Formulation and optimization of a sustained-release tablet of ketorolac tromethamine

The objective of our study was to formulate a sustained-release tablet of Ketorolac tromethamine, which is a nonsteroidal anti-inflammatory agent. A 2 3 full factorial design (8 runs) was selected. The variables studied were the amount of drug (30 and 40 mg), ratio of hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC) (240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-controlled matrix tablets were manufactured by direct compression of formulation ingredients using a Stokes single punch tablet press. Dissolution tests were performed using USP apparatus 3 (Bio-Dis II), at various pHs to mimic the conditions that exist in the gastrointestinal tract. Responses studied included time for 50% of the drug to dissolve ( T 50 ), diffusional exponent ( n ) that characterizes the release mechanism, and percent friability of the tablets. Analysis of variance indicated that the release rate ( T 50 ) was affected by the HPMC/NaCMC ratio, amount of drug, and two-way and three-way interactions; whereas the amount of drug, HPMC/NaCMC ratio, ethylcellulose, and the interaction between drug and HPMC/NaCMC and HPMC/NaCMC and ethylcellulose and also three-way interactions were significantly affecting the diffusional exponent ( n ). The release mechanism was found to be super-case II transport. The friability of the tablets was significantly affected by all three factors: amount of drug, HPMC/NaCMC ratio, and amount of ethylcellulose. The formulation giving the best release characteristics was identified.     

正交试验优选氢溴酸右美沙芬缓释片处方

目的:优选氢溴酸右美沙芬缓释片处方。方法:以羟丙甲基纤维素(HPMC)为缓释材料,制备氢溴酸右美沙芬缓释片。采用正交试验,以体外累积释药率相关指标为评价指标,以处方中HPMC的用量、乳糖用量、乙基纤维素(EC)的浓度为因素进行处方的优化。对优化后处方所制制剂进行体外释药性验证试验及影响因素(高温、强光、高湿)考察。结果:最佳处方为HPMC30mg、乳糖50mg、EC浓度8%。制剂8h累积释药率达70%以上,影响因素试验中除高湿条件外制剂的稳定性均较好。结论:优化所得氢溴酸右美沙芬缓释片处方可行。     

Effect of various surfactants and their concentration on controlled release of captopril from polymeric matrices

Various methods are available to formulate water soluble drugs into sustained release dosage forms by retarding the dissolution rate. One of the methods used to control drug release and thereby prolong therapeutic activity is to use hydrophilic and lipophilic polymers. In this study, the effects of various polymers such as hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC) and sodium carboxymethylcellulose (CMC) and surfactants (sodium lauryl sulphate, cetyltrimethylammonium bromide and Arlacel 60) on the release rate of captopril were investigated. The results showed that an increase in the amount of HPMC K15M resulted in reduction of the release rate of captopril from these matrices. When HPMC was partly replaced by NaCMC (the ratio of HPMC/NaCMC was 5:1), the release rate of the drug significantly decreased. However, there was no significant difference in release rate of captopril from matrices produced with ratios of 5:1 and 2:1 of HPMC/NaCMC. The presence of lactose in matrices containing HPMC and NaCMC increased the release rate of captopril. It was interesting to note that although partial replacement of HPMC by EC reduced the release rate of the drug (ratio of HPMC/EC 2:1), the release rate was increased when the ratio of HPMC/EC was reduced to 1:1. The effects of various surfactants on the release rate of captopril from HPMC/EC (1:1) matrices were also investigated. The results showed that the surfactants did not significantly change the release rate of the drug. Release data were examined kinetically and the ideal kinetic models were estimated for the drug release. The kinetic analysis of drug release data from various formulations showed that incorporation of surfactants in HPMC/EC matrices did not produce a zero-order release pattern.     

Once daily sustained release tablets of venlafaxine, a novel antidepressant.

