Formulation and Evaluation of Dextromethorphan Hydrobromide Sustained Release Tablets

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.     

In Vitro and In Vivo Studies on HPMC-K-100 M Matrices Containing Naproxen Sodium

Controlled release (CR) matrix tablets of naproxen sodium were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. An optimized formulation subjected to accelerated stability studies for 3 months revealed that the developed CR tablets are stable. A complete cross-over bioavailability study of the optimized formulation of the developed CR tablets and marketed immediate release tablets was performed in 6 healthy male volunteers. The extent of absorption of drug from the CR tablets was significantly higher than that for the marketed naproxen sodium tablet due to lower elimination rate and longer half-life.     

In vitro and in vivo studies on HPMC-K-100 M matrices containing naproxen sodium

Controlled release (CR) matrix tablets of naproxen sodium were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. An optimized formulation subjected to accelerated stability studies for 3 months revealed that the developed CR tablets are stable. A complete cross-over bioavailability study of the optimized formulation of the developed CR tablets and marketed immediate release tablets was performed in 6 healthy male volunteers. The extent of absorption of drug from the CR tablets was significantly higher than that for the marketed naproxen sodium tablet due to lower elimination rate and longer half-life.     

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 Kollidon? SR on the release of Albuterol Sulphate from matrix tablets

The objective of this study was to evaluate Kollidon SR for the development of extended release Albuterol Sulphate matrix tablets in comparison with other polymers as Hydroxypropylmethylcellulose K15M, Carbopol 71G NF, and Eudragit L100-55. The mechanical properties of the tablets were improved as concentration of Kollidon SR or other polymers increased. It was found that Kollidon SR 30% (w/w) and HPMC 30% (w/w) tablets have f₂ similarity factor of 83.5 in their Albuterol Sulphate dissolution profile. The marketed product was found to release 99.7% of drug content within 8 h, while Kollidon SR and HPMC tablets with 30% (w/w) polymer concentration level released 92.7% and 92.9% respectively of drug content within 8 h. Kollidon SR has a unique character of maintaining tablets geometric shape until the end of dissolution test, this is mainly due to the water insoluble content, polyvinyl acetate, forming 80% (w/w) of Kollidon SR, while the remaining content 20% (w/w) is the water soluble, polyvinylpyrrolidone, responsible for pore formation causing a diffusion controlled release. Drug release from all previous formulations is best described to be controlled by more than one kinetic mechanism of release.In conclusion, Kollidon SR and HPMC and Carbopol were found to be potential candidates for the development of extended release of Albuterol Sulphate tablets.     

高效液相色谱法测定人血中氢溴酸右美沙芬浓度

目的研究氢溴酸右美沙芬在健康志愿者体内的血药浓度。方法采用高效液相色谱法测定8例健康受试者口服右美沙芬糖浆和片剂后不同时间血浆中的美沙芬浓度。结果右美沙芬在5--500 ng/ml浓度范围内呈良好线性关系（r=0.9965）。结论本法精密,准确,可用于氢溴酸右美沙芬的药动学研究。     

Development of sustained release fast-disintegrating tablets using various polymer-coated ion-exchange resin complexes

Complex formation between drugs and ion-exchange resins was investigated and the effects of coating by various aqueous polymeric dispersions on the complexes were evaluated for developing new sustained-release fast-disintegrating tablets (FDTs). Complexes of ion-exchange resin and dextromethorphan, a model drug, were prepared using different particle sizes of the resins. Aqueous colloidal dispersions of ethylcellulose (EC) and poly(vinyl acetate) (Kollicoat SR30D) were used for fluid-bed coating. Based on drug loading, release profiles, and scanning electron microscopy (SEM) images, the coated particles were granulated with suitable tablet excipients and then compressed into the tablets. Drug release profiles and SEM pictures were compared before and after the manufacturing processes. As the particle size of resins increased, the drug loading and release rate decreased due to the reduced effective diffusion coefficient and surface area. Higher coating level decreased the release rate further. In contrast to EC, Kollicoat SR30D coated particles could be compressed into tablets without any rupture or cracks on the coating since the mechanical properties of the polymer was more resistant to the manufacturing processes. This resulted in no significant changes in release rates. SEM showed the mechanical strength of the polymers affected the morphological change after compression. When the drug release profiles were applied into Boyd model and Higuchi equation, the linear relationship was observed, indicating that the diffusion within the resin matrix is the rate-controlling step.     

