Nidal F. Farraj

Chitosan as a Novel Nasal Delivery System for Peptide Drugs

A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a “pulse-chase” study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.

Nasal administration of gentamicin using a novel microsphere delivery system

Abstract The concept of improving the bioavailability of nasally administered drugs by means of a gelling microsphere delivery system has been investigated in rats and sheep using gentamicin as a model drug. It was found that the combination of gentamicin with the microsphere delivery system increased the uptake of the drug across the nasal membrane. This uptake was further enhanced by incorporation of an absorption enhancer in the form of lysolecithin into the microspheres. In this way the bioavailability for nasally administered gentamicin was increased to about 50% of the i.v. dose as compared to less than 1% for a simple nasal gentamicin solution.

Nasal administration of insulin using bioadhesive microspheres as a delivery system

Abstract The use of the bioadhesive microsphere system for the intranasal delivery of insulin was investigated in sheep. The effect of combining the above system with lysophosphatidylcholine, as a biological absorption enhancer, was also assessed. For comparison, insulin was also administered by the intravenous and subcutaneous routes. The plasma glucose and insulin levels were determined by a glucose oxidase method and a radioimmunoassay, respectively. The bioadhesive system produced large and significant changes in the plasma insulin and glucose levels. The relative bioavailability (± standard error of measurement) of insulin administered with the microsphere system alone was found to be 10.7% (±2.6) and that of insulin administered with the microsphere /enhancer system to be 31.5% (±6.5).

Hyaluronic acid ester microspheres as a nasal delivery system for insulin

Abstract The use of hyaluronic acid ester microspheres for the intranasal delivery of insulin was investigated in sheep. The formulations were based on two types of microspheres produced from the same polymer but using different stabilising agents. Furthermore, the effect of varying the dose of microspheres was also assessed. For comparison, insulin was also administered nasally as a simple solution and subcutaneously as an injectable preparation. Overall, the microsphere system produced large and significant increases in the nasal absorption of insulin similar to what has been obtained for bioadhesive starch microspheres. Generally, the increase in nasal absorption of insulin (AUC and Cmax) achieved by the microsphere system was found to be independent of the dose of microspheres in the range 0.5–2.0 mg/kg. The mean relative bioavailability of the developed system was found to be 11% when compared with insulin administered by the subcutaneous route.

Investigation of the nasal absorption of biosynthetic human growth hormone in sheep—use of a bioadhesive microsphere delivery system

Abstract This paper describes an assessment of the potential of using bioadhesive microspheres as a nasal delivery system for biosynthetic human growth hormone (hGH) in sheep. The microsphere system was used alone and in combination with a biological surfactant, lysophosphatidylcholine (LPC). For comparison, hGH was also administered nasally as a solution and subcutaneously as an injection. The levels of hGH in the blood samples obtained were determined by an ELISA technique. The hGH was absorbed to only a very low extent when administered as a nasal solution. However, the microsphere delivery system without added enhancer was capable of considerably enhancing the nasal absorption of hGH. A delay in absorption was observed with the microspheres alone, which may be partially due to low aqueous solubility of hGH. Rapid and much higher absorption was observed when hGH was administered in combination with the microspheres and LPC as an enhancer.

Nasal Absorption of Desmopressin in Rats and Sheep. Effect of a Bioadhesive Microsphere Delivery System

Abstract— The nasal absorption of desmopressin was studied in two animal models, the rat and the sheep. The bioavailability after nasal administration was found to be 13 times higher in the rat model. This discrepancy is suggested to be due to the impaired mucociliary clearance mechanism in the rat model and possibly differences in enzymatic degradation and elimination rates of the drug. The effect of the addition of L‐α‐lysophosphatidylcholine (LPC) to the formulations as an absorption enhancer was most pronounced in the sheep model. The use of the bioadhesive starch microsphere delivery system, especially in combination with LPC, had a profound effect on the absorption of desmopressin in sheep, with bioavailabilities reaching nearly 10% compared with 1·2% for a simple nasal solution of desmopressin.

