药物制剂辅料在儿童群体中的安全性考量

海莉丽,朱琳,李智平

中国药学杂志 ›› 2019, Vol. 54 ›› Issue (14) : 1121-1125.

PDF(1043 KB)
中国药学杂志
PDF(1043 KB)
中国药学杂志 ›› 2019, Vol. 54 ›› Issue (14) : 1121-1125. DOI: 10.11669/cpj.2019.14.001
综述

药物制剂辅料在儿童群体中的安全性考量

  • 海莉丽1,2,朱琳1,李智平1
作者信息 +

Review of Excipients Safety in Pediatric Patients

  • HAI Li-li1,2, ZHU Lin1, LI Zhi-ping1
Author information +
文章历史 +

摘要

辅料是药物制剂的重要组成,通常认为是惰性成分,较少受到关注。然而,由于儿童群体机体的生长发育及对药物辅料药动学的特殊性,不可否认,儿童正在面临某些药物辅料的危害风险。笔者旨在通过总结对儿童群体确定及可能有危害的药物辅料,回顾国内外药物辅料的使用现状,探讨药物制剂辅料在儿童群体的安全性,以供药师、医生等医务工作者及药品研发生产者参考。

Abstract

Excipients are essential components of pharmaceutical products for use in adults and children. They are generally considered to be inert ingredients and are therefore rarely concerned due to the growth and development of the body of children and the specificity of the pharmacokinetics of pharmaceutical excipients, it is undeniable that children are facing risks of excipient toxicity. This article summarizes some excipients of defined and potential hazardous risks in the pediatric population, and reviews the current status of pediatric use of excipients in China and other countries, therefore to discuss the safety of excipients in children, and to provide a reference to healthcare professionals including pharmacists, physicians, as well as pharmaceutical manufacturers.

关键词

辅料 / 儿童 / 不良反应 / 安全性 / 制剂 / 药物研发

Key words

excipient / children / adverse reaction / safety / formulation / drug development

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用
海莉丽,朱琳,李智平. 药物制剂辅料在儿童群体中的安全性考量[J]. 中国药学杂志, 2019, 54(14): 1121-1125 https://doi.org/10.11669/cpj.2019.14.001
HAI Li-li, ZHU Lin, LI Zhi-ping. Review of Excipients Safety in Pediatric Patients[J]. Chinese Pharmaceutical Journal, 2019, 54(14): 1121-1125 https://doi.org/10.11669/cpj.2019.14.001
中图分类号： R944   

