Development of a prolonged-release gastroretentive tablet formulation of ciprofloxacin hydrochloride: pharmacokinetic characterization in healthy human volunteers

The fluroquinolone anti-biotic ciprofloxacin is primarily dissolved and absorbed from the upper part of the GI tract. We, therefore, aimed to develop a prolonged release gastroretentive (GT) formulation of ciprofloxacin that could be administered once daily with a conventional tablet (CT). A variety of polymers and effervescent properties were utilized to optimize the desired disposition profile. Tablets were prepared by the direct compression technique and evaluated for physical properties, swelling, floating, and drug release. In vivo studies were also carried out on the optimized GT formulation and CT in healthy volunteers. A very sensitive and reliable HPLC method was developed to measure plasma concentration of ciprofloxacin. The duration of floating times were predominantly >24 h and floating lag times <20 s. The drug release mechanism followed zero order kinetics. C(max), T(max), and AUC(0-∞) of GT vs CT were 0.945±0.29 vs 2.1±0.46 μg/ml, 6.0±1.42 vs 1.42±0.59 h and 8.54±1.87 vs 9.45±2.12 μg/ml/h, respectively. Pharmacokinetic parameters indicate that the developed GT formulation extended the pharmacokinetic profile achieved with CT. The C(max)/MIC and AUC(0-∞)/MIC, which are indicative of eradication of pathogens, following co-administration of GT with CT were comparable to those of twice-daily administration of CT alone.     

复方盐酸二甲双胍片的人体生物等效性

目的研究试验制剂国产复方盐酸二甲双胍片与参比制剂格列本脲片、盐酸二甲双胍片的人体生物等效性。方法健康志愿者20名,随机双交叉单剂量口服2种制剂,2次服药间隔为2 wk。分别于服药后24 h内多点抽取静脉血,用RP-HPLC测定血浆中格列本脲和盐酸二甲双胍的浓度。血药浓度经3P97程序处理,用非房室模型估算药动学参数。结果试验制剂和参比制剂血浆中格列本脲的ρmax分别为(190.91±45.01)(、175.71±27.47)μg.L-1,tmax分别为(2.60±0.87)、(2.35±0.71)h,AUC0→24分别为(1 110.85±275.12)(、1 074.77±202.76)μg.h.L-1,AUC0→∞分别为(1 187.91±275.55)(、1 168.52±168.65)μg.h.L-1;二甲双胍的ρmax分别为(3.06±0.63)、(3.06±0.55)mg.L-1,tmax分别为(1.57±0.37)(、1.65±0.37)h,AUC0→12分别为(12.05±1.92)、(12.05±1.79)mg.h.L-1,AUC0→∞分别为(12.47±1.97)(、12.51±1.80)mg.h.L-1。以格列本脲和盐酸二甲双胍计算的人体相对生物利用度分别为(103.8±17.9)%和(100.7±13.0)%。结论2种制剂具有生物等效性。     

复方盐酸二甲双胍片在健康人体的药代动力学和相对生物利用度

目的研究复方盐酸二甲双胍片在健康人体的药代动力学和相对生物利用度。方法用交叉给药方法,22名健康受试者单次口服盐酸二甲双胍片1000mg加格列本脲片5mg(参比制剂)或复方盐酸二甲双胍片(试验制剂:盐酸二甲双胍1000mg,格列本脲5mg)。用HPLC法测定血清中盐酸二甲双胍浓度,用LC-MS方法测定血清中格列本脲浓度。用3P97程序以房室模型计算药代动力学参数。结果主要药代动力学参数,试验与参比制剂中盐酸二甲双胍的达峰时间tmax分别为(2.36±0.69),(2.41±0.70)h;Cmax分别为(1.42±0.28),(1.36±0.28)mg·L-1;t1/2分别为(5.18±1.62),(6.25±1.42)h;AUC0-24分别为(10.22±1.53),(10.07±1.81)mg·h·L-1。试验制剂的相对生物利用度为(99.3±13.2)%。参比与试验制剂中格列本脲的达峰时间tmax分别为(2.70±0.60),(2.60±0.50)h;Cmax分别为(181.1±58.3),(214.3±8.01)ng·mL-1;t1/2分别为(6.79±1.96),(6.67±1.92)h;AUC0-24分别为(0.99±0.28),(1.14±0.42)mg·h·L-1。试验制剂的相对生物利用度为(113.2±23.9)%。结论参比与试验制剂具有生物等效性。     

