氯氮平缓释片的制备及释药特性的研究

目的 :制备氯氮平 (Clozapine)缓释片剂。方法 :以羟丙基甲基纤维素 (Hydroxypropylmethylcellose ,HPMC)为骨架材料 ,制成氯氮平亲水凝胶缓释骨架片。筛选该缓释片的最佳处方并进行稳定性研究。结果 :处方 7具有很好的缓释效果 ,稳定性研究表明该缓释片的稳定性良好。结论 :处方 7为优良缓释片。     

Development of a simple analytical methodology for determination of glucosamine release from modified release matrix tablets

A simple spectrophotometric method for determination of glucosamine release from sustained release (SR) hydrophilic matrix tablet based on reaction with ninhydrin is developed, optimized and validated. The purple color (Ruhemann purple) resulted from the reaction was stabilized and measured at 570 nm. The method optimization was essential as many procedural parameters influenced the accuracy of determination including the ninhydrin concentration, reaction time, pH, reaction temperature, purple color stability period, and glucosamine/ninhydrin ratio. Glucosamine tablets (600 mg) with different hydrophilic polymers were formulated and manufactured on a rotary press. Dissolution studies were conducted (USP 26) using deionized water at 37+/-0.2 degrees C with paddle rotation of 50 rpm, and samples were removed manually at appropriate time intervals. Under given optimized reaction conditions that appeared to be critical, glucosamine was quantitatively analyzed and the calibration curve in the range of 0.202-2.020 mg (r=0.9999) was constructed. The recovery rate of the developed method was 97.8-101.7% (n=6). Reproducible dissolution profiles were achieved from the dissolution studies performed on different glucosamine tablets. The developed method is easy to use, accurate and highly cost-effective for routine studies relative to HPLC and other techniques.     

Effect of solvents on physical properties and release characteristics of monolithic hydroxypropylmethylcellulose matrix granules and tablets

Effect of solvents on physical characteristics and release characteristics of monolithic acetaminophen (APAP) hydroxypropylmethylcellulose (HPMC) matrix granules and tablets were examined. Various types and amounts of solvents were employed for granulation and cOAting. APAP and other excipients were mixed and were then wet-granulated in a high-speed mixer. The dried granules were then directly compressed and film-coated with low viscosity grade HPMC. As the amount of water increased, the size of granules also increased, showing more spherical and regular shape. However, manufacturing problems such as capping and lamination in tableting occurred when water was used alone as a granulating solvent. The physical properties of HPMC matrix granules were not affected by the batch size. The initial release rate as well as the amount of APAP dissolved had a tendency to decrease as the water level increased. Addition of nonaqueous solvent like ethanol to water resulted in good physical properties of granules. When compared to water/ethanol as a coating solvent, the release rate of film-coated HPMC matrix tablets was more sensitive to the conditions of coating and drying in methylene chloride/ethanol. Most of all, monolithic HPMC matrix tablet when granulated in ethanol/water showed dual release with about 50% drug release immediately within few minutes followed by extended release. It was evident that the type and amount of solvents (mainly water and ethanol) were very important for wet granulation and film-coating of monolithic HPMC matrix tablet, because the plastic deforming and fragmenting properties of material were changed by the different strengths of the different solvents.     

Design of pH-independent extended release matrix tablets of minocycline hydrochloride for the treatment of dementia

The aim of this study was to develop a pH-independent extended release matrix tablet of minocycline HCl for the treatment of dementia. The matrix tablets were prepared by wet granulation technique using Eudragit L and S as release modifiers at different w/w ratios (1:0, 1:1 and 0:1) and PEO as a matrix former. In the case of the matrix tablet without any release modifiers, the drug release rate at pH 1.2 was much higher than that of pH 7.4. By adding the release modifier, the drug release rate at pH 7.4 increased close to that of pH 1.2 and the pH-independent release was obtained. In addition, it was shown that lubricants containing a divalent cation such as Mg stearate inhibited minocycline release in basic medium. Therefore, the incorporation of Eudragit L and S (1:1 ratio) as release modifiers and Na stearyl fumarate as a lubricant into PEO-based matrix tablets effectively produced pH-independent minocycline release profiles.     

