Evaluation of chitosaneanionic polymers based tablets for extended-release of highly watersoluble drugs

The objective of this study is to develop chitosaneanionic polymers based extendedrelease tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading.Here,the combination of sodium valproate(VPS)and valproic acid(VPA)were chosen as the model drugs.Anionic polymers studied include xanthan gum(XG),carrageenan(CG),sodium carboxymethyl cellulose(CMC-Na)and sodium alginate(SA).The tablets were prepared by wet granulation method.In vitro drug release was carried out under simulated gastrointestinal condition.Drug release mechanism was studied.Compared with single polymers,chitosaneanionic polymers based system caused a further slowdown of drug release rate.Among them,CS exanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h.Differential scanning calorimetry(DSC)and Fourier transform infrared spectroscopy(FTIR)studies demonstrated that polyelectrolyte complexes(PECs)were formed on the tablet surface,which played an important role on retarding erosion and swelling of the matrix in the later stage.In conclusion,this study demonstrated that it is possible to develop highly water-soluble drugs loaded extendedrelease tablets using chitosaneanionic polymers based system.

Design and evaluation of an extended-release matrix tablet formulation; the combination of hypromellose acetate succinate and hydroxypropylcellulose

The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.

Evaluation Procedure for Quality Consistency of Generic Nifedipine Extended-Release Tablets Based on the Impurity Profile

A procedure to evaluate the quality consistency of generic drugs based on the impurity profile and the similarity analysis methods was presented in this paper. Nifedipine extended-release tablets from six generic factories of China were used to evaluate the uniformity with the original drug in the study. The procedure includes: choice of chromatographic methods, data collection and conformity test, evaluation of intra-batch similarity of drugs, evaluation of generic drugs with the original drug and weighted similarity evaluation of generic drugs. The data were collected via high-performance liquid chromatography (HPLC), and then calculated by correlation coefficient, cosine, principal component analysis (PCA) and hierarchical clustering analysis (HCA). It is more suitable to use peak areas as the vector when calculating the similarity of impurity profile. After weighting the peak areas of the unspecified impurities in further evaluation of the generic quality, the generic level of different factories was differentiated and the best generic factory was picked out.

Design and evaluation of nicorandil extended-release tablet

The aim of this study was to design and evaluate extended-release formulations of a model drug,nicorandil,in order to achieve the desired steady-state plasma concentration of drug in vivo.Simulation was employed to estimate optimum dissolution and absorption rate of nicorandil.The dissolution test was employed using pH 1.2,4.0,6.8 buffer solution,or water,to measure the in vitro release behaviors of nicorandil formulations.A single dose(15 mg)of each formulation was orally administered to four beagle dogs under fasted conditions,and the pharmacokinetic parameters were calculated.The in vitro/in vivo relationship of the extended-release formulation was confirmed using in vitro dissolution profiles and plasma concentrations of drug in beagle dogs.Nicorandil was released completely within 30 min from the immediate-release tablets and released for 24 h from the extended-release tablets.The nicorandil plasma concentration could be modified by adjusting the drug release rate from the extended-release formulation.The release rate of nicorandil was the rate-limiting step in the overall absorption of drug from the extendedrelease formulations.These results highlight the potential of a nicorandil extended-release formulation in the treatment of angina pectoris.

Self-Reported Adherence after Overnight Switching from Immediate- to Extended-Release Pramipexole in Parkinson’s Disease

Background: Drug adherence decreased in patients with Parkinson’ s disease (PD) because of taking many different types of drugs. We evaluated drug adherence after switching from immediate-release (IR) to once-daily extended-release (ER) pramipexole (PPX) in PD. Methods: This study included 35 PD patients (20 men, 15 women);10 were taking oral PPX alone, and 25 were also using another anti-PD drug. PPX-IR was switched overnight to PPX-ER without gradual tapering. One month after switching, improvement in timing adherence and reduction in medication burden were evaluated by a questionnaire using a visual analog scale (VAS) (0: No change;10: Better). Motor function was assessed using part III of the Unified Parkinson’s Disease Rating Scale (UPDRS). Results: The VAS score for improvement in timing adherence was 8.1 ± 0.5 (mean ± standard error), and that for reduction in medication burden was 7.3 ± 0.6. There was a significant negative correlation (ρ = -0.43, p = 0.01) between the VAS score and number of types of medications. The UPDRS part III score improved significantly after switching

Combined use of extended-release niacin and atorvastatin： safety and effects on lipid modification

Background Cholesterol-lowering therapy with statins has been reported to reduce the morbidity and mortality of cardiovascular diseases. This study aimed to investigate the effects of combined application of extended-release niacin and atorvastatin on lipid profile modification and the risks of adverse events in patients with coronary artery disease. Methods Consecutive 108 patients with coronary artery disease and serum total cholesterol （TC） 〉 3.5 mmol/L were randomized into two groups： group A using atorvastatin and group B using extended-release niacin （niacin ER） and atorvastatin. Plasma lipid profile, glucose, and adverse events were assessed at the hospitalization, and 6 and 12 months after treatment. In addition, clinical cardiovascular events were evaluated after 12 months of treatment. Results The levels of TC, low density lipoprotein cholesterol （LDL-C） were significantly decreased （P 〈0.05） in groups A and B, but the levels of high density lipoprotein cholesterol （HDL-C） and ApoA increased by 29.36% and 40.81% respectively after 12 months of treatment in group B （P 〈0.01）. The medications were generally well tolerated in the two groups. No significant difference of adverse events was found between the two groups （group A： 3.2% vs group B 5.1%, P 〉0.05）. Conclusions Combined use of extended-release niacin with atorvastatin was superior to atorvastatin monotherapy alone in lipid profile regulation. Combination therapy with niacin ER and atorvastatin was well tolerated and safe in patients with coronary artery disease.