Influence of methacrylic acid and hydroxypropylmethyl cellulose on the tablet properties and in vitro release of dextromethorphan hydrobromide

The release of dextromethorphan hydrobromide from matrices containing hydroxypropylmethyl cellulose (HPMC K100LV) and methacrylic acid copolymer (Eudragit L100-55) has been evaluated at different ratios of the polymers. The physicochemical properties (including weight, thickness, crushing strengh, friability and disintegration time) were also determined at 1000, 2000 and 4000 p compression forces. No significant differences in weight uniformity and thickness values were observed between the different formulations. The crushing strength of the tablets increased with increasing compression force and it reached a constant level at 4000 p. The formulations containing only HPMC K100LV resulted in an extended release pattern, however, Eudragit L100-55 alone could not effectively prolong the drug release. A combination of HPMC K100LV and Eudragit L100-55 in a 1:1 ratio at the 40% level provided an almost similar drug release profile than the marketed product.     

Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics

The objective of this present investigation was to develop and formulate sustained release (SR) matrix tablets of Itopride HCl, by using different polymer combinations and fillers, to optimize by Central Composite Design response surface methodology for different drug release variables and to evaluate drug release pattern of the optimized product. Sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: hydroxy propyl methyl cellulose (HPMC) and polyvinyl pyrolidine (pvp) and lactose as fillers. Study of pre-compression and post-compression parameters facilitated the screening of a formulation with best characteristics that underwent here optimization study by response surface methodology (Central Composite Design). The optimized tablet was further subjected to scanning electron microscopy to reveal its release pattern. The in vitro study revealed that combining of HPMC K100M (24.65 MG) with pvp(20 mg)and use of LACTOSE as filler sustained the action more than 12 h. The developed sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.     

Design and Development of Polyethylene Oxide Based Matrix Tablets for Verapamil Hydrochloride

In the present investigation an attempt has been made to increase therapeutic efficacy, reduced frequency of administration and improved patient compliance by developing controlled release matrix tablets of verapamil hydrochloride. Verapamil hydrochloride was formulated as oral controlled release matrix tablets by using the polyethylene oxides (Polyox WSR 303). The aim of this study was to investigate the influence of polymer level and type of fillers namely lactose (soluble filler), swellable filler (starch 1500), microcrystalline cellulose and dibasic calcium phosphate (insoluble fillers) on the release rate and mechanism of release for verapamil hydrochloride from matrix tablets prepared by direct compression process. Higher polymeric content in the matrix decreased the release rate of drug. On the other hand, replacement of lactose with anhydrous dibasic calcium phosphate and microcrystalline cellulose has significantly retarded the release rate of verapamil hydrochloride. Biopharmaceutical evaluation of satisfactory formulations were also carried out on New Zealand rabbits and parameters such as maximum plasma concentration, time to reach peak plasma concentration, area under the plasma concentration time curve_(0-t) and area under first moment curve_(0-t) were determined. In vivo pharmacokinetic study proves that the verapamil hydrochloride from matrix tablets showed prolonged release and were be able to sustain the therapeutic effect up to 24 h.     

Design and evaluation of taste masked dextromethorphan hydrobromide oral disintegrating tablets

The present study is aimed to develop dextromethorphan hydrobromide (DXM) oral disintegrating tablets (ODT) with acceptable palatability to help patients of all age groups. The bitter taste of the drug was masked by binding the drug to ion exchange resin. The effect of the particle size of resin on drug loading was studied. In vitro and in vivo disintegration time and in vitro drug release studies were performed. Drug loading increased significantly with a decrease in the particle size of the resin. DSC and XRPD studies reveal that the molecular state of the drug changed from crystalline to amorphous form. The dissolution efficiency calculated for optimized ODT and conventional directly compressed tablet were almost comparable, indicating free dissociation of the drug from the resinate. The bitter taste of DXM can be masked by binding with ion exchange resin and the resinate can be successfully formulated into oral disintegrating tablets.     