Preparation of highly porous gastroretentive metformin tablets using a sublimation method

The present investigation is aimed to formulate floating gastroretentive tablets containing metformin using a sublimation material. In this study, the release of the drug from a matrix tablet was highly dependent on the polymer concentrations. In all formulations, initial rapid drug release was observed, possibly due to the properties of the drug and polymer. The effect of the amount of PEO on swelling and eroding of the tablets was determined. The water-uptake and erosion behavior of the gastroretentive (GR) tablets were highly dependent on the amount of PEO. The water-uptake increased with increasing PEO concentration in the tablet matrix. The weight loss from tablets decreased with increasing amounts of PEO. Camphor was used as the sublimation material to prepare GR tablets that are low-density and easily floatable. Camphor was changed to pores in the tablet during the sublimation process. SEM revealed that the GR tablets have a highly porous morphology. Floating properties of tablets and tablet density were affected by the sublimation of camphor. Prepared floating gastroretentive tablets floated for over 24 h and had no floating lag time. However, as the amount of camphor in the tablet matrix increased, the crushing strength of the tablet decreased after sublimation. Release profiles of the drug from the GR tablets were not affected by tablet density or porosity. In pharmacokinetic studies, the mean plasma concentration of the GR tablets after oral administration was greater than the concentration of glucophase XR. Also, the mean AUC_0–∞ values for the GR tablets were significantly greater than the plasma concentrations of glucophase XR.     

自制盐酸二甲双胍缓释片与原研药格华止XR的体外释放一致性研究

目的 :比较自制盐酸二甲双胍缓释片与原研药格华止XR(Glucophage XR,500 mg/片)的体外释放一致性.方法 :使用羟丙甲纤维素和羧甲基纤维素钠为缓释材料,先将盐酸二甲双胍与羧甲基纤维素钠混匀,加入润湿剂80%乙醇溶液,制粒,过20目筛,干燥,整粒.再将干燥后的颗粒与羟丙甲纤维素等混匀,加入硬脂酸镁,压制成片.比较制得的盐酸二甲双胍亲水凝胶缓释骨架片与默克-雪兰诺公司生产的格华止XR的片剂性质,并分别采用使用pH介质的中国药典桨法和使用生物相关介质的美国药典往复筒法进行体外释放度的检测与比较.结果与结论 :使用羟丙甲纤维素和羧甲基纤维素钠制备的盐酸二甲双胍缓释片与格华止XR的片剂物理性质和体外释放行为极其相似.     

Formulation and evaluation of a gastroretentive dosage form of labetalol hydrochloride

Labetalol hydrochloride (LBT), 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl]-benzamide, a non-selective α, β-adrenoceptor antagonist is used in the treatment of hypertension. It shows variable bioavailability ranging from 10–80% which may be attributed to its minimum solubility in pH range 6 to 10, the pH conditions prevailing at the major site of absorption i.e. small intestine. Also due to its half life of 3 to 6 hrs it is administered twice daily. In the present work non-effervescent sustained release gastroretentive floating tablets of labetalol hydrochloride have been developed using various grades of HPMC and Poloxamer M127 as wetting agent. The tablets were evaluated for in vitro drug release, floating time, floating lag time, swelling studies etc. The tablets formulated with HPMC K4M CR and HPMC K15M CR along with Poloxamer showed negligible floating lag time with a total floating time over 12 hrs with complete release. Formulation was optimized using Stat-Ease Design Expert 7.1 software. Optimized batch was evaluated for the effect of change of osmolarity and pH on drug release, floating and swelling behaviour.     

