Preparation and in-vitro evaluation of indomethacin nanoparticles

BACKGROUND AND THE PURPOSE OF THE STUDY: During the last two decades one of the most important problems in drug formulations has been low aqueous solubility of new molecules. However, numerous techniques, such as milling, co-solvent solubilization and solid dispersion have been used conventionally for aqueous solubility enhancement and the rate of solubility. Recently, nanoparticle engineering processes have been developed and reported for pharmaceutical applications to increase the dissolution rate of low-soluble drugs which in turn may leads to substantial increases in bioavailability. In this study, a controlled precipitation method was used to produce indomethacin nano-solid suspension in a polymeric matrix (as a model), in order to increase the solubility and rate of the dissolution of poorly soluble model drug. METHODS: Nano-solid suspension of indomethacin in polyvinyl pyrrolidine (PVP) was prepared by controlled precipitation technique, characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and evaluated for in vitro solubility and dissolution rate. RESULTS AND MAJOR CONCLUSION: Absence of thermal and diffractional peaks in DSC and XRD studies indicated that indomethacin interacts with PVP in solid phase. The solubility of indomethacin in nano-solid suspension compared to crystalline form was increased to about four-fold. It was found that particle size distribution depend to the polymer MW and drug: polymer ratios. Spectroscopy methods and Transmission Electron Microscopy (TEM) images showed that indomethacin dispersed as amorphous nanosize particles in freeze dried powder. Enhanced solubility and dissolution rate of indomethacin compared to physical mixtures and crystalline form of indomethacin (polymorph I), demonstrated that it interacts with PVP via hydrogen bond and probably forming eutectic mixture.     

磷缓释复混肥的制备及其氮、磷缓释性评价

在实验室条件下制得不同程度磷缓释的复混肥(磷缓释肥),分别测定以水为淋洗剂和以2%柠檬酸溶液为淋洗剂时在特定淋洗装置下水溶性氮、磷及有效磷随时间的溶出率,采用双曲线方程Xt=b a/t对肥料的累计养分溶出率进行分段拟合,在此基础上引入缓释指数评价各养分缓释特性。结果表明:磷缓释肥对磷的缓释作用强于氮,对有效性磷的缓释作用强于水溶性磷;其水溶性氮、磷缓释指数(SR IWN、SR IW P)和有效磷缓释指数(SR IAP)与肥料中加入的缓释剂硫酸镁相对含量(X)具有很好的正相关,其直线相关系数为0.7414、0.8958和0.9829,后两者分别达到显著和极显著水平;2%柠檬酸溶液几乎能溶出肥料中全部有效磷,从而证明了自制磷缓释肥的有效性。     

Preparation and evaluation of ethylcellulose microcapsules of indomethacin

Indomethacin was microencapsulated with ethylcellulose using a modified spherical agglomeration process, aiming at a sustained release preparation without side effects on the stomach. The surface morphology of the microcapsules was examined using scanning electron microscopy. The microcapsules were porous and spherical, and their porosity increased with increasing the viscosity of ethylcellulose.In vitro dissolution process followed Higuchi’s diffusion model for first 3 hr. Release rate of the drug from microcapsules decreased as the viscosity of ethylcellulose or the weight ratio of indomethacin to ethylcellulose was decreased. The release rate also decreased with increasing the microcapsule size. The microcapsules induced less gastric ulcer in rats than raw drug.     

Comparison of slow-release indomethacin and diflunisal in patients with arthrosis

A double-blind, crossover study was carried out in 44 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of treatment with a new slow-release formulation of indomethacin (50 mg) with that of diflunisal (250 mg). After a 1-week wash-out period, patients were allocated at random to receive 2 tablets daily of one or other preparation for 6 weeks before being crossed over to the alternative drug for a further 6 weeks. Aspirin was allowed as a rescue analgesic throughout the study. Subjective assessments of pain and objective assessments of joint mobility were made before the start of treatment and at the end of each period, and details were recorded of rescue analgesic usage and any side-effects. Analysis of the results from 42 patients showed that whilst both treatments helped to alleviate pain, patients' overall evaluation of efficacy at the end of the study indicated that indomethacin was slightly more effective than diflunisal and there was a significant preference for indomethacin. Both drugs were well tolerated and none of the side-effects, reported in about 15% of patients on each drug, resulted in any withdrawals.     

