (1989) Polyethylene glycol derivatioves, modified peptides and production thereof. E.P. 0340741.
23. Garman, A.J. and Kalindjian, S.B. (1987) The preparation and properties of novel reversible polymer-protein conjugates. 2-omega-methoxypolyethylene (5000) glycoxymethylene-3-methylmaleyl conjugates of plasminogen activators. FEBS Lett., 223, 361-365.
24. Lee, S., Greenwald, R.B., McGuire, J. et al. (2001) Drug delivery systems employing 1,6-elimination: releasable poly(ethylene glycol) conjugates of proteins. Bioconjug. Chem., 12, 163-169.
25. Monkarsh, S.P., Spence, C., Porter, J.E. et al. (1997) Isolation of positional isomers of monopoly(ethylene glycol)ylated interferon-2 α and the determination of their biochemical and biological characteristics, in Poly(ethylene glycol) Chemistry and Biological Applications, ACS Symposium Series, vol. 680 (eds J.M. Harris and S. Zalipsky), ACS Books, Washington, DC, pp. 207-216.
26. Na, D.H. and Lee, K.C. (2004) Capillary electrophoretic characterization of PEGylated human parathyroid hormone with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Anal. Biochem., 331, 322-328.
27. Pesek, J.J., Matyska, M.T. and Krishnamoorthi, V. (2004) Separation of polyethylene glyco-modified proteins by open tubular capillary electrochromatography. J. Chromatogr. A, 1004, 317-322.
28. Elliott, S., Lorenzini, T., Asher, S. et al. (2003) Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat. Biotechnol., 21, 414-421.
29. Runkel, L., Meier, W., Pepinsky, R.B. et al. (1998) Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta). Pharm. Res., 15, 641-649.
30. Arakawa, T., Yphantis, D.A., Lary, J.W. et al. (1991) Glycosylated and unglycosylated recombinant-derived human stem cell factors are dimeric and have extensive regular secondary structure. J. Biol. Chem., 266, 18 942-18 948.
31. Langer, B.G., Weisel, J.W., Dinauer, P.A. et al. (1988) Deglycosylation of fibrinogen accelerates polymerization and increases lateral aggregation of fibrin fibers. J. Biol. Chem., 263, 15056-15063s.
32. Sinclair, A.M. and Elliott, S. (2005) Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J. Pharm. Sci., 94, 1626-1635.
33. Egrie, J.C., Dwyer, E., Browne, J.K. et al. (2003) Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp. Hemato., 31, 290-299.
34. Hartley, C., Elliott, S., Begley, C.G. et al. (2003) Kinetics of haematopoietic recovery after dose-intensive chemo/radiotherapy in mice: optimozed erythroid support with darbepoetin alpha. Br. J. Haematol., 122, 623-636.
35. Beals, J.M. and Shanafelt, A.B. (2006) Enhancing exposure of protein therapeutics. Drug Discov. Today Technol., 3, 87-94.
36. Parekh, R.B. (1994) Site-specific protein glycosylation. Adv. Drug Del. Rev., 13, 251-266.
37. Jenkins, N. and Curling, E.M.A. (1994) Glycosylation of recombinant proteins: problems and prospects. Enzyme. Microb. Technol., 16, 354-364.
38. Havelund, S., Plum, A., Ribel, U. et al. (2004) The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm. Res., 21, 1498-1504.
39. Yuan, L., Wang, J. and Shen, W.C. (2005) Reversible lipidization prolongs the pharmacological effect, plasma duration, and liver retention of octreotide. Pharm. Res., 22, 220-227.
40. Knudsen, L.B., Nielsen, P.F., Huusfeldt, P.O. et al. (2000) Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J. Med. Chem., 43, 1664-1669.
41. Foldvari, M., Attah-Poku, S., Hu, J. et al. (1998) Palmitoyl derivatives of interferon α: potential for cutaneous delivery. J. Pharm. Sci., 87, 1203-1208.
42. Wang, J., Shen, D. and Shen, W.C. (1999) Preparation, purification, and characterization of a reversible lipidized desmopressin with potential anti-diurectic activity. Pharm. Res., 16, 1674-1679.
43. Frokjaer, S. and Otzen, D.E. (2005) Protein drug stability: a formulation challenge. Nat. Rev. Drug Discov., 4, 298-306.
44. Gillies, P.S., Figgitt, D.P. and Lamb, H.M. (2000) Insulin glargine. Drugs, 59, 253-260.
45. Luzio, S.D., Beck, P. and Owens, D.R. (2003) Comparison of the subcutaneous absorption of insulin glargine (Lantus) and NPH insulin in patients with Type 2 diabetes. Horm. Metab. Res., 35, 434-438.