高效液相色谱法测定复方盐酸二甲双胍片中盐酸二甲双胍及格列本脲含量

目的测定复方盐酸二甲双胍中盐酸二甲双胍及格列本脲的含量。方法优化高效液相色谱法条件。 (1)盐酸二甲双胍的色谱条件是 :色谱柱 :HypersilCN(2 0 0mm× 4 6mm ,5 μm,大连依利特 ) ;流动相 :乙腈 - 0 0 0 5mol·L-1NH4H2 PO4(pH 3 5 ,5 3∶4 7) ;检测波长 :2 34nm ;柱温 :35℃ ;流速 :1 0mL·min-1。 (2 )格列本脲的测定 :色谱柱 :HypersilODS柱 (2 0 0mm× 4 6mm ,5 μm,大连依利特 ) ;流动相 :甲醇 - 0 0 0 5mol·L-1NH4H2 PO4(pH3 5 ,5∶3) ;检测波长 :30 0nm ;柱温 :35℃ ;流速 :1 0mL·min-1。结果盐酸二甲双胍和格列本脲的线性范围分别为 5 0～ 5 0 0mg·L-1和4 1 2～ 16 4 8mg·L-1;RSD均不超过 1% ;盐酸二甲双胍质量分别为 80 1、10 0 2、12 0 7μg的回收率分别为 99 9%、10 0 1%、10 0 0 % ,格列本脲质量分别为 80 2 4、10 0 30、12 0 36 μg的回收率分别为 10 1 0 %、99 7%、10 0 2 % ;最低检测限分别为 0 2 0和 0 80mg·L-1。结论本法适于复方盐酸二甲双胍的含量测定     

盐酸二甲双胍缓释片体外释放度研究

目的对盐酸二甲双胍缓释片体外释放度相关因素进行研究。方法对溶出介质、转速、测定波长及辅料等因素进行考察,确定盐酸二甲双胍缓释片体外释放度的测定方法,对测定方法进行回收试验,并对三批样品及参比制剂进行测定。结果采用转篮法,以1000ml水为溶出介质,转速为100rpm/min,采用UV法,测定波长为233nm,将溶出液稀释至1～12.5μg/ml进行测定。结论本释放度方法简单,快速,可用于盐酸二甲双胍缓释片体外释放度测定。     

复方盐酸二甲双胍缓释胶囊的制备及体外释放度考察

目的:研制复方盐酸二甲双胍缓释胶囊,并对盐酸二甲双胍(MH)和格列美脲进行释放度研究。方法:采用挤出滚圆法制备MH微丸,以乙基纤维素水分散体进行包衣,得到MH缓释微丸;采用混合物研磨法,结合湿法制粒技术得到格列美脲速释颗粒。将MH缓释微丸与格列美脲颗粒混合灌装成胶囊。结果:释放度测定结果表明,制得胶囊满足格列美脲在45 min内迅速释放,MH可在12 h内持续缓慢释放。结论:优选工艺稳定,复方盐酸二甲双胍缓释胶囊具有较好的速释、缓释效果。     

RP-HPLC法同时测定复方盐酸二甲双胍片中盐酸二甲双胍和格列美脲的含量

目的建立同时测定复方盐酸二甲双胍片中格列美脲和盐酸二甲双胍含量的方法。方法采用RP-HPLC法。色谱柱为Diamonsil C18柱(150 mm×4.6 mm,5μm),流动相为乙腈-20 mmol.L-1磷酸氢二钠溶液(含8 mmol.L-1十二烷基硫酸钠,磷酸调pH值7.5)(体积比为33∶67),流速为1 mL.min-1,检测波长为228 nm。结果格列美脲和盐酸二甲双胍的线性范围分别为0.1～0.6 mg.L-1(r=0.999 1,n=6)和25.0～150.0 mg.L-1(r=0.999 6,n=6);平均回收率分别为99.4%(RSD=1.0%,n=9)和99.8%(RSD=0.39%,n=9)。结论本方法简便、准确,可用于复方盐酸二甲双胍片的质量控制。     

盐酸二甲双胍缓释片的体外释放特性

目的:考察盐酸二甲双胍缓释片体外释放影响因素,建立其释放度测定方法。方法:采用UV法测定盐酸二甲双胍缓释片在不同溶出递质、不同方法和不同转速的释放度。结果:UV法测定盐酸二甲双胍缓释片释放度线性关系良好,r=0.9999(n=5),线性范围为2~10mg·L-1,回收率和稳定性均良好。药物释放受释放方法和递质的影响。盐酸二甲双胍缓释片体外释放曲线在t=0~12h范围内较符合一级动力学方程。结论:方法简便,结果可靠,可作为盐酸二甲双胍缓释制剂生产过程的质量控制依据。     