Preparation and evaluation of taste-masked dextromethorphan oral disintegrating tablet

This study was aimed at preparing and evaluating oral disintegrating tablets (ODTs) using a strongly cationic resin, Amberlite(?) IRP-69, to mask the bitter taste of a delivered drug, i..e. dextromethorphan hydrobromide. The drug was loaded into the resin (referred to as resinate) or physically mixed with the resin (referred to as physical mixture), and was then incorporated into ODTs by direct compression. A variety of formulae was developed to acquire the optimal formulations of taste-masked ODTs that had acceptable hardness and mouth feel (grittiness). The optimized ODTs were further evaluated for thickness, diameter, weight, friability, disintegration time, wetting time, wetting rate, drug content, drug release and degree of bitter taste, respectively. The thickness, diameter, weight and friability of the tablet with resinate were slightly higher than those with physical mixture. The tablet with resinate had a longer disintegration time, corresponding with its slower wetting time and rate. Both tablets with resinate and physical mixture provided a sustained pattern of drug release. However, only tablets with resinate successfully masked the bitter taste of the drug. In conclusion, the combination of drug and ion exchange resin as resinate could increase the palatability and acceptability of ODTs containing bitter drugs.     

Alginate-diltiazem hydrochloride beads: optimization of formulation factors,in vitro and in vivo availability

Alginate beads containing diltiazem hydrochloride (DTZ) were prepared by the ionotropic gelation method. The effects of various factors (alginate concentration, additives type, calcium chloride concentration and curing time) on the efficiency of drug loading were investigated. The formulation containing a mixture of 0.8% methylcellulose (MC) and 4% alginate cured in 2% calcium chloride for 6 h was chosen as the best formula regarding the loading efficiency. The release rate of DTZ from various beads formulations was investigated. The release of drug from alginate beads followed two mechanisms; by diffusion and relaxation of the polymer at pH 1.2, whilst diffusion and erosion are at pH 6.8. The in vitro release of DTZ from MC-alginate beads showed an extended release pattern which was compared with that from commercially available sustained-release (Dilzem SR) and fast release tablets (Dilzem). Thermal analysis revealed that the drug was molecularly dispersed in the beads matrix. Although the release characteristics of DTZ from Dilzem SR and MC-alginate beads were completely different, the bioavailability of DTZ in dogs was comparable as measured by AUC, MRT and relative bioavailability. The absolute bioavailability of MC-alginate beads and Dilzem SR was 88 and 93%, respectively.     

Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets

The objective of this study was to evaluate the potential of Carbopol^® 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC^® K15M) and Eudragit^® L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P?<?0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P?<?0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P?<?0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P?<?0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P?<?0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.     

Bioavailability of dextromethorphan (as dextrorphan) from sustained release formulations in the presence of guaifenesin in human volunteers

A multiple dose bioavailability study with six healthy male human volunteers was conducted. The bioavailability of an experimental sustained release tablet containing dextromethorphan hydrobromide (DXP-HBr), was compared with a marketed sustained release DXP-HBr suspension in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analysed for the major metabolite of dextromethorphan (DXP), dextrorphan (DX), using a specific HPLC method with fluorescence detection. The bioavailability parameters; area under the concentration–time curve (AUC), maximum plasma concentration (C_max), and time to peak (T_max), were obtained from the plasma concentration–time data. Additionally, pharmacokinetic parameters such as mean residence time (MRT), accumulation factor (R), fluctuation index (F_i), total body clearance (Cl), and the average concentration (C ¯) were estimated by using model independent kinetics approach. Analysis of variance of the data revealed that the presence of guaifenesin in the test formulation does not appear to have a statistically significant (p >0.05) effect on the bioavailability of dextromethorphan as dextrorphan. The relative bioavailability of the tablet dosage form with respect to the suspension was found to be 113% on Day 1 and 110% on Day 6. Copyright © 1998 John Wiley & Sons, Ltd.     

