Evaluation of bioadhesive buccal tablets containing triamcinolone acetonide in healthy volunteers

The behaviour of bioadhesive buccal tablets prepared from different ratios of poly(acrylic acid-2,5-dimethyl-1,5-hexadiene) (PADH) and hydroxypropylmethylcellulose (HPMC) with and without triamcinolone acetonide (TAA) has been investigated in the buccal cavities of healthy human volunteers. The results indicate that tablets with a higher ratio of PADH swell faster, causing the disintegration of the tablets and consequently give rise to more rapid release of drug. The inclusion of higher percentages of HPMC provides more prolonged release of drug through its properties of gelling and slow dissolution. However, adhesion of the tablet is reduced in the excessive flow of saliva and there is also a tendency for the tablet to be dislodged from the mucosa. The tablet with a PADH/HPMC ratio of 50:50 seems to provide a suitable compromise for good bioadhesion and prolonged release of drug.     

Enhanced permeation of triamcinolone acetonide through the buccal mucosa.

To develop new formulations that have suitable bioadhesive force and provide sustained release in buccal area for an extended period of time, bioadhesive gels containing triamcinolone acetonide were prepared using two polymers, carbopol 934 and poloxamer 407 which were selected for their bioadhesiveness and gelling property, respectively. The drug release profiles from the gels were studied as a function of drug concentration and temperature. Different enhancers such as bile salts, glycols and non-ionic surfactants were used for the enhancement of its permeation through buccal mucosa. Among the enhancers used, sodium deoxycholate showed the best enhancing effects.     

Design of a dissolution apparatus suitable for in situ release study of triamcinolone acetonide from bioadhesive buccal tablets

A new and simple dissolution apparatus which is capable of evaluating the release of drug and bioadhesive properties of buccal tablets has been developed. The apparatus consists of a dissolution cell and an outer assembly. The cell has been designed to hold the chicken pouch membrane and bioadhesive tablet together and also to allow the dissolution medium to flow over them. The outer assembly is to provide adjustment of the angle of flow of the medium over the cell. The release study of triamcinolone acetonide from various bioadhesive buccal tablets containing different proportions of poly(acrylic acid-2.5-dimethyl-1,5-hexadiene) (PADH) and hydroxypropylmethyl-cellulose (HPMC) with the apparatus reveals that the bioadhesion of the tablet and the release of drug are influenced by the different proportions of polymers. With higher concentrations of PADH, the tablets disintegrate much more rapidly, leading to a faster release of the drug and they give better adhesion to the membrane. Tablets with higher concentrations of HPMC provide more prolonged release of the drug. However, they can be dislodged from the membrane more easily. The results produced by the apparatus concur with the predicted patterns.     

Enhanced transdermal delivery of pranoprofen from the bioadhesive gels

Percutaneous delivery of NSAIDs has advantages of avoiding hepatic first pass effect and delivering the drug for extended period of time at a sustained, concentrated level at the inflammation site that mainly acts at the joint and the related regions. To develop the new topical formulations of pranoprofen that have suitable bioadhesion, the gel was formulated using hydroxypropyl methylcellulose (HPMC) and poloxamer 407. The effects of temperature on drug release was performed at 32 degrees C, 37 degrees C and 42 degrees C according to drug concentration of 0.04%, 0.08%, 0.12%, 0.16%, and 0.2% (w/w) using synthetic cellulose membrane at 37+/-0.5 degrees C. The increase of temperature showed the increased drug release. The activation energy (Ea), which were calculated from the slope of lop P versus 1000/T plots was 11.22 kcal/ mol for 0.04%, 10.79 kcal/mol for 0.08%, 10.41 kcal/mol for 0.12% and 8.88 kcal/mol for 0.16% loading dose from the pranoprofen gel. To increase the drug permeation, some kinds of penetration enhancers such as the ethylene glycols, the propylene glycols, the glycerides, the non-ionic surfactants and the fatty acids were incorporated in the gel formulation. Among the various enhancers used, propylene glycol mono laurate showed the highest enhancing effects with the enhancement factor of 2.74. The results of this study suggest that development of topical gel formulation of pranoprofen containing an enhancer is feasible.     

