Design and gamma scintigraphic evaluation of colon specific pectin-EC pellets of secnidazole prepared by powder layering technology

The aim of the present study was to prepare a colon targeted pellet formulation of secnidazole and to evaluate the formulation in vitro and in vivo by a gamma scintigraphy method. Pectin/ethyl cellulose in different ratios and in different coating labels with plasticizer was used to prepare secnidazole pellets by a powder layering technique. The formulations were tagged with 99mTC-DTPA, a tracer in gamma scintigraphy to evaluate its transit behavior in rabbits. Morphology and compatibility were studied using Scanning Electron Microscopy, IR spectroscopy and Differential Scanning Calorimetry were used for the characterization of prepared pellets. The in-vitro study suggested that pectin (59%) esterification and ethyl cellulose 45cps at 20% coating label led to an optimum bacterial enzyme dependent released behavior. The optimized formulation was subjected to an in-vivo transit study. Scintigraphy images clearly indicated that the formulation can delay the drug release prior to the colon. The average time of gastric emptying and colon arrival was 57 min and 6.08 h, respectively. The coated pellets prepared by powder layering technology successfully released drug in the colon indicating that site specificity has been achieved with pectin 59% esterification and ethyl cellulose 45 cps at 1:2 ratio with 20% coating label.     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluations of ketoprofen extended release pellets prepared using powder layering technique in a rotary centrifugal granulator

In the present study, an extended release pellet dosage form of ketoprofen was prepared using powder layering technique. A combination of ethyl cellulose (45 cps) and shellac polymers was used as a binder (12% w/w polymer) during drug layering and an extended release coating (1:3 ratio at 2%, 4% and 7% w/w polymer) within the same apparatus. The coated pellets were characterized for sphericity, Hardness-Friability Index, and drug content, and also underwent scanning electron microscopy. In vitro dissolution was performed in 900 mL of phosphate buffer (pH 6.8) using paddle apparatus at 100 rpm. Ethyl cellulose and shellac when used as binders during drug loading did not extend ketoprofen release beyond 3 h. However, coating of the drug loaded pellets using ethyl cellulose and shellac resulted in an extended release profile of about 10 h. Using Higuchi’s model and the Korsmeyer equation, the drug release mechanism from the pellets was found to be an anomalous type involving diffusion and erosion. Scanning electron microscopy was used to visualize the pellet morphology and drug release mechanism during dissolution testing. In vivo evaluations of the extended release pellets in rats indicated a significant increase in the time to reach maximum concentration (t_max) and extent of absorption (AUC_0-∞) compared to the ketoprofen immediate release tablet blend dispersed and dosed. In conclusion, extended release pellets of ketoprofen could perform therapeutically better than conventional dosage forms, leading to improved efficacy for a prolonged period.     

Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release

The gastrointestinal transit and in vivo drug release behaviour of a film-coated tablet formulation was investigated in five healthy human subjects using the technique of gamma scintigraphy. The film coating system consisted of a mixture of pectin, chitosan and HPMC in a ratio of 6:1:0.37 applied to 750 mg cores at a coat weight gain of 9%. The estimated mean values of the gastric emptying time (62±17 min), small intestinal transit time (219±53 min), ileocaecal junction lag time (79±30 min) and the colon arrival time (345±33 min), were similar to published values for the transit of similar sized tablets in humans. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach and the small intestine. There was increased release of radioactivity when the tablets were in the colon due to increased degradation of the film coatings by pectinolytic enzymes resident in the colon. The pectin/chitosan/HPMC film coating system thus acts as a colonic delivery system.     

Colon-Specific Delivery of 5-Fluorouracil from Zinc Pectinate Pellets through In Situ Intracapsular Ethylcellulose–Pectin Plug Formation

Conventional fluid-bed and immersion film coating of hydrophilic zinc pectinate pellets by hydrophobic ethylcellulose is met with fast drug release. This study explored in situ intracapsular pellet coating for colon-specific delivery of 5-fluorouracil (5-FU). The solid coating powder constituted ethylcellulose and pectin in weight ratios of 11:0 to 2:9. Its weight ratio to pellets varied between 2:3 and 3:2. Pectin was used as excipient of core pellets and coating powder in view of its potential use in colon cancer treatment. Delayed 5-FU release and core pectin dissolution were attainable when the weight ratio of solid coating powder to pellets was kept at 3:2, and weight ratio of ethylcellulose and pectin in coating powder was kept at 8:3 with particle size of ethylcellulose reduced to 22 μm. In situ intracapsular wetting of pectin coat by dissolution medium resulted in the formation of ethylcellulose plug interconnecting with pellets through the binding action of pectin. Less than 25% of drug was released at the upper gastrointestinal tract. The majority of drug was released upon prolonged dissolution and in response to colonic enzyme pectinase, which digested core pellets.     