帕利哌酮缓释片与利培酮片对女性首发精神分裂症患者糖脂代谢影响的对比研究

目的 观察对比帕利哌酮缓释片与利培酮片对女性首发精神分裂症患者糖脂代谢影响。方法 将85例在德阳市精神卫生中心治疗的女性首发精神分裂症患者随机分为观察组42例和对照组43例,分别给予帕利哌酮缓释片和利培酮片单药治疗2个月。治疗前后测量体质量指数（BMI）、腰围、三酰甘油（TG）、总胆固醇（TC）、高密度脂蛋白（HDLC）、低密度脂蛋白（LDLC）、空腹血糖（FPG）、餐后2 h血糖（2 h PG）,采用阳性和阴性症状量表（PANSS）进行疗效评价。结果 治疗前两组PANSS总分及各因子分（阳性症状、阴性症状和精神病性分）及治疗后两组PANSS总分及各因子分分别比较,差异均无统计学意义。与治疗前相比,治疗后两组PANSS总分[观察组（47.94±13.64）分,对照组（49.07±12.56）分]及各因子分均显著低于治疗前PANSS总分[观察组（86.31±9.21）分,对照组（85.95±9.77）分]及各因子分,差异具有统计学意义（P<0.05）。治疗前两组患者糖、脂各指标比较,差异无统计学意义。治疗后对照组TG、TC、LDLC、BMI和腰围上升,HDLC降低,与治疗前比较,差异具有统计学意义（P<0.05）;观察组BMI和腰围与治疗前比较明显变大,差异具有统计学意义（P<0.05）。观察组治疗后TG、TC、LDLC、BMI和腰围均显著低于对照组,HDLC显著高于对照组,差异具有统计学意义（P<0.05）。两组FPG、2hPG、SBP和DBP比较,差异无统计学意义。观察组患者不良反应发生率明显低于对照组（P<0.05）。结论 帕利哌酮缓释片和利培酮对女性首发精神分裂症患者具有相同的疗效,但是帕利哌酮缓释片对女性患者血脂、BMI和腰围的影响较小,要优于利培酮片。     

Process analytical technology (PAT): effects of instrumental and compositional variables on terahertz spectral data quality to characterize pharmaceutical materials and tablets

The aim of this study was to use terahertz spectroscopy to characterize pharmaceutical materials and tablets, and to understand the effects of measuring conditions and compositional variability on the data quality. Tests were performed on five formulation components (theophylline, lactose, starch, Avicel, magnesium stearate) and a series of tablets composed of various concentrations of theophylline and excipients. Transmission spectra of polyethylene (PE) disks derived from each of the samples were analyzed. Three factors (component loading, component chemistry, and disk drying time) were screened as critical factors associated with the magnitude and location of THz absorbance peaks. Applying the standard sample spectra divided by PE reference spectra ratio method revealed that, to a large extent, PE was responsible for the disk drying time dependence. Direct spectral feature analysis along with mass-transfer analysis of the disk drying process revealed THz absorption peak maxima of lactose (255 cm(-1)) and water (54 and 210 cm(-1)) which is also supported by literature values for the peak maxima assignment for water. Particle scattering due to specimen and PE was found to be also partially responsible for the observed spectral intensities. The importance of THz spectroscopy was demonstrated for characterization of pharmaceutical materials and tablet.     

The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X(1)), PEO (X(2)), and lactose (X(3)). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

Optimization and prediction of drug release from matrix tablets using response surface methodology and near infrared chemical imaging

The purpose of this work was to understand the formulation effect on the drug release from a hydrophilic matrix tablet of niacin using a multivariate statistical technique and Near Infrared Chemical Imaging (NIR-CI). Tablets were composed of ethyl cellulose (EC) and polyethylene oxide (PEO) as release retarding polymers and lactose as the release modulator. D-optimal experimental design was composed of three formulation variables: the content of EC(X₁), PEO (X₂), and lactose (X₃). Response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to predict the optimal formulation. Results showed that the interaction effect of lactose with the polymers PEO and EC and lactose by itself were the most influential factors on the drug release rate. While lactose enhances the drug release rate by forming pores it also promotes water penetration into the tablet core. This in turn helps the formation of the gel layer which acts as barrier to drug diffusion. NIR-CI showed that tablets with higher level of PEO swells at a faster rate and greater extent than formulations with higher level of EC. NIR-CI was thus found to be a very useful technique to predict the drug release rate from hydrophilic matrix systems.     