Venlafaxine is a unique antidepressant that differs structurally from other currently available antidepressants. Sustained release tablets of venlafaxine to be taken once daily were formulated with venlafaxine hydrochloride equivalent to 75 mg of venlafaxine base. Matrix system based on swellable as well as non-swellable polymers was selected for sustaining the drug release. Different polymers viz. hydroxypropylmethylcellulose (HPMC), cellulose acetate, Eudragit RSPO, ethylcellulose etc. were studied. Combinations of non-swellable polymers with HPMC were also tried in order to get the desired sustained release profile over a period of 16 h. The effect of drug to polymer ratio on in vitro release was studied. The marketed formulation was evaluated for different parameters such as appearance, weight variation, drug content and in vitro drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. These were evaluated for appearance, weight variation, thickness, hardness, friability, drug content and in vitro drug release at selected time intervals. In vivo studies were carried out for the optimized formulation in 12 healthy human volunteers and the pharmacokinetic parameters were compared with the marketed one.     

复方阿仑膦酸钠缓释片的制备及体外释放度考察

目的:制备复方阿仑膦酸钠缓释片并考察其体外释放度。方法:以羟丙基甲基纤维素(HPMC)、乙基纤维素(EC)、无水乳糖处方用量为因素,体外释放度为指标,用正交试验优化处方,以湿法制粒压片制备制剂,并考察其体外释放度。结果:筛选最优处方为HPMC 80mg、EC 20mg、无水乳糖20mg。所制制剂可持续12h释药,释放行为符合Higuchi方程。结论:所制缓释片的处方合理,具有良好的缓释效果。     

Matrix properties of a new plant gum in controlled drug delivery

A new plant gum, Okra (extracted from the pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in modified release matrices, in comparison with sodium carboxymethyl cellulose (NaCMC) and hydroxypropylmethyl cellulose (HPMC), using Paracetamol as a model drug. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastro intestinal system, for 6 h. Okra gum matrices provided a controlled-release of Paracetamol for more than 6 h and the release rates followed time-independent kinetics. The release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients, lactose and Avicel, altered the dissolution profile and the release kinetics. Okra gum compared favourably with NaCMC, and a combination of Okra gum and NaCMC, or on further addition of HPMC resulted in near zeroorder release of paracetamol from the matrix tablet. The results indicate that Okra gum matrices could be useful in the formulation of sustained-release tablets for up to 6 h.     

Development and optimization of metoprolol succinate gastroretentive drug delivery system

Metoprolol succinate (MS) gastroretentive (GR) controlled release system was formulated to increase gastric residence time leading to improved drug bioavailability. Box-Behnken model was followed using novel combinations of sodium alginate (SA), sodium carboxymethylcellulose (NaCMC), magnesium alumino metasilicate (MAS) as independent variables. Floating lag time (Flag), t25, t50, t75, diffusion exponent as dependent variables revealed that the amount of SA, NaCMC and MAS have a significant effect (p < 0.05) on t25, t50, t75 and Flag. MSGR tablets were prepared and evaluated for mass, thickness, hardness, friability, drug content and floating property. Tablets were studied for dissolution for 24 h and exhibited controlled release of MS with floating for 16 h. The release profile of the optimized batch MS01 fitted first-order kinetics (R2 = 0.9868, n = 0.543), indicating non-Fickian diffusion or anomalous transport by diffusion and swelling.     

Release of propranolol hydrochloride from matrix tablets containing sodium carboxymethylcellulose and hydroxypropylmethylcellulose.

