The physicodynamic properties of mucoadhesive polymeric films developed as female controlled drug delivery system

Phenoporlamine hydrochloride is a novel compound that is used for the treatment of hypertension. The purpose of this study was to develop a sustained release tablet for phenoporlamine hydrochloride because of its short biological half-life. Three floating matrix formulations of phenoporlamine hydrochloride based on gas forming agent were prepared. Hydroxypropyl methylcellulose K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system. Incorporation sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of phenoporlamine hydrochloride were conducted in six healthy male human volunteers to compare the sustained release tablets with immediate release tablets. Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).     

In Vitro and in Vivo Evaluation in Dogs and Pigs of a Hydrophilic Matrix Containing Propylthiouracil

A hydrophilic matrix tablet containing 300 mg of propylthiouracil was formulated with several types of hydroxypropylmethylcellulose. The influence of polymer and drug granule particle size, polymer concentration, crystallinity and geometry of the polymer particles, the polymer incorporation outside or inside the granule, addition of a filler and tablet hardness were studied. Polymer concentration, polymer particle size and geometry, filler addition and type of the filler used had a major influence on in vitro drug dissolution profiles. The bioavailability of propylthiouracil in dogs from the hydrophilic matrices investigated was low, because of the short gastro-intestinal transit times of the matrix tablets in the dogs. The matrix tablets reached the colon in fasted dogs within 2–3 hours after administration. The results indicated the poor predictability of bioavailability experiments in dogs with hydrophilic matrices. Although the bioavailability data in pigs seemed promising, a transit time study revealed a long stomach residence time of the matrix tablets in pigs. These data suggested that pigs are an inappropriate animal model for bioavailability studies of erodible matrix tablets.     

Imperatorin sustained-release tablets: <Emphasis Type="Italic">In Vitro</Emphasis> and pharmacokinetic studies

We prepared and evaluated imperatorin (IMP) sustained-release tablets. IMP is an active compound in Angelica dahuricae, a Chinese herbal medicine. We used different polymers, such as hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), carbopol 934P, sodium carboxymethyl cellulose (CMC-Na), and their combinations to prepare the matrix tablets and achieve the desired sustained release profile. The in vitro release profiles of these formulations were examined and fit to various kinetic release models. We also tested the effects of polymer combination ratios on the in vitro release rate. In vivo studies were performed for the optimized formulation in six beagle dogs, and pharmacokinetic parameters were compared with plain IMP tablets. IMP sustained-release tablets exhibited a more sustained plasma concentration than the plain tablets, with a relative bioavailability of 127.25%. The in vitro releases rates and in vivo absorption correlated for the initial 8 hours. These results demonstrate that the sustained-release tablet system can effectively control the release of IMP.     

Pharmacokinetics of metformin gastric-retentive tablets in healthy volunteers

The single-dose pharmacokinetics of two gastric-retentive, extended-release tablet formulations of metformin hydrochloride in fed, healthy volunteers were compared with those of the currently marketed immediate-release metformin hydrochloride product. The plasma concentration-time profiles demonstrated extended-release characteristics from the gastric-retentive tablets. The mean bioavailability from each gastric-retentive tablet was approximately 115%, relative to the immediate-release (IR) product. Cmax values were lower and tmax values were greater for the gastric-retentive tablets compared with the IR product. In contrast to conventional extended-release metformin tablets reported in the literature, these gastric-retentive tablets showed extended-release plasma concentration profiles of metformin hydrochloride and increased bioavailability compared with the immediate-release tablet.     

The dissolution rate and bioavailability of hydrochlorothiazide in pellet formulations

The influence of non-active ingredients in the manufacture of pellets on in-vitro dissolution rate and on bioavailability of hydrochlorothiazide has been studied. Pellets were formulated using either microcrystalline cellulose or microcrystalline cellulose-carboxymethylcellulose sodium blends as matrix, and hydrochlorothiazide as the active ingredient. In-vitro drug release from the different pellet formulations was retarded in comparison to a conventional tablet formulation and was dependent on the nature of the non-active ingredient and, for the microcrystalline cellulose-carboxymethylcellulose sodium blend, of the dissolution medium. In-vivo bioavailability of both pellet formulations was low compared with that of the conventional tablet and the plasma concentration-time profiles did not suggest slow release.     