A pharmacokinetic study to evaluate the absolute bioavailability of triamcinolone acetonide following inhalation administration.

Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in the management of asthma. With oral inhalation of glucocorticoids, systemic absorption can come from oropharyngeal, gastrointestinal, or airway deposition of the drug. The objectives of this study were to determine the absolute bioavailability of triamcinolone acetonide following inhalation administration and to delineate the airway contribution of triamcinolone acetonide absorption relative to the absolute bioavailability. All subjects received a 5-minute 400 mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of inhaled triamcinolone acetonide with and without oral charcoal administration in a randomized three-way crossover fashion. The oral charcoal allowed for isolating the pulmonary component of absorption by adsorbing the oropharyngeal and gastrointestinal deposited drug. The mean (+/- SD) absolute bioavailability value for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway contribution of triamcinolone acetonide absorption showed that 10.4% of an inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (+/- SD) total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (+/- SD) apparent volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg. No significant differences were noted in the apparent terminal elimination half-life of triamcinolone acetonide (approximately 2.4 hr) between treatments.     

Topical bioavailability of triamcinolone acetonide: effect of occlusion

BACKGROUND/AIMS: Occlusion by covering the skin with an impermeable wrap enhances skin hydration, affects drug absorption and can induce the formation of a drug reservoir within the stratum corneum. This is desired in local therapy with topical corticosteroids. The aim of the study was to investigate the effect of occlusion before (experiment 1) and after (experiment 2) application on the penetration of triamcinolone acetonide (TACA) into the stratum corneum. METHODS: The experiments were conducted on the forearms of 10 healthy volunteers. In experiment 1, 100 microg/cm(2) TACA in acetone were applied on 3 sites per arm, one arm having been pre-occluded for 16 h. In experiment 2, the same dose was applied on 2 sites per arm, and one arm was occluded after application until skin sampling. Stratum corneum samples were removed by tape stripping at 0.5, 4 and 24 h (experiment 1) and 4 and 24 h (experiment 2) after application. Corneocytes and TACA were quantified by ultraviolet-visible spectroscopy and HPLC, respectively. The total TACA amount penetrated into the stratum corneum was evaluated by multifactor ANOVA. RESULTS: TACA penetration into the stratum corneum with and without pre-occlusion (experiment 1) showed no significant difference and decreased with time. Occlusion after application (experiment 2) produced a marked TACA accumulation within the stratum corneum, which persisted for 24 h. CONCLUSION: Pre-occlusion showed no effect on the topical bioavailability of TACA in the stratum corneum. In contrast, post-occlusion enhanced the TACA penetration by a factor of 2, favouring the development of a drug reservoir.     

Enhanced bioavailability of atenolol by transdermal administration of the ethylene-vinyl acetate matrix in rabbits.

The pharmacokinetics and bioavailability of atenolol, a antihypertensive, were studied to determine the feasibility of enhanced transdermal delivery of atenolol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rabbits. The atenolol-EVA matrix (20 mg/kg) was applied to abdominal skin of rabbits. Blood samples were collected via the femoral artery for 32 h and the plasma concentrations of atenolol were determined by high-performance liquid chromatography. Pharmacokinetic parameters was calculated using Lagran computer program. The area under the curve (AUC) was significantly higher in the enhancer group (12,402+/-3061 ng/ml.h) than that in the control group (8507+/-2092 ng/ml.h), showing about 46% increased bioavailability (P<0.05). The average C(max) was increased in the enhancer group (1361+/-340 ng/ml) compared with the control group (1168+/-293 ng/ml), but not significantly. The T(max) was significantly decreased in the enhancer group (1.3+/-0.36 h) compared with the control group (2.0+/-0.51 h). The elimination time (t(1/2)) and mean residence time were significantly increased in the transdermal group compared with the IV group. The absolute bioavailability was 19.7% in the control group, 28.6% in the enhancer group and 77.4% in the oral administration group compared with IV the group. As the atenolol-EVA matrix containing polyoxyethylene-2-oleyl ether as an enhancer and tributyl citrate as a plasticizer was administered to rabbits via the transdermal routes, the relative AUC% increased about 1.46-fold compared to the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. The results of this study show that atenolol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.     

