Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted relative bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

Oral transmucosal opioids

The oral transmucosal routes are buccal and sublingual. The absorption of drugs across the oral mucosa involves a process of passive absorption, and may involve either the transcellular route or the paracellular route. A number of drug factors affect the absorption of drugs across the oral mucosa. Oral transmucosal drug delivery does not require expertise, preparation, or technical equipment. Oral transmucosal administration may be associated with rapid onset of analgesia. A number of fentanyl-based formulations are commercially available to manage breakthrough cancer pain. A variety of other opioids have been subject to oral transmucosal administration. However, many of these opioids are not very lipophilic and, therefore, not suited for buccal or sublingual administration. Some of the more successful ones are alfentanil and sufentanil.

Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes

New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles.

Effects of Transmucosal Thyroxine Administration on the Tooth Movement in an Animal Model

Objective The aim of this study was to investigate the effects of transmucosal administration of thyroxine on the tooth movement and osteoclastic activity in Beagle dogs. Materials and Methods Eight Beagles were randomly divided into control group (n = 4) and thyroxine group (4-week group, n = 2 and 8-week group, n = 2). Buttons were bonded on the labial surfaces of the second premolar and anchorage teeth. Nickel-titanium closed-coil springs were connected. In the thyroxine group, thyroxine tablets were bonded to the hooks attached to the second premolar. Results The mean rate of orthodontic tooth movement (OTM) in the thyroxine group was slightly higher than that in the control group. Microscopic evaluation showed that the number of osteoclasts in the thyroxine group significantly increased. Conclusion The protocol for transmucosal administration of thyroxine could not significantly accelerate OTM. An increase in the number of osteoclasts was observed through microscopic evaluation during the 4th week.