Buccal Administration of Insulin
Nanotechnology as a Promising Strategy for Alternative Routes of Insulin Delivery
Catarina Pinto Reis, Christiane Damgé, in Methods in Enzymology, 2012
Chapter fourteen
The buccal mucosa has excellent accessibility, low enzymatic activity, a large absorptive area with a spread of vascularization, and a relatively immobile mucosa which may be an important factor for increasing the residence time of the drugs. In addition, the ease of access to the systemic circulation through the internal jugular vein allows drugs to bypass the hepatic first-pass metabolism, which may also increase bioavailability of drugs. Other advantages of buccal administration include the convenient route and painless administration, facility to modulate the selection of excipients, versatility in the design of multidirectional or unidirectional release systems for local or systemic action, and a predictable drug concentration in the blood. The major disadvantage of this route is that insulin may enter directly into peripheral circulation resulting in peripheral hyperinsulinemia similar to that seen with injectable insulin.
The exact mechanism of insulin absorption via this route is still not known, but one study showed that peptide transport across the buccal mucosa may occur via passive diffusion (Veuillez et al., 2001). The role of absorption enhancers in the buccal transport of proteins is crucial. Reductions in blood glucose of up to 30% relative to intramuscular insulin have been reported, but those studies have lacked reproducibility (Aungst and Rogers, 1988). Besides the reproducibility, many absorption enhancers have some side effects, often causing irritation of the buccal mucosa. An additional problem of the buccal delivery of insulin is the unpleasant taste of buccal formulations.
In terms of multiparticulate system strategies, Ishida et al. (1981) were among the first to pioneer the mucoadhesive drug delivery system by administering insulin across the buccal mucosa in beagle dogs.
Copilot says: Yes, Ishida et al. (1981) made significant strides in the field of mucoadhesive drug delivery systems. Their pioneering work involved administering insulin across the buccal mucosa in beagle dogs, which was a novel approach at the time. This method aimed to enhance the bioavailability of insulin by bypassing the gastrointestinal tract and avoiding enzymatic degradation.
Mucoadhesive drug delivery systems leverage the adhesive properties of certain polymers to prolong the retention time of the drug at the site of application, thereby improving drug absorption and therapeutic efficacy. This approach has since been explored for various drugs and delivery routes, including buccal, nasal, ocular, and vaginal applications
Later, transferosomes have also been developed to enhance insulin bioavailability. Compared with s.c. administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability in the experimental group treated with vesicles were 15.59% and 19.78%, respectively. It is also anticipated that the effects of salivary scavenging and accidental swallowing of the delivery system, in addition to the barrier properties of the buccal mucosa, will remain major limitations in the development of buccal drug delivery systems.
Pelleted mucoadhesive polymeric nanoparticles for the buccal delivery of insulin were an attempt to develop an alternative buccal delivery system for insulin (Venugopalan et al., 2001). A significant hypoglycemic response was observed after 7 h. In another related work, insulin was formulated into mucoadhesive buccal tablets using Carbopol 934, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose and different absorption promoters. Additionally, Insulin Buccal Spray, a formulation with soybean lecithin and propanediol combined as an absorption enhancer, improved the hypoglycemic effect of insulin in diabetic rabbits and rats (Xu et al., 2002). The hypoglycemic effect lasted over 5 and 4 h in diabetic rabbits and rats, respectively. Biodel, Inc. is developing a rapid-acting sublingual insulin called Viatab™. This formulation has been tested in laboratory models and was not toxic.
One strategy to deliver insulin through the buccal mucosa in humans is already being tested by Generex Biotechnology Corp.: Oral-Lyn. Oralyn® involves a miceller insulin liquid formulation made from a combination of absorption enhancers and is administered through a RapidMist™ as a fine spray into the mouth (Modi et al., 2002). Studies with healthy and type 1 diabetic individuals showed that it was fast acting (around 25 min) and had a rapid glycemic response (maximum effect at 45–50 min). This oral insulin formulation controlled postprandial glucose levels in both type 1 and 2 diabetics (Cernea et al., 2005). The spray was thought effective for meal-related insulin requirements, since it was adsorbed and acted rapidly. Local tolerability appeared acceptable, but bioavailability remained low, necessitating repeated administrations.
The multitude of techniques already tested illustrates the inherent difficulties associated with the buccal route of insulin administration. So far, efficacy studies have only been presented as abstracts in conference proceedings, and safety reports of buccal insulin are not usually presented.