Enhanced bioavailability and antihistamine effects by transdermal administration of loratadine gels containing an enhancer in rats

The present study examined the feasibility of transdermal administration of loratadine gels containing an enhancer to rats by comparing the pharmacokinetic parameters of loratadine after transdermal, oral, or intravenous administration. Transdermal administration of loratadine gel (12 mg/kg applied to the abdominal skin) with an enhancer produced a significantly higher plasma concentration of loratadine than the loratadine gel without the enhancer (control). The average areas under the serum concentration‐time curves (AUC) was 929±148 h·ng/ml for oral administration, and 3,318±530.9 h·ng/ml for intravenous administration. The AUC of transdermal administration with and without the enhancer was 2,054±328.0 h·ng/ml and 1,094±176.5 h·ng/ml, respectively. The enhancer increased the relative bioavailability by 1.88‐fold (P<0.01). Transdermal application of the loratadine gel containing polyoxyethylene 2‐stearyl ether inhibited the increase in vascular permeability induced by histamine by 28.62%, whereas the loratadine gel without enhancer inhibited the permeability by 20.33%. In conclusion, the loratadine gel system containing an enhancer could be developed as a transdermal delivery system providing the increased constant plasma concentration and antihistamine effects. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

高效液相色谱法测定醋酸曲安奈德注射液中醋酸曲安奈德含量

目的建立醋酸曲安奈德注射液中醋酸曲安奈德含量测定的方法。方法采用高效液相色谱法,流动相为甲醇-水（70：30）,流动速度为1.0ml/min,检测波长为240nm。结果醋酸曲安奈德的线性范围为0.0064～0.128mg/ml,线性方程：y=1.8683×10^-6＋5.3174x（r=0.999976,n=7）,回收率99.9%,RSD为0.36%（n=9）。结论采用高效液相色谱法测定醋酸曲安奈德注射液中醋酸曲安奈德含量的方法具有简便、准确、重现性好等优点,可作为该制剂的质量控制方法。     

高效液相色谱法测定曲安奈德乳膏的含量

目的建立曲安奈德乳膏的含量测定方法。方法采用高效液相色谱法测定曲安奈德乳膏的含量,色谱柱为Nova-Park C18柱(4.0mm×300mm,4μm),流动相为甲醇-乙醚-水(68∶2∶30),流速为1mL.min-1,检测波长为240nm。结果曲安奈德浓度在6.8~108.8mg.L-1浓度内与其峰面积呈良好的线性关系(r=0.9996)。回收率为101.45%,RSD为0.50%。结论本法简便,准确,灵敏度高,重现性好,可用于曲安奈德乳膏的含量测定。     

Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits

The aim of this study was to investigate the effect of quercetin on the bioavailability of diltiazem after administering diltiazem (15 mg/kg) orally to rabbits either co-administered or pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of diltiazem in the rabbits pretreated with quercetin were increased significantly (p<0.05, at 2 mg/kg; p<0.01, at 10 and 20 mg/kg) compared with the control, but the plasma concentrations of diltiazem co-administered with quercetin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of the diltiazem in the rabbits pretreated with quercetin were significantly higher (p<0.05, at 2 mg/kg; p<0.01, at 10 and 20 mg/kg) than the control. The absolute bioavailability (AB%) of diltiazem in the rabbits pretreated with quercetin was significantly (p<0.05 at 2 mg/kg, p<0.01 at 10 and 20 mg/kg) higher (9.10-12.81%) than the control (4.64%). AUC, AB% and Cmax of diltiazem co-administered with quercetin were higher than the control, but these were not significant. The bioavailibility of diltiazem in the rabbits pretreated with quercetin is increased significantly compared with the control, but not in the rabbits co-administered with quercetin. The increased bioavailability of diltiazem in the rabbits pretreated with quercetin might have been resulted result from the quercetin, which inhibits the efflux pump P-glycoprotein and the first-pass metabolizing enzyme CYP 3A4.     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

