Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides

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Abstract

This paper investigates the effect of starch microspheres on the absorption enhancing efficiency of various enhancer systems in formulations with insulin after application in the nasal cavity of sheep. The enhancers studied were lysophosphatidylcholine, glycodeoxycholate and sodium taurodihydroxyfusidate, a bile salt derivative. The enhancers were selected on the basis of their perceived or proven mechanism of action and worked predominantly by interacting with the lipid membrane. The bioadhesive starch microspheres were shown to increase synergistically the effect of the absorption enhancers on the transport of the insulin across the nasal membrane. Dependent on the potency of the enhancer system the increment in absorption enhancement was shown to be from 1.4 times to 5 times that obtained for the absorption enhancer in solution.

Introduction

It has been established that bioadhesive systems based on microspheres are able to increase significantly the systemic absorption of conventional drugs as well as polypeptides across the nasal membrane without the use of absorption enhancing agents that have the potential for irritation or damage (Illum, 1998). Hence, Illum et al. (1994) investigated the use of hyaluronic acid ester microspheres as a nasal delivery system for insulin and found that the mean relative bioavailability obtained in sheep was 11%, compared to 1.2% for a simple nasal insulin solution. Pereswetoff-Morath and Edman, 1995, Pereswetoff-Morath and Edman, 1996 and Pereswetoff-Morath et al. (1996) studied the effect of particle size and swellability of dextran microspheres for the improved nasal absorption of insulin in rats. They also showed that the microspheres were non-immunogenic and non-toxic, and conducted measurements of cilia beat frequency (rat tracheal rings) and histology studies (rat nasal mucosa). Similar microspheres were used by Cornaz et al. (1996) for improving the nasal absorption of nicotine. El-Shafy et al. (2000) studied the nasal absorption of the model material FITC-dextran in combination with various bioadhesive formulations to include chitosan and carbopol.

A range of studies has been performed on starch microspheres as a nasal delivery system for polar small molecules and for peptides and proteins. Illum et al. (1988) found that the bioavailability of gentamicin was increased ten fold when administered nasally in combination with starch microspheres as a freeze dried powder formulation in sheep. Similarly, the nasal absorption of insulin was increased five fold when given with starch microspheres as compared to a simple insulin solution in sheep (Farraj et al., 1990) and the bioavailability of the same drug was increased 30 fold in rats over a solution control when using the microsphere option (Bjork and Edman, 1988, Bjork and Edman, 1990). Morphological examination of the rabbit nasal mucosa after the nasal administration of starch microspheres for up to 8 weeks has shown that the system can be considered to be biocompatible and not induce serious histopathological changes in the nasal mucosa (Bjork et al., 1991).

The mechanism of action of the bioadhesive starch microsphere system can be explained as follows: Firstly, deposition of the starch microsphere formulation in the anterior part of the nasal cavity where none or only few cilia are present. The drug-microsphere system is then presented slowly to the absorptive regions of the nose. Secondly, the formulation is retained in the nasal cavity for an extended time period due to its bioadhesive nature. Thirdly, the gelled system provides a local high drug concentration in close contact with the epithelial absorptive surface. Finally, the absorption of water by the microspheres from the mucus layer as it hydrates and gels could affect the passage of the drug through the paracellular tight junctions (Illum, 1991, Edman et al., 1992, Bjork et al., 1995).

For polypeptides, in excess of 6000 Da, the absorption enhancing effect of the bioadhesive system is not normally sufficient to provide clinically relevant plasma levels but Illum et al. (1988) and Farraj et al. (1990) have shown that the bioadhesive microsphere system can be combined with biological absorption promoters such as lysophospholipids to form effective nasal delivery systems. Hence, l-α-lysophosphatidylcholine when administered nasally in combination with insulin in sheep gave a bioavailability of 5.9% (relative to subcutaneous administration) but this increased to 31.5% when administered with insulin in a freeze dried starch microsphere formulation (Farraj et al., 1990). Lysophospholipids are metabolites of phospholipids and are natural constituents of cell membranes (Stafford & Dennis, 1988). They are surfactant-like molecules and their mode of action in enhancing the transport of drugs across the nasal membrane are considered to be a combination of a mucolytic effect, changes in the physicochemical properties of the cell membrane lipid bilayer and possibly the opening of tight junctions between the cells (Martin et al., 1978, Martin et al., 1992, El-Hariri et al., 1991, Ropke et al., 1996, Marttin et al., 1995). Dependent on their nature (eg the chain length of the fatty acid side chains) the lysophospholipids can be categorised as mild enhancers with little or no toxic effect on the nasal membrane in vivo (Chandler et al., 1991).

The purpose of the present work was to evaluate the influence of the bioadhesive microsphere system on the nasal absorption enhancing effect of lysophosphatidylcholine (LPC) and two other well known absorption enhancing agents, the bile salt sodium glycodeoxycholate (GDC) and the bile salt derivative sodium taurodihydroxyfusidate (STDHF). The last two enhancer systems have been shown to enhance greatly the nasal absorption of polypeptides such as insulin, growth hormone and calcitonin in animal models and in man (Duchateau et al., 1986, Deurloo et al., 1989, Moses et al., 1983, Wearley, 1991), whereas LPC has been shown to be a less effective enhancer when given nasally as a solution with insulin (Farraj et al., 1990) or with human growth hormone (Fisher et al., 1991). For both GDC and STDHF the mode of action is considered to be a combination of enzyme inhibition, mucolytic activity, an interaction with the lipid bilayer of the cell membrane and possibly the opening of tight junctions (Duchateau et al., 1986, Duchateau et al., 1987, Ennis et al., 1990, Shao and Mitra, 1992, Marttin et al., 1995, Marttin et al., 1996).

In the present work, the different enhancer systems were administered nasally to sheep with insulin either in solution or as a freeze-dried microsphere formulation on an identical mg/kg body weight basis. Insulin was chosen as a model polypeptide drug since it has a suitable molecular weight, it is a good candidate for nasal delivery and the effect of the drug on the blood glucose level and the plasma insulin levels are readily detectable.

Section snippets

Materials

Semi-synthetic sodium-human insulin (SHI) was obtained from Novo-Nordisk A/S, Denmark. Sodium glycodeoxycholate and lysophosphatidylcholine were purchased from Sigma Chemical Company (Poole, Dorset, UK) and used as supplied. Sodium taurodihydrofusidate was kindly provided by California Biotechnology (CA). All other chemicals were of reagent grade. Degradable starch microspheres 24/45 (DSM) manufactured by emulsion polymerisation of hydrolysed potato starch was obtained from Kabi Pharmacia A/B

Results and discussion

The effect of GDC at a dose of 0.08 mg/kg on the transport of insulin across the nasal membrane after administration as a solution and as a bioadhesive starch microsphere powder formulation in sheep in terms of the resultant plasma glucose levels is shown in Fig. 1. The decreases in glucose levels were 40% for the GDC solution formulation and 55% for the bioadhesive GDC microsphere formulation. For both systems the minimum glucose levels were reached within 50 min. Hence, the biological effect

Acknowledgements

The authors would like to acknowledge the help of other personnel at West Pharmaceutical Services in performing the animal studies.

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