Hydroxypropylmethylcellulose (HPMC) and three viscosity grades of sodium carboxymethylcellulose (NaCMC), namely NaCMC (Blanose 7H 4XF), NaCMC (Courlose P 800), and NaCMC (Courlose P 350), were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. The effects of changing the ratio of HPMC to NaCMC (Blanose) and the drug/total polymer ratio were examined. The release rates decreased as the proportion of NaCMC in the matrices increased. Zero-order release of propranolol hydrochloride was obtained from matrices containing 285 mg 3:1 NaCMC (Blanose)/HPMC. Differential scanning calorimetry was used to quantify the moisture uptake by the polymers at 37 degrees C. Wafers containing NaCMC (Blanose) or 1:1 HPMC/NaCMC (Blanose) absorbed water similarly. A study of the erosion rates of matrices containing polymer only indicated that NaCMC (Blanose) eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC (Blanose), the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC (Blanose) was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.     

Microporous bilayer osmotic tablet for colon-specific delivery

Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting. The tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan-coating process. The developed microporous bilayer osmotic pump tablet (OPT) did not require laser drilling to form the drug delivery orifice. The colon-specific biodegradation of pectin could form in situ delivery pores for drug release. The effect of formulation variables like inclusion of osmogen, amount of HPMC and NaCMC in core, amount of pore former in semipermeable membrane was studied. Scanning electron microscopic photographs showed formation of in situ delivery pores after predetermined time of coming in contact with dissolution medium. The number of pores was dependent on the amount of the pore former in the semipermeable membrane. In vitro dissolution results indicated that system showed acid-resistant, timed release and was able to deliver drug at an approximate zero order up to 24 h. The developed tablets could be effectively used for colon-specific drug delivery to treat IBS.     

Formulation study and drug release mechanism of a new theophylline sustained-release preparation

Two matrix theophylline tablets with different release mechanisms were compared. Tablet A was a swelling/disintegration-type wax matrix made of hydrophobic wax granules, consisting of stearic acid, hydrogenated oil and glycerol esters of fatty acids, and hydrophilic polymer granules composed primarily of hydroxypropyl methylcellulose (HPMC). We named Tablet A the cluster tablet. Tablet B was a gel matrix made of hydrophobic ethylcellulose granules, consisting of ethylcellulose and hydrogenated oil, and hydrophilic polymer granules consisting of HPMC and hydroxylpropylmethylcellulose acetate succinate (HPMCAS). The formulations were screened in vitro according to their dissolution characteristics. The drug release from each preparation was analyzed using release kinetics theories. In Tablet A, the value of the exponent(n) representing the apparent diffusion mechanism determined from the Korsmeyer-Peppas model equation was about 0.6 and was unlikely to be affected by the rotation speed. In Tablet B, the value of the exponent(n) by the Korsmeyer-Peppas model equation changed with the paddle rotation speed. These results suggested that the drug release mechanism of Tablet B is greatly affected by the extent of physical force in the gastrointestinal tract.     

双氯芬酸钾羟丙基甲基纤维素骨架片体外释药的影响因素

目的考察影响双氯芬酸钾羟丙基甲基纤维素(HPMC)骨架片体外释放的各种因素。方法以HPMC为骨架材料,采用湿颗粒法制备双氯芬酸钾缓释片,考察药物/HPMC比、HPMC黏度、HPMC粒径、释放介质pH、压片压力及桨转速对药物体外释放行为的影响。结果药物/HPMC比、HPMC黏度和释放介质pH显著影响双氯芬酸钾释药速率,HPMC粒径、压片压力和桨转速对双氯芬酸钾释药速率影响较小。结论通过使用合适黏度的HPMC及调节药物/HPMC比可获得具有理想释药行为的双氯芬酸钾HPMC缓释片。     

Formulation design and optimization of fast dissolving clonazepam tablets by sublimation method

Fast dissolving tablets of clonazepam were prepared by sublimation method with a view to enhance patient compliance. A 3(2) full factorial design was applied to investigate the combined effect of two formulation variables: amount of croscarmellose sodium and camphor. Croscarmellose sodium (2-8% w/w) was used as superdisintegrant and camphor (20-40% w/w) was used as subliming agent, to increase the porosity of the tablets, since it helps water to penetrate into the tablets, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 11 s); the formulation containing 5% w/w croscarmellose sodium and 40% w/w camphor was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). Short-term stability (at 40°/75% relative humidity for 3 mo) and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables on the in vitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design checkpoints. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly nine-fold faster drug release (t(50%) 1.8 min) compared to the conventional commercial tablet formulation (t(50%) 16.4 min). Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (P<0.05).     