Design and Development of Mixed Film of Pectin: Ethyl Cellulose for Colon Specific Drug Delivery of Sennosides and Triphala

The present study was aimed at developing colon specific drug delivery system for sennosides and Triphala. These drugs are reputed Ayurvedic medicines for constipation in India. The proposed device explored the application of pectin and ethyl cellulose as a mixed film for colon specific delivery. This mixed film was prepared using non-aqueous solvents like acetone and isopropyl alcohol. A 32 factorial design was adopted to optimize the formulation variables like, ratio of ethyl cellulose to pectin (X1) and coat weight (X2). The rate and extent of drug release were found to be related to the thickness and the ratio of pectin to ethyl cellulose within the film. Statistical treatments to the drug release data revealed that the X1 variable was more important than X2. Under simulated colonic conditions, drug release was more pronounced from coating formulations containing higher proportions of pectin. The surface of the device was coated with Eudragit S100 to ensure that the device was more pH dependent and trigger the drug release only at higher pH. The final product is expected to have the advantage of being biodegradable and pH dependant. This type of a film effectively releases the drug while maintaining its integrity.     

Statistical optimization and in vivo evaluation of colon specific delivery system of herbal rhubarb extract

The present research effort was aimed to develop colon targeted drug delivery system (CTDDS) of rhubarb, herbal drug using a mixed film of pectin and ethyl cellulose (EC). Pectin and ethyl cellulose were mixed in various proportions to coat the core tablet to target colon. The methanolic extract of rhubarb was used and the dose of the extract in each formulation was finalized by estimating the emodin content in it by high performace thin layer chromatography (HPTLC). In vitro drug release, erosion study in presence and absence of pectinase enzyme and release constant (K) of zero order was measured for each formulation. The formulation was optimized by using 3² full factorial design. Formulation having 50% pectin as a coating polymer with 12% coat weight was selected as an optimized formulation (OF) on the basis of % similarity with maximum desirability but this formulation was not able to retard the release of drug in stomach and upper intestine fully. So it was further coated with Eudragit S100 (ES) (3% coat weight). The optimized formulation, coated with ES indicated significant laxative activity on loperamide induced constipation in rats. The results revealed that CTDDS of rhubarb using two combined approaches of biodegrable microflora-activated system and pH-sensitive system exhibited a promising colon targeting performance.     

盐酸青藤碱缓释微丸的研制

目的制备盐酸青藤碱缓释微丸,并对其体外释药情况进行研究。方法采用离心造粒技术制备微晶纤维素空白丸核和盐酸青藤碱含药丸芯,以聚丙烯酸树脂Eudragit NE 30D为包衣液制成膜控缓释微丸,考察包衣增重、抗粘剂用量等因素对缓释微丸释放度的影响。结果通过单因素考察确定了包衣液处方,所制备的微丸具有明显的缓释特征,体外释药过程符合一级动力学模型。结论用聚丙烯酸树脂Eudragit NE30D作为包衣材料所得缓释微丸符合24 h缓释要求。     

离心造粒法制备罗红霉素缓释小丸

目的：制备罗红霉素缓释小丸,并对其体外释药情况进行研究。方法：采用离心造粒技术制备微晶纤维素空白丸核和罗红霉素含药丸芯,以聚丙烯酸树脂Eudragit NE30D为包衣液制成膜控缓释小丸,考察包衣增重、致孔剂用量等因素对缓释小丸释放度的影响。结果：通过单因素考察确定了包衣液处方,所制备的小丸具有明显的缓释特征,体外释药过程符合一级动力学模型。结论：制备的罗红霉素缓释小丸符合12h缓释要求。     

A novel pH- and time-based multi-unit potential colonic drug delivery system. I. Development

