**16. Pulmonary absorption**

Pulmonary drug delivery is effective due to fast and convenient drug absorption. Lungs have rich vasculature and their blood output bypasses the liver metabolism, resulting in high drug bioavailability. It is commonly used to deliver anti-inflammatory therapeutics such as in asthma treatment. To maximize drug permeation through the lungs, reducing particle size may be appropriate. Particle size less than 5 µm ensures high absorbability but very low particle size (1 µm or less) makes particle-expulsion most likely and thus renders drug ineffective (Agu et al. 2001a; Agu et al. 2001b). Administration of insulin through inhalation may be effective but faces many challenges including mucous, mucociliary clearance, lung surfactants and proteases and peptidases at the alveolar surface (Heinemann et al. 2000). The addition of bile acids to insulin should minimise such challenges through enhancing mucus permeation and reducing enzymatic degradation. This is particularly interesting since current subcutaneous insulin injection causes wide range of side effects such as irritation and scarring as well as being highly unfavourable by patients due to its invasiveness and discomfort. In one study (45), the bioavailability of inhaled insulin was

The rectum is the final part of the intestinal tract and about 4-5 inches long. It is the part of the gastrointestinal tract that extends from the colon in the lower left part of the abdomen to the anus. Its temperature is the same as the body temperature, constant at 37 oC. For insulin to be administered rectally, it needs to pass through the rectal epithelia, lamina propria and muscularis mucosa. The rectum has a rich vasculature making it a good site for drug

For maximum absorption, insulin suppositories should not be inserted too high into the rectum since the superior rectal vein takes blood straight to the liver, where first pass effect is taking place. Inserting insulin to the lower part of the rectum will result in insulin permeation to the inferior or middle rectal veins which drain into the inferior vena cava bypassing the liver and avoiding first pass metabolism. However, reaching the higher part of the colon is not feasible thus rendering insulin rectal delivery ineffective. Enhancing

Bile acids have shown good efficacy in enhancing rectal absorption when complexed with or added to drug formulations. In human, INF-α, an antiviral, antineoplastic and immunoregulatory molecule, was not absorbed when administered rectally in a hydrophilic suppository, but when sodium ursodeoxycholate was incorporated into the suppository base, detectable levels were obtained (Lee et al. 1991; Lee 1991). By the same token, the effect of bile salts in insulin rectal absorption was investigated. Rectal administration with 5% sodium glycocholate produced a large increase in the effect of a 10 U/kg dose. Rectal and nasal administration reduced plasma glucose approximately half as effectively as intramuscular insulin in the presence of this bile salt (Aungst & Rogers 1988). This method of administration may be beneficial to those requiring only small doses of insulin or those uncomfortable with injection. Thus, it is clear that bile salts are effective promoters for rectal administration of insulin. The proposed mechanism of action involves enhanced membrane permeability, lipid solubilizing and the inhibition of proteolytic enzymes at the absorption site. However, rectal drug administration remains unfavorable and invasive and thus

Pulmonary drug delivery is effective due to fast and convenient drug absorption. Lungs have rich vasculature and their blood output bypasses the liver metabolism, resulting in high drug bioavailability. It is commonly used to deliver anti-inflammatory therapeutics such as in asthma treatment. To maximize drug permeation through the lungs, reducing particle size may be appropriate. Particle size less than 5 µm ensures high absorbability but very low particle size (1 µm or less) makes particle-expulsion most likely and thus renders drug ineffective (Agu et al. 2001a; Agu et al. 2001b). Administration of insulin through inhalation may be effective but faces many challenges including mucous, mucociliary clearance, lung surfactants and proteases and peptidases at the alveolar surface (Heinemann et al. 2000). The addition of bile acids to insulin should minimise such challenges through enhancing mucus permeation and reducing enzymatic degradation. This is particularly interesting since current subcutaneous insulin injection causes wide range of side effects such as irritation and scarring as well as being highly unfavourable by patients due to its invasiveness and discomfort. In one study (45), the bioavailability of inhaled insulin was

insulin rectal absorption can be achieved using bile salts (Sayani & Chien 1996).

remains a major limitation for such a drug delivery system.

**16. Pulmonary absorption** 

**15. Rectal absorption** 

administration.

measured with and without the addition of bile acids. The bioavailability of inhaled insulin was 7.8% but, with the addition of a bile acid, absolute bioavailability reached 10.2% (p < 0.05). This was a small but significant increase which presents bile acids as permeation enhancers in pulmonary drug applications. Bile acids could have enhanced insulin effect through exerting their own hypoglycemic effect causing a further reduction in glucose levels after administration with insulin. The study also reported that the onset of the hypoglycemic effect after insulin inhalation with bile acids was more than ten times faster, then when insulin was injected SC alone. However, interpatient variation was large in terms of hypoglycemia, which was a disadvantage for such a method of insulin delivery. In other studies (Agu et al. 2001a; Agu et al. 2001b), insulin was administered via the lung with and without sodium glycocholate. The addition of 1% sodium glycocholate inhibited insulin degradation within the lung. Although neither the types of proteolytic enzymes involved in insulin hydrolysis nor the specific mode of stabilization by bile acids were investigated, sodium glycocholate was suggested to be an aminopeptidase inhibitor. Bile acids wide use in pulmonary drug formulation is limited by their safety profile. at the dose required to increase absorption, bile acids are non-toxic and relatively safe. However, when aspirated in large amounts, bile acids have been shown to cause pulmonary oedema and haemorrhage due to dissolution of pulmonary membranes (Kaneko et al. 1990).
