Erik Bechgaard

Pharmacokinetic and Pharmacodynamic Response after Intranasal Administration of Diazepam to Rabbits

Nasal application of drugs might be an alternative to intravenous administration in acute situations such as epileptic or fever seizures. In the search for a nasal formulation leading to a peak plasma concentration of diazepam at a tmax ≤5 min bioavailability in rabbits has been studied after intranasal administration of the drug in ten vehicles of different polarity.

THE INFLUENCE OF INSULIN AND SOME EXCIPIENTS USED IN NASAL INSULIN PREPARATIONS ON MUCOCILIARY CLEARANCE

Abstract The potential local toxicity to the nasal mucosa of insulin, various absorption promoters and vehicles has been tested in the frog palate model. The influence on mucociliary transport rate was used as an estimate of toxicity. Full inhibition of this rate was observed with 1% l -α-lysophosphatidylcholine, 1% polyoxyethylene-9-lauryl ether, 1% sodium deoxycholate and 1% sodium dihydrotaurofusidate, whereas 1% sodium glycocholate and 1% didecanoyl- l -α-phosphatidylcholine had no effect. 0.1% sodium dihydrotaurofusidate increased the mucociliary transport rate and the insulin formulation Novolin ® reduced the rate slightly, but these latter effects were always reversible.

INTRANASAL ADMINISTRATION OF INSULIN TO HUMANS

The purpose of this review is to summarize the information and experience at present available on the intranasal administration of insulin to human subjects and to describe some of the anatomical, physiological, pharmaceutical and technological factors which can affect the absorption of insulin. An overview is given of those absorption promoters which have been used in clinical insulin studies, and the possible absorption-promoting mechanisms are discussed. This review shows that the nasal route offers a promising alternative to parenteral administration. The easier administration and the acceptance by the patients is encouraging the development of new intranasal insulin preparations.

Nasal bioavailability of peptide T in rabbits: absorption enhancement by sodium glycocholate and glycofurol

The aim of the present study was to investigate the absolute nasal bioavailability of Peptide T from aqueous formulations containing sodium glycocholate, an absorption enhancer with known effect on epithelial tight junctions, and/or glycofurol in a crossover study in rabbits. Additionally, the reversibility of the absorption enhancing effect of sodium glycocholate was studied by applying enhancer and peptide T with different time intervals and calculating Area Under the Curve of the peptide in plasma. It was shown that the bioavailability of Peptide T was significantly enhanced when glycofurol or sodium glycocholate was added to a nasal formulation. The nasal bioavailability of Peptide T in water (control formulation), 5% glycofurol, 5% glycofurol+1% sodium glycocholate and 1% sodium glycocholate was 5.9, 22, 29 and 59%, respectively. As indicated by the differences in t(max), C(max) and time-concentration profiles different patterns of Peptide T absorption were seen from the vehicles containing glycofurol and sodium glycocholate. In the reversibility study, the enhancing effect of sodium glycocholate on nasal absorption of Peptide T was found to be reversible within 4 h. It was concluded, that nasal absorption of Peptide T in rabbits was effectively enhanced by co-administration of sodium glycocholate, which also provided very fast absorption rates as well as a relatively short lasting effect of the absorption enhancing effect. Co-administration of glycofurol leads to enhanced and prolonged absorption of the peptide. Combining the two enhancers did not lead to increased peptide T absorption compared to 5% glycofurol alone.

The viability of isolated rabbit nasal mucosa in the Ussing chamber, and the permeability of insulin across the membrane

The viability of isolated rabbit nasal mucosa (lateral wall) and the permeability of insulin across the membrane have been tested in an Ussing chamber. The short-circuit current (Isc) was relatively stable between 1 and 10 h. Average Isc for this period (Isc,1–10) was 92 ± 13 μA/cm2. The viability of the tissue was longer than 10–12 h, where Isc was about 85 and 66% of Isc,1–10, respectively. During 1–10 h the average potential difference (PD) was 6.4 ± 1.5 mV (mucosal side was negative) and the average tissue resistance (TR) was 69 ± 8 Ω cm2. The appearance of insulin at the serosal side is expressed as ‰ of the initial insulin concentration (8 mg/ml) at the mucosal side. Mean appearance rate was 0.44 ± 0.34‰ h−1, equivalent to an apparent penetration coefficient (Papp) of 0.24 × 10−6 cm/s. The same value, corrected for possible degradation and/or adsorption at the serosal side, is 0.73 ± 0.42‰ h−1 (Papp = 0.4 × 10−6 cm/s). The concentration of insulin at the mucosal side between 5 and 90 min was relatively constant, the average recovery being about 85%. The method is found to be useful for physiological and toxicological studies. Whether it is useful to screen absorption enhancers for peptides remains to be confirmed.

