Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.     

Development of sustained release gastroretentive drug delivery system for ofloxacin: in vitro and in vivo evaluation

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%.     

Preparation,<Emphasis Type="Italic">In vitro</Emphasis>, preclinical and clinical evaluations of once daily sustained release tablets of aceclofenac

The objective of the present study was to develop "once daily" sustained release tablets of aceclofenac by direct compression using hydroxypropyl methylcellulose-K4M (HPMC). The solubility studies of aceclofenac were conducted to select suitable dissolution media. The drug-excipient mixtures were subjected to preformulation studies. The tablets were subjected to physicochemical, in vitro drug release and stability studies. Preclinical (anti-inflammatory, analgesic, pharmacokinetic and toxicity studies) and clinical pharmacokinetic studies were conducted for optimized tablets. Based on the preformulation results, microcrystalline cellulose (MCC), dicalcium phosphate and spray dried lactose (SDL) were selected as directly compressible vehicles. Because of the incompatibility with aceclofenac, SDL was excluded from the study. The physicochemical properties of tablets were found within the limits. By comparing the dissolution profiles with the marketed product, the tablet containing HPMC (45%) and MCC (30%) along with talc and magnesium stearate (1% w/w, each) (Tablet B7) was considered as a better formulation. This tablet exhibited almost similar drug release profile in different dissolution media as that of marketed tablet. Tablet B7 was stable in accelerated conditions for 6 months. The composition of this tablet showed almost similar preclinical pharmacological activities compared to marketed tablet composition and did not exhibit any toxicity in rats and mice with respect to tested haematological and biochemical parameters along with body weight, food and water intake. The pharmacokinetic study in healthy human volunteers indicated that B7 tablet produced an extended drug release of drug upto 24 h as that of marketed product with almost identical pharmacokinetic parameters.     

包衣处方对盐酸文拉法辛微孔渗透泵型控释片体外释药的影响

目的考察包衣处方对盐酸文拉法辛口服微孔渗透泵控释片体外释药的影响,并优选最佳包衣处方。方法考察聚乙二醇400(PEG400)的用量、包衣增量、邻苯二甲酸二丁酯(DBP)的种类和用量4个因素对释放的影响,并通过正交设计优化包衣处方。结果盐酸文拉法辛微孔渗透泵控释片的体外释药符合零级释放规律,释药速率受致孔剂、增塑剂、衣膜厚度的影响均较大。结论通过对包衣处方的优化,盐酸文拉法辛口服微孔渗透泵控释片能够恒速释药。     

Formulation and Evaluation of Tramadol hydrochloride Rectal Suppositories

Rectal suppositories of tramadol hydrochloride were prepared using different bases and polymers like PEG, cocoa butter, agar and the effect of different additives on in vitro release of tramadol hydrochloride was studied. The agar-based suppositories were non-disintegrating/non-dissolving, whereas PEGs were disintegrating/dissolving and cocoa butter were melting suppositories. All the prepared suppositories were evaluated for various physical parameters like weight variation, drug content and hardness. The PEG and cocoa butter suppositories were evaluated for macromelting range, disintegration and liquefaction time. In vitro release study was performed by USP type I apparatus. The prepared suppositories were within the permissible range of all physical parameters. In vitro drug release was in the order of PEG>Agar>cocoa butter. Addition of PVP, HPMC in agar suppositories retards the release. The mechanism of drug release was diffusion controlled and follows first order kinetics. The results suggested that blends of PEG of low molecular weight (1000) with high molecular weight (4000 and 6000) in different percentage and agar in 10% w/w as base used to formulate rapid release suppositories. The sustained release suppositories can be prepared by addition of PVP, HPMC in agar-based suppositories and by use of cocoa butter as base.     

In vitro controlled release of alfuzosin hydrochloride using HPMC-based matrix tablets and its comparison with marketed product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r2 value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

Formulation and development of hydrodynamically balanced system for metformin: in vitro and in vivo evaluation.

