Oral administration improving bioavailability

The nasal tissue is highly vascularized and provides efficient systemic absorption. Compared with oral or subcutaneous administration, nasal administration enhances bioavailability and improves safety and efficacy. Chitosan enhances the absorption of proteins and peptide drugs across nasal and intestinal epithelia. Gogev et al. demonstrated that the soluble formulation of glycol chitosan has potential usefulness as an intranasal adjuvant for recombinant viral vector vaccines in cattle [276]. 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Polyoxometalates are poorly absorbed following oral administration, and even when they are delivered directly into the bloodstream, they may be retained by various plasma proteins before reaching their site of action. Therefore improvements in the bioavailability of polyoxometalates are required. 

Hauss et al. [26] investigated the absorption of ontazolast, a poor water-soluble (0.14 pg/mL) LTB4 inhibitor, following oral administration of a few formulations to rats. All the oil-containing formulations markedly improved ontazolast bioavailability, with the most profound effect observed following the emulsion administration. Bioavailability following a nonoily suspension of ontazolast was 0.5%, whereas an oily solution improved bioavailability to 5.3%, and the emulsion formulation caused total bioavailability of 9.6%>. 

When taken with meals, a 30% increase in absorption of the drug was observed, with peak plasma concentrations occurring within 2.5-4 h after oral administration. When coadministered with ritonavir, the overall half-life is improved to 15 h.20 Darunavir (1) has been shown to be metabolized by liver enzyme CYP450 (3A4).21 22 Thus when administered with low-dose ritonavir—a CYP450 and protease inhibitor—bioavailability increases from 37% to 84%. Absorption of darunavir occurs primarily in the intestine through passive intracellular diffusion. Darunavir and its metabolites are excreted primarily in the feces and urine.23 Metabolism occurs via, carbamate hydrolysis, aliphatic hydroxylation, aromatic hydroxylation, and other metabolites. 

Despite their favourable properties, peptide-based drugs are under-represented in the pharmaceutical market. This discrimination is usually due to their poor bioavailability, which sometimes necessitates non-oral administration or even special medical devices such as inhalers. Another related major disadvantage of peptides is their low metabolic stability due to proteolytic degradation, hi addition, costs of goods for the drug substance are sometimes tremendous. Therefore, there is considerable interest to transform the active principle of biologically active peptides into small molecules with improved pharmacokinetic properties, hi this chapter, we present an overview of... 

Another example is the calcium channel blocker, cinnarizine. This drug exhibits a very low and erratic bioavailability after oral administration as a suspension (F = 8 4%) or capsule (F = 0.8 0.4%o). When it was administered as a complex with SBE4-p-CD or HP-p-CD,l either as a solution (F = 55-60 /o) or in a capsule (F = 38 12%), the bioavailability was significantly enhanced. The improvement in bioavailability was attributed to enhanced dissolution and solubilization via the complexation. 

Furthermore, pharmacokinetic administration, distribution, metabolism and excretion (ADME) factors affect drug bioavailability, efficacy and safety, and, thus, are a vital consideration in the selection process of oral drug candidates in development pipelines. Since solubility, permeability, and the fraction of dose absorbed are fundamental BCS parameters that affect ADME, these BCS parameters should prove useful in drug discovery and development. In particular, the classification can used to make the development process more efficient.For example, in the case of a drug placed in BCS Class II where dissolution is the rate-limiting step to absorption, formulation principles such as polymorph selection, salt selection, complex formation, and particle size reduction (i.e., nanoparticles) could be applied earlier in development to improve bioavailability. 

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