A novel coating concept for ileo-colonic drug targeting: Proof of concept in humans using scintigraphy

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT® S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT® S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT® S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1 N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1 N HCl for 2 h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT® S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT® S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.     

The relationship between mucoadhesive polymers and surface coating in tablets for the controlled colonic delivery of a poorly water-soluble drug

BackgroundThe mucoadhesive polymers play an important role in targeted and controlled drug delivery.ObjectivesThis study aimed to investigate the drug release behaviour and interpret the role of mucoadhesive polymers involved in the coating layer of mucoadhesive tablets for the sustained release of a poorly water-soluble drug.MethodsA solid dispersion of prednisolone and zein was used in the core tablets created with two mucoadhesive polymers, which included Carbopol 940 and hydroxypropyl methylcellulose K4M. In addition, the properties of a single-layer coating, created from the combination of zein and Kollicoat MAE 100P to delay release through the upper parts of the gastrointestinal tract, were investigated in the presence of the above mucoadhesive polymers; these properties included drug dissolution, mucoadhesion, surface morphology, swelling and erosion.ResultsThe mucoadhesive polymer concentrations and types were integrated not only into the core tablets through a swelling/erosion mechanism but also into the surface polymer coatings for controlled drug release. HPMC was preferred in the formulations due to the ability to form pores on the surface coating, allowing water uptake so that the coating could control drug release for a later stage via a swelling/erosion mechanism.ConclusionThe proposed mechanism determined in this project could be beneficial in the selection of polymers for applications targeting the colon with coated mucoadhesive tablets. Open in a separate windowGraphical abstract     

Formulation and evaluation of omeprazole tablets for duodenal ulcer

Omeprazole pellets containing mucoadhesive tablets were developed by direct punch method. Three mucoadhesive polymers namely hydroxypropylemethylcellulose K4M, sodium carboxy methylcellulose, carbopol-934P and ethyl cellulose were used for preparation of tablets which intended for prolong action may be due to the attachment with intestinal mucosa for relief from active duodenal ulcer. Mucoadhesive tablets were coated with respective polymer and coated with Eudragit L100 to fabricate enteric coated tablets. The prepared tablets were evaluated for different physical parameters and dissolution study were performed in three dissolution mediums like 0.1N hydrochloric acid for 2h, pH 6.5 and pH 7.8 phosphate buffer solution for 12hr. Sodium carboxymethylcellulose showed above 95% release within 10 h where as carbopol-934P showed slow release about 88% to 92% over a period of 12 h. having excellent mucoadhesive strength but ethyl cellulose containing tablets showed less than 65% release. The release mechanism of all formulation was diffusion controlled confirmed from Higuchi's plot. Thus, the present study concluded that, carbopol-934P containing mucoadhesive tablets of omeprazole pellets can be used for local action in the ulcer disease as well as for oral controlled release drug delivery.     

Preparation of Controlled-Release Coevaporates of Dipyridamole by Loading Neutral Pellets in a Fluidized-Bed Coating System

Purpose. The purpose of this study was to demonstrate that it is possible to prepare controlled-release drug-polymer coevaporates on an industrial scale, omitting the recovery problems and the milling and sieving processes encountered when coevaporates are prepared by the conventional solvent-evaporation technique. Methods. Controlled-release coevaporates were prepared by spraying organic solutions of dipyridamole-Eudragit^® blends onto neutral pellets using the fluidized-bed coating method. Enteric acrylic polymers Eudragit^® L100-55, L, and S were used as dispersing agents and drug/polymer ratio 2:8 was selected for all formulations. Polarized light microscopy, X-ray diffraction spectroscopy, and differential scanning calorimetry were used to determine whether the drug was amorphous or crystalline in the coating films. Moreover, in vitro dissolution tests were performed on the dipyridamole coated pellets in test media simulating the pH variations in the GI tract and the results were compared to the release data obtained from coevaporates prepared by the conventional solvent-evaporation method. Results. All the results clearly indicate that dipyridamole is amorphous in the coating films deposited on neutral pellets as well as in coevaporate particles obtained by the conventional solvent-evaporation method. When the release patterns of the dipyridamole coated pellets are compared to those of the drug coevaporate particles prepared with the same enteric acrylic polymers, the results show similar dissolution trends. Conclusions. The results obtained indicate that pelletization can be considered as a method of choice for pilot plant and/or full-scale production of controlled-release dosage forms based on the formation of amorphous solid dispersions.     

