Preparation of Codeine-Resinate and Chlorpheniramine-Resinate Sustained-Release Suspension and its Pharmacokinetic Evaluation in Beagle Dogs

Abstract

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS). Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60 degrees C, the outlet air temperature was 32-38 degrees C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeration of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content. In the present study, the rates of drug release from both drug resinate beads were measured in 0.05 M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chlorpheniramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05 M KCl solution for codeine and 0.5 M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance. Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of Tmax and the lower value of Cmax, which meant an obviously sustained release effect, and its relati...

Formulation, Development and Stability of Granisetron Sustained Release Oral Dispersible Tablets

“…As in a multi-particulate system of drug-resin complex encapsulated in a microsphere, there is an increased amount of stability of the drug. The only limiting factor in the stability study was the degradation of the polymer, which might affect the release rate of the drug from the microcapsule [24][25][26] . However, there was no significant change in the release profile of the three polymer formulations during the stability study as observed in the figs.…”

“…The ion-exchange resin not only imparts a sustained release property to the multiparticulate formulation but also improves the stability of the drug. Many reports include the polymeric encapsulation of the resin complex to improve the extended release property [15][16][17][18][19] .…”