帕利哌酮缓释片与利培酮治疗精神分裂症的对照研究

目的为了比较帕利哌酮缓释片与利培酮治疗精神分裂症患者的疗效及安全性的差异。方法选取某精神病院60例精神分裂症患者,随机分成帕利哌酮组和利培酮组各30例,分别采用帕利哌酮缓释片和利培酮进行治疗,观察8周。以阳性及阴性症状量表(PANSS)减分率评定疗效,用治疗中出现的症状量表(TESS)评定不良反应,以个人和社会功能量表(PSP)评定社会功能。结果帕利哌酮组与利培酮组的总显效率(痊愈+显效)和总有效率(痊愈+显效+有效)的差异不显著(P>0.05)。患者治疗后,两组的PANSS总分及各因子分明显降低(P<0.05)。与利培酮组比较,帕利哌酮组的不良反应出现频率低、程度轻微,个人和社会功能恢复快。结论帕利哌酮缓释片是一种安全有效的新型抗精神病药,可以明显改善精神分裂症和分裂样精神病患者的精神病性症状及社会功能。

Quantitative analysis of 3-isopropylamino-1,2-propanediol as a degradation product of metoprolol in pharmaceutical dosage forms by HILIC-CAD

Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.

Extended tacrolimus release via the combination of lipid-based solid dispersion and HPMC hydrogel matrix tablets

The objective of this study is to evaluate the feasibility of obtaining extended release of tacrolimus by a novel combination of lipid-based solid dispersion and matrix-type extended release tablet techniques. Tacrolimus solid dispersion was prepared using glycerylbehenate(Compritol~?ATO888) and Pluronic F127 as the carrier materials with hot-melt method, which was then blended with hydrogel matrix materials, such as HPMC and lactose, the powders were directly compressed into tablets. In vitro drug release tests were carried out to evaluate the performance of the solid dispersions and the tablets. The dissolution rate of tacrolimus was significantly improved by the lipid-based solid dispersion, and the incorporation of HPC into the solid dispersion obviously improved its stability after storage. Extended release tablets loaded with tacrolimus solid dispersion showed prolonged drug release patterns over 24 h, the release patterns of the tablets can be tailored by the compositions of the matrix materials, including the types and content of HPMCs. A modified processing method that directly mixed the melted solid dispersion with HPMC powders improved the uniformity of the solid dispersion inside the tablet matrix and release profile. The release data of the extended release tablet fitted well to the Korsmeyer–Peppas model with n value of 0.85, which suggested diffusion-and erosion-controlled release mechanism. The combination of lipid-based solid dispersion and HPMC hydrogel matrix may find wide applications in the extended release dosage forms of high potent, water-insoluble drugs.

Effect of formulation variables on in vitro release of a water-soluble drug from chitosanesodium alginate matrix tablets

The objective of this study is to investigate the feasibility of using chitosanesodium alginate(CSeSA)based matrix tablets for extended-release of highly water-soluble drugs by changing formulation variables.Using trimetazidine hydrochloride(TH)as a water-soluble model drug,influence of dissolution medium,the amount of CSeSA,the CS:SA ratio,the type of SA,the type and amount of diluents,on in vitro drug release from CSeSA based matrix tablets were studied.Drug release kinetics and release mechanisms were elucidated.In vitro release experiments were conducted in simulated gastric fluid(SGF)followed by simulated intestinal fluid(SIF).Drug release rate decreased with the increase of CSeSA amount.CS:SA ratio had only slight effect on drug release and no influence of SA type on drug release was found.On the other hand,a large amount of water-soluble diluents could modify drug release profiles.It was found that drug release kinetics showed the best fit to Higuchi equation with Fickian diffusion as the main release mechanism.In conclusion,this study demonstrated that it is possible to design extended-release tablets of watersoluble drugs using CSeSA as the matrix by optimizing formulation components,and provide better understanding about drug release from CSeSA matrix tablets.

The influence of genetic polymorphisms in drug metabolism enzymes and transporters on the pharmacokinetics of different fluvastatin formulations

The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics.In addition,we compared the fluvastatin pharmacokinetics differences between extended-release(ER)80 mg tablet and immediate-release(IR)40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study(n=24),effects of ABCG2,SLCO1B1,ABCB1,CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed.The administration dosage for IR 40 mg and ER 80 mg were twice and once daily,respectively,for total 7 d.Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d.The lower exposure following ER was observed.For ER tablets,SLCO1B1 T521C genotype correlated with AUC 0-24 of repeat doses(P=0.010).SLCO1B1 T521C genotype had no statistically significant effect on AUC 0-24 of IR capsule of fluvastatin after single or repeated doses.In vitro study demonstrated that when the concentration of fluvastatin was low(<1μmol/l),the uptake of fluvastatin in the HEK293-OATP1B1 with SLCO1B1521TT(K m=0.18μmol/l)was faster than that with SLCO1B1521CC(K m=0.49μmol/l),On the other hand,when concentration reached to higher level(>1μmol/l),transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1521TT(K m=11.4μmol/l)and with SLCO1B1521TCC(K m=15.1μmol/l)tend to be the same.It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations.We recommend that formulation should be incorporated into future pharmacogenomics studies.