RP-HPLC法测定复方十一烯酸锌曲安奈德软膏中醋酸曲安奈德含量

目的建立测定中复方十一烯酸锌曲安奈德软膏中醋酸曲安奈德含量的方法。方法采用C18柱(4.6 mm×250 mm,5μm),以甲醇-水-乙醚(68∶32∶1)为流动相,检测波长240 nm,流速为1.0 ml.min-1。结果醋酸曲安奈德在0.08936~0.8936μg范内呈良好线性关系,r=0.9996,回收率分别为99.3%,99.2%,98.8%,RSD分别为0.56%,0.23%,0.48%。结论该方法准确,可靠,可用于复方十一烯酸锌曲安奈德软膏的质量控制。     

Enhanced bioavailability of paclitaxel by bamboo concentrate administration

The purpose of this study was to investigate the effect of a cotreatment of bamboo concentrates (Jukcho solution; 0.75, 1.5, and 3.0 mL/kg) with the chemotherapeutic agent paclitaxel on the bioavailability of orally administered paclitaxel (50 mg/kg) in rats. The effect of a pretreatment of bamboo concentrates (1.5 and 3.0 mL/kg for 1.0 h or a consecutive 3 day) was also examined. The paclitaxel plasma concentrations of rats orally administered paclitaxel plus bamboo concentrates (coadministration, 3.0 mL/kg and pretreatment, 1.5 and 3.0 mL/kg) were significantly higher than those of rats treated with paclitaxel alone. Plasma concentrations of paclitaxel in groups pretreated with bamboo concentrates for 3 day were markedly higher than those of a paclitaxel control group at the measured time points. The areas under plasma concentration-time curves (AUCs) of paclitaxel in groups pretreated with bamboo concentrates were elevated and the absolute bioavailability (AB%) and relative bioavailability (RB%) of paclitaxel were also significantly higher than those in the control group. The peak concentration (Cmax), half-life (t1/2), and the elimination rate constant (Kel) of paclitaxel after 3 day of pretreatment with bamboo concentrates were also significantly higher than those in the control, but the time required to reach the maximum plasma concentration (Tmax) of paclitaxel was unaffected by the bamboo concentrates. Western blot analyses demonstrated that the level of CYP3A4 was increased in the livers of rats treated orally with paclitaxel, but this was reversed by pretreating with bamboo concentrates. These results show that bamboo concentrates enhance the bioavailability of orally administered paclitaxel and this effect may be associated with a diminished expression of CYP3A4 in the liver.     

HPLC法测定复方醋酸曲安奈德溶液中的醋酸曲安奈德与水杨酸含量

目的 :建立同时测定醋酸曲安奈德和水杨酸的方法。方法 :高效液相色谱法分离并紫外2 54nm检测。结果 :线性、精密度及回收率结果良好。结论 :本法可以完成该复方溶液中两组分的同时测定。     

Evaluation of triamcinolone acetonide following intravitreal injection in New Zealand white rabbits

