Assessment of acyclovir absorption enhancement using rat single-pass intestinal perfusion model

The absorption enhancement of acyclovir [ACV], an antiviral agent, by mean of bile salt [sodium taurocholate, NaTC] and medium chain glycerides [capmul MCM, mono-/di-glycerides] was determined. MCG employing the rat model with perfused intestinal loop along with the mesenteric vein cannulation technique was used. The drug formulation containing 0.1 mM ACV were perfused through a rat intestinal segment [lower jejunum and ileum, 15 cm segment ending at the ileocecal junction] in which the corresponding mesenteric venous flow was isolated and cannulated. Each enhancer and the drug [NaTC and capmul MCM] were combined with non-ionic amphiphile surfactant with high HLB such as cremphor RH40 as a solubilizer. Collected perfusate and blood samples were analyzed for ACV by HPLC to determine intact drug concentration. The percentage absorbed [%A] and permeability coefficients corrected for surface area of absorption [intestinal radius and length] were calculated from the appearance of drug in blood [P blood] or the disappearance of drug from the perfusate as it flows through the intestinal lumen [P lumen]. Phenol red [PR] was used as a nonabsorbale marker, in a concentration of 23 mg/l, to determine net water absorption or secretion. The average C[1]/C[0] ratios [C[perfusate final concentration]/C[perfusate initial concentration]] for the perfusate suggest that the appearance of ACV in blood reaches a steady state within 15 minutes and that there is a difference in the steady state between formulations with NaTC and MCG. Both enhancers produced enhancement of ACV absorption in the rat intestine, by 3 to 4 folds for capmul and NaTC, respectively. Acyclovir permeability coefficients [P blood, cm/sec], corrected for surface area of absorption, were 4.73 +/- 0.39 x 10-6 for NaTC, 2.47 +/- 0.41 x 10-6 for MCG and 0.77 +/- 0.08 x 10-6 for perfusate without any absorption enhancer [in buffer at pH 7.5], respectively. Thus NaTC and MCG significantly increased the mucosal membrane permeability of ACV in the rat lower jejunum and ileum segment. The constant C[1]/C[0] [0.96] ratios for PR suggest that formulation did not alter intestinal water flux. These results suggest that NaTC and MCG can be used as intestinal absorption promoters for ACV in the lower jejunum and ileum which may enhance drug absorption after oral absorption, as the lack of absorption in lower jejunum and colon probably caused the lower bioavailability of ACV

Formulation and evaluation of sulindac capsules

Sulindac, a non-steroidal anti-inflammatory drug [NSAID], was introduced in this work as capsules. Drug excipient interaction study applying DSC and TLC proved the sulindac compatibility with lactose as filler, primojel as disintegrant and magnesium stearate as lubricant. Such excipients were combined in different proportions according to 23 factorial design that helped in studying the effect of each adjuvant in the presence of other ones. The prepared capsules were checked for drug content and its uniformity that was conformed to the pharmaceutical standards. The formulated capsules were evaluated according to their dissolution profiles, disintegration time, bulk density, flowability and compressibility. The results were statistically evaluated according to Yate's analysis of variance

Formulation and pharmaceutical evaluation of sulindac suspensions

Sulindac has been introduced in suspension dosage form which has suited its low aqueous solubility, its use in the fields of pediatrics and geriatrics, and its requirement of dose flexibility. A wettability study showed that 0.05% tween 20 was the wetting agent of choice. Controlled flocculation was adopted to prepare the flocculated suspensions. 32 deflocculated as well as 20 flocculated suspension formulations were prepared using different classes of suspending agents. The parameters used for evaluation were the sedimentation volume ratio [Vu/Vo], easiness of sediment redispersibility, clarity and color of supernatant, the time of the suspension has remained dispersed after being shaken, degree of flocculation, pH stability, conductivity, specific gravity, rheological properties, and dissolution. The deflocculated formula of choice was formula 18 containing 0.5% xanthan gum. The best flocculated suspension was formula 19 containing 10% glycerin, 10% propylene glycol, and 40% sorbitol as density modifiers

Further evaluation of certain sulindac suspensions

Microscopical characteristics and crystal growth, chemical stability, accelerated stability and the effect of dilution on physical and chemical stability were studied. Stable suspensions of choice were pharmacologically evaluated regarding anti-inflammatory, analgesic, and antipyretic effects as well as ulcerogenesis using laboratory animals. Clinoril tablet, the only marketed sulindac product, was taken as standard for comparison. The deflocculated formula 3 [containing 0.5% w/v xanthan gum] and the flocculated formula c [containing 10% glycerin, 10% propylene glycol, and 40% sorbitol as density modifiers] were the most stable among the tested formulae. The pharmacological evaluation of both suspension formulae showed anti-inflammatory, analgesic and antipyretic effects comparable to those of clinoril tablets; while ulcerogenesis was less. The flocculated suspension was the least ulcerogenic. Moreover, it showed earlier anti-inflammatory, analgesic, and antipyretic responses reflecting faster absorption

Interaction of terfenadine with cyclodextrin

The potentiality of molecular interaction of terfenadine with alpha- cyclodextrin [alpha-CyD] and beta-cyclodextrin [beta-CyD] was investigated by spectrophotometric methods. Differential UV spectrophotometry revealed an increase in the optical density of terfenadine in presence of cyclodextrins. Application of the continuous variation method to spectrophotometric measurements revealed equimolar stoichiometry of interaction. The apparent solubility of the drug in presence of alpha- and beta-CyD was investigated and the stability constants [Kc] were estimated from the straight portion of the phase-solubility diagram and found to be higher for the drug beta-CyD system pointing out that the larger the cyclodextrin cavity, the more profitable it would be to include that, bulky terfenadine molecule. Complexes of the drug alpha- and beta- CyDS were prepared and the process of complexation was also monitored by IR spectrophotometry. The dissolution profiles of the drug, physical mixtures of the drug and cyclodextrins as well as the prepared complexes showed enhanced drug dissolution properties of the prepared complexes compared to physical mixtures or the drug per se. The dissolution rate of the drug-beta-CyD complex was found to be higher than that of alpha-CyD complex which runs parallel with their stability constants confirming the great role played by cyclodextrin complexation in enhancing the dissolution rate of the drug