不同厂家盐酸二甲双胍缓释片体外释放度考察

目的对不同厂家的盐酸二甲双胍缓释片进行体外释放度考察,为临床合理用药提供依据。方法根据盐酸二甲双胍缓释片标准(进口药品注册标准JX20010451)及相关参考文献,采用溶出度转篮法的装置进行体外释放实验,以pH 6.8磷酸盐缓冲液1 000 mL为释放介质,转速为100 r·min-1,温度为(37±0.5)℃,用紫外分光光度法进行含量测定。分别对不同厂家的盐酸二甲双胍缓释片,进行体外释放试验,计算累积释放百分率,绘制释放曲线;计算f2相似因子。结果两种进口制剂的相似因子f2为93.54。不同国产制剂与进口制剂的相似因子f2依次为:47.80、48.10、49.67、66.27、47.65、70.53、67.05;各国产制剂与BIOVAIL制剂的相似因子f2依次为:49.21、49.49、51.25、67.00、49.05、68.22、67.21。结论不同国产制剂与进口制剂的体外释药行为存在明显差异。     

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

Aim:

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus.

Methods:

Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs.

Results:

The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm². The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%.

Conclusion:

SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.     

Bioequivalence of a generic metformin tablet preparation.

OBJECTIVE: The bioavailability of a generic preparation of metformin (Diabetmin from Hovid Sdn Bhd) was evaluated in comparison with a proprietary product (Glucophage from Lipha Pharma Ltd., UK). PATIENTS AND METHODS: Twenty-four healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters total area under the plasma concentration-time curve (AUC0-infinity), peak plasma concentration (Cmax and time to reach peak plasma concentration (Tmax). RESULTS: No statistically significant difference was observed between the values of the two products in all three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic-transformed AUC0-infinity and Cmax values of Diabetmin over those of Glucophage was found to lie between 0.94-1.03 and 0.94-1.06, respectively, being within the acceptable bioequivalence limit of 0.80-1.25. CONCLUSION: These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, elimination rate constant (k(e)) and apparent volume of distribution (Vd) were calculated. There was no statistically significant difference between the values of the two preparations in the k(e) and Vd. Moreover, the values are comparable to those reported in the literature.     

Compressibility of gastroretentive pellets coated with Eudragit NE using a single-stroke and a rotary tablet press

In this study, 15 kinds of powders with different compression mechanisms were used in the process of filling-binding substances in tablets with pellets. Applied substances possessed dominant brittle time-independent mechanism or time-dependent viscoplastic, viscoelastic mechanism of compression. Using 6 kN compression force in a single-stroke tablet press during 150 ms of compression, damage to the polymer film and pellet core was found in all formulations. As a result, the authors observed an increase of releasing rate of verapamil hydrochloride (VH). A larger contact area between powders and pellets and connected with this better protective properties were ensured by powders with time-independent compression mechanism (eg, D-sorbitol or D-mannitol). Unsymmetrically applied compression force was a reason for inconsistent densification and insufficient protection of the pellets. Taking into consideration the low rotation speed of the turret (10 rpm) in the rotary tablet press, the total compaction time was much longer than in the single-stroke tablet press. The compression time in the case of the rotary tablet press should be considered as the sum of the precompression (about 130 ms) and main compression (about 280 ms) phase times. Compression force applied by upper and lower punch in the precompression and main compression phase was affected uniformly on the pellets' surface, and when protected against fragmentation, allowed only some slight deformation. The powders in tablet formulation were fragmentized and rearranged independent of their compression mechanisms. It was found that the releasing rate of VH from pellets compressed by rotary tablet press with 6, 12, and 18 kN of compression force was similar to the releasing rate from uncompressed pellets.     

Preparation and in vitro/in vivo evaluation of sustained-release metformin hydrochloride pellets.

In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustained-release pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit L30D-55 and Eudragit NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The Cmax, Tmax and relative bioavailability for F-2 and F-3 coated pellets were 1.21 microg/ml, 6 h, 97.6% and 1.65 microg/ml, 8 h, 165%, respectively. Combined use of two Eudragit polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.     