The objective of the present study was to develop a hydrodynamically balanced system of metformin as a single unit floating capsule. Various grades of low-density polymers were used for the formulation of this system. They were prepared by physical blending of metformin and the polymers in varying ratios. The formulation was optimized on the basis of in vitro buoyancy and in vitro release in simulated fed state gastric fluid (citrate phosphate buffer pH 3.0). Effect of various release modifiers was studied to ensure the delivery of drug from the HBS capsules over a prolonged period. Capsules prepared with HPMC K4M and ethyl cellulose gave the best in vitro percentage release and were taken as the optimized formulation. By fitting the data into zero order, first order and Higuchi model it was concluded that the release followed zero order release, as the correlation coefficient (R(2) value) was higher for zero order release. It was concluded from R(2) values for Higuchi model that drug release followed fickian diffusion mechanism. In vivo studies were carried out in rabbits to assess the buoyancy, as well as the pharmacokinetic parameters of the formulation using gamma scintigraphy. The formulation remained buoyant during 5h of study in rabbits. The comparative pharmacokinetic study was performed by administration of the optimized HBS capsules and immediate release capsules, both with radiolabeled metformin, using gamma counter. There was an increase in AUC in optimized HBS capsules of metformin when compared with immediate release formulation.     

In Vitro Controlled Release of Alfuzosin Hydrochloride Using HPMC-Based Matrix Tablets and Its Comparison with Marketed Product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r² value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

Design and evaluation of gastroretentive mucoadhesive cephalexin tablets

The aim of this investigation was to develop gastroretentive mucoadhesive tablets of cephalexin, which will retain in the stomach for 10?h. Cephalexin, a first-generation cephalosporin, becomes ionized in intestinal pH because pKa is 4.5 and thus reducing its bioavailability. The various batches were prepared by wet granulation method using variety of mucoadhesive polymers such as hydroxyl propyl methyl cellulose K4M, hydroxyl propyl cellulose, chitosan, carbopol 934P and sodium carboxymethylcellulose and subjected to various evaluation parameters such as mucoadhesive strength, in vitro drug release profile, swelling characteristics and physical properties. It was evident from the study that the formulation containing HPMC K4M and carbopol 934P in combination exhibited maximum mucoadhesive strength of 144.42?gms, in vitro residence time was 8.73?h and in vitro drug release was found to be 75.03% in 10?h with non-Fickian diffusion mechanism. So, the optimized formulation F₂ was further subjected to in vivo retention time in rabbit by X-ray technique, SEM and Accelerated stability studies. Regarding all the properties evaluated, the formulation containing HPMC K4M and carbopol 934P in combination was found to be the best to achieve the aim of this study.     

Formulation optimization of hydrodynamically balanced oral controlled release bioadhesive tablets of tramadol hydrochloride

The directly compressible floating-bioadhesive tablets of tramadol were formulated using varying amounts Carbopol 971P (CP) and hydroxy-propylmethyl cellulose (HPMC), along with other requisite excipients. In vitro drug release profile, floatational characteristics and ex vivo bioadhesive strength using texture analyzer were determined, and systematically optimized using a 3² central composite design (CCD). The studies indicated successful formulation of gastroretentive compressed matrices with excellent controlled release, mucoadhesion and hydrodynamic balance. Comparison of the dissolution profiles of the optimized formulation, with optimal composition of CP:HPMC :: 80.0:125.0, with that of the marketed controlled release formulation other indicated analogy of drug release performance with each other. Validation of optimization study using eight confirmatory experimental runs indicated very high degree of prognostic ability of CCD with mean ± SEM of −0.06% ± 0.37. Further, the study successfully unravels the effect of the polymers on the selected response variables.     