Comparison of slow-release indomethacin and diflunisal in patients with arthrosis

Summary

A double-blind, crossover study was carried out in 44 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of treatment with a new slow-release formulation of indomethacin (50?mg) with that of diflunisal (250?mg). After a 1-week wash-out period, patients were allocated at random to receive 2 tablets daily of one or other preparation for 6 weeks before being crossed over to the alternative drug for a further 6 weeks. Aspirin was allowed as a rescue analgesic throughout the study. Subjective assessments of pain and objective assessments of joint mobility were made before the start of treatment and at the end of each period, and details were recorded of rescue analgesic usage and any side-effects. Analysis of the results from 42 patients showed that whilst both treatments helped to alleviate pain, patients' overall evaluation of efficacy at the end of the study indicated that indomethacin was slightly more effective than dif lunisal and there was a significant preference for indomethacin. Both drugs were well tolerated and none of the side-effects, reported in about 15% of patients on each drug, resulted in any withdrawals.     

Pharmacokinetics and tolerance of slow-release indomethacin tablets in rheumatoid arthritis

Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (t_max 3.7 h and < 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.     

Comparison of a slow-release indomethacin tablet and naproxen in osteoarthrosis

A double-blind, crossover study was performed in 21 out-patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of a new slow-release formulation (multiple units dose preparation) of indomethacin (50 mg) with those of naproxen (250 mg). After a wash-out period of 1 week, the patients were randomized to receive 2 tablets daily of one or other preparation for 3 weeks. This was followed by another wash-out period of 1 week, whereafter the patients were crossed over to the alternative drug for another 3 weeks. Subjective assessments of pain and objective assessment of joint mobility and the use of acetylsalicylic acid as rescue analgesic were used to evaluate the efficacy of the treatment. Analysis of results from 19 patients showed that both drugs effectively alleviated pain, and there was no difference between indomethacin and naproxen in this respect. There were 2 withdrawals, 1 on naproxen due to inefficacy and 1 on indomethacin due to gastro-intestinal side-effects. Otherwise, the drugs were well tolerated and side-effects occurred to the same extent on both drugs. This study confirms the good efficacy and tolerability of the new slow-release indomethacin preparation.     

Preparation and in vivo evaluation of indomethacin loaded true nanoemulsions

Indomethacin, a potent nonsteroidal anti-inflammatory drug, has been used in the treatment of various kinds of pains, inflammation and arthritis. However, oral administration of indomethacin produces serious gastrointestinal adverse effects. Therefore the aim of the present investigation was to evaluate the anti-inflammatory effects, skin irritation, activation energy and histopathology of indomethacin from transdermally applied true nanoemulsion. The anti-inflammatory effects of true nanoemulsions were compared with marketed Indobene^® gel on carrageenan-induced paw edema in rats. Skin irritation tests were performed on Wistar rats for 14 days. The % inhibition value after 12 h application was significant for optimized formulation F6 (83) as compared to marketed Indobene^® gel (P<0.01). Results of skin irritation test indicated that developed true nanoemulsion is safe for human use. The significant decrease in activation energy (1.396 kcal/mol) for indomethacin across rat skin indicated that the stratum corneum lipid bilayers were significantly disrupted (P<0.05). From these results it was concluded that the developed nanoemulsion have great potential for transdermal application of indomethacin.     

克拉霉素肠溶掩味颗粒的制备与评价

采用熔融法和流化床包衣技术制备克拉霉素肠溶掩味颗粒,将克拉霉素与药用辅料基质在一定温度下熔融后制成颗粒,再进行流化床包衣。分别用X-射线粉末衍射法(X-ray)和扫描电镜法(SEM)研究药物存在形式和载药颗粒的形态,并考察其体外释放情况。结果表明,载药颗粒的粒径范围为0.2～0.6 mm;颗粒中克拉霉素的晶型未发生变化;肠溶颗粒在0.1 mol.L-1盐酸中2 h累积释放百分数<10%,pH 6.8磷酸缓冲液中1 h累积释放百分数>80%。所制备的克拉霉素颗粒不仅有较好的掩味效果,还有较好的释放,有望更好地应用于临床。     