参考文献

[1] KURAI J, CHIKUMI H, KODANI M, et al. Acute eosinophilic pneumonia caused by calcium stearate, an additive agent for an oral antihistaminic medication[J] . Int Med, 2006, 45(17):1011-1016.
[2] EUROPEAN MEDICINES AGENCY. Reflection paper: Formulations of choice for the paediatric population[EB/OL] . London:2006 [2018-11-01] . https://www. ema. europa. eu/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population_en. pdf.
[3] THE INTERNATIONAL PETROLEUM ENVIRONMENTAL CONFERENCE (IPEC). The joint good manufaceuring practices guide for pharmaceutical excipients[EB/OL] . [2018-10-03] . http://www.ipec-china.org/aploadfiles/file/2008/579159c9616e478e95f583c7572c3fb2.pdf
[4] KALASZ H, ANTALl I. Drug excipients[J] . Curr Med Chem, 2006, 13(21):2535-2563.
[5] LISTED N A. What are excipients doing in medicinal products?[J] . Drug Ther Bull, 2009, 47(7):81-84.
[6] MCINTYRE J, CHOONARA I. Drug toxicity in the neonate[J] . Biol Neonate, 2004, 86(4):218-221.
[7] HANNSJORG W, MATTHIAS S. Pediatric Clinical Pharmacology[M] . Berlin Heidelberg: Springer-Verlag, 2011: 102-103.
[8] FABIANO V, MAMELI C, ZUCCOTTI G V. Paediatric pharmacology: remember the excipients[J] . Pharmacol Res, 2011, 63(5):362-365.
[9] AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON DRUGS. "Inactive" ingredients in pharmaceutical products: update (subject review)[J] . Pediatrics, 1997, 99(2):268-278.
[10] EUROPEAN COMMISSION. The Rules Governing Medicinal Products in the European Union:Excipients in the Label and Package leaflet of Medicinal Products for Human Use[EB/OL] . Brussels:2003 [2018-11-01] https://www.pharmaexcipients.com/news/excipients-in-the-label-and-package-leaflet-of-medicinal-products-for-human-use/.
[11] ROWE R C, SHESKEY P J, QUINN M E, et al. Handbook of Pharmaceutical Excipients[M] . 6th ed. London: Pharmaceutical Press, 2009.
[12] COSTELLO I, LONG P, WONG I K, et al. Paediatric Drug Handling[M] . London: Pharmaceutical Press, 2007.
[13] ROSA SOLÀ, BOJ M, HERNANDEZFLIX S, et al. Silica in oral drugs as a possible sarcoidosis-inducing antigen[J] . Lancet, 2009, 373(9679):1943-1944.
[14] ROWE R C, SHESKEY P J, COOK W G, et al. Handbook of Pharmaceutical Excipients[M] . 7th ed. London: APhA/Pharmaceutical Press, 2012.
[15] HANKE U, MAY K, ROZEHNAL V, et al. Commonly used nonionic surfactants interact differently with the human efflux transporters ABCB1 (p-glycoprotein) and ABCC2 (MRP2)[J] . Eur J Pharm Biopharm, 2010, 76(2):260-268.
[16] FISHER A A.Allergic paraben and benzyl alcohol hypersensitivity relationship of the "delayed" and "immediate" varieties[J] . Contact Dermatitis, 1975,1(5):281-284.
[17] BROWN W, BUIST N M, GIPSON H C, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit[J] . Lancet, 1982, 319(8283):1250-1250.
[18] MENON A A, LANDT M, HILLMAN K L, et al. Benzyl alcohol toxicity in a neonatal intensive care unit[J] . Am J Perinatol, 1984, 1(4):288-292.
[19] FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS/WORLD HEALTH ORGANIZATION.Summary of evaluations performed by the joint FAO/WHO expert committee on food additives(JECFA) [EB/OL] . 1994. [2018-11-01] http://www.averynicerestaurant.com/summary-of-evaluations-performed-by-the-joint-fao-who-expert.pdf.
[20] RAFFERTY P, BEASLEY R, HOLGATE S T.Comparison of the efficacy of preservative free ipratropium bromide and atrovent nebuliser solution[J] . Thorax, 1988, 43(6):446-450.
[21] FLIGNER C L, JACK R, TWIGGS G A, et al. Hyperosmolality induced by propylene glycol: a complication of silver sulfadiazine therapy[J] . JAMA, 1985, 253(11):1606-1609.
[22] MURCH S, COSTELOE K.Hyperosmolality related to propylene glycol in an infant[J] . BMJ, 1990, 301(6742):19-20.