46. Brown, L.R. (2005) Commercial challenges of protein drug delivery. Expert Opin. Drug Deliv., 2, 29-42.
47. DeFelippis, M.R., Bakaysa, D.L., Bell, M.A. e t al. (1998) Preparation and characterization of cocrystalline suspension of [LysB28, ProB29]-human insulin analogue. J. Pharm. Sci., 87, 170-176.
48. Home, P.D., Barriocanal, L. and Lindholm, A. (1999) Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers . Eur. J. Clin. Pharmacol., 55, 199-203.
49. Madhusudan, S., Muthuramalingam, S.R., Braybrooke, J.P. et al. (2005) Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. J. Clin. Oncol., 23, 5950-5959.
50. Ghetie, V., Popov, S., Borvak, J. et al. (1997) Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat. Biotechnol., 15, 637-640.
51. Reff, M.E. and Heard, C. (2001) A review of modifications to recombinant antibodies: attempt to increase efficacy in oncology applications. Crit. Rev. Oncol. Hematol., 40, 25-35.
52. Jazayeri, J.A. and Carroll, G.J. (2008) Fc-based cytokines: prospects for engineering superior therapeutics. BioDrugs, 22, 11-26.
53. Osborn, B.L., Sekut, L., Corcoran, M. et al. (2002) Albutropin: a growth hormone-albumin fusion with improved pharmacokinetics and pharmacodynamics in rats and monkeys. Eur. J. Pharmacol., 456, 149-158.
54. Sung, C., Nardelli, B., LaFleur, D.W. et al. (2003) N-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J. Interferon Cytokine Res., 23, 25-36.
55. Duttaroy, A., Kanakaraj, P., Osborn, B.L. et al. (2005) Development of a long-acting insulin analog using albumin fusion technology. Diabetes, 54, 251-258.
56. Prior, C.P. (2007) Modified transferrin fusion proteins. United States Patent, 7176278.
57. Degim, I.T. and Celebi, N. (2007) Controlled delivery of peptides and proteins. Curr. Pharm. Design, 13, 99-117.
58. Brown, L.R. (2005) Commercial challenges of protein drug delivery. Expert Opin. Drug Deliv., 2, 29-42.
59. Shi, Y. and Li, L.C. (2005) Current advances in sustained-release systems for parenteral drug delivery. Expert Opin. Drug Deliv., 2, 1039-1058.
60. Mundargi, R.C., Babu, V.R., Rangaswamy, V. et al. (2008) Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives . J. Control. Release, 125, 193-209.
61. Akers, M.J., Nail, S.L. and Saffell-Clemmer, W. (2007) Top ten hot topics in parenteral science and technology. PDA J. Pharm. Sci. Technol., 61, 337-361.
62. Zambaux, M.F., Bonneaux, F., Gref, R. et al. (1999) Preparation and characterization of protein C-loaded PLA nanoparticles. J. Control. Release, 60, 179-188.
63. Blanco-Prieto, M.J., Besseghir, K., Zerbe, O. et al. (2000) In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres. J. Control. Release, 67, 19-28.
64. Jackson, J., Liang, L., Hunter, W. et al. (2002) The encapsulation of ribozymes in biodegradable polymeric matrices. Int. J. Pharm., 243, 43-47.
65. Kostanski, J.W., Thanoo, B.C. and DeLuca, P.P. (2000) Preparation, characterization, and in vitro evaluation of 1-and 4-month controlled release orntide PLA and PLGA microspheres. Pharm. Dev. Technol., 5, 585-596.
66. Cho, S.W., Song, S.H. and Choi, Y.W. (2000) Effects of solvent selection and fabrication on the characteristics of biodegradable poly(lactide-co-glycolide) microspheres containing ovalbumin . Arch. Pharm. Res., 23, 385-390.
67. Zhu, K.J., Jiang, H.L., Du, X.Y. et al. (2001) Preparation and characterization of hCG loaded polylactide or poly(lactide-co-glycolide) microspheres using a modified water-in-oil-in water (w/o/w) emulsion solvent evaporation technique. J. Microencapsul., 18, 247-260.
68. Schrier, J.A. and DeLuca, P.P. (1999) Recombinant human bone morphogenetic protein-2 binding and incorporation in PLGA microsphere delivery systems. Pharm. Dev. Technol., 4, 611-621.
69. Prabhu, S., Sullivan, J.L. and Betageri, G.V. (2002) Comparative assessment of in vitro release kinetics of calcitonin polypeptide from biodegradable microspheres. Drug Deliv., 9, 195-198.