氢溴酸高乌甲素亲水凝胶骨架片的制备及体外释放

目的为了减少给药次数,方便患者,并提高镇痛效果,制备氢溴酸高乌甲素亲水凝胶骨架片,优化制剂处方,并探讨释放机制。方法以羟丙甲纤维素(HPMC)为骨架材料,乳糖、微晶纤维素(MCC)、淀粉为填充剂,硬脂酸镁为润滑剂制备氢溴酸高乌甲素骨架片,考察各因素对药物释放度的影响,筛选优化处方,并拟合讨论其释放机制。结果 HPMC的用量及分子量,微晶纤维素和硬脂酸镁的用量对药物释放有显著影响。所制缓释片无突释现象,缓释周期12 h,根据拟合方程,药物释放符合一级释放模型,其释放既有扩散,又有骨架溶蚀。结论本方法制备的氢溴酸高乌甲素缓释片工艺简单,生产成本低,且具有良好的释放性能。     

In vitro characterization and release study of Ambroxol hydrochloride matrix tablets prepared by direct compression

A series of either hydrophilic or hydrophobic polymers were used to prepare controlled release Ambroxol hydrochloride (AMX) matrix tablets by direct compression. Both the compatibility and flow properties of AMX/polymer mixtures were investigated. The effect of the amount and type of polymer on the physical properties and in vitro drug release was studied and compared to commercially available Ambroxol(?) SR capsules. A kinetic study of the release profile of AMX from the prepared matrix tablets was performed. All excipients used in the study were compatible with the model drug. AMX/drug mixtures containing sodium alginate (NA) and hydroxypropylmethyl cellulose (HPMC) showed better flow properties than other polymers used in the study. The in vitro drug release studies showed that matrix tablets formulae containing 10% HPMC (S7) or a combination of 30% NA and 5% HPMC (Ah) exhibited a higher ability to control the release of AMX. The kinetic study revealed that a diffusion controlled mechanism prevailed except when carbopol was used. Formula Ah followed a non-fickian diffusion mechanism similar to Ambroxol(?) SR capsules. Both formulae S7 and Ah could be considered as potential candidates for formulation of AMX controlled release matrix tablets.     

Hydrophobic weak acid polymers as controlled release carriers

Poly(carboxyalkyl methacrylates) were studied as a cationic-drug delivery system, at pH 6.8 and 8.0. Different polymer/drug complexes were used to prepare compressed tablets. By kinetics experiments, we have found that drug release is dependent on both the hydrophobicity of the whole complex and the pH of the environment. Furthermore, a mechanism of dissociation/erosion clearly describes the drug release from a complex formed by a polymer soluble at target pH; otherwise, a mechanism of dissolution/diffusion is depicted. Additionally, we have observed that hydrophilic fillers increase the drug release rate. Since our results using different polymer/drug complexes exhibit pH-sensitive drug release, we propose that the poly(carboxyalkyl methacrylates) have potential as a colon-specific drug-delivery system.     

Hydrophobic weak acid polymers as controlled release carriers

Poly(carboxyalkyl methacrylates) were studied as a cationic-drug delivery system, at pH 6.8 and 8.0. Different polymer/drug complexes were used to prepare compressed tablets. By kinetics experiments, we have found that drug release is dependent on both the hydrophobicity of the whole complex and the pH of the environment. Furthermore, a mechanism of dissociation/erosion clearly describes the drug release from a complex formed by a polymer soluble at target pH; otherwise, a mechanism of dissolution/diffusion is depicted. Additionally, we have observed that hydrophilic fillers increase the drug release rate. Since our results using different polymer/drug complexes exhibit pH-sensitive drug release, we propose that the poly(carboxyalkyl methacrylates) have potential as a colon-specific drug-delivery system.     

1H核磁共振定量法测定氢溴酸右美沙芬片含量

目的采用1H核磁共振定量法(quantitative proton nuclear magnetic resonance,qHNMR)测定氢溴酸右美沙芬片中氢溴酸右美沙芬含量。方法 qHNMR以氢溴酸右美沙芬化学位移δ7.05~7.15 ppm处质子峰为定量峰,苯甲酸苄酯δ5.38ppm处为内标峰,在温度为300 K,采样时间为4.01 s,弛豫延迟时间10 s,扫描次数为32次条件下采集混合物qHNMR图谱。比较qHNMR与HPLC的含量测定结果。结果 qHNMR专属性较高,线性范围5.88~23.08mg·mL^-1,回收率为98.4%~99.7%,定量限为0.45 mg·mL^-1,检测限为0.10 mg·mL^-1。qHNMR含量测定结果与HPLC的测定结果基本一致。结论 qHNMR可用于氢溴酸右美沙芬片中氢溴酸右美沙芬的含量测定。