[23] NAHATA M C.Safety of “inert” additives or excipients in paediatric medicines[J] . Archiv Dis Childhood(Fetal Neonatal Ed), 2009, 94(6):392-393.
[24] NATIONAL TOXICOLOGY PROGRAM.NTP-CERHR Monograph on the potential human reproductive and developmental effect of propylene glycol (PG)[J] . Ntp Cerhr Mon, 2004, 3(12):1-117.
[25] ARULANANTHAM K, GENEL M.Central nervous system toxicity associated with ingestion of propylene glycol[J] . J Pediat, 1978, 93(3):515-516.
[26] BEDICHEK E, KIRSCHBAUM B.A case of propylene glycol toxic reaction associated with etomidate infusion[J] . Archiv Int Med, 1991, 151(11):2297-2298.
[27] MATTILA M A, RUOPPI M, KORHONEN M, et al. Prevention of diazepam-induced thrombophlebitis with cremophor as a solvent[J] . Br J Anaesth, 1979, 51(9):891-894.
[28] FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATION/WORLD HEALTH ORGANIZATION.WHO food additives series no. 5[EB/OL] . Geneva: World Health Organization, 1974 [2018-11-01] . http://www.inchem.org/documents/jecfa/jecmono/v05je90.htm.
[29] WHITTAKER A, CURRIE A E, TURNER M A, et al. Toxic additives in medication for preterm infants[J] . Archiv Dis Childhood( Fetal Neonatal Ed), 2009, 94(4):236-240.
[30] SCHAB D.Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A Meta-analysis of double-blind placebo-controlled trials[J] . J Develop Behavi Pediat, 2004, 25(6):423-434.
[31] MCCANN D, BARRETT A, COOPER A, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial[J] . Lancet, 2007, 370(9598):1560-1567.
[32] MICHAËLSSON G, PETTERSSON L, JUHLIN L.Purpura caused by food and drug additives[J] . Archiv Dermatol, 1974, 109(1):49-52.
[33] PARODI G, PARODI A, REBORA A.Purpuric vasculitis due to tartrazine[J] . Dermatology, 1985, 171(1):62-63.
[34] BELL R T, FISHMAN S.Eosinophilia from food dye added to enteral feeding[J] . N Engl J Med, 1990, 322(25):1822.
[35] HARIPARSAD D, WILSON N, DIXON C, et al. Oral tartrazine challenge in childhood asthma: effect on bronchial reactivity[J] . Clin Allergy, 1984, 14(1):81-85.
[36] SETTIPANE G A.Adverse reactions of aspirin and related drugs[J] . Archiv Int Med, 1981, 141(3):328-332.
[37] SUPRAMANIAM G, WARNER J O.Artificial food additive intolerance in patients with angio-oedema and urticaria[J] . Lancet, 1986, 328(8512):907-909.
[38] BEDINE M S, BAYLESS T M.Intolerance of small amounts of lactose by individuals with low lactase levels[J] . Gastroenterol, 1973, 65(5):735-743.
[39] VAN ASSENDELFT A H.Bronchospasm induced by vanillin and lactose[J] . Eur J Respiratory Diseases, 1984, 65(6):468-472.
[40] MILLER R, WHITE L W, SCHWARTZ H J, et al. A case of episodic urticaria due to saccharin ingestion[J] . J Allergy Clin Immunol, 1974, 53(4):240-242.
[41] LISTED N A.Saccharin:review of safety issues[J] . JAMA, 1985, 254(18):2622-2624.
[42] DURO D, RISING R, CEDILLO M, et al. Association between infantile colic and carbohydrate malabsorption from fruit juices in infancy[J] . Pediatrics, 2002, 109(5):797-805.
[43] STEGINK L D, FILER L J, BELL E F, et al.Repeated ingestion of aspartame-sweetened beverages: further observations in individuals heterozygous for phenylketonuria[J] . Metabol-clinical Exp, 1990, 39(10):1076-1081.
[44] LIPTON R B, NEWMAN L C, COHEN J S, et al. Aspartame as a dietary trigger of headache[J] . Headache J Head Face Pain, 1989, 29(2):90-92.
[45] SCHANZ C, BUTCHKO H H, STARGEL W W, et al. The Clinical Evaluation of A Food Additive: Assessment of Aspartame[M] . Boca Raton, FL: CRC Press, 1996.
[46] TOLLEFSON L, BARNARD R J.An analysis of FDA passive surveillance reports of seizures associated with consumption of aspartame[J] . J Am Dietetic Assoc, 1992, 92(5):598-601.
