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.     

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.     

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。     

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.     

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.     

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.     

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。     

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。     

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。     

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。     

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.     

Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets

The aim of this study was to develop sustained-release matrix tablets by means of injection moulding and to evaluate the influence of process temperature, matrix composition (EC and HPMC concentration) and viscosity grade of ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) on processability and drug release. The drug release data were analyzed to get insight in the release kinetics and mechanism. Formulations containing metoprolol tartrate (30%, model drug), EC with dibutyl sebacate (matrix former and plasticizer) and hydrophilic polymer HPMC were extruded and subsequently injection moulded into tablets (375 mg, 10 mm diameter, convex-shaped) at temperatures ranging from 110 to 140 °C. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4 mPa s) showed an incomplete drug release within 24 h (<50%). Increasing production temperatures resulted in a lower drug release rate. Substituting part of the EC fraction by HPMC (HPMC/EC-ratio: 20/50 and 35/35) resulted in faster and constant drug release rates. Formulations containing 50% HPMC had a complete and first-order drug release profile with drug release controlled via the combination of diffusion and swelling/erosion. Faster drug release rates were observed for higher viscosity grades of EC (Mw > 20 mPa s) and HPMC (4000 and 10,000 mPa s). Tablet porosity was low (<4%). Differential scanning calorimetry (DSC) and X-ray powder diffraction studies (X-RD) showed that solid dispersions were formed during processing. Using thermogravimetrical analysis (TGA) and gel-permeation chromatography no degradation of drug and matrix polymer was observed. The surface morphology was investigated with the aid of scanning electron microscopy (SEM) showing an influence of the process temperature. Raman spectroscopy demonstrated that the drug is distributed in the entire matrix, however, some drug clusters were identified.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH 7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr < alg < pectin < NaCMC < trgh < HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

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.     

吡嘧司特钾水凝胶骨架缓释片的研究

目的研制吡嘧司特钾(TBX)水凝胶缓释骨架片.方法以羟丙甲基纤维素(HPMC)为骨架材料,考察HPMC用量、黏度及压片压力等对主药体外释放速度的影响,优化处方工艺.结果所得片剂体外释放实验表明10h累积释放度＞75%,其释放行为符合Hguchi方程.HPMC的用量、黏度、制备方法及压片片力的大小等对TBX的释放速率均有显著影响.结论用高黏度的HPMC作为亲水凝胶骨架片的基质能达到较好的缓释作用.     

Mixed Polymer Coating for Modified Release from Coated Spheroids

Modified-release drug spheroids coated with an aqueous mixture of high-viscosity hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were formulated. The preparation of core drug spheroids and the coating procedures were performed using the rotary processor and a bottom-spray fluidized bed, respectively. Dissolution studies indicated that incorporation of suitable additives, such as poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) 400 (PEG) improved the flexibility and integrity of the coat layer by retarding the drug release. An increase in coating levels applied generally retarded the release rate of the drug. However, the ratio of HPMC to NaCMC in the mixed, plasticized polymeric coat played a more dominant role in determining the dissolution T_50% values. The optimal ratio of HPMC to NaCMC for prolonged drug release was found to be 3:1, whereas an increase in the amount of NaCMC in the mixed polymer coat only increased drug release. The synergistic viscosity effect of HPMC and NaCMC in retarding drug release rate was greater in distilled water than in dissolution media of pH 1 and 7.2. Cross-sectional view of the scanning electron micrograph showed that all of the coated spheroids exhibited a well-fused, continuous, and distinct layer of coating film. The drug release kinetics followed a biexponential first-order kinetic model.     

Mixed polymer coating for modified release from coated spheroids

Modified-release drug spheroids coated with an aqueous mixture of high-viscosity hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were formulated. The preparation of core drug spheroids and the coating procedures were performed using the rotary processor and a bottom-spray fluidized bed, respectively. Dissolution studies indicated that incorporation of suitable additives, such as poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) 400 (PEG) improved the flexibility and integrity of the coat layer by retarding the drug release. An increase in coating levels applied generally retarded the release rate of the drug. However, the ratio of HPMC to NaCMC in the mixed, plasticized polymeric coat played a more dominant role in determining the dissolution T50% values. The optimal ratio of HPMC to NaCMC for prolonged drug release was found to be 3:1, whereas an increase in the amount of NaCMC in the mixed polymer coat only increased drug release. The synergistic viscosity effect of HPMC and NaCMC in retarding drug release rate was greater in distilled water than in dissolution media of pH 1 and 7.2. Cross-sectional view of the scanning electron micrograph showed that all of the coated spheroids exhibited a well-fused, continuous, and distinct layer of coating film. The drug release kinetics followed a biexponential first-order kinetic model.     

Formulation development of Carvedilol compression coated tablet

Purpose: The aim of present research was to produce carvedilol compression coated tablet to provide biphasic drug release.

Method: A compressed coated tablet made of a sustained release core tablet and an immediate release coat tablet. Both the core and the coat contained carvedilol. The sustained release effect was achieved with polymers (HPMC K₄M and PEO WSR 205) to modulate the release of the drug. The powder blends for core and coat tablets were evaluated for angle of repose, bulk density, compressibility index, and drug content. Compressed coated tablets were evaluated for thickness, diameter, weight variation test, drug content, hardness, friability, disintegration and in vitro release studies.

Result: The powder blends showed satisfactory flow properties, compressibility, drug content and all the tablet formulations showed acceptable pharmaco-technical properties. Carvedilol contained in the fast releasing component was released within 3?min, whereas the drug in the core tablet was released at different times up to 24?h, depending on the composition of the matrix tablet. The mechanism of drug release was fickian diffusion or anomalous behavior.

Discussion: Batch F7, containing 10?mg PEO WSR 205 and 5?mg HPMC K₄M, showed maximum similarity with theoretical profile and zero order drug release kinetic.     

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 (diltiazamhydrochloride,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 (Tlag)及释药速率常数 (k)将各因素 (外衣层中的HPMC用量和粘度 ,PVPK30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 ,Tlag延长 ,k减慢 ;PVPK30用量增大 ,Tlag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。