Partial least square projections to latent structures analysis (PLS) in evaluating and predicting drug release from starch acetate matrix tablets

The aim of this study was to evaluate whether or not starch acetate can act as a release-controlling excipient with physicochemically different drugs, using multivariate data analyses (PLS) for the modelling of drug release from starch acetate tablets. In addition, variables contributing to drug release at certain points of time were studied. Physicochemical properties of drugs were calculated by the VolSurf method. Nine different formulations were produced with six different model drugs. In vitro dissolution studies were carried out for the determination of the drug release profiles for each formulation. PLS analysis was used to evaluate the properties dominating the drug release. Drug release profiles varied widely, depending on the formulation, process, and physicochemical properties of drugs. PLS models were developed to describe the release phenomena. It was observed that at the beginning of the dissolution process, formulation and process variables played a major role in the drug release. Later in the dissolution process, the molecular properties of drugs became the dominant variables. Starch acetate was able to act as a release-controlling excipient with different drugs. Multivariate data analyses were found to be a powerful tool for the evaluation and prediction of drug-release characteristics from the tableted starch acetate matrix.     

Analysis of surface properties of cellulose ethers and drug release from their matrix tablets.

Detailed knowledge based on new developments, especially in analytical techniques, is needed for characterizing polymer excipients. Inverse gas chromatography (IGC) is a useful method for investigating polymer surfaces in terms of thermodynamic parameters. The aim of our work was to study the correlation between polymer surface properties determined with IGC and the mechanisms of release of water-soluble pentoxifylline and vancomycin hydrochloride from cellulose ether matrices. Tablets were made of hydroxypropyl (HPC), hydroxyethyl (HEC) or hydroxypropylmethyl (HPMC) cellulose and contained 25% of drug. Differences in dispersive component of the surface free energy for these polymers were relatively small and ranged from 26 to 33mN/m. However, polar properties, expressed as specific component of the enthalpy of adsorption and as acid-base properties show larger differences between the polymers and demonstrate their relative polarity in the order HEC>HPMC>HPC, which correlates well with water sorption on bulky polymers and with the swelling degree of polymer matrices. The release of pentoxifylline and vancomycin from HPC is governed mainly by Fickian diffusion, whereas from HEC the relaxation of polymer chains is important too. The analysis of the release profiles in the light of Peppas-Sahlin model lead to the conclusion that the surface properties of the cellulose ethers influence the interactions with water and the release mechanisms of the drug. It was found out, that data obtained by IGC enable rapid inference about the behaviour of polymers in water and the release of water-soluble drugs.     

Naproxen-Eudragit microspheres: screening of process and formulation variables for the preparation of extended release tablets

The objectives of the present study were to screen the formulation and process variables for the preparation of extended release naproxen tablets with Eudragit L100-55. The tablets were prepared by compression of microspheres that were obtained by a coprecipitation technique. The process involved dissolution of naproxen and Eudragit L 100-55 in alcohol USP followed by the addition of an aqueous solution containing a surfactant and deaggregating agents. The mixture was stirred for a specified time period to obtain microspheres, which were filtered and air-dried to a constant weight. The microspheres were then compressed to obtain plain tablets with a diameter of 12 mm. A 7-factor 12-run Plackett-Burman screening design was employed to evaluate the main effects of homogenization time (X1), rate of water addition (X2), amount of polymer (X3), amount of precipitating solution (X4), concentration of electrolytes (X5), compression pressure (X6), and the concentration of lubricant (X7) on the rate of drug release. The response variable was cumulative percent of naproxen dissolved in 12 h in simulated intestinal fluid with constraints on responses that included percent yield, hardness, thickness, and the angle of repose. Mathematical relationship for percent of naproxen dissolved in 12 h (Y5) with various factors yielded the following polynomial equation; Y5 (% dissolved in 12 h) = 95.48 + 0.53 X1 + 3.51 X2 + 3.84 X3 - 3.80 X4 - 2.46 X5 - 2.90 X6 - 3.91 X7. The results showed that all the seven factors affected, with varying order, the release of naproxen from its compressed tablets.     