70. Kissel, T., Li, Y. and Unger, F. (2002) ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins. Adv. Drug Deliv. Rev., 54, 99-134.
71. Otsuka, H., Nagasaki, Y. and Kataoka, K. (2003) PEGylated nanoparticles for biological and pharmaceutical applications. Adv. Drug Deliv. Rev., 55, 403-419.
72. Choi, S., Baudys, M. and Kim, S.W. (2004) Control of blood glucose by novel GLP-1 delivery using biodegradable triblock copolymer of PLGA-PEG-PLGA in type 2 diabetic rats. Pharm. Res., 21, 827-831.
73. Sinha, V.R., Bansal, K., Kaushik, R. et al. (2004) Poly-epsilon-caprolactone microspheres and nanospheres: an overview. Int. J. Pharm., 278, 1-23.
74. Shenoy, D.B., D'Souza, R.J., Tiwari, S.B. and Udupa, N. (2003) Potential applications of polymeric microsphere suspension as subcutaneous depot for insulin. Drug Dev. Ind. Pharm., 29, 555-563.
75. Kumar, N., Langer, R.S. and Domb, A.J. (2002) Polyanhydrides: an overview. Adv. Drug Deliv. Rev., 54, 889-910.
76. Heller, J. and Barr, J. (2005) Biochronomer technology. Expert Opin. Drug Deliv., 2, 169-183.
77. Rothen-Weinhold, A., Schwach-Abdellaoui, K., Barr, J. et al. (2001) Release of BSA from poly (ortho ester) extruded thin strands. J. Control. Release, 71, 31-37.
78. Bai, X.L., Yang, Y.Y., Chung, N.T.S. et al. (2001) The effect of polymer compositions on controlled release of protein from poly(ortho esters) microspheres. J. Appl. Polym. Sci., 80, 1630-1642.
79. Xu, X., Yu, H., Gao, S. et al. (2002) Polyphosphoester microspheres for sustained release of biologically active nerve growth factor. Biomaterials, 23, 3765-3772.
80. Sinha, V.R. and Trehan, A. (2003) Biodegradable microspheres for protein delivery. J Control. Release, 90, 261-280.
81. Bittner, B., Morlock, M., Koll, H. et al. (1998) Recombinant human erythropoietin (rHEPO) loaded poly(lactide-co-glycolide) microspheres: influence of the encapsulation technique and polymer purity on microspheres characteristics. Eur. J. Pharm. Biopharm., 45, 295-305.
82. Cui, F., Cun, D., Tao, A. et al. (2005) Preparation and characterization of melittin-loaded poly (DL-lactic acid) or poly (DL-lactic-co-glycolic acid) microspheres made by the double emulsion method. J. Control. Release, 107, 310-319.
83. Nam, Y.S., Song, S.H., Choi, J.Y. and Park, T.G. (2000) Lysozyme microencapsulation within biodegradable PLGA microspheres: urea effect on protein release and stability. Biotechnol. Bioeng., 70, 270-277.
84. Yang, Y.Y., Chung, T.S. and Ng, N.P. (2001) Morphology, drug distribution and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double emulsion solvent extraction/evaporation method. Biomaterials, 22, 231-241.
85. Redding, T.W., Schally, A.V., Tice, T.R. and Meyers, W.E. (1984) Long acting delivery systems for peptides: inhibition of rat prostate tumors by controlled release of DTrp6 leutinizing hormone releasing hormone injectable microcapsules. Proc. Natl. Acad. Sci. USA., 81, 5845-5848.
86. Stenekes, R.J., Franssen, O., van Bommel, E.M. et al. (1999) The use of aqueous PEG/dextran phase separation for the preparation of dextran microspheres. Int. J. Pharm., 183, 29-32.
87. Houchin, M.L. and Topp, E.M. (2008) Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J. Pharm. Sci., 97, 2395-2404.
88. Cleland, J.L., Powell, M.F. and Shire, S.J. (1993) Development of stable protein formulations: a close look at protein aggregation, deamidation, and oxidation. Crit. Rev. Ther. Drug Carrier Syst., 10, 307-377.
89. Ye, Q., Ashherman, J., Stevenson, M. et al. (2000) DepToam ™ technology: a vehicle for controlled delivery of protein and peptide drugs. J. Control. Release, 64, 155-166.
90. Howell, S.B. (2001) Clinical application of a novel sustained-release injectable drug delivery system: DepoFoam ™ technology. Cancer J., 7, 219-227.