丙硫氧嘧啶缓释片与普通片的犬体内药动学及生物利用度比较

目的:研究丙硫氧嘧啶缓释片在beagle犬体内的药动学过程,测定其药动学参数、相对于普通片的生物利用度和生物等效性。方法:采用双交叉试验设计法,取6条健康beagle犬随机分成2组,分别服用丙硫氧嘧啶缓释片和普通片,用高效液相色谱法测定丙硫氧嘧啶的血药浓度,利用3P97软件包计算主要的药动学参数以及相对生物利用度,并判断生物等效性。结果:犬口服丙硫氧嘧啶后符合二房室模型特征,缓释片和普通片的MRT分别为(5.3±s0.6)h和(3.0±0.6)h,tmax分别为(2.4±0.5)h和(1.1±0.3)h,cmax分别为(15.6±2.0)和(23.3±2.9)mg·L-1,缓释片的相对生物利用度为(114±4)%。结论:丙硫氧嘧啶缓释片和普通片具有生物等效,且缓释片具有12h缓释效果。     

Pharmacokinetics of verapamil and norverapamil in patients with hypertension: a comparison of oral conventional and sustained release formulations

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.     

吲达帕胺缓释片的研制及释药机理考察

目的：研制吲达帕胺缓释片，并考察其释药机理。方法：以HPMC为骨架材料，以微晶纤维素、乳糖和可压性淀粉调节释放度，对吲达帕胺缓释片的影响因素进行了考察，并采用正交试验设计筛选处方。结果：吲达帕胺缓释片的组成为：HPMC K4M 37．5mg，HPMC K15M7．5mg，乳糖45．0mg，可压性淀粉37．5mg，微晶纤维素21．0mg，硬脂酸镁1．5mg，药物的释放符合零级动力学方程，释放机制为骨架溶蚀机制；释药速率受介质pH值的影响，几乎不受压片压力的影响。结论：研制的吲达帕胺缓释片体外释放符合国外同类产品的释药特性。     

多剂量口服5-单硝酸异山梨酯缓释片及普通片的药代动力学和生物利用度研究

对10名健康男性受试者连续6d多剂量交叉poIS-5-MN缓释片和普通片的药代动力学性质和相对生物利用度进行了研究。结果表明:IS-5-MN缓释片和普通片的T_max分别为5.0h和1.4h(P<0.05),前者的缓释效果十分明显;AUC经对数转换后的多种统计分析表明,IS-5-MN缓释片(40mg)与IS-5-MN普通片(20mg×2)生物等效;IS-5-MN缓释片的相对生物利用度为108.95%;IS-5-MN缓释片和普通片的C_min分别为74.20ng·ml^-1和134.42ng·ml^-1(P<0.05),而两种制剂的其他药代动力学参数如C_max,AUC²⁴₀,AUC^∞₀,Ke,T_1/2以及波动系数(FI)等均无显著性差异(P<0.05)。多次给药后两种制剂都无明显的蓄积。     

Formualtion and evaluation of floating drug delivery system containing clarithromycin for Helicobacter pylori

Floating matrix tablets are designed to prolong the gastric residence time after oral administration, at a particular site and controlling the release of drug especially useful for achieving controlled plasma level as well as improving bioavailability. With this objective, floating dosage form containing clarithromycin as drug was designed for the treatment of Helicobacter pylori. Tablets containing hydroxypropylmethylcellulose (HPMC), drug and different additives were compressed using wet granulation and D-optimal design technique. The study shows that tablet composition and mechanical strength have great influence on the floating properties and drug release. Incorporation of gas-generating agent together with polymer improved drug release, besides optimal floating (floating lag time < 30 s; total floating time > 10 h). The drug release was sufficiently sustained (more than 8 h) and anomalous diffusion as well as zero-order was confirmed. Optimization of the evaluating parameters with 'design expert' software was employed to get final optimized formulation. The optimized formulation was obtained using 62.5% clarithromycin, 4.95% HPMC K15M, 18.09% HPMC K4M, 12.96% sodium bicarbonate which gave floating lag time < 30 s with a total floating time > 10 h, in vitro release profile very near to the target in vitro release profile and follows anomalous diffusion as well as zero order pattern of release.     

