Abstract：OBJECTIVE To provide reference and consideration for pharmaceutical development by expounding the basic considerations for the selection of freeze-dried injection excipients. METHODS The excipients in freeze-dried injections approved by FDA in recent years have been listed, and the composition of excipients in the preparations and the maximum amount of excipients contained were summarized. The issues to be considered in the selection of freeze-dried injections were discussed. RESULTS One quarter of the freeze-dried injections that have been marketed do not use excipients, while the most commonly used excipients are bulking agents, buffering agents and pH adjusters. Other excipients include solubilizing agent, antioxidants, etc.. CONCLUSION The selection of freeze-dried injection excipients should focus on safety, formulation rationality, functionality-related characteristics and control of excipients.
马骏威, 安娜. 冻干注射剂中辅料选择的考虑[J]. 中国药学杂志, 2020, 55(7): 568-572.
MA Jun-wei, AN Na. Consideration of Excipient Selection in Freeze-dried Injections. Chinese Pharmaceutical Journal, 2020, 55(7): 568-572.
BAHETI A, KUMAR L, BANSAL A K. Excipients used in lyophilization of small molecules[J]. J Excip Food Chem,2016,1(1):1135.
[2]
FDA. Using the Inactive Ingredient Database Guidance for Industry.[EB/OL]. [2019-07]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/using-inactive-ingredient-database-guidance-industry.
[3]
JENNINGS T A. Effect of formulation on lyophilization, part 1[J]. IVD Technol Mag, 1997,3(2):42-49.
[4]
FRANKS F, AUFFRET T. Freeze-Drying of Pharmaceuticals and Biopharmaceuticals[M]. Cambridge: RSC Publishing, 2007.
[5]
SEARLES J A. Freezing and annealing phenomena in lyophilization, in: L. Rey, J. C. May (Eds.), Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products[M]. New York:Marcel Dekker, Inc., 2004.
[6]
JENNINGS T. The importance of process water, in: Lyophilization, Introduction and Basic Principles[M]. Englewood:Interpharm Press, 1999.
[7]
PATEL S M, PANSARE S K. Optimized ratios of amino acids and sugars as amorphous stabilizing compounds in pharmaceutical compositions containing high concentrations of protein-based therapeutic agents, 2017.
[8]
GOMEZ G, PIKAL M J, RODRIGUEZ-HORNEDO N. Effect of initial buffer composition on pH changes during far-fromequilibrium freezing of sodium phosphate buffer solutions[J]. Pharm Res, 2001, 18(1): 90-97.
[9]
STRICKLEY R G, VISOR G C, LIN L H, et al. An unexpected pH effect on the stability of moexipril lyophilized powder[J]. Pharm Res, 1989,36(6):971-975.
[10]
RAMPRAKASH G, KOUSTUV C, LARRY G, et al. Impact of freeze-drying on ionization of sulfonephthalein probe molecules in trehalose-citrate systems[J]. J Pharm Sci, 2010, 95(7):1498-1510.
[11]
HAIKALA R, EEROLA R, TANNINEN V P, et al. Polymorphic changes of mannitol during freeze-drying: effect of surface-active agents[J]. PDA J Pharm Sci Technol, 1997, 51(2): 96-101.
[12]
GOVINDARAJAN R, CHATTERJEE K, GATLIN L, et al. Impact of freeze-drying on ionization of sulfonephthalein probe molecules in trehalose-citrate systems[J]. J Pharm Sci, 2006, 95(7):1498-1510.
[13]
TELANG C, SURYANARAYANAN R. Crystallization of cephalothin sodium during lyophilization from tert-butyl alcohol-water cosolvent system[J]. Pharm Res, 2005, 22(1):153-160.
[14]
LOFTSSON T, BREWSTER M E. Pharmaceutical applications of cyclodextrins.1.Drug solubilization and stabilization[J]. J Pharm Sci, 1996, 85(10):1017-1025.
[15]
GOULD S, SCOTT R C. 2-Hydroxypropyl-beta-cyclodextrin(HP-beta-CD):atox-icologyreview[J]. Food Chem Toxicol, 2005, 43(10):1451-1459.
[16]
National Medical Products Administration. Announcement on Further Improving Related Issues Concerning Drug Review and Approval and Supervision Work (Draft for Comment) [EB/OL]. [2017-12-22]. http://www.nmpa.gov.cn/WS04/CL2101/336058.html.
[17]
RAVIN H A, SELIGMAN A M, FINE J. Polyvinyl pyrrolidone as a plasma expander[J]. New Engl J Med, 1952, 247(24):921-929.
[18]
FEDERAL REGISTER, VOL. 43, NO. 68-FRIDAY, APRIL 7, 1978. [EB/OL]. [2018-11-19]. https://s3.amazonaws.com/archives.federalregister.gov/issue_slice/1978/4/7/14742-14744.pdf#page=2.
[19]
European Medicines Agency. Guideline, Information for the package leaflet regarding polysorbates used as excipients in medicinal products for human use. [EB/OL]. [2018-11-19] . https://www.ema.europa.eu/en/documents/scientific-guideline/draft-information-package-leaflet-regarding-polysorbates-used-excipients-medicinal-products-human_en.pdf.
[20]
HERMAN B D, SINCLAIR B D, MILTON N, et al. The effect of bulking agent on the solid-state stability of freeze dried methylprednisolone sodium succinate[J]. Pharm Res, 1994, 11(10): 1467-1473.
[21]
SERIGO A, RAMBHATLA S, PIKAL M J. Heat and mass transfer scale-up issues during freeze drying, I: atypical radiation and the edge vial effect[J]. AAPS Pharm Sci Tech, 2003, 4(2):114-127.
[22]
LAM T, STRICKLY R G, VISOR G C. An unexpected pH effect on stability of moexipril lyophilized powder[J]. Pharm Res, 2004, 6(11):971-975.
[23]
KASPER J C, WINTER G, FRIESS W. Recent advances and further challenges in lyophilization[J]. Eur J Pharm Biopharm, 2013, 85(2):162-169.
[24]
The Drug Evaluation Center of National Medical Products Administration. Notice on Publicly Soliciting Opinions on Technical Requirements for Consistency Evaluation of Listed Chemical Generic Drugs (Injections) [EB/OL]. [2017-12-22] .http://www.cde.org.cn/news.do?method=viewInfoCommon&id=314268.
[25]
LU E, EWING S, GATLIN L, et al. The effect of bulking agents on the chemical stability of acid-sensitive compounds in freeze-dried formulations: sucrose inversion study[J]. J Pharm Sci, 2009, 98(9):3387-3396.
2020, Vol. 55 
