New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs

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Abstract

The purpose of this study was to develop a novel clopidogrel napadisilate-loaded solid dispersion with improved stability and bioequivalence to the clopidogrel bisulphate-loaded commercial product. Clopidogrel napadisilate prepared in this study appeared as a white crystalline powder unlike clopidogrel base. However, this salt did not improve the solubility of clopidogrel, even with improved stability compared to clopidogrel bisulphate. To improve the solubility of clopidogrel napadisilate, a novel clopidogrel napadisilate-loaded solid dispersion was prepared by the spray-drying technique using HPMC and colloidal silica, and the physicochemical properties, dissolution and bioavailability in beagle dogs were evaluated compared to the clopidogrel bisulphate-loaded commercial product. The solid dispersion composed of clopidogrel napadisilate, HPMC and colloidal silica at a weight ratio of 11.069/3/3.5 improved solubility by 6.5-fold compared to clopidogrel napadisilate, even if it did not improve drug solubility compared to clopidogrel bisulphate. However, unlike clopidogrel bisulphate, this formulation improved the stability of clopidogrel. Furthermore, the clopidogrel napadisilate solid dispersion-loaded tablet showed similar dissolution to the clopidogrel bisulphate-loaded commercial product and was bioequivalent to the commercial product in beagle dogs. Thus, this clopidogrel napadisilate-loaded solid dispersion could be a promising candidate for improving the stability and bioavailability of clopidogrel.

Graphical abstract

Stability (A) and pharmacokinetics (B and C) of clopidogrel bisulphate (commercial salt) and clopidogrel napadisilate-loaded solid dispersion; (B) clopidogrel; (C) SR26334.

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Introduction

Clopidogrel [methyl(+)-(S)-alpha-(o-chlorophenyl)-6,7-dihydrothieno[3,2-a]pyridine-5(4H)-acetate] (Fig. 1) is a routine component of the clinical management of patients after acute coronary syndrome, in whom it has been reported to reduce rates of major cardiovascular adverse events (Diener et al., 2005, Fox and Chelliah, 2007). It is approved for the reduction of atherosclerotic events in patients with stroke, myocardial infarction, cardiovascular disease and acute coronary syndrome. Its action may be related to an adenosine diphosphate (ADP) receptor on platelet cell membranes (Antić et al., 2007, Savi et al., 2006). It specifically and irreversibly inhibits the platelet P2Y12 subtype of the ADP receptor, which is important in the aggregation of platelets and cross-linking by the protein fibrin. As a result, activation of the glycoprotein IIb/IIIa complex, which is involved in platelet activation and stabilisation of the platelet aggregate, is also inhibited (Park et al., 2010a, Park et al., 2010b, Shim et al., 2010).

Clopidogrel, a prodrug, has no activity in itself. To exert its anti-aggregatory effect, it requires biotransformation into its active metabolite, 2-oxo-clopidogrel by the hepatic cytochrome P450. Furthermore, the other active metabolite, a thiol derivative, is formed by subsequent hydrolysis of 2-oxo-clopidogrel. Mostly, carboxylesterase converts clopidogrel to an inactive carboxylic acid metabolite, clopidogrel carboxylic acid derivative [(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid; SR26334] (Antić et al., 2007, Savi et al., 2006, Silvestro et al., 2010). Following oral administration in humans, the plasma levels of clopidogrel are very low due to extensive metabolism and are difficult to quantify. Furthermore, the active metabolites such as 2-oxo-clopidogrel and the thiol derivative are highly labile and remain undetected in plasma. Thus, neither the parent drug nor the active metabolite is detected in plasma. However, the main circulating metabolite (the carboxylic acid derivative; SR26334) represents 85% of the circulating metabolites in plasma, even if it is pharmacologically inactive. Thus, the quantification of the inactive carboxylic acid metabolite of clopidogrel, which is the most abundant species circulating in the blood, has emerged as an indirect approach for studying the pharmacokinetics of clopidogrel (Mitakos and Panderi, 2002, Silvestro et al., 2010, Singh et al., 2005).

Clopidogrel base has not been used as a commercial drug, since it is an oil phase which is difficult to purify and handle. Thus, clopidogrel bisulphate, a salt form, has been mainly used in a commercial product (Plavix®; Sanofi-Aventis Korea Co.) because of its crystalline form and improved solubility of about 90 mg/ml (Di Girolamo et al., 2010, El Ahmady et al., 2009). However, this commercial drug has been reported to be unstable under accelerated moisture and heat condition, resulting in the production of significant amounts of degradants (Gomez et al., 2004, Raijada et al., 2010, Skillman et al., 2010). At accelerated conditions of 40 °C/75%RH, the compound is hydrolyzed to the hydrolyzed degradant, which has no biological activity. Moreover, it can be transformed into the isomer, racemized degradant with much less pharmacological activity (Mitakos and Panderi, 2002, Mitakos and Panderi, 2004). Thus, another salt must be developed in order to improve the stability and bioavailability of clopidogrel.

Section snippets

Materials

Clopidogrel base was obtained from Hanmi Pharm. Co. (Hwasung, South Korea). Hydroxypropylmethylcellulose (HPMC 2910) was purchased from Shin-Etsu Co. (Tokyo, Japan). d-Mannitol, crospovidone, colloidal silica and sucrose ester of fatty acid supplied by Hanmi Pharm. Co. (Hwasung, South Korea) were of USP grade. The commercial product (Plavix®; in tablet form) was purchased from Sanofi-Aventis Korea Co. (Seoul, South Korea). All other chemicals were of reagent grade and were used without further

Clopidogrel napadisilate

Clopidogrel base is very unstable, and appears as an oil form which is difficult to purify and handle. Thus, its ester salt, clopidogrel bisulphate, has been used as a commercial drug. The aqueous solubility of clopidogrel bisulphate is about 90 mg/ml, which indicated that this salt was water-soluble (Di Girolamo et al., 2010, El Ahmady et al., 2009). As shown in Fig. 2, the solubility of clopidogrel bisulphate in the medium was in the order of pH 6.8 < pH 4.0 < water < pH 1.2. In particular, the

Conclusion

In conclusion, the clopidogrel napadisilate-loaded solid dispersion composed of clopidogrel napadisilate, HPMC and colloidal silica at a weight ratio of 11.069/3/3.5 improved the solubility of clopidogrel napadisilate, even if it did not improve drug solubility compared to clopidogrel bisulphate. However, unlike clopidogrel bisulphate, this formulation improved the stability of clopidogrel. Furthermore, the clopidogrel napadisilate solid dispersion-loaded tablet showed similar dissolution to

Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2010-0000363) and by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A092018).

References (35)

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