卡托普利缓释片的实验研究

采用羟丙基甲基纤维素(HPMC)凝胶制备的巯甲丙脯酸(卡托普利)缓释片,其体外释放曲线符合 Higuchi 动力学。HPMC 在片剂中含量达到30%以上才能控制巯甲丙脯酸的释放。HPMCK_4M、K_(15)M和 K100M 的粘度差异对凝胶片释放并无影响,释放介质的 pH 及压片压力对该制剂的药物释放影响不大。     

Application of mixture experimental design in the formulation and optimization of matrix tablets containing carbomer and hydroxy-propylmethylcellulose

Using mixture experimental design, the effect of carbomer (Carbopol® 971P NF) and hydroxypropylmethylcellulose (Methocel® K100M or Methocel® K4M) combination on the release profile and on the mechanism of drug liberation from matrix tablet was investigated. The numerical optimization procedure was also applied to establish and obtain formulation with desired drug release. The amount of TP released, release rate and mechanism varied with carbomer ratio in total matrix and HPMC viscosity. Increasing carbomer fractions led to a decrease in drug release. Anomalous diffusion was found in all matrices containing carbomer, while Case — II transport was predominant for tablet based on HPMC only. The predicted and obtained profiles for optimized formulations showed similarity. Those results indicate that Simplex Lattice Mixture experimental design and numerical optimization procedure can be applied during development to obtain sustained release matrix formulation with desired release profile.     

Pharmacokinetics and dose proportionality of D2-agonist MK-458 (HPMC) in parkinsonism.

To investigate the pharmacokinetic profile, bioavailability, and dose proportionality of the D2-agonist MK-458 (hydroxypropylmethylcellulose tablet, a sustained release formulation), a 4-period crossover study was conducted in 10 patients with mild to moderate Parkinson's disease (mean age = 63 y; 1 woman, 9 men). Following a titration phase to induce tolerance, each patient was given single oral doses of 6, 12 and 18 mg and a single intravenous 40 micrograms dose (5 micrograms/h over 8h). The maximum concentrations of MK-458 observed in plasma after oral administration were 139, 240 and 344 ng/L for the 6, 12 and 18 mg doses, respectively, and occurred after 8.0, 9.0 and 5.5 h, respectively. Mean areas under the plasma concentration-time curves were 1728, 2849 and 5484 ng/L.h, respectively. The mean plasma half-life was 3.8 h and mean plasma clearance was 3390 ml/min (203.4 L/h). The bioavailability (approximately 5%) was very similar for the 3 tablet formulations tested. The disposition of MK-458 was independent of the dose over the range of doses studied.     

羟丙基甲基纤维素对水溶性药物释放的影响

以维生素Ｃ为水溶性药物的模型物，三种不同粘度的羟丙基甲基纤维素制成的凝胶骨架片，以Ｋ１００Ｍ规格对维生素Ｃ的释放有延缓作用。维生素Ｃ民羟丙基甲基纤维素的四种不同比例量制成的凝胶骨架片，其中以１：１的比例量，对维生素Ｃ的释放更缓慢。在凝胶骨架片中含有乳糖时，可加快维生素Ｃ的释放。     

效应面法优化尼美舒利双层缓释片处方

采用正交设计及星点设计-效应面法对尼美舒利双层缓释片处方进行优化。优化后的处方如下：（Ⅰ）速释层：尼美舒利,50 mg;乳糖,92 mg;淀粉,22 mg;CCMC-Na,14 mg;PVP K30,1 mg;微粉硅胶,1 mg;硬脂酸镁,0.9 mg;氧化铁红,0.1 mg;（Ⅱ）缓释层：尼美舒利,150 mg;HPMC K100LV,26 mg;HPMC K4M,33 mg;乳糖,54 mg;PVP K30,1 mg;微粉硅胶,1 mg;硬脂酸镁,0.9 mg。优化后的处方在初期药物快速释放（10 min释放15%）,后期缓慢释放持续一段时间（16 h）,具有双相释放特征,且放置6个月后无明显变化。     