Process analytical technology: nondestructive evaluation of cyclosporine A and phospholipid solid dispersions by near infrared spectroscopy and imaging

The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess phospholipid compartment within its solid dispersion with cyclosporine A (CyA). By varying dimyristoyl phosphatidylcholine (DMPC) to CyA weight ratio, five batches were prepared by the kneading technique and characterized by DSC and FTIR. A drug/DMPC ratio of 50:1 provided an enhanced dissolution of CyA. FTIR spectra and DSC thermograms revealed a significant interaction between the drug and DMPC which suggested incorporation of CyA within the formed DMPC liposomes. The developed NIR calibration model was able to assess DMPC concentrations within the kneaded products. The calibration and prediction linear plots showed slopes of 0.9711 and 0.9915, offsets of 0.1247 and 0.1080, correlation coefficients of 0.9854 and 0.9889 and root mean square standard errors of 0.43% and 0.42%, respectively. In contrast, NIR spectral imaging was capable of clearly distinguishing the kneaded products, both qualitatively and quantitatively. NIR imaging revealed the poor powder blending efficiency of the method used to prepare physical mixture compared to the efficient distribution of the kneaded products. In conclusion, NIR spectral imaging system provides a rapid approach for acquiring high-resolution spatial and spectral information on solid dispersions.     

Process analytical technology: non-destructive assessment of anastrozole entrapment within PLGA microparticles by near infrared spectroscopy and chemical imaging

The objective of this study was to evaluate near-infrared (NIR) spectroscopy and imaging as approaches to assess anastrozole entrapment within PLGA microparticles. By varying the polymer concentration, three batches containing the same amount of the drug were prepared. The spectral features that allow NIR drug quantitation were evaluated and compared with a best fit line algorithm. Actual entrapment efficiencies (EEF) determined via a destructive method were used for construction of calibration models using partial least square regression (PLS) or the algorithm. On the other hand, a chemical imaging system based on array detector technology was used to rapidly collect high contrast NIR images of the formulated microparticles. A quantitative measure of anastrozole entrapped was determined by calculating the percentage standard deviation of the distribution of pixel intensities in the PLS score images and histograms. Concerning conventional NIR analysis, both methods were equivalent for the prediction of EEF over the range of polymer levels studied. Correlation coefficients of more than 0.992 were obtained for either the calibration or prediction of EEF by the two methods; 0.392% and 0.374% were the standard errors of calibration and prediction (SEC and SEP) obtained for the prediction of EEF using the fit line, respectively, whereas the prediction of the EEF by the partial least square regression showed a SEC of 0.195% and SEP of 0.179%. As a result, the spectral best fit algorithm method compared favourably to the multivariate PLS method, but was easier to develop. In contrast, NIR spectral imaging was capable of clearly differentiating the three batches, both qualitatively and quantitatively. The percentage standard deviation increased progressively by increasing the ratio of drug-to-polymer concentrations. In conclusion, both NIR approaches were capable of accurate assessment of drug entrapment within microparticles. In addition, the NIR spectral imaging system provides a rapid approach for acquiring spatial and spectral information on microparticles.     