A novel delivery system was developed for delivering drugs to the colon by selecting polymethacrylates with appropriate pH dissolution characteristics for the distal end of the small intestine and relying upon the relatively constant transit time of the small intestine. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5-0.6 mm) in a conventional coating pan. Drug-layered pellets were coated with an inner layer of a combination of two pH-independent polymers Eudragit RL and RS (2:8), and an outer layer of a pH-dependent polymer, Eudragit FS. Scanning electron micrograph (SEM) pictures of the coated pellets showed the uniformity of both the coatings. The release profile of 5-ASA was studied in three phosphate buffers after a simulated gastric pre-soak for 2 h in pH 1.2 media. There was no drug release for 12 h at pH 6.5. There was a sustained release of 5-ASA for over 12 h both at pH 7.0 and 7.5 after a lag time at pH 7.0 and no lag time at pH 7.5. The release rate was faster at pH 7.5 than at pH 7.0. The delivery system demonstrated its potential for colonic delivery by resisting drug release until pH 6.5 and the combination of Eudragit RL and RS proved successful for the sustained delivery of 5-ASA at the expected pH of the colon.     

Investigation of the Gastrointestinal Transit and In Vivo Drug Release of Isosorbide-5-Nitrate Pellets

An oral formulation of controlled-release isosorbide-5-nitrate pellets has been used to investigate the location of pellets in the gastrointestinal (GI) tract and, in parallel, to measure the drug absorption from these locations. Using the method of gamma scintigraphy the transit times and spreading of pellets in the GI tract have been determined. The method of numeric deconvolution was applied to calculate the drug input into the systemic circulation. The results indicate that a well-absorbed substance such as isosorbide-5-nitrate is absorbed from the stomach and small intestinal in a manner that is controlled by the properties of the pellets. Drug absorption is reduced in the colon. The average transit time from mouth to colon is 6 to 8 hr, which represents the maximum acceptable time for drug release for this oral controlled-release preparation. Taking into account these relations an isosorbide-5-nitrate pellet formulation with a bioavailability of 84% has been developed that maintained the minimal therapeutic plasma level for more than 16 hr after application.     

In vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery

Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to evaluate a formulation with a considerably reduced coat weight and gum concentration for colonic drug delivery in vivo using gamma scintigraphy. In vitro studies have found this formulation to be useful for delivery of 5-fluorouracil to the colon. Rapidly disintegrating core tablets containing (99m)Tc-DTPA were prepared and compression coating with 150 mg of granules containing a mixture of xanthan (XG), guar gum (GG) and starch. The ratios of the two gums XG:GG in the coat was kept 10:20. In vitro dissolution studies on XG:GG::10:20 tablets containing (99m)Tc-DTPA were carried out in simulated upper GIT conditions and also in presence of colonic contents. Cumulative percent release of technetium in the upper GIT conditions and transit time amounted to 4%. The total amount of technetium released in the 24 h of the dissolution study was 53+/-3.23%. Upon introduction of cecal content into the dissolution medium (4%), the release of technetium from the compression-coated tablet increased to 78.34+/-5.34%. Gamma scintigraphy studies carried out in six healthy human volunteers showed that the tablet remained intact during its transit through the upper GIT. The anatomical site of disintegration was found to be the ascending colon/hepatic flexure and the disintegration of the tablet started between 4 and 6 h post-dose in all the volunteers with a further spread of tracer into the ascending, transverse, descending and sigmoidal colon.     

Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique

Pellets are one of multiparticulate pharmaceutical forms and can offer numerous technical and biopharmaceutical advantages compared with single dose unit formulations, e.g. tablets and capsules. This study aimed at formulation of controlled-release pellets of doxazosin mesylate (DM), a widely used treatment for antihypertensive and benign prostatic hyperplasia. DM was loaded onto microcrystalline cellulose CELLETS^® pellets using hydroalcoholic solution and alcoholic suspension layering techniques to achieve a minimum drug load of 4 mg DM/g pellets. DM-layered CELLETS were coated by Aquacoat dispersion (ready-made ethylcellulose dispersion) using a coating pan technique as a simple and widely utilized technique in pharmaceutical industry. Controlled-release DM-layered pellets showed a release profile comparable to the controlled-release commercial product Cardura^® XL Tablet. Also, the mechanism of DM release from Aquacoat CELLETS was mathematically modeled and imaged by scanning electron microscopy to elucidate drug release mechanisms from the prepared pellet formulations. Accelerated stability studies of the prepared pellets were performed under stress conditions of 40 °C, and 75 % RH for 3 months. In conclusion, preparation of controlled-release DM-layered CELLETS^® is feasible using a simple and conventional coating pan technology.     