Development of enzyme-controlled colonic drug delivery using amylose and hydroxypropyl methylcellulose: optimization by factorial design

The aim of the present study is to develop colon-targeted drug delivery systems for diclofenac sodium which release the drug specifically and instantly at target site using amylose as a carrier. Coating formulations were designed based on the full factorial design. The evaluated responses were lag time prior to drug release and T90. Compression-coated tablets of diclofenac sodium containing various proportions of amylose and HPMC were prepared. In vitro drug release studies were done by changing pH method with enzyme. In vivo studies were done to confirm the potential of formulation to release the drug at target site. The dissolution data revealed that the ratio of polymers is very important to achieve optimum formulation. Results showed that the tablet prepared according to the above formulation released drug instantly at pH 6.8 (simulating colonic pH). An in vivo study shows that optimized formulation disintegrated in the target region. The results of this study revealed that factorial design is a suitable tool for optimization of coating formulations to achieve colon delivery. It was shown that coating formulation consisting of amylose 285 mg and HPMC 150 mg coating has the potential for colonic delivery of diclofenac sodium irrespective of change in pH in a patient with IBD.     

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。     

阿奇霉素缓释阴道栓的处方优化

目的:优化阿奇霉素缓释阴道栓的处方。方法:采用硬脂酸聚烃氧酯(S-40)为基质,以羟丙基甲基纤维素(HPMC)为缓释材料、甘油为保湿剂等制备阿奇霉素缓释阴道栓。以累积释药百分率和栓剂硬度为考察指标、8%HPMC和甘油在处方中的用量为考察因素,采用正交设计法进行处方优化,并进行验证试验及体外释药模型拟合。结果:优化后处方组成为阿奇霉素6g,8%HPMC23.52g,甘油29.40g,无水乙醇3g,尼泊金乙酯0.59g,S-40294g。由优化后处方制备的3批栓剂平均含量99.5%,硬度符合要求,体外释放重复性和均一性良好,180min时累积释药百分率均大于98%,体外释药动力学符合Higuchi方程。结论:优化后的阿奇霉素缓释阴道栓处方可行,制备工艺稳定,重复性好,符合缓释制剂要求。     

Development of mucoadhesive buccal films for the treatment of oral sub-mucous fibrosis: a preliminary study

The objective of the present study was to develop the mucoadhesive buccal film of valdecoxib for the treatment of oral sub mucous fibrosis, a localized buccal disease. Valdecoxib, a novel COX-2 inhibitor has been reported to be used in various osteopathic and rheumatoid conditions as oral therapy. The films were made out of chitosan and HPMC K4M as polymers. Sodium taurocholate was used as a permeation enhancer. All the formulations were examined for film thickness, swelling properties, drug content, weight variation, in vitro release studies, bioadhesive force, tensile strength, diffusion studies using pig mucosa and pharmacokinetic study in healthy male volunteers. Prepared films were thin, flexible, smooth and transparent. Bioadhesive force and tensile strength of the optimized formulation were found to be 75 ± 4 kg m^?1 S^?2 and more than 2.5 kg/3 cm², respectively. The percent drug content was 98.5 ± 1.3%. The in vitro drug release from the selected formulation showed that about 69.34% of the drug payload was released up to 6 hours. The drug permeation through the dialysis sac and pig buccal mucosa was found to be 62.70% and 54.39%, respectively. Pharmacokinetic studies of the buccal mucoadhesive film showed that the drug was released locally at the target site of action, and a very small amount might have absorbed systemically.     

盐酸美金刚缓释片的制备及其体外释放度考察

目的制备盐酸美金刚缓释片,并对其体外释放行为进行考察。方法以HPMC K15M和HPMC K4M为骨架材料压制缓释片。以HPMC(X1)用量和HPMC K15M/K4M用量之比(X2)为考察因素,以盐酸美金刚在2,6和10h的累积释放度Y2h,Y6h,Y10h为考察指标,利用2因素3水平中心复合设计-效应面法优化处方。在4种介质中考察了盐酸美金刚缓释片的体外释药行为。结果最终优化处方中的HPMC用量为片质量的60.0%,HPMCK15M/K4M用量之比为70∶30,所得缓释片在2,6和10h三点的累积释放度符合20%≤Y2h≤30%,40%≤Y6h≤60%和Y10h≥80%的要求,在12h内释放平稳、完全。结论采用中心复合设计-效应面法优化的处方预测性良好,制得的盐酸美金刚缓释片体外释放符合要求。     

