Development and characterization of a gastroretentive dosage form composed of chitosan and hydroxyethyl cellulose for alendronate

Abstract

In this study, alendronate, the most commonly used biphosphonate for treating osteoporosis, was formulated as gastroretentive dosage form (GRDF) tablets to enhance its oral bioavailability. GRDF tablets were characterized with the effects of different molecular weights (MWs) of chitosan (CS) and hydroxyethyl cellulose (HEC) at various ratios on swelling, floating, and physical integrity. The CS component was formed using various acids: acetic, lactic, malic, succinic, and citric, and a high viscosity grade of HEC was selected. The results demonstrated that the swelling ratios of the formulations comprising high MW CS were lower than those of low or medium MW CS when salts were formed with any countering acids except for acetic acid. The decreasing ranking of the swelling rates was: CS-citrate > CS-malate > CS-lactate > CS-succinate > CS-acetate. A negative correlation was found between the pKa of the respective countering acid and the swelling rate. The swelling rate was promoted if an acidic salt of CS with a lower water content was incorporated, while it became slower when tablet hardness was higher or the compression force to form tablets was increased. Although HEC did not contribute to swelling or floating, it played a role in maintaining structural integrity. A prolonged dissolution profile of alendronate GRDF tablets developed in this study was observed.

Keywords: alendronate; chitosan; gastroretentive dosage form; hydrogel; hydroxyethyl cellulose; swelling.

Figure 1

Swelling ratio of different HEC ratios to (A) LCS-acetate; (B) LCS-lactate; (C) LCS-malate; (D) LCS-succinate; and (E) LCS-citrate in simulated gastric fluid. Abbreviations: A, acetic acid; L, lactic acid; M, malic acid; S, succinic acid; C, citric acid; LCS, chitosan 50–190 kDa; HEC, hydroxyethyl cellulose.

Figure 2

Swelling ratio of different HEC ratios to (A) MCS-acetate; (B) MCS-lactate; (C) MCS-malate; (D) MCS-succinate; and (E) MCS-citrate in simulated gastric fluid. Abbreviations: A, acetic acid; L, lactic acid; M, malic acid; S, succinic acid; C, citric acid; MCS, chitosan 190–310 kDa; HEC, hydroxyethyl cellulose.

Figure 3

Swelling ratio of different HEC ratios to (A) HCS-acetate; (B) HCS-lactate; (C) HCS-malate; (D) HCS-succinate; and (E) HCS-citrate in simulated gastric fluid. Abbreviations: A, acetic acid; L, lactic acid; M, malic acid; S, succinic acid; C, citric acid; HCS, chitosan 310–375 kDa; HEC, hydroxyethyl cellulose.

Figure 4

Swelling ratio of chitosan with various molecular weights dissolved in various acids.

Figure 5

Hardness of tablets formulated with (A) LCS and (B) MCS. Abbreviations: A, acetic acid; S, succinic acid; C, citric acid; LCS, chitosan 50–190 kDa; MCS, chitosan 190–310 kDa; HEC, hydroxyethyl cellulose.

Figure 6

The correlation between MCS(1)-HEC(0.1)-acetate/MCS(1)-HEC(0.1)-succinate/MCS(1)-HEC(0.1)-citrate and slope (♦), water content (■), hardness (▲), and pK_a(•). Abbreviations: MCS, chitosan 190–310 kDa; HEC, hydroxyethyl cellulose.

Figure 7

Swelling ratio of (A) LCS-acetate, (B) LCS-succinate, and (C) LCS-citrate, with various ratios of HEC compressed at 0.5, 1, and 1.5 tons. Abbreviations: A, acetic acid; S, succinic acid; C, citric acid; LCS, chitosan 50–190 kDa; HEC, hydroxyethyl cellulose.

Figure 8

Swelling ratio of (A) MCS-acetate, (B) MCS-succinate, and (C) MCS-citrate, with various ratios of HEC compressed at 0.5, 1, and 1.5 tons. Abbreviations: A, acetic acid; S, succinic acid; C, citric acid; MCS, chitosan 190–310 kDa; HEC, hydroxyethyl cellulose.

Figure 9

Dissolution profile of (A) CS-acetate, (B) CS-succinate, and (C) CS-citrate. Abbreviations: CS, chitosan; A, acetic acid; S, succinic acid; C, citric acid; LCS, chitosan 50–190 kDa; MCS, chitosan 190–310 kDa; HEC, hydroxyethyl cellulose.