The effect of pectin on swelling and permeability characteristics of free films containing Eudragit RL and/or RS as a coating formulation aimed for colonic drug delivery

BACKGROUND AND THE PURPOSE OF THE STUDY: The potential of pectin as a bacterially degradable polysaccharide for colon drug delivery has been demonstrated. Due to the high solubility and swelling properties of pectin in aqueous media, it is frequently used in combination with water insoluble polymers for targeting drugs to the colon. The aim of this study was to evaluate free films containing pectin as a bacterially-degradable polysaccharide in combination with Eudragit RL (ERL) and/or RS (ERS) as a coating formulation for colonic drug delivery. METHODS: Isolated free films comprising 20% pectin and 80% ERL or ERS and their combination in 1:1 ratio were prepared by casting method. Then, free films were evaluated by water vapor transmission (WVT), swelling and permeability experiments for theophylline and indomethacin in different media. RESULTS: Formulations containing ERL exhibited higher WVT, swelling and permeability compared with formulations containing ERS. The permeability of theophylline through free films composed of pectin and eudragit polymers in simulated colonic media was not significantly different from those obtained in other media. However indomethacin free films containing pectin and ERL showed higher permeation in simulated colonic fluid (SCF) compared to the other media. MAJOR CONCLUSION: Formulation containing pectin and ERL may be suitable as a coating formulation for colon targeted delivery of drugs of low solubility such as indomethacin.     

Gastrointestinal transit monitoring and absorption of controlled-release pellets of diltiazem

The gastrointestinal (GI) transit and absorption of a multiparticulate controlled-release diltiazem formulation were investigated with reference to an innovator preparation. Transit of controlled-release pellets in GI tract was monitored using two marker drugs, namely paracetamol and sulfasalazine. Both formulations had little intersubject variation in gastric emptying and small intestine transit time. In both formulations, about 51% to 64% of the drug was absorbed while pellets were in the small intestine and the remaining amount while in the colon. The results found in this study were comparable to the other workers who used gamma scintigraphy or indirect method. Therefore, the method used in this study is a reliable alternative for studying GI transit of pellets.     

伊贝沙坦脉冲微丸的制备方法

目的：考察伊贝沙坦脉冲控释微丸的制备工艺。方法：采用流化床工艺,将伊贝沙坦原料黏附在空白丸芯上,制成含药微丸;以低取代羟丙基纤维素为包溶胀层材料,乙基纤维素水分散体为包控释层材料,采用同样的工艺包溶胀层和控释层,并通过正交试验优选最佳工艺条件。按最佳包衣工艺操作,以低取代羟丙基纤维素、吐温-80、乙基纤维素水分散体和葵二酸二丁酯为包衣材料,以释药时滞及时滞后的突释药量为指标,优选最佳处方。结果：最佳工艺条件为：上药、包溶胀层、包控释层工艺中使用的风量分别为20、30、40 m3.h-1;进风温度分别为45、50、50℃;喷雾压力均为0.2 MPa;喷液速度分别为8、9、9.gs-1。4种包衣材料在微丸中所占的最佳质量百分比分别为25%、1%、25%和0.5%,制得的脉冲控释微丸的平均时滞约为7小时,时滞后2小时突释量均大于70%。结论：在该工艺条件下制备的伊贝沙坦脉冲控释微丸的体外释放能够达到脉冲控释效果,制备工艺简单、可控。     

Effect of intragranular porosity on compression behaviour of and drug release from reservoir pellets

In this study, reservoir pellets were prepared and their compression behaviour as well as the importance of their porosity for compression-induced changes in drug release was investigated. Pellets of three different porosities, consisting of microcrystalline cellulose and salicylic acid, were prepared by extrusion–spheronisation and spray-coated with ethyl cellulose (ethanol solution). Lubricated reservoir pellets were compressed and retrieved by deaggregation of the tablets. The retrieved pellets were analysed regarding porosity, thickness, surface area, shape and drug release. It was found that the coating did not significantly affect their compression behaviour. Compaction of pellets of high original porosity considerably affected densification and degree of deformation, whereas the effect on drug release was minor. For low porosity pellets the influence of compaction on drug release was appreciable, but only slight regarding densification and degree of deformation. In conclusion, the porosity of pellets is a potential factor that the formulator can use to optimize drug release and one that can affect the robustness of a formulation during manufacture. Moreover, the coating may be able to adapt to the densification and deformation of the pellets.     

