The absorption route of the administered molecules depends on their size (c), with molecules larger than about 16 kDa being mostly absorbed into lymphatic capillaries and those smaller than 1 kDa into blood capillaries [48]. Candiotti K, Rodriguez Y, Koyyalamudi P, Curia L, Arheart KL, Birnbach DJ. In the same study, the 5-bevel needle tip geometry was perceived by diabetic patients as less painful. This discomfort has been reported with all products and has not been directly linked to the citrate content of the injection. PubMed  The most common silicone oil used in medical applications is polydimethylsiloxane, which is available in different viscosities and can be used to coat syringe barrels and needles [20]. A review by Meyer et al. Eur Diabetes Nurs. Thus, in a study carried out to identify the pain-causing substance in epoetin alfa (EPO-alfa) preparations, the authors found that citrate buffer (approx. This work was supported by a FAPESP grant to A. Rossi. Adv Ther 36, 2986–2996 (2019). 2015;9:121–31. On the basis of the data, we would recommend the concentration of phosphate to be limited to 10 mM and the concentration of citrate be lower than 7.3 mM. The author of this study concluded that the use of citrate as a buffer caused more pain immediately after SC injection than the solution with histidine. Correspondence to The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. Blauvelt A, Lacour JP, Fowler JF Jr, et al. Iris Usach has nothing to disclose. A 45° injection angle is particularly recommended when needles of 8 mm length or longer are used [10]. with 100 mM NaOH (þ) and 20 mM MES (50 ml) with 100 mM NaOH (þ ). Relative diameter of needles according to the gauge system (G). Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain. PubMed  This review, the Rapid Service, and Open Access Fees were funded by Sandoz SA. Values in the upper part indicate the external diameter in millimeters. 0.1 M Citric acid: 19.2 g/L (MW 192.1) 0.2 M Dibasic sodium phosphate: 35.6 g/L (dihydrate; MW 178.0) Mix citric acid and sodium phosphate solutions in the proportions indicated and adjust the final volume to 100mL with deionized water. European Medicines Agency. (A) Titration curves of 5 mM citric acid (50 ml) Sim KH, Hwang MS, Kim SY, Lee HM, Chang JY, Lee MK. However, another study concluded that solutions of up to 3 ml were well tolerated without pain when injected in the abdomen of healthy volunteers [32]. When the injection is performed with an angle of approximately 45°, the needle should be placed bevel up to reduce pain [24]. CAS  from 3.1 to 5.4 (Fig. Accessed Nov 2018. Weinblatt ME, Keystone EC, Furst DE, et al. information about the buffering range of this weak acid is However, some studies have shown that citrate concentrations lower than 50 mM may also be painful. A total of 188 articles were identified and reviewed, and both their text and references were analyzed. this in mind, we determined the pKa values of citric acid at 2015;8:473–84. the most employed in buffers for the culture of many The most relevant articles were used to write this review. 2016;50(1):7–9. In spite of the fact that large SC injected volumes have been generally associated with pain and adverse events at the injection site [29], the published data is somewhat conflicting. The present review addresses the role of the above factors in the subjective sensation of pain in individuals receiving SC injections. Hirsch L, Byron K, Gibney M. Intramuscular risk at insulin injection sites–measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy. Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain, Department of Medical Affairs, Sandoz SA PE Parque Norte, Edificio Roble, C/Serrano Galvache, Madrid, Spain, Department of Global Medical Affairs, Sandoz Biopharmaceuticals, Holzkirchen, Germany, You can also search for this author in Robb DM, Kanji Z. Australian Diabetes Educators Association (ADEA). Citrate-Phosphate Buffer; pH range 2.6 to 7.0. Citrate buffer is commonly used in parenteral formulations at concentrations in the range 5–15 mM, and it is assumed that increasing the concentration to more than 50 mM can result in excessive pain upon SC injection . 2018;12(1):163–8. Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site.


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