Subcutaneous Absorption of Insulin

Mesiha, M.S., M.B. Sidhom, and B. Fasipe. 2005. Oral and subcutaneous absorption of insulin poly(isobutylcyanoacrylate) nanoparticles. Int J Pharm 288 289. 

Recent work with insulin provides evidence that the total lung volume at the end of the delivery impacts the kinetics of absorption of this peptide delivery of fine particle insulin aerosol resulted in faster absorption with a higher plasma peak level in humans when the inhalation was done with a deep breath (close to vital capacity), as compared with a more shallow breath (about 50% of the vital capacity).The kinetics following the latter was similar to subcutaneous absorption of insulin. The exact reasons for this observation are unknown. However, the lung does have the above-described water channels that could expand during breathing. If the size of the peptide or protein molecule approaches the diameter of these channels, it would be expected that the channel expansion would lead to faster absorption. For molecules whose size exceeds the channel diameter, the lung volume does not play a role in their pulmonary absorption rate. ... 

Systemic absorption of pulmonary-deUvered peptides and proteins has been the objective of many investigations [2]. The most successful work in this field is the development of insulin formulations for inhalation.These dosage forms might, in the near future, become a suitable alternative for the current subcutaneous injection of insulin that is used to obtain meal-time glucose control [3]. In spite of the strict requirements regarding dose variability for insulin, the pulmonary products under development seem to be as safe as the subcutaneous injections. 

The effects of insulin are modified by various factors. The speed and extent of absorption of insulin depends, for example, on the site of injection (1), the depth of the subcutaneous injection, skin temperature (2), the presence of lipodystrophy, and variation in the extent of inactivation of injected insulin. The disposal of insulin depends on many factors. Exercise and hard work lower the blood glucose and thereby increase the effect of insulin. Infections and obesity reduce its effect. The timing of food intake and the composition of meals are also related to the action of insulin. A thin layer of fat, as sometimes occurs in the upper arm or in the thighs of thin men, can result in intramuscular injection, leading to faster absorption of long-acting insulins. This can reduce the absorption time by half (3). The major factors that affect the fate of injected insulin (and thereby also its risks) are listed in Table 1 (4). 

Injection technique has pharmacokinetic consequences according to whether the insulin is delivered into the subcutaneous tissue or (inadvertently) into muscle. The introduction of a range of appropriate length needles and pen-shaped injectors has enabled patients to inject perpendicularly to the skin without risk of intramuscular injection. The absorption of insulin is as much as 50% more rapid from shallow i.m. injection. Clearly factors such as heat or exercise which alter skin or muscle blood flow can markedly alter the rate of insulin absorption. 

The effects of insulin are modified by various factors. The speed and extent of absorption of insulin depends, for example, on the site of injection (1), the depth of the subcutaneous injection, skin temperature (2), the presence of lipodystrophy, and variation in the extent of inactivation of injected insulin. The disposal of insulin depends on many factors. Exercise and hard work lower the blood glucose and thereby increase the effect of... 

Absorption of insulin is faster from injections administered subcutaneously in the arms than in the thighs. Insulin absorption in some patients may be poor because the subcutaneous tissue acts as a mechanical barrier... 

Absorption of insulin is mainly dependent on the preparation used (see Section 2). Insulin is fairly rapidly absorbed from subcutaneous tissues and although its half-life in blood is very short (see below), the duration of action of most preparations is considerably longer because of their formulation (see Section 2). The rate of absorption from different anatomical sites may be different and may also be increased by exercise. The absorption of insulin after intramuscular administration is more rapid than that after subcutaneous administration (Martindale, 1989). Apart from the fact that absorption depends on the site of injection, it is most rapid from the subcutaneous fat tissue in the abdominal region rather than from the leg or the arm. It can be modified by massage of the tissue or by heat, both inducing an increase in subcutaneous blood flow (Berger et al., 1982). 

