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 bioavailability by buccal administration of triamcinolone acetonide from the bioadhesive gels in rabbits

The pharmacokinetics and bioavailability of triamcinolone acetonide were determined to investigate buccal absorption from the mucoadhesive gels in rabbits. The enhancing effect of sodium deoxycholate as an enhancer on the buccal absorption of triamcinolone acetonide from the mucoadhesive gels was evaluated in rabbits. Thus, 2 mg/kg of triamcinolone acetonide was administered from the mucoadhesive gels containing an enhancer (enhancer group) or not (control group) via the buccal routes and compared with intravenous routes (1 mg/kg, i.v. group). AUC of the control, enhancer and i.v group were 2374+/-915, 3778+/-1721 and 3945+/-2085 h ng/ml, respectively, and the absolutive bioavailability of enhancer or i.v to control group were 159.14 or 332.35%, respectively. The average C(max) of control and enhancer group were 263+/-159 and 362+/-201 ng/ml, and the mean T(max) of the control group and enhancer group were 5.00+/-1.67 and 4.33+/-0.82 h, respectively, but there was no significant difference. As the triamcinolone acetonide gels containing sodium deoxycholate as an enhancer was administered to rabbits via the buccal routes, the relative bioavailability showed about 1.59-fold compared with the control group. Buccal administration of triamcinolone acetonide gels containing sodium deoxycholate as an enhancer to rabbits showed a relatively constant, sustained blood concentration with minimal fluctuation.     

Formulation of triamcinolone acetonide pellets suitable for coating and colon targeting

Spherical pellets containing 5% of triamcinolone acetonide (TA) were formed by extrusion/spheronization following formulation with microcrystalline cellulose (MCC) and/or a hydrophilic excipient (lactose, sodium carboxymethylcellulose or beta-cyclodextrin, beta-CD). Their suitability for coating, with a view to colonic drug delivery, was assessed in terms of their size, sphericity and dissolution test response. Best results were afforded by 5:90:5 MCC-beta-CD-TA pellets obtained by complexation of TA with beta-CD prior to addition of MCC, extrusion and spheronization.Copyright     

尼莫地平控释片释放度试验研究

本文研究了尼莫地平控释片的释放度试验方法——转篮法，释放介质为含有２２％异丙醇的０．１ｍｏｌ·Ｌ－１盐酸液；磷酸盐缓冲液（ｐＨ５．８）和ｐＨ７．２的溶液。含量测定方法：紫外分光光度法，在三种介质中尼莫地平分别在１～３０μｇ·ｍｌ－１，１０～５０μｇ·ｍｌ－１和１０～５０μｇ·ｍｌ－１的范围内，浓度与吸收度有较好的线性关系。回归方程分别为Ａ＝０．６１５Ｃ＋０．０２３（ｒ＝０．９９９９）；Ａ＝０．０６１４Ｃ＋０．０１２（ｒ＝０．９９９５）；Ａ＝０．０６１２Ｃ＋０．００８８（ｒ＝０．９９９９）。平均回收率分别为９９．６３％，９９．９８％及１００．７７％，ＲＳＤ（％）分别为１．３４％，１．５９％及１．４１％。本方法的体外释放百分率与体内吸收分数有较好的相关性（ｒ＝０．９９１）。     

野菊花总黄酮口腔生物黏附双层贴片成型工艺优化

目的:研究野菊花总黄酮口腔生物黏附双层片的成型工艺。方法:采用Franz扩散法优选可阻止有效成分渗透的保护层;以黏附力和释放度为指标,采用单因素试验筛选生物黏附材料,以正交试验优选载药量、黏附材料的比例及填充剂用量。结果:该贴片的黏附层为卡波普934P和羟丙基纤维素1:2混合物,占75.8%,总黄酮20%,乳糖4%,微粉硅胶0.2%,以乙基纤维素作为黏附片的保护层。结论:该成型处方制成的野菊花生物黏附双层片具有较好的生物黏附性,背衬层可阻滞药物释放。     

Development and in vitro/in vivo evaluations of bioadhesive buccal tablets for nicotine replacement therapy

Buccal bioadhesive tablet formulations of nicotine hydrogen tartrate (NHT) for nicotine replacement therapy (NRT) were developed using chitosan and carbomer at different ratios. Magnesium hydroxide was incorporated into the formulations as pH increasing agent. In vitro release and bioadhesion properties of the tablets were investigated. Release of NHT from the tablets was increased with the increasing amount of chitosan in formulations whilst the bioadhesion of the tablet was decreased. In vivo studies were carried out in healthy, non-smoker volunteers in comparison to a commercially available transdermal patch. Plasma nicotine and cotinine levels were determined using gas chromatography-mass spectrophotometry. No significant difference was found between the maximum plasma nicotine concentrations (Cmax) obtained with the buccal tablet and the transdermal patch (p > 0.05). Time to reach the Cmax was 2.9 +/- 0.2 h and 11.5 +/- 1.3 h, and AUC0-24 values were 59.3 +/- 5.1 ng x h x mL(-1) (0-12 h) and 204.1 +/- 31.2 ng x h x mL(-1) for buccal tablet and transdermal patch, respectively.     