Intranasal permeation of thyrotropin-releasing hormone: in vitro study of permeation and enzymatic degradation

Abstract The enzymatic degradation and permeation of thyrotropin-releasing hormone (TRH) were studied in vitro. No enzymatic degradation was observed in human nasal wash. The degradation rate in rabbit nasal mucosal homogenate and supernatant was about 0.5 μg/h (initial amount 1 μg), but it was possible to reduce the degradation rate by about 90% on the addition of 0.3% sodium glycocholate (GC). The apparent permeability coefficients of TRH over isolated rabbit nasal tissue mounted in the Ussing chamber were 4.94 × 10−6, 12.63 × 10−6, and 3.85 × 10−6 cm/s for an aqueous solution without enhancer, added 1% GC, and added 1% glycofurol 75 (GF), respectively. At the same time, the viability of the tissue in the Ussing chamber was studied by measurement of the electrophysiological properties. Addition of GC, but not GF, changed these properties significantly (p

Intranasal absorption of buprenorphine — in vivo bioavailability study in sheep

The bioavailability of buprenorphine, HCl (BPP) in sheep after nasal administration of two formulations has been studied. 0.9 mg BPP in 150 microl was administered nasally and compared to 0.6 mg i.v. The test solutions were formulated with 30% polyethylene glycol 300 (PEG 300) and 5% dextrose, respectively. The bioavailability for PEG 300 was 70% (S.D.+/-27%, n=6), whereas the bioavailability for 5% dextrose was 89% (S.D.+/-23%, n=6). A two-compartment model with initial and terminal serum half-lives of 10 and 23 min, respectively, may describe the pharmacokinetics. The rate of absorption for both nasal formulations was very fast (t(max)=10 min). The C(max) was 37 ng/ml (S.D.+/-17) and 48 (S.D.+/-10) for PEG 300 and dextrose, respectively. No significant difference was found between the two formulations, but PEG 300 has advantages in relation to freezing point depression and solubility, which may be considered if further studies are going to be initiated. The high nasal bioavailability and short time to maximal plasma concentration suggests that it is possible to make a clinically relevant nasal formulation of BPP for the treatment of pain.

Toxicological and absorption enhancing effects of glycofurol 75 and sodium glycocholate in monolayers of human intestinal epithelial (Caco-2) cells

Abstract The effects of glycofurol 75 (GF) and sodium glycocholate (GC) on the toxicity and permeability of the human intestinal cell line Caco-2 were studied. The intracellular dehydrogenase activity of the cells was used as a measure of the toxicity. Concentrations of GC from approx. 10 mM inhibited the intracellular dehydrogenase activity and above 40 mM the activity was less than 10% of the initial level. The concentrations resulting in 50% inhibition (IC 50 ) were 24.2 mM (1.2%) and 380 mM (6.8%) for GC and GF respectively. GF concentrations of less than 100 mM did not affect the activity. The effects of GF and GC on the absorption of the hydrophilic marker molecule [ 14 C]mannitol were studied at concentration levels corresponding to no (23.7 mM GF and 5.1 mM GC), about 25% (117 mM GC and 17.2 mM GC) and 50% (380 mM GF and 24.2 mM GC) inhibition in dehydrogenase activity. The apparent permeability coefficient for mannitol in control monolayers was 5.7 × 10 −8 cm/s. 5.1 mM GC did not enhance the permeability, whereas 17.2 and 24.2 mM enhanced it significantly ( p −8 cm/s, but varied considerably. 24.2 mM GC enhanced the P app significantly ( p

Intranasal absorption of melatonin in vivo bioavailability study

The bioavailability of melatonin in rabbits after nasal administration of two formulations has been studied. In each case, a total amount of 1.5 mg melatonin in 50 microl was administered and compared with 1.5 mg i.v. The test solutions were formulated with 40% polyethylene glycol 300 (PEG 300), one with 1% sodium glycocholate (+GC) and one without (-GC). The bioavailability for +GC was 94% (S.D.+/-29%, n=4), whereas the bioavailability for -GC was 55% (S.D.+/-17%, n=6). These results indicate that GC has an enhancer effect (P<0.05). However, the relatively high bioavailability without GC shows that it might not be necessary to use an enhancer for a clinical relevant formulation. The pharmacokinetics of melatonin could be described by a one-compartment model, and the serum half-life was about 13 min. The absorption rate for both formulations was very fast (tmax=5 min) and Cmax mean was 493+/-290 ng/ml (n=4) and 249+/-125 ng/ml (n=6) for +GC and -GC, respectively.

Intranasal bioavailability of diazepam in sheep correlated to rabbit and man

The purposes of the present study were to estimate the nasal bioavailability of diazepam in sheep and to compare this to earlier results in rabbits and humans. Additional, to compare the absorption during various initial periods in the two animal models and man, due to the importance of early absorption in emergency treatment. In a cross-over design, diazepam was nasally administered (7 mg) and intravenously (3 mg), respectively, to six sheep. Diazepam was solubilised in polyethylene glycol 300 in the nasal formulation. The mean nasal bioavailability, t(max) and C(max) were 15% (S.D.+/-8), 5 min (S.D.+/-3) and 934 ng/ml (S.D.+/-593), respectively. Sheep bioavailability was lower than rabbit 54% (P<0.001) and man 34% (P<0.05). In conclusion, the nasal absorption of diazepam was found to be fast, indicating the potential of nasal delivery in acute treatment. The initial (30 min) nasal bioavailability (30 min) for sheep and rabbit is a factor of 2.3 lower and 1.6 higher than man, respectively. The correlation of bioavailability was not optimal between sheep, man and rabbit with differences both in relation to extend and rate.