Nasal absorption of insulin has been of interest since 1983 (Moses et al., 1983). More recent clinical studies tested its long-term acceptability and efficacy in Type-I diabetic patients (Fraumann et al., 1987) and assessed the kinetics of intranasal insulin with a medium-chain phospholipid (Drejer et al., 1990). Nasal irritation was only slight and proportional to the insulin dosage. Compared with subcutaneous injection, intranasal insulin has a quicker onset of action and a much more uniform time course of absorption. Bioavailability was 8-11% and 24% in the meal-relevant period. Further studies, however, are needed before widespread clinical use can be recommended. 

FACTORS THAT AFFECT INSULIN ABSORPTION The degree of control of plasma glucose may be modified by changes in insulin absorption, factors that alter insulin action, diet, exercise, and other factors. Factors that determine the rate of absorption of insulin after subcutaneous... 

Charman S A, McLennan D N, Edwards G A, et al. (2001). Lymphatic absorption is a significant contributor to the subcutaneous bioavailability of insulin in a sheep model. Pharm. Res. 18 1620-1626. 

Radwan, M.A. Enhancement of absorption of insulin-loaded polyisobutylcyanoacrylate nanospheres by sodium cholate after oral and subcutaneous administration in diabetic rats. Drug Deliv. Int. Pharm., 9, 981, 2001. 

Lung homogenates metabolize insulin (Liu et al, 1992), although the proteolytic enzyme activity of the lung in degrading insulin is weaker than that of subcutaneous tissue (Hori et al, 1983). In accordance with this finding, addition of protease inhibitors has been reported to increase the pulmonary absorption of insulin (Okumura et al, 1992 Yamamoto et al, 1994). 

Hddebrandt, P., Birch, K., Sestoft, L., and Volund, A., 1984a, Dose-dependent subcutaneous absorption of porcine, bovine and human NPH insulins, Acta Med. Scand 215 69-73. 

Hildebrandt, P., Berger, A., Volund, A., and Kiilil, C., 1985a, The subcutaneous absorption of human and bovine ultralente insulin formulations. Diabetic Med 2 355-359. 

Regular insulin is unmodified crystalline insulin commonly referred to as natural insulin. It is a clear solution that has a relatively rapid onset and short duration of action. On subcutaneous injection, regular insulin forms small aggregates called hexamers that undergo conversion to dimers followed by monomers before systemic absorption can occur. Therefore, patients should be counseled to inject regular insulin subcutaneously 30 minutes prior to consuming a meal. Regular insulin is the only insulin that can be administered intravenously. 

Insulin pump therapy consists of a programmable infusion device that allows for basal infusion of insulin 24 hours daily, as well as bolus administration following meals. As seen in Fig. 40-3, an insulin pump consists of a programmable infusion device with an insulin reservoir. This pump is attached to an infusion set with a small needle that is inserted in subcutaneous tissue in the patient s abdomen, thigh, or arm. Most patients prefer insertion in abdominal tissue because this site provides optimal insulin absorption. Patients should avoid insertion sites along belt lines or in other areas where clothing may cause undue irritation. Infusion sets should be changed every 2 to 3 days to reduce the possibility of infection. 

B13. Binder, C., Vokmd Nielsen, A., and Jorgensen, K., The absorption of an acid and a neutral insulin solution after subcutaneous injection into different regions in diabetic patients. Scand. J. Clin. Lob. Invest. 19, 156-163 (1967). 

InsuUn is usually administered subcutaneously. Depending on the type of insulin being administered, the rate of insulin absorption can be modulated by al-... 

Geriatric Considerations - Summary Ensure that the older adult can demonstrate the appropriate use of insulin by assessing his or her ability to draw up the correct dose from a multidose bottle, read syringe markings, and administer the dose subcutaneously. Comorbidities such as poor vision, arthritis, tremor, or cognitive impairment may impair this process. Insulin pens maybe advantageous for some patients. Administration of insulin in the arm results in slower absorption than seen with abdominal administration. 

The non-irritant substances can be injected by this route. The rate of absorption of drug is constant and slow to provide a sustained effect. The site of injection is usually the outer surface of the arm, or front of the thigh. Self medication (e.g. insulin) is possible because deep penetration is not needed. Other drugs which are administered subcutaneously are adrenaline, morphine and certain hormonal preparations. 

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