The safety of intravitreally injected triamcinolone acetonide suspension (TA) was evaluated in rabbits. Each animal received 0.1 ml (1) balanced salt solution (BSS) vehicle, (2) formulation vehicle, (3) 4% TA (4-mg dose), (4) 16% TrAc (16-mg dose) or (5) 25% TA (25-mg dose) as a single intravitreal injection into the right eye. The left eyes served as untreated controls. All animals were observed for 1 month following treatment. In-life evaluations included clinical signs, body weights, slit-lamp biomicroscopic and indirect ophthalmoscopic examinations, intraocular pressure and corneal thickness measurements, and electroretinograms (ERGs). Ocular tissues were harvested following a 1-month post-treatment observation period, fixed, processed, and evaluated by light microscopy. No significant or treatment-related clinical signs were observed for any animals during the study. The opaque white test article was clearly visible in the eye for all TrAc-treated groups, and remained so throughout the study. No statistically significant differences in mean body weights were present between the control and treatment groups, though changes in body weight varied. Corneal thickness was slightly reduced for some treated groups. Intraocular pressures were not statistically significantly different from controls for any treatment group. No significant changes in ERG were evident between treatment groups or from baseline readings. Microscopically, basophilic material (presumed to be drug) was seen in the vitreous of all or most treated eyes, with accumulations in the vitreous or in clumps adjacent to the retinal surface. No pathological changes were observed in the retina or other ocular structures. Triamcinolone acetonide suspension was safe and well tolerated following intravitreal injection in New Zealand white rabbits.     

Percutaneous absorption of the 21-β-benzoylamino iso-butyrate of triamcinolone acetonide by rats and rabbits

The percutaneous absorption of the β-benzoylaminoisobutyrate of [³H]-triamcinolone acetonide (TBI) has been studied in rats and rabbits. Up to about 5% and 20% of the applied dose was absorbed by rats and rabbits respectively during 5 days. In both species, absorption was mainly complete after about 3 days, although most of the dose was still present at the site of application. Of the absorbed radioactivity, the rat excreted about 1% and 2% of the dose respectively in the urine and faeces and the rabbit 9% and 4% respectively in 5 days. Peak plasma concentrations of drug equivalents occurred in rats at about 48 h (1.9 ng/ml) and in rabbits at about 72 h (2.6 ng/ml).     

高效液相色谱法同时测定复方确炎舒松霜中氯霉素和曲安奈德含量

目的建立复方确炎舒松霜中氯霉素和曲安奈德(确炎舒松)含量测定方法,用于制剂质量控制。方法利用高效液相色谱法,优化色谱条件进行测定,色谱柱μBondapakC18(10μm,3.9×300mm),流动相为甲醇-0.025 mol.L-1磷酸二氢钠(65∶35),检测波长240nm,流速1.2mL.m in-1,柱温45℃,灵敏度0.02AUFS。结果测定氯霉素的线性范围为200.0~500.0mg.L-1,平均回收率为103.1%(RSD 0.63~1.48%);测定确炎舒松的线性范围为15.0~75.0 mg.L-1,平均回收率为98.9%(RSD 0.77~1.75%)。结论本方法简便、准确,适合于复方确炎舒松霜的质量控制。     

高效液相色谱法测定醋酸曲安奈德含量

目的:建立高效液相色谱法测定强力皮炎灵中醋酸曲安奈德的含量.方法:以C18反相键合硅胶为固定相,甲醇-水(80:20)为流动相,流速1.0 mL·min-1,醋酸地塞米松为内标,检测波长为240 nm.结果:醋酸曲安奈德在3.0～60.0 mg·L-1浓度范围内呈良好线性关系,r=0.999 9,方法平均回收率为99.7%,RSD为0.4%(n=6).结论:该方法测定醋酸曲安奈德的含量简便快捷,适于医院制剂的含量测定.     

Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits

The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of the nimodipine in the rabbits pretreated with morin were significantly higher (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg), but only the Cmax of nimodipine coadministered with morin 10 mg/kg was increased significantly (p < 0.05). The absolute bioavailability (A.B%) of nimodipine in the rabbits pretreated with morin was significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) higher (54.1-65.0%) than the control (36.7%). The increased bioavailability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the effiux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).