Enhanced oral bioavailability of novel mucoadhesive pellets containing valsartan prepared by a dry powder-coating technique

The aim of this study was to develop novel mucoadhesive pellets containing valsartan (VAL) with enhanced oral bioavailability. Two types of VAL loaded core pellets were prepared by an extrusion/spheronization method, and further dry-coated with a mixture of hydroxypropylmethylcellulose (HPMC) and carbomer (CB) at different ratios. The effects of the pellet core composition, HPMC:CB ratio and coating level on the drug release from the coated pellets were investigated. The physicochemical properties of the core and coated pellets were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). In addition, the in vitro and in vivo mucoadhesion properties as well as the bioavailability of the coated pellets in rats were evaluated by using VAL suspension and core pellets as control preparations. The results of the release study demonstrated that the two types of core pellets, especially the pellets formulated with a solubilizer and a pH modulator gave considerably faster drug release than the VAL powder. However, the core and coated pellets exhibited similar release profiles indicating that the dry powder-coating did not retard the drug release. Strong molecular interactions were observed between the drug and the carriers in FT-IR analysis. The coated pellets displayed distinct mucoadhesive property in vitro and delayed gastrointestinal (GI) transit in vivo. Furthermore, the coated pellets exhibit significantly higher AUC(0-12h) and C(max), as compared to the core pellets and drug suspension. It was concluded that the mucoadhesive pellets could render poorly water soluble drugs like VAL with a rapid drug release, delayed GI transit and enhanced oral bioavailability.     

甲硝唑胃部滞留制剂的制备

目的为更好地清除幽门螺旋杆菌,制备同时具有缓释、漂浮、黏附特性的甲硝唑胃部滞留制剂。方法采用挤出滚圆法制备丸心,流化床包衣法制备甲硝唑缓释漂浮黏附微丸。EudragitNE30D为缓释层,NaHCO3为产气层,EudragitRL 30D为阻滞层,Carbopol 934P为黏附层,考察不同包衣增量情况下,各微丸的释药行为,在0.1 mol.L-1HCl中的漂浮性能,及离体大鼠胃黏膜上的黏附能力。结果丸心外包质量分数为3%的EudragitNE 30D,质量分数为9%的NaHCO3,质量分数为10%的EudragitRL 30D,质量分数为5%的Carbopol 934P的微丸,能实现缓释12 h、4 min起漂、持续漂浮12 h,漂浮率大于95%、黏附率为100%。结论所制备的甲硝唑胃部滞留制剂,同时具备缓释的释药行为、优良的漂浮能力、良好的黏附特征。进而能增加甲硝唑的胃部滞留时间,延长药物与幽门螺旋杆菌的接触时间,提高甲硝唑抗幽门螺旋杆菌的疗效。     

苦参碱结肠靶向微丸的制备及体外释放性能评价

目的:优选苦参碱结肠靶向微丸的制备工艺。方法:采用挤出-滚圆法制备苦参碱载药丸芯,利用流化床包衣技术对苦参碱载药丸芯进行包衣,并进行体外释放度的考察。结果:苦参碱载药丸芯的优化处方工艺为:苦参碱10g,微晶纤维素40g,羧甲基纤维素钠0.5g,纯化水46mL。其包衣微丸外层衣尤特奇L30D-55增重20%,内层衣尤特奇EPO增重30%。体外释放度实验表明,苦参碱包衣微丸在模拟的胃液中基本不释放,在pH 5.0磷酸缓冲液中较快释放,在pH 6.8磷酸缓冲液中则释放缓慢。结论:苦参碱载药丸芯处方工艺简单稳定。苦参碱包衣微丸结肠靶向性较好,同时模拟实验提示在结肠pH发生明显下降时苦参碱结肠靶向微丸仍具有结肠靶向性。     

酒石酸美托洛尔延迟起释缓释微丸的制备

目的制备酒石酸美托洛尔延迟起释缓释微丸;研究该制剂的体外释放影响因素。方法采用挤出滚圆法制备含药丸芯,以丙烯酸树脂(Eudragit NE 30D)为内层包衣材料,乙基纤维素与丙烯酸树脂(Eudragit L100)的混合膜材为外层包衣材料制备延迟起释缓释微丸。通过改变内层包衣质量增加、外层包衣质量增加及外层包衣液中乙基纤维素与Eudragit L 100的质量比来达到一定时滞后缓慢释放药物的目的。考察了处方因素和溶出条件对体外释放度的影响。结果制得时滞为4 h,4、6、10、14 h的累积释放量分别为<10%、20%~35%、50%~70%、≥75%的延迟起释缓释微丸。结论内层包衣质量增加、外层包衣液中乙基纤维素与Eudragit L100的比例及外层包衣质量增加对延迟起释缓释微丸的释药时滞和释药速率具有显著影响,药物的体外释放情况不受溶出转速和溶出装置的影响。     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

pH-dependent release of platycodin mitigates its gastrointestinal mucosa irritation after oral administration in rats

The present study aimed to evaluate the gastrointestinal mucosa irritation of three platycodin formulations. Platycodin-loaded core pellets were prepared via extrusion–spheronization method and coated with Eudragit^® L100-55 (L100) or Eudragit^® S100 (S100) for pH-dependent release. The release of platycodin D from coated pellets exhibited pH dependent release profiles. The pharmacokinetic study in rats showed that T_max of the coated pellets were prolonged as compared to that of un-coated pellets. The S100-coated pellets possess a lower C_max and decreased AUC_0–24h as compared to the L100-coated and uncoated pellets. Hematoxylin-eosin staining and nuclear factor Kappa B (NF-κB) measurement were carried out to observe the gastrointestinal mucosa irritations. The results revealed that the irritations of platycodin on the upper gastrointestinal mucosa are dose-dependent. However, no obvious irritation effect on the gastrointestinal tissues of rats was detected after oral administration of the coated pellets. In addition, the amount of NF-κB in the stomach of rats treated with the uncoated pellets was about fivefold higher as compared to that of the coated pellets. In summary, the L100-coated platycodin pellets exhibited higher oral bioavailability and less gastrointestinal mucosa irritations as compared to the other two formulations.     