Preparation and evaluation of granules with pH-dependent release by melt granulation

This study had two objectives: (1) to prepare, by melt granulation in a high-shear mixer, granules containing acetaminophen (APAP) as a model drug and aminoalkyl methacrylate copolymer E (AMCE) as a pH-sensitive polymer that readily dissolves at pH values lower than 5, and (2) to investigate the effects of AMCE loading (5-15%) on granule properties and the in vitro release profile of drug from the granules. Compared with polymer-free granules, the granules containing 5% and 10% AMCE were found to have higher median diameters and wider particle size distributions. For the formulation containing 15% AMCE, on the other hand, the diameters and distribution were similar to those for polymer-free granules. From compression testing, load-displacement curves revealed that AMCE enhanced particle strength at ambient temperature and induced plastic strain, while suppressing fragmentation of the granules. In addition, from dissolution testing using media with pH 4.0 and pH 6.5, granules containing AMCE, except 15% AMCE loading, exhibited drug release with significant pH dependence. When the pH 4.0 and pH 6.5 dissolution profiles were further compared by calculating the difference factor (f(1)), the 5% AMCE granules showed the strongest pH dependence of drug release among all formulations in this study. Large cracks and breakage were observed on the surface of 10% AMCE granules after they were used in dissolution testing. The obtained results are attributed to the plastic strain properties of AMCE above its glass transition temperature, and to the irregular distribution of AMCE within granules. Hence, this study has demonstrated for the first time that the combination of melt granulation and AMCE incorporation enables the formulation of novel functional granules that exhibit pH-dependent release of the active ingredient.     

Preparation and in vitro/pharmacokinetic/pharmacodynamic evaluation of a slow-release nano-liposomal form of prednisolone

A nano-liposomal carrier was prepared for the anti-inflammatory drug prednisolone acetate (PA). The drug showed remarkable loading in the nano-carriers. The drug-loaded nano-liposmes with average sizes of about 186?nm and zeta potentials of??20?mV were obtained. Our drug release studies showed an apparently zero-order trend with only 18% of the drug released in the first 120 h. Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analyses showed no chemical interaction between the drug and carrier. Transmission electron microscopy (TEM) imaging showed near-spherical drug-containing nano-carriers. The intramuscular (IM) trial of the nanoformulation compared with the free drug showed both pharmacokinetic (lower C_max, higher area under the curve (AUC)) and pharmacodynamic (higher and longer lasting anti-inflammatory effect, both macroscopically and biochemically) superiority for the nano-liposomal drug above the free prednisolone in rats.     

Preparation of magnetic granules containing bleomycin and its evaluation using model esophageal cancer

Presuming a clinical application to targeting therapy for esophageal cancer, magnetic granules containing bleomycin (BLM) as an anticancer drug with bioadhesive polymers (hydroxypropyl cellulose-H/Carbopol 934® mixture, 3:2 w/w) and ultrafine ferrite (γ-Fe₂O₃) in weight ratio of 2:5:3 were prepared based on preliminary experiments in vitro using brilliant blue FCF (B.B.) as a model of anticancer drug. A high holding ratio on a target site was obtained when the granules were administered to normal rabbits using a mouth holder under magnetic guidance for the initial 2 min. However, residence time of the granules due to their bioadhesiveness after removal of the magnetic circuit was not sufficient. The BLM granules were administered once a day for 2 weeks to esophageal cancer model in rabbits prepared by transplantation of VX₂ cancer fragment. In spite of the granules being held at the targeting site, no difference in cancer growth was observed between the rabbits with and without administration of the granules. The results suggest that targeting drug delivery to esophageal mucosa by oral administration of the magnetic granules containing more drastic anticancer drug than BLM is promising if the bioadhesive property and release property of the granules could be improved.     

Sustained release of indomethacin from chitosan granules in beagle dogs

The potential of chitosan granules as an oral sustained-release dosage form of indomethacin has been compared with conventional capsules in beagle dogs. When a commercial capsule was administered orally, the plasma concentrations reached the maximum level in 30 min. The granules did not give a sharp peak to the plasma concentration, but produced a sustained plateau of the drug. This may be due to the slow rate of release and a longer residence time in the stomach. Thus, in terms of reducing the peak in plasma concentration and maintenance of drug concentration in plasma, the chitosan granules were superior to conventional capsules.     