Nasal Absorption Enhancers for Biosynthetic Human Growth Hormone in Rats

The effects of several prospective absorption enhancers were assessed on the nasal absorption of biosynthetic human growth hormone (hGH) in the rat. These enhancers function by alternative mechanisms that include enzyme inhibition, reduction in mucus viscosity, and enhancement of membrane fluidity. The levels of plasma hGH achieved were determined by an enzyme-linked immunosorbent assay. The increase in peak height was calculated relative to nasal administration of hGH alone without any enhancers and the relative bioavailability was calculated with reference to subcutaneous injection data. A lysophospholipid, lysophosphatidylcholine, gave the highest peak concentration, with an increase in peak height of 450% and a relative bioavailability of 25.8%. However, the greatest increase in AUC (291%) was achieved with the aminopeptidase inhibitor, amastatin, which gave a relative bioavailability of 28.9%. A mucolytic agent, N-acetyl-L-cysteine, and a transmembrane fatty acid transporter, palmitoyl-DL-carnitine, were also found to promote the nasal absorption of hGH in this model, with relative bioavailabilities of 12.2 and 22.1%, respectively. Bestatin, an enzyme inhibitor, was not an effective absorption enhancer for hGH in this model.

Enhanced nasal absorption of insulin in rats using lysophosphatidylcholine

Abstract The effectiveness of l -α-lysophosphatidylcholine (LPC) as an enhancer for the nasal delivery of large peptide drugs was investigated in rats using insulin as a model drug. Intranasal insulin (16.7 IU/kg) solutions in combination with 0.5% of this enhancer produced a 65% decrease in blood glucose levels, which was similar to the decrease obtained using laureth-9 as a known enhancer. The two main constituents of LPC, namely, the palmitoyl component (72%) and the stearoyl component (24%) produced similar effects, at a concentration of 0.5%, to that of LPC, thus indicating that both of these lysophospholipids are equally potent absorption enhancers with potential in nasal delivery.

Gamma-scintigraphy as a novel method to study the distribution and retention of a bioadhesive vaginal delivery system in sheep

Abstract The distribution and the retention time of a novel bioadhesive intravaginal delivery system based on HYAFF microspheres were studied in a sheep model. In a preliminary experiment, the vagina of the ewe was outlined by gamma scintigraphy following vaginal administration of a radiolabelled gel and this data was used as a reference for subsequent evaluation of the distribution of bioadhesive vaginal formulations. Technetium-labelled HYAFF microspheres were administered intravaginally, either as a dry powder or suspended in a vaginal pessary, and the intensity and distribution of radioactivity in the genital tract was determined for a period of 12 h. With both HYAFF formulations, the radiolabelled microspheres were dispersed along the length of the vagina and were retained at this site for the duration of the study. Twelve hours after administration, between 60 and 80% of the radioactivity remained within the vagina with retention of the microspheres being slightly higher for the dry powder formulation than for the vaginal pessary. Importantly, there was no indication of movement of the microspheres from the vagina to the upper levels of the genital tract. These studies further demonstrated the potential of HYAFF microspheres as a long-acting intravaginal delivery system and illustrated the utility of the sheep model and the gamma-scintigraphy methodology for a direct assessment of the distribution, spreading and retention time of bioadhesive formulations.

Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption of insulin and histopathology of nasal membrane

Abstract An in vivo rat model was used to study the nasal absorption of insulin in the presence of selected enhancers (Laureth 9, glycodeoxycholate and L-α-lysophosphatidylcholine) either alone or in combination with 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin. All the enhancers when administered alone with insulin produced about 50% decrease in the blood glucose concentrations, an indirect measure of the absorption of insulin across the rat nasal mucosa. In the presence of cyclodextrins the enhancing effect of L9 was maintained, whereas that of GDC and LPC was considerably reduced, but the duration of action of insulin was prolonged. Concomitantly, the histological effect of these agents on the rat nasal epithelium was studied using a perfusion fixation technique. The absorption of insulin did not consistently correlate with the histological observations and the results obtained in previous haemolysis studies. However, the histological and haemolysis observations complemented each other in that the formulations [L9:HPβC (1:4), GDC:γ-CD (1:2) and LPC:HPβC (1:12)] which caused the least damage to the spithelial membrane had been shown to completely prevent haemolysis. In conclusion, the combination of L9 and possibly LPC with cyclodextrins may provide formulations which have almost the required balance between activity and safety, for nasal delivery of insulin and could possibly be used as an adjunct to subcutaneous therapy.