曲尼司特缓释片的制备及其释药影响因素研究

目的　制备了曲尼司特凝胶骨架片。方法　采用HPMCK4M、K15M为凝胶骨架材料 ,进行了处方研究 ;通过测定制剂体外释放度 ,评价了该缓释片处方。结果　曲尼司特缓释片体外释药符合Higuchi方程 ,其释药速率常数Kr为 0 193h-1/ 2 。影响缓释片体外释药的因素有骨架材料的种类、用量、粘合剂的种类和释药介质的pH等。结论　缓释片具有明显的缓释作用 ,可缓慢释药 12h。     

Bioavailability of propranolol hydrochloride tablet formulations: application of multiple dose crossover studies

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.     

Design and in vitro testing of a floatable gastroretentive tablet of metformin hydrochloride

Metformin hydrochloride, which is better absorbed in the upper intestine, was formulated as a floating (buoyant) matrix tablet using a gas generating agent (sodium bicarbonate) and a gel forming hydrophilic polymer (hydroxypropyl methylcellulose). The formulation was optimized on the basis of floating ability and in vitro drug release. The resulting formulation produced robust tablets with optimum hardness, consistent weight uniformity and low tablet friability. All tablets but one exhibited satisfactory (gradual and near complete) drug release and buoyancy. In vitro drug release tests of these tablets indicated controlled sustained release of metformin hydrochloride and 96-99% released at the end of 8 h. Two formulations of fabricated tablets containing metformin hydrochloride (500 mg), sodium bicarbonate (75 mg), hydroxypropyl methylcellulose-K 4M (170-180 mg), citric acid (between 15 and 20 mg) and polyvinyl pyrrolidone K90 (32-40 mg) with hardness between 6.8 to 7.5 kg/cm2 showed a floating time of more than 8 h and promising drug release results. The release followed the Higuchi kinetic model, indicating diffusion dominated drug release.     

Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam.

The purpose of this study was to investigate the influence of hydroxypropyl methylcellulose (HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of controlled release formulations containing alprazolam. Tablet formulations contained alprazolam, excipients, and either HPMC K4MP or HPMC K100LVP. A ten patient in vivo clinical trial using a randomized, open-label, four-way crossover design was conducted in the fed and fasted states. Plasma alprazolam concentrations were determined for 72 h. The pharmacodynamic effects of alprazolam were monitored using subject rated sedation on visual analogue scale for wakefulness, observer rated sedation, and symbol digit modalities test (SDMT). Results indicated that the tablet formulations containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles, and the dissolution profiles did not change through 6 months at 40 degrees C/75% RH or 12 months at 25 degrees C/65% Relative Humidity (RH). The area under the plasma concentration-time curve, time to peak concentration, and peak plasma concentration were not significantly different between the two tablet formulations investigated in either the fed or fasted states. Pharmacodynamically, no significant differences in SDMT scores between the two formulations were found. In vitro dissolution results predicted in vivo pharmacokinetic and pharmacodynamic results irrespective of formulation or diet used in the controlled release tablet. The controlled release tablets were bioequivalent and pharmacodynamically equivalent irrespective of the tablet formulation.     

Formulation and optimization of sustained release matrix tablet of metformin HCl 500 mg using response surface methodology

The aim of the current study was to design an oral sustained release matrix tablet of metformin HCl and to optimize the drug release profile using response surface methodology. Tablets were prepared by non-aqueous wet granulation method using HPMC K 15M as matrix forming polymer. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile. HPMC K 15M (X(1)) and PVP K 30 (X(2)) were taken as the independent variables. The dependent variables selected were % of drug released in 1 hr (rel(1 hr)), % of drug released in 8 hrs (rel(8 hrs)) and time to 50% drug release (t(50%)). Contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. The formulated tablets followed Higuchi drug release kinetics and diffusion was the dominant mechanism of drug release, resulting in regulated and complete release within 8 hrs. The polymer (HPMC K 15M) and binder (PVP K 30) had significant effect on the drug release from the tablets (p<0.05). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (p<0.05). Validation of optimization study, performed using 8 confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (+/-S.D.) 0.0437+/-0.3285. Besides unraveling the effect of the 2 factors on the in vitro drug release, the study helped in finding the optimum formulation with sustained drug release.