盐酸二甲双胍胃漂浮片的制备及体外释放研究

目的探讨盐酸二甲双胍胃漂浮片的制备及体外释放。方法采用干法直接压片法,以羟丙甲纤维素为主要骨架材料,以十八醇和碳酸氢钠作助漂剂制备盐酸二甲双胍胃漂浮缓释片。对影响释药的因素如骨架材料、碳酸氢钠含量、释放介质等进行考察,并在此基础上采用正交试验设计筛选出最优处方。结果片剂具有良好的漂浮特性,药物释放时间可达6 h以上。最优处方:每片含盐酸二甲双胍60 mg,HPMC 108 mg,十八醇10 mg,NaHCO35.2 mg,乙基纤维素14 mg,聚乙二醇(PEG6000)0.1mg。结论药物通过扩散和凝胶骨架溶蚀共同作用释放,释药曲线较好地符合单指数加Higuchi平方根律方程。     

单方和复方给药后格列美脲在Beagle犬体内药物动力学的比较

目的比较复方二甲双胍格列美脲片与单方格列美脲片中的格列美脲在Beagle犬体内的药物动力学差异。方法6只Beagle随机分为2组,犬单剂量口服单方格列美脲片和复方二甲双胍格列美脲片后,利用LC-MS/MS法分析血浆中格列美脲的浓度。采用DAS 2.1.1软件对主要药物动力学参数进行计算,并用SPSS 16.0软件对其进行配对t检验和非参数检验。结果Beagle犬单剂量口服单方格列美脲片与复方二甲双胍格列美脲片的主要药物动力学参数如下:ρmax分别为(1 722.9±237.8)和(1 860.6±315.2)μg·L-1,tmax分别为(3.3±0.3)和(3.2±0.3)h,AUC0→t分别为(12 456.9±31 93.6)和(12 048.1±3 577.8)μg·h·L-1,AUC0→∞分别为(12 578.4±3 167.2)和(12 330.4±3 756.8)μg·h·L-1。经统计学检验,各药物动力学参数间无显著性差异(P>0.05)。结论复方二甲双胍格列美脲片中的格列美脲在Beagle犬体内的药物动力学过程与单方相比无显著差异。     

盐酸普萘洛尔药物树脂渗透泵控释制剂的设计

目的:制备以盐酸普萘洛尔药物树脂复合物为含药片芯的渗透泵控释片。方法:通过单因素考察,以2f相似因子法筛选适宜的辅料。结果:聚氧乙烯PEO(N80)和NaCl被选为主要辅料。结论:药物树脂复合物可压性极差,需要一种黏度大、可压性好的辅料使之成型。通过验证PEO满足实验要求。离子交换树脂所载药物需要一定离子强度才能被交换释放,NaCl作为离子型促渗剂,与非离子型促渗剂相比能更快、更多地释放药物。此外,NaC l还具有补充渗透泵外环境中用于交换药物所消耗的离子的作用,预防患者由于长期服用诱发体内电解质紊乱。     

QbD-enabled systematic development of gastroretentive multiple-unit microballoons of itopride hydrochloride

Abstract

The objectives of present studies were to develop the systematically optimized multiple-unit gastroretentive microballoons, i.e. hollow microspheres of itopride hydrochloride (ITH) employing quality by design (QbD)-based approach. Initially, the patient-centric QTPP and CQAs were earmarked, and preliminary studies were conducted to screen the suitable polymer, solvent, solvent ratio, pH and temperature conditions. Microspheres were prepared by non-aqueous solvent evaporation method employing Eudragit S-100. Risk assessment studies carried out by constructing Ishikawa cause-effect fish-bone diagram, and techniques like risk estimation matrix (REM) and failure mode effect analysis (FMEA) facilitated the selection of plausible factors affecting the drug product CQAs, i.e. percent yield, entrapment efficiency (EE) and percent buoyancy. A 3³ Box–Behnken design (BBD) was employed for optimizing CMAs and CPPs selected during factor screening studies employing Taguchi design, i.e. drug–polymer ratio (X₁), stirring temperature (X₂) and stirring speed (X₃). The hollow microspheres, as per BBD, were evaluated for EE, particle size and drug release characteristics. The optimum formulation was embarked upon using numerical desirability function yielding excellent floatation characteristics along with adequate drug release control. Drug-excipient compatibility studies employing FT-IR, DSC and powder XRD revealed absence of significant interaction among the formulation excipients. The SEM studies on the optimized formulation showed hollow and spherical nature of the prepared microspheres. In vivo X-ray imaging studies in rabbits confirmed the buoyant nature of the hollow microspheres for 8?h in the upper GI tract. In a nutshell, the current investigations report the successful development of gastroretentive floating microspheres for once-a-day administration of ITH.