[47] PERES K G, OLIVEIRA C T, PERES M A, et al. Sugar content in liquid oral medicines for children[J] . Rev Saude Publica, 2005, 39(3):486-489.
[48] AIRES C P, TABCHOURY C P, DEL BEL CURY A A, et al. Effect of sucrose concentration on dental biofilm formed in situ and on enamel demineralization[J] . Caries Res, 2006, 40(1):28-32.
[49] LISTED N A.Sulfite update[J] . FDA Drug Bull, 1984, 14(3):24.
[50] BAKER G J, COLLETT P, ALLEN D H.Bronchospasm induced by metabisulphite-containing foods and drugs[J] . Med J Aust, 1981, 2(11):614-617.
[51] KOEPKE J W, CHRISTOPHER K L, CHAI H, et al. Dose-dependent bronchospasm from sulfites in isoetharine[J] . Jama the J Am Med Assoc, 1984, 251(22):2982-2983.
[52] SCHWARTZ H. Sensitivity to ingested metabisulfite: variations in clinical presentation[J] . J Allergy Clin Immunol, 1983, 71(5):487-489.
[53] KAN S Y, YU Q K, WANG H L, et al. Medicine information annotation about package inserts of pediatric drugs and children′s risk in medication [J] . Chin J Hosp Pharm(中国医院药学杂志), 2016, 36(20):1801-1804.
[54] QUIJANO RUIZ B, DESFONTAINE E, ARENAS-LÓPEZ S, et al. Pediatric formulation issues identified in paediatric investigation plans[J] . Expert Rev Clin Pharmacol, 2014, 7(1):25-30.
[55] PATEL V, DESAI T, CHAVDA B, et al. Extemporaneous dosage form for oral liquids[J] . Pharmacophore, 2011, 2(2):86-103.
[56] EUROPEAN MEDICINES AGENCY.Guideline on pharmaceutical development of medicines for paediatric use[EB/OL] . London: European Medicines Agency, 2013 [2018-10-14] . https://www.ema.europa.eu/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf.
[57] SALUNKE S, TULEU C.The STEP database through the end-users eyes-usability study[J] . Int J Pharm, 2015, 492(1-2):316-331.
[58] BUCKLEY L A, SALUNKE S, THOMPSON K, et al. Challenges and strategies to facilitate formulation development of pediatric drug products: safety qualification of excipients[J] . Int J Pharm, 2018, 536(2):563-569.
[59] PAUL J S, WALTER G C, COLIN G C.Handbook of Pharmaceutical Excipients[M] . 8th ed.London: Pharmaceutical Press, 2017.
[60] FOOD AND DRUG ADMINISTRATION.Inactive Ingredient Database[DB/OL] . [2018-12-14] . https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
[61] LASS J, NAELAPÄÄ K, SHAH U, et al. Hospitalised neonates in estonia commonly receive potentially harmful excipients[J] . Bmc Pediatr, 2012, 12(1):136-147.
[62] KUMAR A, RAWLINGS R D, BEAMAN D C.The mystery ingredients: sweeteners, flavorings, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations[J] . Pediatrics, 1993, 91(5):927-933.
[63] PANDYA H C, MULLA H, HUBBARD M, et al. Essential medicines containing ethanol elevate blood acetaldehyde concentrations in neonates[J] . Eur J Pediatr, 2016, 175(6):841-847.
[64] AKINMBONI T O, DAVIS N L, FALCK A J, et al. Excipient exposure in very low birth weight preterm neonates[J] . J Perinatol, 2018, 38(2):169-174.
[65] ALCIDÉSIO SOUZA, SANTOS D, FONSECA S, et al. Toxic excipients in medications for neonates in Brazil[J] . Eur J Pediatr, 2014, 173(7):935-945.
[66] NELLIS G, METSVAHT T, VARENDI H, et al. Potentially harmful excipients in neonatal medicines: a pan-European observational study[J] . Archiv Dis Childhood, 2015, 100(7):694-699.
[67] NELLIS G, METSVAHT T, VARENDI H, et al. Product substitution as a way forward in avoiding potentially harmful excipients in neonates[J] . Paediatr Drugs, 2016, 18(3):221-230.

基金

中国-世界卫生组织2016~2017双年度合作项目资助:儿童用药安全性和可及性相关因素对策研究资助(2016/647672-0);上海市卫生计生系统薄弱学科建设项目资助(2016ZB0305);2017年上海市临床药学重点专科建设项目资助(沪卫计药资助〔2017〕5号)
PDF(1043 KB)

Accesses

Citation

Detail
段落导航
相关文章

/

〈 〉