Clinical challenges with excipients in insulin formulations and role of concentrated insulin

Authors

  • K. D. Modi Department of Endocrinology, Care Hospital, Nampally, Hyderabad, India
  • Pradeep V. Gadge Department of Diabetology, Dr. Gadge’s Diabetes Care Centre, Mumbai, Maharashtra, India
  • Pradeep Jain Department of Medicine, Kashi Ganga Nursing Home, Varanasi, India
  • Sudhir Pawar Department of Pharmacology, LTMMC and GH, Sion, Mumbai, India
  • Ruchi D. Shah Department of Medical Affairs, Wockhardt Ltd., Mumbai, Maharashtra, India
  • Shahu A. Ingole Department of Medical Affairs, Wockhardt Ltd., Mumbai, Maharashtra, India
  • Rishi Jain Department of Medical Affairs, Wockhardt Ltd., Mumbai, Maharashtra, India

DOI:

https://doi.org/10.18203/2319-2003.ijbcp20191125

Keywords:

Concentrated insulin, Excipients, Insulin, Meta-cresol, Preservatives

Abstract

Most of the insulin formulations in clinical use contain phenol, meta-cresol or both as excipients. These excipients in insulin preparations provide stability and have antimicrobial properties. However, they are reported to be associated with undesirable side-effects especially localised allergic reactions. Amount of excipients injected per unit dose of insulin is a major determining factor in causation of these reactions. This review discusses the excipients in different insulin formulations available in India with potential of precipitating undesirable effects and the use of concentrated insulins to reduce these complications. To avoid the detrimental effects associated with excipients, removal of preservatives or use of insulin preparations devoid of excipients can be an option. Besides these approaches, one approach that can be considered is the use of concentrated insulin to reduce the volume of insulin dose and thereby the excipients. Concentrated insulins address the high insulin requirements of the growing population of patients with type 2 diabetes who require higher insulin doses. Concentrated insulins help in reduction of dose volume as well as amount of excipients injected per unit dose of insulin. U200 (concentrated r-DNA Human Insulin Premix 30/70-200 IU/ml) can be advantageous with better absorption from smaller quantity injected, lesser variability in absorption, lesser pain and discomfort due to smaller quantity, lesser chances of hypoglycaemia all of which can lead to better patient compliance. Thus, concentrated insulin U200 can be one of the alternatives to prevent/reduce clinical complications with excipients in insulins.

References

Paulose KP. History of insulin. J Assoc Physicians India. 1999;47(2):255.

Gualandi-Signorini AM, Giorgi G. Insulin formulations - a review. Eur Rev Med Pharmacol Sci. 2001;5:73-83.

Derewenda U, Derewenda Z, Dodson GG, Hubbard RE, Korber F. Molecular structure of insulin: the insulin monomer and its assembly. Br Med Bull. 1989;45(1):4-18.

Teska BM, Alarcõn J, Pettis RJ, Randolph TW, Carpenter JF. Effects of phenol and meta-cresol depletion on insulin analog stability at physiological temperature. J Pharm Sci. 2014;103(8):2255-2267.

Wheeler BJ, Taylor BJ. Successful management of allergy to the insulin excipient metacresol in a child with type 1 diabetes: a case report. J Med Case Rep. 2012;6(1):263.

Clerx V, Van Den Keybus C, Kochuyt A, Goossens A. Drug intolerance reaction to insulin therapy caused by metacresol. Contact Dermatitis. 2003;48(3):162-163.

Matheu V, Perez E, Hernández M, Díaz E, Darias R, González A et al. Insulin allergy and resistance successfully treated by desensitisation with Aspart insulin. Clin Mol Allergy. 2005 Dec;3(1):16.

Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol. 2003;4(10):661-667.

Weber C, Kammerer D, Streit B, Licht AH. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release. Toxicol Rep. 2015;2:194-202.

Do HD, Lohsoonthorn V, Jiamjarasrangsi W, Lertmaharit S, Williams MA. Prevalence of insulin resistance and its relationship with cardiovascular disease risk factors among Thai adults over 35 years old. Diabetes Res Clin Pract. 2010;89(3):303-308.

Ioannou GN, Bryson CL, Boyko EJ. Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes. J Diab Complications. 2007;21(6):363-370.

Bermudez V, Salazar J, Martinez MS, Castillo MC, Olivar LC, Calvo MJ et al. Prevalence and Associated Factors of Insulin Resistance in Adults from Maracaibo City, Venezuela. Adv Prev Med. 2016;2016:9405105.

Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diab Care. 1984;7(2):188-199.

Lamos EM, Younk LM, Davis SN. Concentrated insulins: The new basal insulins. Ther Clin Risk Manag. 2016;12:389-400.

Anthony K, Thomas S. Insulin analogues. C Bull Endocrinol Diab. 2002;4(1):18-21.

