Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide and insulin

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Abstract

Novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) have recently been developed in our laboratory. In this report the following issues were studied: release of the peptide drugs buserelin, octreotide and insulin from SPH and SPHC polymers and the developed delivery systems, stability of these peptides during the release and the integrity of insulin in the polymeric matrix of SPHC. Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer. All peptides studied in contact with SPHC polymer were stable under different environmental conditions (ambient temperature, 37 °C, light and darkness and at pH values 3.2 and 7.2). FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. Release profiles of all peptides from the developed delivery systems showed a time-controlled release profile: after a short lag time of 10–15 min, a burst release of peptides occurred during which more than 80% of peptide was released within 30–45 min. In conclusion, the present delivery systems based on SPH and SPHC show appropriate in vitro properties for application in peroral peptide drug delivery of buserelin, octreotide and insulin, and are therefore promising for further in vivo evaluation.

Introduction

Many novel drug delivery systems have been developed during the last decades for peptide delivery due to the rapid progress in biotechnology, resulting in the ample availability of hydrophilic macromolecular drugs such as (poly)peptides, proteins, and polysaccharides (Maeda et al., 1999, Yoshino, 1993). This has encouraged researchers to investigate possible routes of administration for delivery of this category of drugs including peroral administration, which is still the most convenient route for patients (Lee and Amidon, 1995, Luessen et al., 1994).

A serious problem in the delivery of macromolecular and hydrophilic drugs is the inefficient absorption of these compounds across mucosal membranes. Generally, such molecules are unable to cross the enterocytes if administered to the GI tract or to other absorptive epithelia like buccal, vaginal, and nasal mucosae due to their high molecular weight. Therefore, if at all, they are mainly absorbed via the paracellular pathway (Bai et al., 1995). Recent studies with drugs such as insulin, vasopressin, and heparin have shown that the mucosal absorption of these compounds can be substantially increased after coadministration with absorption enhancers. These absorption enhancing materials include enzyme inhibitors, mucoadhesive polymers, and compounds which are able to open the intercellular tight junctions (Luessen et al., 1996). In addition, new advanced polymer technologies play an important role in developing appropriate formulations for such hydrophilic compounds, resulting in novel drug delivery systems (Okuyama et al., 1993, Wang and Wu, 1997).

Since the most desired and convenient way of drug delivery is oral administration, numerous efforts have been undertaken in the development of appropriate oral dosage forms for peptide drugs. Despite significant advances, there are merely a few products on the market such as desmopressin (Fjellestad-Paulsen et al., 1993). It has been reported that transient inactivation of proteolytic enzymes and reversible opening of tight junctions are key factors for effective absorption of large hydrophilic molecules such as peptides which are sensitive to enzymatic cleavage (Bai et al., 1995, Kotzé et al., 1999). Most peptide drugs have a very short half-life in the GI tract, so rapid release and absorption is essential for achieving significant and effective plasma levels (Fasano, 1998, Luessen et al., 1996, Pappenheimer et al., 1994). Another important factor for improved bioavailability of these hydrophilic drugs is keeping the dosage form at specific site(s) of drug absorption, for which mucoadhesive polymers have been aimed at for prolongation of the residence time of delivery systems in the gut and for intensified contact with intestinal membranes (Bai et al., 1995, Lehr, 1994, Luessen et al., 1995). However, the sole use of mucoadhesion failed to prolong the intestinal residence time in vivo. Another possibility to prolong the residence time of dosage forms is by mechanical interaction of the delivery system with the gut wall. Recently, we have developed novel delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC), which are able to achieve mechanical fixation of the dosage form at desirable site(s) of absorption in the intestine by controlled rapid swelling (Dorkoosh et al., 2001). SPH and SPHC are a new generation of hydrogels, which are able to swell within a couple of minutes by absorbing a large amount of water due to their highly porous structure (Dorkoosh et al., 2000, Park et al., 1998). This delivery system has been designed as two types, i.e. (1) core inside the conveyor system and (2) core attached to the surface of the conveyor system (Dorkoosh et al., 2001). Since these systems are based on novel SPH and SPHC polymers, it is essential to investigate the release of peptide drugs from these polymers, to study the release pattern of peptides from both types of delivery systems and to evaluate the stability of peptides in contact with SPH and SPHC polymers during the release studies.

In this study, various peptide drugs with different molecular weights (buserelin, octreotide and insulin) were used to further characterize SPH- and SPHC-based delivery systems for their peptide release properties and peptide drug stability.

Section snippets

Chemicals

Buserelin and human insulin were kindly donated by Aventis Research and Technologies (Frankfurt, Germany), and octreotide acetate by Novartis Pharma (Basel, Switzerland). PEG 6000 (polyethylene glycol) was obtained from Fluka (Zwijndrecht, The Netherlands). Histoacryl® (super-glue) was from B. Braun Surgical (Melsungen, Germany). MQ water used was filtered by a Milli-Q UF plus ultrapure water system from Millipore (Etten-Leur, The Netherlands). All other materials were of analytical grade.

Peptide loading and release studies using SPH and SPHC polymers

SPH

Release of peptides from SPH and SPHC polymers

The results of buserelin and octreotide release from SPH and SPHC polymers showed that the release rate from SPH was slightly higher than from SPHC; more than 80% of peptides was released from SPH during the first 15 min, whereas from SPHC polymer it took 30 min (Fig. 1A). The remaining 20% of both peptide drugs were released up to the end of experiments (120 min) for both polymers.

In the case of insulin, the amount of peptide released from both SPH and SPHC polymer within the first 10 min was

Discussion

The interaction of peptides and proteins with polymeric matrices may be a major issue when they are formulated as a solid dosage form. The stereochemical structure of peptides and proteins should remain intact during the formulation in order to fully achieve the desired therapeutic effect. Moreover, it is important to determine how much of the peptide will be released from the delivery system in order to check the release kinetics and to choose the appropriate dose of peptide drug in the

Conclusion

From the present studies it is confirmed that buserelin, octreotide and insulin do not bind chemically to SPH and SPHC polymers. The release rate from the polymers is controlled by the swelling rate and pore size of the two polymers, i.e. a slightly quicker peptide release was found from SPH in comparison with SPHC. All peptides were found to be stable during release from SPHC polymer under various environmental and pH conditions. Moreover, FTIR studies showed that insulin, after loading in the

Acknowledgments

The authors would like to thank Aventis Research and Technologies (Frankfurt, Germany) for financial support in performing these studies and Ms. S.S. Khokhar for her technical assistance. They are also grateful to Mr. G.A. van Albada (Leiden Institute of Chemistry, Leiden University, The Netherlands) for his support in the FTIR studies.

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