An approach to formulating an oral floating drug delivery system for dexchlorpheniramine maleate using factorial design

The purpose of this research was to formulate and evaluate a floating tablet formulation of dexchlorpheniramine maleate (DCPM) using full factorial design. A 32 factorial design (nine runs) was utilized to optimize the formulation, the contents of hydroxypropyl methyl cellulose (HPMC) (X1) and Carbopol 934P (X2) being taken as independent variables and t50% (Y1), % drug release after 6 h (Y2), % drug release after 12 h (Y3), and floating lag time (FLT) (Y4) as the dependent variables. The tablets showed 99.2635 to 102.4709 of the labeled amount of dexchlorpheniramine maleate indicating uniformity of content. The tablets containing DCPM released 72.28 to 99.461% of drug at the end of 12 h by an in vitro release study. Hardness, friability, floating capacity, weight variation and content uniformity were also examined. In addition,the tablets were evaluated for in vitro release characteristics for 24 h. The optimal batch (F9) was selected by regression analysis and followed Higuchi kinetics. The drug release mechanism was found to be a complex mixture of diffusion, swelling and erosion. The floating tablets of DCPM developed may be used clinically for prolonged drug release for at least 16 hrs, thereby improving bioavailability and patient compliance.     

Optimization of sustained-release propranolol dosage form using factorial design and response surface methodology

The purpose of this study was to develop propranolol extended release formulations containing hydroxypropylmethylcellulose (HPMC). The results indicate that the drug release from the tablet form containing a high amount of HPMC was incomplete, and avicel addition could increase the release percent at a later stage. In order to readily obtain an optimal formulation, response surface methodology and multiple response optimization utilizing a quadratic polynomial equation was used. The model formulations were prepared according to a factorial design. The effects of causal factors including the HPMC/drug ratio (X1) and avicel level (X2), on drug release were also measured. The drug release percentage at 1.5, 4, 8, 14 and 24 h were the target response and were restricted to not more than 25%, 35-50%, 55-70%, 75-90%, and 95-110%, respectively. The results showed that the optimized formulation provided a dissolution pattern equivalent to the predicted curve, which indicated that the optimal formulation could be obtained using response surface methodology. The mechanism of drug release from HMPC matrices tablets followed quasi-Fickian diffusion.     

吲哚拉辛HPMC骨架片药物释放因素研究

目的 考察影响吲哚拉辛亲水性骨架片体外释药的各种因素。方法 以羟丙基甲基纤维素（HPMC）为骨架材料,用湿法制粒和粉末直接压片法制备缓释骨架片,并考察HPMC用量、粒度、制备方法、片子大小及其它辅料对吲哚拉辛HPMC骨架片的体外释药的影响。结果 吲哚拉辛HPMC骨架片的体外释药均符合Higuchi方程。HPMC的用量,粒度和制法,片子大小对吲哚拉辛的释放速率随HPMC粒度和片子的减小而减慢。淀粉、PVP、MCC的加入（每片HPMC的含量不变）均加快吲哚拉辛释药速率,且加入量不同,其释药速率问具有显著性差异。随着EC加入量的增加（≥40mg。片^-1）．吲哚拉辛释放速率显著加快。结论 HPMC用量和粒度、制备方法、片子大小及其它辅料为影响吲哚拉辛骨架片释放速率主要因素。     

Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: I. Characterization and mechanistic study.

