Category: Formulation and Quality
Purpose: Aceclofenac (AC), a BCS class II non-steroidal anti-inflammatory drug shows dissolution-rate limited absorption which may lead to variable bioavailability and difficulty in formulating to maximum oral absorption. Inclusion complexation of poorly water soluble drug employing cyclodextrins is one of the potential approaches for dissolution and bioavailability enhancement of poorly soluble drugs. The purpose of present investigation was to study in vitro dissolution and assess various pharmacokinetic parameters of immediate release (IR) AC tablets incorporating its inclusion complex with hydroxypropyl-β-cyclodextrin (HPβCD).
Methods: The IR tablets were formulated by direct compression incorporating previously characterized kneaded inclusion complex of AC:HPβCD in 1:1 molar ratio (TKN)1,2 and pure drug (TAC); and evaluated for hardness, friability, uniformity of weight, assay, disintegration test. In vitro dissolution tests were performed using USP 23 type II dissolution apparatus at 37°C and 100 rpm in phosphate buffer pH 7.5 (900 ml), analyzed spectrophotometrically at 275 nm, and compared with three marketed AC tablet brands (100 mg). The dissolution data were treated to obtain various model independent parameters and select one brand for pharmacokinetic studies (MKT).
The pharmacokinetic study was carried out on male Wistar rats (weighing 200–250 g) as per the preclinical study protocol approved by the Institutional Animal Ethical Committee. The overnight-fasted rats were divided and treated in three groups (n=3) as Group I: pure aceclofenac (10 mg/kg) in 0.5% CMC; p.o.; Group II: powdered marketed aceclofenac tablet formulation (10 mg/kg) in 0.5% CMC; p.o.; Group III: powdered formulated tablet containing aceclofenac inclusion complex (10 mg/kg) in 0.5% CMC; p.o. Blood samples (0.2 ml) were withdrawn through the jugular vein into heparinized tubes at predetermined time intervals, plasma was separated immediately using cold centrifugation at 2500 rpm for 20 min and stored at −20°C until analysis. A HPLC method used to quantify AC in plasma was validated for accuracy, precision, linearity, level of detection, level of quantification. The pharmacokinetic parameters were directly determined by the standard compartmental model of independent analysis. The maximum plasma concentration (Cmax) and time to peak plasma concentration (tmax) were obtained directly from the data. Other pharmacokinetic parameters such as AUC0-∞, t1/2, Kel, Ka, t1/2ab, AUMC, MRT were computed using standard formulae. Parametric statistical evaluation of the data was performed by Student’s t-test and one-way variance analysis employing GraphPad InStat 8.0 for Windows3.
Results: Tablet formulations were found satisfactory in quality with respect to compendial standards. The percentage drug released at 10 min for TAC, MKT, and TKN were 6.39, 52.82, and 100.69, respectively. The HPLC method used for quantification of AC in plasma was found to be precise, accurate, linear and sensitive with no interference in rat plasma (Fig.1, Fig. 2). The plasma concentration versus time profiles were generated (Fig.3) and the pharmacokinetic parameters were assessed. The results indicated that AC absorption after oral administration was rapid with all three groups as evidenced by tmax values. However, the Cmax value was significantly higher with TKN (Cmax 2.58 μg/ml) compared to the TAC (Cmax=0.96 μg/ml) and MKT (Cmax=1.65 μg/ml) (P< 0.05), indicating a higher absorption rate of the drug from the tablet incorporating the inclusion complex as compared to that of the marketed tablet and the pure drug. Following the administration of tablets, AUC values were found to be 6.237±0.550 μg.h/ml, 3.571±0.319 μg.h/ml, and 5.061±0.154 μg.h/ml for TKN, TAC and MKT, respectively. The results revealed that there was about 1.75- and 1.2-fold enhancements in the extent of absorption of AC from TKN as compared to the TAC and MKT, respectively. Moreover, maximum plasma concentration appeared at a shorter time after dosing with TKN (tmax= 0.67 h) than with pure AC (tmax = 1 h) and the marketed tablet (tmax = 1 h).
Conclusion: The IR tablets of AC incorporating its inclusion complex with HPβCD produced shorter tmax, higher Cmax and better extent of absorption indicating rapid and enhanced absorption of the drug which might reduce total dose of the drug in formulation addressing the side effects related issues of the drug; eventually would give rise to improved patient compliance. The study results proved that the inclusion complexation with highly water-soluble amorphous cyclodextrin derivative is a valuable approach for enhancing both in vitro dissolution and in vivo absorption of poorly soluble aceclofenac and could be utilized as an effective strategy for bioavailability enhancement of other BCS class II drugs.
References:1. Dahiya S., Pathak K. (2006) ‘Physicochemical characterization and dissolution enhancement of aceclofenac-hydroxypropyl β-cyclodextrin binary systems’, PDA J. Pharm.Sci.Tech.,Vol. 60, No. 6, pp. 378-388. http://journal.pda.org/content/60/6/378.short
2. Dahiya S., Pathak K. (2007) ‘Influence of amorphous cyclodextrin derivatives on aceclofenac release from directly compressible tablets’, Pharmazie, Vol. 62, No. 4, pp. 278-283. http://www.atyponink.com/GVR/doi/abs/10.1691/ph.2007.4.6129?cookieSet=1&journalCode=phmz
3. Dahiya S., Kaushik A, Pathak K. (2015) ‘Improved pharmacokinetics of aceclofenac immediate release tablets incorporating its inclusion complex with HP-β-CD’, Sci. Pharm., Vol. 83, No. 3, pp. 501-10. http://www.scipharm.at/default.asp?id=1679&lid=2