Enhancement of dissolution rate and bioavailability of aceclofenac: A chitosan-based solvent change approach

https://doi.org/10.1016/j.ijpharm.2007.09.006Get rights and content

Abstract

In this study the significant effect of chitosan on improving the dissolution rate and bioavailability of aceclofenac has been demonstrated by simple solvent change method. Chitosan was precipitated on aceclofenac crystals using sodium citrate as the salting out agent. The pure drug and the prepared co-crystals with different concentrations of chitosan (0.05–0.6%) were characterized in terms of solubility, drug content, particle size, thermal behaviour (differential scanning calorimetry, DSC), X-ray diffraction (XRD), morphology (scanning electron microscopy, SEM), in vitro drug release and stability studies. The in vivo performance was assessed by preclinical pharmacodynamic (analgesic and anti-inflammatory activity) and pharmacokinetic studies. The particle size of the prepared co-crystals was drastically reduced during the formulation process. The DSC showed a decrease in the melting enthalpy indicating disorder in the crystalline content. The XRD also revealed a characteristic decrease in crystallinity. The dissolution studies demonstrated a marked increase in the dissolution rate in comparison with pure drug. The considerable improvement in the dissolution rate of aceclofenac from optimized crystal formulation was attributed to the wetting effect of chitosan, decreased drug crystallinity, altered surface morphology and micronization. The optimized co-crystals exhibited excellent stability on storage at accelerated conditions. The in vivo studies revealed that the optimized crystal formulation provided a rapid pharmacological response in mice and rats besides exhibiting improved pharmacokinetic parameters in rats.

Introduction

The rate of absorption and bioavailability of poorly water-soluble drugs is often controlled by the rate of dissolution of the drug in the gastrointestinal tract. Many technological methods of enhancing the dissolution characteristics of slightly water-soluble drugs have been reported in various literatures (Moneghini et al., 2001). These include reducing particle size to increase surface area (Nijlen et al., 2003), solubilization in surfactant systems, formation of water-soluble complexes, use of pro-drug, drug derivatization and manipulation of solid state of drug substance to improve drug dissolution, i.e. by decreasing crystallinity of drug substance (Nokhodchi, 2005). Recently, natural polymers such as polysaccharides and proteins have received much attention in the pharmaceutical field owing to their good biocompatibility and biodegradability (Imai et al., 1991, Zhang et al., 2002, Cai et al., 2005). Among polysaccharides, chitosan has been considered to be one of the most promising biopolymer for drug delivery purposes. Chitosan (β-(1-4)-2-amino-2-deoxy-d-glucose) is a linear hydrophilic polysaccharide polymer of d-glucosamine. It is a non-toxic natural poly cationic polymer that is degraded by the microflora in the colon. It is abundant in nature and is present in the exoskeleton of crustaceans such as crabs and shrimp (Fukuda et al., 2006). Chitosan, being a cationic polysaccharide in neutral or basic pH conditions, contains free amino groups and hence, it is insoluble in water. In acidic pH, amino groups can undergo protonation thus, making it soluble in water. It breaks down slowly to harmless products (amino sugars), which are completely absorbed by the human body (Agnihotri et al., 2004). Chitosan has been demonstrated to be a good vehicle for enhancing the dissolution properties and bioavailability of a number of poorly water-soluble drugs (Portero et al., 1998). Low molecular weight chitosan can function as drug release enhancers for poorly water-soluble drugs due to an improvement in wettability resulting from the solubility of low molecular weight chitosan in water (Fukuda et al., 2006).

Aceclofenac (2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid) is an orally effective non-steroidal anti-inflammatory drug (NSAID) of the phenyl acetic acid group, which possesses remarkable anti-inflammatory, analgesic and antipyretic properties (British Pharmacopoeia, 2005, Parfitt, 1999). The analgesic efficacy of aceclofenac 100 mg is more prolonged than that of acetaminophen 650 mg. Aceclofenac appears to be particularly well-tolerated among the NSAIDs, with a lower incidence of gastrointestinal adverse effects (Gowda et al., 2006).

Aceclofenac exhibits very slight solubility in water and as a consequence it exhibits low bioavailability after oral administration (Lee and Jung, 1999, Kim et al., 2001). Therefore, the improvement of aceclofenac dissolution from its oral solid dosage forms is an important issue for enhancing its bioavailability and therapeutic efficacy. In an earlier study, we have reported the enhancement in the dissolution rate and in vivo effectiveness of aceclofenac when prepared in the form of spherical agglomerates (Mutalik et al., 2007a). The solid systems for several drugs using chitosan have been reported with solid dispersions, co-ground mixture and solid complexes, physical mixture and co-ground products and spray dried products at different ratios (Portero et al., 1998, Hel et al., 1999, Mura et al., 2003, Maestrelli et al., 2004, Kumar and Mishra, 2006). There are hardly any reports on the improvement of dissolution rate and bioavailability of poorly water-soluble drugs by precipitation of chitosan using a simple solvent change method. Hence the objectives of present study were (i) to assess the feasibility of chitosan in enhancing the solubility and dissolution rate of acelofenac by preparing its co-crystals using solvent change method and (ii) to evaluate the in vivo performance of optimized co-crystals with respect to pharmacodynamics and pharmacokinetics in animal models.

Section snippets

Materials

Aceclofenac was obtained as gift sample from Lupin Research Park, Pune, India. Chitosan (from crab shells; minimum 85% deacetylated) and Tween-80 (Specific gravity: 1.07 at 25 °C; HLB value: 15.0; critical micellar concentration: 13–15 mg/L; viscosity: 400–620 cps at 25 °C) were purchased from Sigma–Aldrich, MO, USA. Hydrochloric acid (35–38%) and glacial acetic acid (99.5%) were purchased from Labort Fine Chem Pvt. Ltd., Surat, India and Qualigens Fine Chemicals, Mumbai, India, respectively.

Results and discussion

The solubility, dissolution behaviour and permeability of a drug are the key determinants of its oral bioavailability. The solubility data of aceclofenac reveals that it is poorly soluble in water. Therefore, the improvement of aceclofenac dissolution from its oral solid dosage forms is of great concern.

Conclusion

The present study demonstrated a successful and simple method to prepare aceclofenac-chitosan crystals to enhance its aqueous solubility and dissolution rate. The prepared crystals also exhibited exceptional stability and better in vivo performance in comparison with pure drug. If this process can be scaled-up to manufacturing level, this technique has the potential to develop into an invaluable technology in future.

Acknowledgements

Authors are thankful to Lupin Research Park, Pune, India for the gift samples of aceclofenac and other excipients. They are grateful to Dr. K. Narayana Prabhu, NITK, Suratkal, Karnataka, India for his kind help and co-operation in SEM studies.

References (37)

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