The influence of HPMC viscosity as FRC parameter on the release of low soluble drug from hydrophylic matrix tablets

The importance of functionality-related characteristics (FRC) of hydroxypropyl methylcellulose (HPMC) described in the pharmacopeia monograph can be evaluated only for selected formulation or technological process. The aim of our work was to investigate the influence of apparent viscosity as one of the FRC for two batches of the same HPMC grade on the release properties of diclofenac sodium from HPMC matrix tablets. Our results show that two batches of HPMC differ in viscosity significantly and as a consequence, the significant differences were observed in the release profiles as well. HPMC-B sample has higher viscosity and therefore higher average molecular weight, thus the erosion and drug release were slower compared to HPMC-A sample with lower apparent viscosity. It can be concluded that batch-to-batch viscosity variation of the same HPMC grade can lead to the different release profiles; therefore the specification limits of some FRC should be postulated during the development of each individual formulation. However, the viscosity interval as FRC can not be generalized, because it is different for different tablet compositions.     

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.     

Preparation of scopolamine hydrobromide nanoparticles-in-microsphere system

This study is to prepare scopolamine hydrobromide nanoparticles-in-microsphere system (SH-NiMS) and evaluate its drug release characteristics in vitro. SH nanoparticles were prepared by ionic crosslinking method with tripolyphosphate (TPP) as crosslinker and chitosan as carrier. Orthogonal design was used to optimize the formulation of SH nanoparticles, which took the property of encapsulation efficiency and drug loading as evaluation parameters. With HPMC as carrier, adjusted the parameters of spray drying technique and sprayed the SH nanoparticles in microspheres encaposulated by HPMC was formed and which is called nanoparticles-in-microsphere system (NiMS). SH-NiMS appearances were observed by SEM, structure was obsearved by FT-IR and the release characteristics in vitro were evaluated. The optimized formulation of SH nanoparticles was TPP/CS 1:3 (w/w), HPMC 0.3%, SH 0.2%. The solution peristaltic speed of the spray drying technique was adjusted to 15%, and the temperature of inlet was 110 degrees C. The encapsulation product yeild, drug loading and particle sizes of SH-NiMS were 94.2%, 20.4%, and 1256.5 nm, respectively. The appearances and the structure of SH-NiMS were good. The preparation method of SH-NiMS is stable and reliable to use, which provide a new way to develop new dosage form.     

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.     

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

The objective of this study was to prepare different venlafaxine hydrochloride sustained-release products and to elucidate the influence of composition of the coating film on the in vitro drug release profiles and in vivo pharmacokinetics. Pellets were prepared by a standardized process of extrusion/spheronization. A selected fraction size (0.8-1.0 mm diameter) of pellets of each formulation was coated with Eudragit NE30D or ethylcellulose (10 cps). Many efforts have been made to tailor drug release rate by choosing different coating materials, different percent of pore forming components and coating weight variation to achieve a desired sustained-release effect. The dissolution studies were performed and data were analyzed in terms of cumulative release as a function of time. The influence on the release of venlafaxine from sustained-release capsules was observed in dissolution media of different pH and gradient pH. Scanning electron microscope (SEM) micrographs revealed morphological changes of the pellet coating surface which were related to in vitro drug release profiles. The relative bioavailability for Formulation 1 and Formulation 2 was evaluated in six healthy beagle dogs after oral administration in a fast state using sustained-release capsules (Effexor XR) as a reference. The results suggested that Formulation 1 and Formulation 2 both had better bioavailability compared with Effexor XR. It could be found that there existed quite difference in the in vivo release and oral absorption performances, despite the similar in vitro drug release behavior for the two formulations. It might be attributable to complex in vivo environment and then variation in the release behavior. Thus differences in the film micro-structure and surface roughness caused by aqueous dispersion and organic solvent coating techniques strongly influence the in vivo release and oral absorption performances.