Actrapid 100 international units / ml , Solution for Injection in a vial. Package leaflet : Information for the user. 2018. Available at : https://www.medicines.org.uk/emc/files/pil.3849.pdf. Accessed 8 January 2019.

FDA. AFREZZA® (insulin human) Inhalation Powder. Prescribing information 2014. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf. Accessed 8 January 2019.

FDA. HUMALOG® ((insulinlispro [rDNA origin] injection) Prescribing information 1996. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020563s115lbl.pdf. Accessed 8 January 2019.

FDA. NOVOLOG® (insulin aspart [rDNA origin] injection). Prescribing information 2000. Available at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020986s082lbl.pdf.

FDA. APIDRA® (insulin glulisine [rDNA origin] injection). Prescribing information 2004. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021629s015lbl.pdf.

FDA. LANTUS® (insulin glargine [rDNA origin] injection). Prescribing information [Internet] 2000. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf.

FDA. LEVEMIR® (insulin detemir [rDNA origin] injection). Prescribing information 2005. Available from : https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021536s037lbl.pdf.

EMA. TRESIBA® (insulin degludec [rDNA origin] injection).Summary of product characteristics 2013. Available at: https://www.ema.europa.eu/documents/product-information/tresiba-epar-product-information_en.pdf.

FDA. TOUJEO® (insulin glargine U 300 injection). Prescribing information 2015. Available at : https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206538s006lbl.pdf.

Angelo R, Rousseau K, Grant M, Leone-Bay A, Richardson P. Technosphere® insulin: defining the role of technosphere particles at the cellular level. J Diab Sci Tech. 2009;3(3):545-54.

Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev. 2007;28(6):625-652.

Badik J, Chen J, Letvak K, So T-Y. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report. J Pediatr Pharmacol Ther. 2016;21(1):85-91.

Simpson AJH, Wuthiekanun V. Interaction of insulin with burkholderia pseudomallei may be caused by a preservative. J Clin Pathol. 2000;53(2):159-160.

Moorthy SS, Pond W, Rowland RG. Severe circulatory shock following protamine (An anaphylactic reaction). Anesth Analg. 1980;59:77-78.

Maheshwari M, Goyal D, Desouza P, Goyal RK. Spotted dermopathy in a diabetic patient due to insulin allergy. J Assoc Physicians India. 2004;52:926-927.

Feinglos MN, Jegasothy B V. “Insulin” Allergy Due To Zinc. Lancet. 1979;313(8108):122-124.

Ben Ammar I, Ksouri H, Trabelsi N,Mellouli F, Ben Mami F, Dakhli S et al. Generalized allergy due to zinc in insulin treated with zinc-free insulin. Acta Diab. 2012;49(3):239-241.

Paiva TO, Bastos AEP, Marques JT, Viana AS, Lima PA, de Almeida RFM. m-Cresol affects the lipid bilayer in membrane models and living neurons. Rsc Adv. 2016;6(107):105699-105712.

Akinci B, Yener S, Bayraktar F, Yesil S. Allergic reactions to human insulin: a review of current knowledge and treatment options. Endocrine. 2010 Feb 1;37(1):33-9.

Eriksson H. Removal of toxic preservatives in pharmaceutical preparations of insulin by the use of ultra-stable zeolite Y. Biotechnol Tech. 1998;12(4):329-334.

Elaince C. The Use of U-500 in Patients With Extreme Insulin Resistance. Diab Care. 2005;28(5):1240-44.

Painter NA, Sisson E. An overview of concentrated insulin products. Diab Spectr. 2016;29(3):136-140.

Tandon N, Kalra S, Balhara YP, Baruah MP, Chadha M, Chandalia HB et al. Forum for injection technique and therapy expert recommendations, India: The Indian recommendations for best practice in insulin injection technique, 2017. Ind J Endocrinol Metab. 2017;21(4):600.

Thacker H, Kesavadev J, Singh G, Shukla K, Puppalwar G, Shrimanker R. Continuous Glucose Monitoring Guided Assessment of Concentrated U200 r-DNA Human Premix 30/70 Insulin. Diab. 2018; 67(Supplement 1).

Peyrot M, Rubin RR, Kruger DF, Travis LB. Correlates of Insulin Injection Omission. Diab Care. 2010;33(2): 240–245.

Downloads

Published

2019-03-23

How to Cite

Modi, K. D., Gadge, P. V., Jain, P., Pawar, S., Shah, R. D., Ingole, S. A., & Jain, R. (2019). Clinical challenges with excipients in insulin formulations and role of concentrated insulin. International Journal of Basic & Clinical Pharmacology, 8(4), 821–826. https://doi.org/10.18203/2319-2003.ijbcp20191125

Issue

Section

Review Articles