琥珀酸去甲文拉法辛缓释微丸的制备及释放特性的研究

目的 采用乙基纤维素水分散体(Surelease(R))为包衣材料制备琥珀酸去甲文拉法辛(DVS)缓释微丸,并评价其体外释药性能.方法 采用溶液上药法,在蔗糖空白丸芯的基础上旋转锅包衣法上药,通过正交筛选优化上药工艺,再以Surelease(R)为缓释材料进行包衣,以原研缓释片为参比对微丸的体外释放进行评价,并将释放数据用常用模型拟合,探讨其释放机制.结果 所得缓释微丸的载药量和上药率均较高,含量均匀,当聚合物包衣增重32.4％时可达到与原研缓释片一致的释放特性,在piH1.2、pH4.5、水、pH6.8的释放介质中两者的相似因子分别为86.65、69.94、67.47、67.97,体外释放曲线符合一级方程.结论 制备的DVS缓释微丸具有较理想的缓释效果.     

Immersion coating of pellets with calcium pectinate and chitosan

This study has investigated the potential of immersion coating calcium containing pellet cores first with pectin, and then with two different cross-linkers, calcium or chitosan. The interaction between pectin and calcium, and between pectin and chitosan, are believed to slow down the drug release, and thereby, the coated pellets might possibly be used for colon specific drug delivery. Both the calcium coated pellets and the chitosan coated pellets had a reduced drug release compared to uncoated pellets in 0.1M HCl (1 h) and phosphate buffer pH 6.8 (4 h). The most successful combination had a drug release of only 17% during the entire test period in comparison to the uncoated pellets that had a drug release of 80%. When chitosan was used as a cross-linker, a higher reduction in drug release was obtained than by using calcium as the cross-linker. For the pellets coated with pectin in combination with chitosan, the type of pectin with a degree of methoxylation (DM) of 35 was superior to the pectin type with DM 17. The drug release was further slowed down by choosing a type of chitosan with a high degree of deacetylation (Dda) 89% and by coating at low concentrations (0.1%) in the immersion solution.     

A novel pH- and time-based multi-unit potential colonic drug delivery system. II. Optimization of multiple response variables

The objective of this work was to optimize a novel potential colonic drug delivery system by using a statistical procedure. Pellets were prepared by powder layering of 5-aminosalicylic acid (5-ASA) on nonpareils (0.5--0.6 mm) in a coating pan. Drug-layered pellets were coated with an inner layer of a combination of Eudragit RL and RS and an outer layer of Eudragit FS in a fluidized-bed apparatus. Central composite design was used to study the effect of three independent variables. The proportion of the more hydrophilic polymer Eudragit RL had the most significant effect on drug release--higher proportion gave faster release; the amount of inner and outer coat did not have a significant effect on the rate of drug release at either 6 or 12 h in the range studied. A second order polynomial equation was fitted to the data, and the resulting equation was used to predict the responses in the optimal region. An optimized formulation was prepared and evaluated for individual responses. The experimental values of the response variables highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of coated pellets having predictable drug release for colonic delivery of 5-ASA.     

Box-Behnken效应面法优化烟酸缓释微丸处方

目的应用Box-Behnken效应面法对烟酸缓释微丸进行处方优化,以达到12 h缓释效果。方法以微晶纤维素(MCC)、乙基纤维素(EC)和硬脂酸的用量为考察因素,以微丸收率和体外释放度为评价指标,采用Box-Behnken试验设计,通过方程拟合建立因素和响应值之间的数学模型以优化处方,并对体外释药数据进行方程拟合,探讨其释药机制。结果最佳处方为MCC用量50.92%,EC用量5.49%,硬脂酸用量10.93%,试验的实测值与模型的预测值之间偏差较小。药物的体外溶出具有明显的缓释作用,体外释放曲线符合Higuchi和Riger-Peppas方程。结论 Box-Behnken效应面法可用于烟酸缓释微丸的处方优化,所建模型具有较好的实用性和预测能力。