Calcium-induced crosslinking of pectin acts as the dominating factor controlling drug release from pectin-based matrices. The same interaction was employed to modify indomethacin release from HPMC/pectin/calcium matrix in this study. The aim was to characterize the release profiles, and to study the formulation variables and the underlying mechanisms. The matrix tablet was made up of pectin HM 70, calcium chloride and HPMC K4M, and prepared by the wet granulation method. In vitro release was performed in water and characterized by the power law. Matrix erosion was evaluated by studying the weight loss and pectin release. Biphasic release of indomethacin from the HPMC/pectin/calcium matrix tablet was observed, and extraordinary power law exponent n values of over 1.0 were observed. Increase in calcium amount led to more significant retardation on drug release. The two power law parameters, n and K, correlated to the amount of calcium in the matrix. A lag time of over 4 h can be achieved at HPMC/pectin/calcium chloride amount of 100 mg/100 mg/100 mg. Both matrix weight loss and pectin release were linearly correlated to indomethacin release, indicating erosion-controlled drug release mechanisms. The hybrid matrix showed retarded erosion and hydration rate, which served as the basis for retarded indomethacin release. It is concluded that the pectin/calcium interaction can be employed to modify drug release from HPMC/pectin/calcium matrix tablet with biphasic release patterns for potential timed or site-specific drug delivery.     

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.     

布洛芬HPMC骨架片药物释放因素研究

目的 考察影响布洛芬亲水性骨架片体外释药的各种因素。方法 以羟丙基甲基纤维素（HPMC）为骨架材料，用湿法制粒和粉末直接压片法制备缓释骨架片，并考察HPMC用量，粒度，制备方法，片子大小及其它辅料对布洛芬HPMC骨架片的体外释药的影响。结果 布洛芬HPMC骨架片的体外释药均符合Higuchi方程。HPMC的用量，粒度和制法，片子大小对布洛芬的释放速率均有显著影响。湿法制片的释药速率比干法慢。布洛共姝释药速率随HPMC粒度的减小和片子的增大而减慢。淀粉，PVP、MCC、EC的加入（每片HPMC的含量不变）均减慢布洛芬释药速率。结论 HPMC用量、粒度、制备方法、片子大小及其它辅料为布洛芬骨架片释放速率的主要因素。     

乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价

目的进行乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价。方法以中药赶黄草和贯叶连翘的提取物为原料药,以HPMC K4M和PVP K30两种粘度不同,水合行为差异较大的亲水高分子材料联合使用作为骨架材料,制备缓释12 h的"乙肝清骨架缓释片"。以"HPMC+PVP K30"总量在处方中的百分量和HPMC在"HPMC+PVP K30"总量中的百分量为考察因素,通过处方单因素考察和星点设计—效应面法进行优化,得到最佳的制剂处方。并通过均一性实验和体外释药行为研究进行体外评价。结果本片剂优化处方中最低HPMC K4M与PVP K30用量不得低于20%。最佳制剂处方为骨架材料HPMC+PVP K30总量占片剂质量的27.03%,HPMC占HPMC+PVP K30总量的49.04%。本处方具有良好的重现性与稳定性;片剂药物释放符合一级释放模型。结论制备了载药量40%的乙肝清提取物缓释片,并优化得到了其最佳的制剂处方。     

盐酸地尔硫延迟起释型缓释片的研制

目的制备盐酸地尔硫(diltiazam hydrochloride,DIL)延迟起释型缓释片,解析释药机制,并考察外衣层组成对药物释放的影响。方法用干压包衣技术制备盐酸地尔硫的延缓片,用释药时滞(T_lag)及释药速率常数(k)将各因素(外衣层中的HPMC用量和粘度,PVP K30用量、EC粘度及压片压力)对药物的释放效果进行评价。结果 HPMC用量或粘度增大,T_lag延长,k减慢;PVP K30用量增大,T_lag减短,k加快;在一定范围内EC粘度及压片压力波动对释药行为无影响。结论延缓片中药物主要是通过溶蚀机制释放,外衣层的溶蚀速率是决定释药时滞的关键因素。