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AAPS PharmSciTech. 2006 March; 7(1): E131–E137.
Published online 2006 March 10. doi:  10.1208/pt070119
PMCID: PMC2750726

Formulation of a dry powder influenza vaccine for nasal delivery

Abstract

The purpose of this research was to prepare a dry powder vaccine formulation containing whole inactivated influenza virus (VIIV) and a mucoadhesive compound suitable for nasal delivery. Powders containing WIIV and either lactose or trehalose were produced by lyophilization. A micro-ball mill was used to reduce the lyophilized cake to sizes suitable for nasal delivery. Chitosan flakes were reduced in size using a cryo-milling technique. Milled powders were sieved between 45 and 125 μm aggregate sizes and characterized for particle size and distribution, morphology, and flow properties. Powders were blended in the micro-ball mill without the ball. Lyophilization followed by milling produced irregularly shaped, polydisperse particles with a median primary particle diameter of ≈21 μm and a yield of ≈37% of particles in the 45 to 125 μm particle size range. Flow properties of lactose and trehalose powders after lyophilization followed by milling and sieving were similar. Cryo-milling produced a small yield of particles in the desired size range (<10%). Lyophilization followed by milling and sieving produced particles suitable for nasal delivery with different physicochemical properties as a function of processing conditions and components of the formulation. Further optimization of particle size and morphology is required for these powders to be suitable for clinical evaluation.

Keywords: Intranasal delivery, dry powder, influenza vaccine, mucoadhesive, lyophilization