Process analytical technology: Non-destructive assessment of anastrozole entrapment within PLGA microparticles by near infrared spectroscopy and chemical imaging

The objective of this study was to evaluate near-infrared (NIR) spectroscopy and imaging as approaches to assess anastrozole entrapment within PLGA microparticles. By varying the polymer concentration, three batches containing the same amount of the drug were prepared. The spectral features that allow NIR drug quantitation were evaluated and compared with a best fit line algorithm. Actual entrapment efficiencies (EEF) determined via a destructive method were used for construction of calibration models using partial least square regression (PLS) or the algorithm. On the other hand, a chemical imaging system based on array detector technology was used to rapidly collect high contrast NIR images of the formulated microparticles. A quantitative measure of anastrozole entrapped was determined by calculating the percentage standard deviation of the distribution of pixel intensities in the PLS score images and histograms. Concerning conventional NIR analysis, both methods were equivalent for the prediction of EEF over the range of polymer levels studied. Correlation coefficients of more than 0.992 were obtained for either the calibration or prediction of EEF by the two methods; 0.392% and 0.374% were the standard errors of calibration and prediction (SEC and SEP) obtained for the prediction of EEF using the fit line, respectively, whereas the prediction of the EEF by the partial least square regression showed a SEC of 0.195% and SEP of 0.179%. As a result, the spectral best fit algorithm method compared favourably to the multivariate PLS method, but was easier to develop. In contrast, NIR spectral imaging was capable of clearly differentiating the three batches, both qualitatively and quantitatively. The percentage standard deviation increased progressively by increasing the ratio of drug-to-polymer concentrations. In conclusion, both NIR approaches were capable of accurate assessment of drug entrapment within microparticles. In addition, the NIR spectral imaging system provides a rapid approach for acquiring spatial and spectral information on microparticles.     

Drug release from matrix tablets: physiological parameters and the effect of food

Introduction: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process.

Areas covered: The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pK_a, diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus.

Expert opinion: With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more biologically based with the view of obtaining more in vitro–in vivo correlations.     

Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression

The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8–12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct compression.     

Profile of paliperidone extended release: review of efficacy and safety data

Paliperidone, an active metabolite of risperidone, is the most recent second-generation antipsychotic to become available on the market. This article addresses the pharmacology, clinical efficacy and tolerability of paliperidone. A comprehensive review of studies on MEDLINE using terms, such as paliperidone, 9-hydroxy risperidone, efficacy and tolerability, was conducted. Paliperidone, a 9-hydroxy derivative of risperidone is an antagonist at the dopamine and serotonin receptor sites. As paliperidone is an active metabolite of the parent compound risperidone, it is not metabolized hepatically, has minimal drug–drug interactions and is largely excreted unchanged by the kidneys. It follows linear pharmacokinetics. Evidence from short- and long-term trials supports the efficacy and tolerability of paliperidone extended release (ER) in the treatment of schizophrenia. Randomized, double-blind, placebo-controlled, multicenter studies have demonstrated both paliperidone 6 and 12 mg result in symptom improvement, increase in time of first recurrence of psychotic symptoms as well as significant improvements in personal and social performance. Studies demonstrated increases in plasma prolactin levels and extrapyramidal symptoms with paliperidone ER treatment compared with placebo. Changes in blood glucose and lipid levels with paliperidone ER were comparable to placebo. Overall, paliperidone is an efficacious, well-tolerated addition to the treatment armamentarium for schizophrenia.     

A process analytical technology approach based on near infrared spectroscopy: tablet hardness, content uniformity, and dissolution test measurements of intact tablets

Near infrared spectroscopy (NIRS) is a nondestructive analytical technique that enables simultaneous measurements of chemical composition (viz. the content in active pharmaceutical ingredient, API) and various physical properties (viz. tablet hardness and dissolution profile) in pharmaceutical tablets. In this work, partial least squares (PLS) calibration models and discriminant partial least squares (DPLS) classification models were constructed by using calibration sets consisting of laboratory samples alone. The laboratory samples were mixtures of the API and excipients that were pressed into tablets. API content, tablet hardness, and dissolution measurements of intact tablets were made by using three different calibration models that are fast--results can be obtained within a few seconds--, simple and robust--they involve minimal analyst intervention--, and clean--they use no toxic reagent and produce no toxic waste. Based on the results, the proposed NIR method is an effective alternative to current reference methods for the intended purpose. The advantages provided by NIR spectroscopy in this context confirm its potential for inclusion in process analytical technologies in the pharmaceutical industry.