Preparation and characterization of indomethacin magnetic nanoparticles

Nanoparticles of polymethylmethacrylate were prepared by the emulsion polymerization technique. The drug was embedded in the nanoparticles. The controlled growth of ferric hydroxide particles in the presence of non-ionic surfactant was effected to obtain nano-size particles and these were subsequently heated to obtain ferroso-ferric oxide (magnetite). The effect of various parameters, i.e. monomer concentration and magnetite concentration, as well as the stirring rate were studied to characterize the particle size and its distribution. Similarly, the factors which affect the total drug payload were assessed. The magno-responsive indomethacin nanoparticles were successfully prepared.     

冬黄颗粒剂的制备及其含量测定

目的制备冬黄颗粒剂,并建立盐酸小檗碱的含量测定方法。方法冬瓜皮、黄连、麦冬分别提取,加可溶性淀粉和糊精制成颗粒。采用HPLC法测定制剂中主要有效成分盐酸小檗碱的含量。十八烷基硅烷键合硅胶为填充剂,流动相:乙腈-0.05mo/LKH2PO4溶液(30:70),流速lmL/min,柱温35℃。检测波长:429nm。结果盐酸小檗碱在0.059～0.178μg范围与峰面积线性关系良好,辅料及其他组分对含量测定无干扰。平均回收率为98.3%。颗粒剂中盐酸小檗碱平均含量为77.7mg/g。结论采用HPLC法测定盐酸小檗碱含量操作简便,方法可靠,可用于冬黄颗粒剂的质量控制。     

糯稻根颗粒剂制备及其游离氨基酸的鉴别与含量测定

目的制备糯稻根颗粒剂，并建立其质量标准。方法将糯稻根水煎液加ZTC1＋1天然澄清剂处理后，浓缩至稠膏，并制成颗粒剂。用TLC对游离氨基酸定性，用氨基酸分析仪测定其总含量。结果糯稻根颗粒剂中含有15种游离氨基酸，且总含量≥2．23mg·g^-1。连续3个批号产品的各项指标均符合中国药典2005版一部附录颗粒剂项下的规定。结论糯稻根颗粒剂制备工艺合理，所建立的方法简便、准确、可靠。该制剂也是首次研制。     

川芎配方颗粒剂的制备工艺研究

目的　通过考察川芎配方颗粒剂的含量稳定性,确定最佳制剂工艺。方法　将制剂置于恒温恒湿条件下,按规定时间取样,考察主要有效成分含量。结果　制剂Ⅱ含量稳定性优于制剂Ⅰ。结论　将川芎挥发油制成β环糊精包合物,稳定性好,可推广至其它中药配方颗粒剂的制备。     

川芎配方颗粒剂的制备工艺研究

目的通过考察川芎配方颗粒剂的含量稳定性,确定最佳制剂工艺.方法将制剂置于恒温恒湿条件下,按规定时间取样,考察主要有效成分含量.结果制剂Ⅱ含量稳定性优于制剂Ⅰ.结论将川芎挥发油制成β-环糊精包合物,稳定性好,可推广至其它中药配方颗粒剂的制备.     

更年平颗粒的制备工艺研究

目的 确定更年平颗粒制备的最佳工艺条件。方法 采用正交试验法，以有效成分淫羊藿苷的含量和浸膏收得率为指标，对更年平颗粒的提取工艺进行优选。结果 提取工艺为淫羊藿、当归、熟地黄、丹参等药材加10倍量水煎煮3次，每次1h。结论 该制备工艺生产的产品，质量稳定。     

复凝聚法制备吲哚美辛缓释微囊的研究

目的:通过吲哚美辛微囊的制备研究,为吲哚美辛的缓释制剂提供科学依据。方法:以微囊的药物包封率为制备工艺优化指标,利用复凝聚法,通过正交实验得出微囊的最佳制备工艺条件。结果:该法所制备微囊的粒度分布在2.2~32.3μm之间,收率可达80%以上。结论:实验证明,吲哚美辛微囊比吲哚美辛片剂具有明显的缓释作用。