91. Thauvin, C., Rickling, S., Schultz, P. et al. (2008) Carbon nanotubes as templates for polymerized lipid assemblies. Nat. Nanotechnol., 3, 743-748.
92. Packhaeuser, C.B., Schnieders, J., Oster, C.G. and Kissel, T. (2004) In situ forming parenteral drug delivery systems: an overview. Eur. J. Pharm. Biopharm., 58, 445-455.
93. He, C., Kim, S.W. and Lee, D.S. (2008) In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J. Control. Release, 127, 189-207.
94. Berges, R. and Bello, U. (2006) Effect of a new leuprorelin formulation on testosterone levels in patients with advanced prostate cancer. Curr. Med. Res. Opin., 22, 649-655.
95. Okumu, F.W., le Dao, N., Fielder, P.J. et al. (2002) Sustained delivery of human growth hormone from a novel gel system: SABER. Biomaterials, 23, 4353-4358.
96. Choi, S. and Kim, S.W. (2003) Controlled release of insulin from injectable biodegradable triblock copolymer depot in ZDF rats. Pharm. Res., 20, 2008-2010.
97. Zentner, G.M., Rathi, R., Shih, C. et al. (2001) Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J. Control. Release, 72, 203-215.
98. Qiu, B., Stefanos, S., Lalloo, A. et al. (2002) A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery. Biomaterials, 24, 11-18.
99. Molinaro, G., Leroux, J.C., Damas, J. and Adam, A. (2002) Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials. Biomaterials, 23, 2717-2722.
100. Cleland, J.L., Daugherty, A. and Mrsny, R. (2001) Emerging protein delivery methods. Curr. Opin. Biotechnol., 12, 212-219.
101. Perry, C.M. and Brogden, R.N. (1996) Goserelin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in benign gynaecological disorders. Drugs, 51, 319-346.
102. Moul, J.W. and Civitelli, K. (2001) Managing advanced prostate cancer with Viadur (leuprolide acetate implant). Urol. Nurs., 21, 385-388.
103. Chertin, B., Spitz, I.M., Lindenberg, T. et al. (2000) An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer. J. Urol., 163, 838-844.
104. Basu, S.K., Govardhan, C.P., Jung, C.W. and Margolin, A.L. (2004) Protein crystals for the delivery of biopharmaceuticals. Expert Opin. Biol. Ther., 4, 301-317.
105. Pechenov, S., Shenoy, B., Yang, M.X. et al. (2004) Injectable controlled release formulations incorporating protein crystals. J. Control. Release, 16, 149-158.
106. Margolin, A.L. and Navia, M.A. (2001) Protein crystals as novel catalytic materials. Angew. Chem. Int. Ed., 40, 2204-2222.
107. Hallas-Møller, K., Petersen, K. and Schlichtkrull, J. (1952) Crystalline and amorphous insulin-zinc compounds with prolonged action. Science, 116, 394-399.
108. Peterson, G.E. (2006) Intermediate and long-acting insulins: a review of NPH insulin, insulin glargine and insulin detemir. Curr. Med. Res. Opin., 22, 2613-2619.
109. Ayvazian, J.H. and Ayvazian, L.F. (1960) Effect of intravenous administration of crystalline pancreatic desoxyribonuclease in patients with gout. N. Engl. J. Med., 263, 999-1002.
110. Yang, M.X., Shenoy, B., Disttler, M. et al. (2003) Crystalline monoclonal antibodies for subcutaneous delivery. Proc. Natl. Acad. Sci. USA., 100, 6934-6939.
111. Brunton, S. (2008) Initiating insulin therapy in type 2 diabetes: benefits of insulin analogs and insulin pens. Diabetes Technol. Ther., 10, 247-256.
112. Haak, T., Edelman, S., Walter, C. et al. (2007) Comparison of usability and patient preference for the new disposable insulin device Solostar versus Flexpen, lilly disposable pen, and a prototype pen: an open-label study. Clin. Ther., 29, 650-660.
113. Pfützner, A., Asakura, T., Sommavilla, B. and Lee, W. (2008) Insulin delivery with FlexPen: dose accuracy, patient preference and adherence. Expert Opin. Drug Deliv., 5, 915-925.
114. Imoto, J. and Konishi, E. (2005) Needle-free jet injection of a mixture of Japanese encephalitis DNA and protein vaccines: a strategy to effectively enhance immunogenicity of the DNA vaccine in a murine model. Viral Immunol., 18, 205-212.
115. Bennett, S. and Potter, C. (2008) Solid dose injection of therapeutics and vaccines: effective, convenient and cost-effective alternative to needles. OndrugDelivery, 1, 11-13.