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. WHO . Influenza. Geneva, Switzerland: World Health Organization; 2003.
2. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA. 1999;282:137–144. doi: 10.1001/jama.282.2.137. [PubMed] [Cross Ref]
3. Dyer O. Factory’s loss of licence halves supply of flu vaccine to US. BMJ. 2004;329:876–876. doi: 10.1136/bmj.329.7471.876-b. [PMC free article] [PubMed] [Cross Ref]
4. Illum L. Nasal drug delivery: new developments and strategies. Drug Discov Today. 2002;7:1184–1189. doi: 10.1016/S1359-6446(02)02529-1. [PubMed] [Cross Ref]
5. Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97:382–387. doi: 10.1053/rmed.2002.1457. [PubMed] [Cross Ref]
6. Roth Y, Chapnik JS, Cole P. Feasibility of aerosol vaccination in humans. Ann Otol Rhinol Laryngol. 2003;112:264–270. [PubMed]
7. Gonda I. The ascent of pulmonary drug delivery. J Pharm Sci. 2000;89:940–945. doi: 10.1002/1520-6017(200007)89:7<940::AID-JPS11>3.0.CO;2-B. [PubMed] [Cross Ref]
8. Singh M, Briones M, O’Hagan DT. A novel bioadhesive intranasal delivery system for inactivated influenza vaccines. J Control Release. 2001;70:267–276. doi: 10.1016/S0168-3659(00)00330-8. [PubMed] [Cross Ref]
9. Muszkat M, Friedman G, Schein MH, et al. Local SIgA response following administration of a novel intranasal inactivated influenza virus vaccine in community residing elderly. Vaccine. 2000;18:1696–1699. doi: 10.1016/S0264-410X(99)00509-5. [PubMed] [Cross Ref]
10. Hirabayashi Y, Kurata H, Funato H, et al. Comparison of intranasal inoculation of influenza HA vaccine combined with cholera toxin B subunit with oral or parenteral vaccination. Vaccine. 1990;8:243–248. doi: 10.1016/0264-410X(90)90053-O. [PubMed] [Cross Ref]
11. Russell MW, Moldoveanu Z, White PL, Sibert GJ, Mestecky J, Michalek SM. Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the Cholera toxin B subunit. Infect Immun. 1996;64:1272–1283. [PMC free article] [PubMed]
12. Brgquist C, Johansson EL, Lagergard T, Holmgren J, Rudin A. Intranasal vaccination of humans with recombinant cholera toxin B subunit induces systemic and local antibody responses in the upper respiratory tract and the vagina. Infect Immun. 1997;65:2676–2684. [PMC free article] [PubMed]
13. Smith DJ, Bot S, Dellamary L, Bot A. Evaluation of novel aerosol formulations designed for mucosal vaccination against influenza virus. Vaccine. 2003;21:2805–2812. doi: 10.1016/S0264-410X(03)00224-X. [PubMed] [Cross Ref]
14. Anderson J, Fishbourne E, Corteyn A, Donaldson AI. Protection of cattle against rinderpest by intranasal immunisation with a dry powder tissue culture vaccine. Vaccine. 2000;19:840–843. doi: 10.1016/S0264-410X(00)00228-0. [PubMed] [Cross Ref]
15. LiCalsi C, Christensen T, Bennett JV, Phillips E, Witham C. Dry powder inhalation as a potential delivery method for vaccines. Vaccine. 1999;17:1796–1803. doi: 10.1016/S0264-410X(98)00438-1. [PubMed] [Cross Ref]
16. LiCalsi C, Maniaci MJ, Christensen T, Phillips E, Ward GH, Witham C. A powder formulation of measles vaccine for aerosol delivery. Vaccine. 2001;19:2629–2636. doi: 10.1016/S0264-410X(00)00503-X. [PubMed] [Cross Ref]
17. Illum L, Jabbal-Gill I, Hinchcliffe M, Fisher AN, Davis SS. Chitosan as a novel nasal delivery system for vaccines. Adv Drug Deliv Rev. 2001;51:81–96. doi: 10.1016/S0169-409X(01)00171-5. [PubMed] [Cross Ref]
18. Maa YF, Ameri M, Shu C, Payne LG, Chen D. Influenza vaccine powder formulation development: spray-freeze-drying and stability evaluation. J Pharm Sci. 2004;93:1912–1923. doi: 10.1002/jps.20104. [PubMed] [Cross Ref]
19. Maa YF, Shu C, Ameri M, et al. Optimization of an alum-adsorbed vaccine powder formulation for epidermal powder immunization. Pharm Res. 2003;20:969–977. doi: 10.1023/A:1024493719236. [PubMed] [Cross Ref]
20. Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine. 1999;18:899–906. doi: 10.1016/S0264-410X(99)00334-5. [PubMed] [Cross Ref]
21. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338:1405–1412. doi: 10.1056/NEJM199805143382002. [PubMed] [Cross Ref]
22. FluMist [package insert]. Medlmmune Vaccines Inc., Gaithersburg, MD; 2003.
23. Soane RJ, Frier M, Perkins AC, Jones NS, Davis SS, Illum L. Evaluation of the clearance characteristics of bioadhesive systems in humans. Int J Pharm. 1999;178:55–65. doi: 10.1016/S0378-5173(98)00367-6. [PubMed] [Cross Ref]
24. Huang J, Garmise RJ, Crowder TM, et al. A novel dry powder influenza vaccine and intranasal delivery technology: induction of systemic and mucosal immune responses in rats. Vaccine. 2004;23:794–801. doi: 10.1016/j.vaccine.2004.06.049. [PubMed] [Cross Ref]
25. Martin AN, Bustamante P. Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences. Philadelphia, PA: Lea & Febiger; 1993.
26. Carr RL. Evaluating flow properties of solids. Chem Eng. 1965;72:163–168.
27. Carstensen JT. Pharmaceutical Principles of Solid Dosage Forms. Lancaster, PA: Technomic Pub; 1993.
28. Hickey AJ, Ganderton D. Pharmaceutical Process Engineering. New York, NY: Marcel Dekker; 2001.
29. Hinds WC. Aerosol Technology: Properties, Behavior, and Measurement of Airborne Particles. New York, NY: J Wiley; 1999.
30. Cleland JL, Langer RSAmerican Chemical Society. Division of Biochemical Technology . Formulation and Delivery of Proteins and Peptides. Washington, DC: American Chemical Society; 1994.
31. Hageman M. Water sorption and solid state stability of proteins. In: Ahern TJ, Manning MC, editors. Stability of Protein Pharmaceuticals. New York, NY: Plenum Press; 1992. pp. 273–309.

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