Design of a dissolution system for the evaluation of the release rate characteristics of artemether and dihydroartemisinin from tablets

As none of the pharmacopoeial dissolution methods are suitable to evaluate the release rate of artemether and dihydroartemisinin from tablets, a 'two-phase partition-dissolution' method, based on the one of [J. Pharm. Sci. 85 (1996) 1060] was developed. It consists of an organic solvent in the upper part and the aqueous phase, in which the dissolution test was executed. The main requirements for the selection of the solvent are: the density should be lower than 1; the analyte should dissolve in the organic part as much as required for 'sink' conditions; if possible, the cut off should be near 200 nm, which allows direct HPLC measurement at 215 nm. The most suitable solvent for artemether is isooctane in a ratio of 100/150 ml aqueous phase. Samples could be analysed without further treatment. For dihydroartemisinin, chlorobutane was selected in a ratio 150/150 ml water. In the latter method, the solvent disturbed in the HPLC analysis and therefore samples were evaporated and then reconstituted in methanol. Repeatability of the test was satisfactory and discrimination ability tests on Artenam tablet batches and self-made dihydroartemisinin tablets, respectively, showed good results, confirmed via calculation of the similarity factor f2 (value <50). Dissolution determination of Cotecxin tablets was proven not to be conform as immediate-release tablet.     

Correlation of absorption of sulfamethazine boluses with dissolution using a new dissolution apparatus for veterinary tablets.

A rotating-basket apparatus for dissolution testing of veterinary bolus tablets was designed and constructed. Sulfamethazine boluses containing different disintegrating agents were evaluated in vitro and by blood level data following administration to cattle. The dissolution t50 and various pharmacokinetic parameters showed directly compressible starch and carboxymethylstarch to be the most effective disintegrants in the concentrations employed while magnesium aluminum silicate and microcrystalline cellulose were about equal but less effective than the previous disintegrants. A bolus formulation containing no disintegrant gave even less satisfactory results. A correlation was established between the dissolution t50 and the time to peak plasma level and also between the t50 and the area under the plasma-time curve for the first 36 hr.     

小檗碱生物黏附缓释片的制备及体外评价

目的 测定小檗碱生物黏附缓释片和大鼠离体胃组织的黏附力,探究其体外释药作用,制备小檗碱生物黏附缓释片。方法 以羟丙基甲基纤维素(HPMC)和卡波姆(carbopol,CP)为生物黏附材料,通过正交试验对辅料用量进行优化。测定生物黏附缓释片的释放度,溶出介质为人工胃液(pH=1.2)。通过自制黏附力测定装置测定、比较小檗碱生物黏附缓释片和盐酸小檗碱片对大鼠离体胃组织的黏附力。结果 每片生物黏附缓释片中974P/971P为1/3,卡波姆用量为20 mg,羟丙基甲基纤维素为15 mg。生物黏附缓释片的体外释放达到缓释制剂要求,与普通片剂相比其对大鼠离体胃组织的黏附力更大。结论 小檗碱生物黏附缓释片的处方和工艺能够达到设计要求。     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

IVIVR in oral absorption for fenofibrate immediate release tablets using dissolution and dissolution permeation methods

In a previous study it has been demonstrated that a dissolution/permeation (D/P) system can discriminate between different immediate release fenofibrate formulations. The fractions permeated were correlated with fenofibrate's in vivo exposure in rats following p.o. administration. In the present study more detailed investigations are presented using data from six fenofibrate tablets tested in vivo in humans. In these pharmacokinetic studies no significant differences between formulations in AUC but in Cmax were found. Differences between the Cmax values were not explained by the dissolution characteristics of the tablets but were rationalized on the basis of micellar entrapment and diminished mobility of the active ingredient by surfactants in the formulations. This was demonstrated by a permeation system using dialysis membranes. Thus a permeation step in addition to dissolution measurement may significantly improve the establishment of an IVIV relationship.     

Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation

Bioadhesive buccal tablet formulations for delivery of nicotine into the oral cavity were developed. Carbomer (Carbopol)974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the NHT released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC. The bioadhesive properties of the tablets containing NaAlg:HPMC was not affected by the concentration of the NaAlg (P>0.05) but increased significantly with the increasing CP concentration (P>0.05). A decrease in pH of the dissolution medium to acidic values was avoided by incorporation of magnesium hydroxide into the formulations. The developed formulations released NHT for 8h period, and remained intact except for the formulation containing CP:HPMC at 20:80 ratio.     

Transdermal delivery system of triamcinolone acetonide from a gel using phonophoresis

Triamcinolone acetonide (TA) is a corticosteroid that is used in the systemic and topical treatment of many inflammatory diseases. In this study, a phonophoretic drug delivery system was designed to enhance the TA permeability and the influence of ultrasound was examined. In order to establish the transdermal delivery system for TA, a hydrophilic carbopol gel containing TA was prepared after adopting phonophoresis. A permeation study through mouse skin was performed at 37 degrees C using a Franz diffusion cell, and the ultrasound treatment was carried out for 10 h. The level of TA permeation through the skin was evaluated under various ultrasound conditions including the frequency (1.0, 3.0 MHz), intensity (1.0, 2.5 W/cm2), and duty cycle (continuous, pulse mode) using a 0.5% TA gel. The highest permeation was observed under the ultrasound treatment conditions of low frequency, high intensity, and in continuous mode.     

光纤药物溶出仪实时测定布洛芬片溶出度的研究

目的采用光纤药物溶出度实时测定(fiber-optic in situ dissolution testing,FODT)仪监测布洛芬片溶出度。方法取不同厂家和批号的布洛芬片,用FODT仪分别监测其溶出曲线和开始溶出、溶出50%及溶出70%的时间,以及与药典法比较30min时平均累积溶出百分率。结果FODT仪测定布洛芬糖衣片和普通片的溶出曲线不同;3个溶出段的时间各异;与中国药典2005年版二部法相比,尽管各药片溶出度均达合格标准,但30min时平均累积溶出百分率数值有差异。结论FODT法可用于布洛芬片溶出度检查。     

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.     

Formulation and evaluation of a bioadhesive patch for buccal delivery of tizanidine

Tizanidine hydrochloride (THCl) is an antispasmodic agent which undergoes extensive first pass metabolism making it a possible candidate for buccal delivery. The aim of this study was to prepare a monolayered buccal patch containing THCl using the emulsification solvent evaporation method. Fourteen formulations were prepared using the polymers Eudragit^® RS 100 or Eudragit^® RL 100 and chitosan. Polymer solutions in acetone were combined with a THCl aqueous solution (in some cases containing chitosan) by homogenization at 9000 rpm for 2 min in the presence of triethyl citrate as plasticizer and cast in novel Teflon molds. Physicochemical properties such as film thickness, in vitro drug release and in vitro mucoadhesion were evaluated after which permeation across sheep buccal mucosa was examined in terms of flux and lag time. Formulations prepared using a Eudragit^® polymer alone exhibited satisfactory physicomechanical properties but lacked a gradual in vitro drug release pattern. Incorporation of chitosan into formulations resulted in the formation of a porous structure which did exhibit gradual release of drug. In conclusion, THCl can be delivered by a buccal patch formulated as a blend of Eudragit^® and chitosan, the latter being necessary to achieve gradual drug release.     

Development and evaluation of a buccal bioadhesive system for smoking cessation therapy

The objective of the present study was to develop a bilayered buccal bioadhesive film formulation of nicotine hydrogen tartrate for smoking cessation therapy, comprising a bioadhesive drug layer and a backing layer, which releases the drug at a pre-determined rate for a period of 4 h. Formulations were prepared using various bioadhesive polymers and were evaluated for physical parameters like peelability, flexibility, softness, bioadhesive strength, tensile strength, dispersion time and pharmaceutical parameters such as thickness, swelling, content uniformity, water vapour permeability and drug release. Based on these parameters formulation N2, containing hydroxypropyl methylcellulose and polycarbophil as the bioadhesive polymers, was selected as the optimized formulation. The formulation showed suitable adhesion and an initial burst release of 40% drug in first 15 min followed by a total 80% drug release in a characteristic manner until 4 h; which is the desired time of application. This release pattern is beneficial for patients suffering from emergent cravings. Backing layers of the films were studied by a moisture vapor permeability test and it was observed that the percentage of moisture which permeated through single layered films was much higher than through bilayered films implying that a backing layer would prevent washing out of drug by the saliva.