Development of novel mucoadhesive pellets of metformin hydrochloride

Mucoadhesive polymer-coated pellets containing metformin hydrochloride were prepared by the powder-layering technique using a centrifugal fluidizing (CF)-granulator. Four high-viscosity polymers were applied to make the pellets: 1) hydroxymethylcellulose (HPMC), 2) sodium alginate (Na-Alg), 3) HPMC/Carbopol, and 4) sodium carboxylmethylcellulose (Na-CMC). The physical crushing test, mucoadhesive test, zeta-potential test, in vitro release study and observation of gastroretention state of the dosage form were performed to investigate the pellets. The strong adhesive interaction between the Na-CMC-coated pellets and the mucin disc was obtained by mucoadhesive test. Na-Alg was most effective among the polymers used in changing the value of zeta potential of the mucin solution by the interaction between a polymer and a mucin particle. Results from drug dissolution study showed that over 95% of the drug from all the four pellets was released before 2 h, while Na-CMC- and Na-Alg-coated pellets showed a moderate sustained-release in SGF (simulated gastric fluid) and SIF (simulated intestine fluid), respectively. In conclusion, Na-CMC and Na-Alg seem to be promising candidates for mucoadhesive formulation and further studies to improve the sustained-release property are underway for achieving the ultimate goal of once-a-day formulation of metformin hydrochloride.     

Drug delivery to inflamed colon by nanoparticles: Comparison of different strategies

For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug-loaded polymeric nanoparticles target the site of inflammation and to analyse the influence of different colon-specific delivery strategies. Three different polymeric nanoparticles were formulated using ovalbumin (OVA) as a model drug. pH-sensitive nanoparticles were made with Eudragit^® S100. Mucoadhesive nanoparticles were created with trimethylchitosan (TMC). A mix of polymers, PLGA, PEG-PLGA and PEG-PCL, were used to obtain a sustained drug delivery. Furthermore, ligands targeting immune cells (i.e. mannose) or the inflamed colon (i.e. a specific peptide) were grafted on the PEG chain of PCL. Interaction of nanoparticles with the intestinal epithelium was explored using Caco-2 monolayers designed to mimic an inflamed epithelium and then visualized using confocal laser microscopy. TMC nanoparticles had the highest apparent permeability for OVA in the untreated model. However, in the inflamed model, there were no difference between TMC, PLGA-based and Eudragit^® nanoparticles. The uptake of nanoparticles in the inflamed mouse colon was assessed in a horizontal diffusion chamber. Mannose-grafted PLGA nanoparticles showed the highest accumulation of OVA in inflamed colon. Based on these results, active targeting of macrophages and dendritic cells may be a promising approach for targeting the colon in IBD.     

Starch-based coatings for colon-specific delivery. Part II: Physicochemical properties and in vitro drug release from high amylose maize starch films

This work reports an investigation into free-film properties of a high amylose maize starch-based film coating that has been used in the preparation of formulations for drug delivery to the colon (WO 2008/012573 A1) and relates these properties to in vitro drug release from pellets.Maize starch/ethylcellulose free films were prepared and characterised by scanning electron microscopy (SEM), light microscopy, modulated differential scanning calorimetry (mDSC), Fourier-transform infrared (FT-IR), X-ray and % swelling in aqueous fluids with pH conditions similar to the stomach and small intestine. 5-ASA release from film-coated pellets was tested in enzyme free simulated gastric fluid and phosphate buffer pH 7.2. Selected formulations were further assessed in simulated gastric and intestinal fluids containing pepsin and pancreatin, respectively.The free films prepared were smooth and homogeneous in their appearance. The two polymers are immiscible, and neither mDSC nor FT-IR could detect interactions between them. Films made from high amylose starches were found to have a considerably lower swelling ability than high amylopectin-based films, and they suppressed drug release in the enzyme free media successfully.5-ASA release from pellets coated with mixtures of high amylose starches (Hylon^® VII, Hylon^® V or LAPS) and Surelease^® in a ratio of 1 to 2 w/w was found to be minimal in simulated gastric and intestinal fluids. This suggests that these mixed films provide starch domains that are resistant to the enzymes present in the upper GI tract and thus can potentially be used in the preparation of colon-specific delivery devices. Starches with a minimum amylose content of 56% such as the starches used in this study (Hylon^® VII and Hylon^® V) are preferred, and although pure amylose can also be used this is not essential.     

Development of shellac-coated sustained release pellet formulations

Shellac is an important coating material for food products. Since the introduction of aqueous ammoniacal solutions it also regained importance for pharmaceutical applications. Because of the comparatively high dissolution pH of this material, further additives are required if shellac is used as enteric coating material. However, this dissolution behaviour of shellac may be of interest for sustained release or colon targeting applications. In the present study different subcoats containing calcium chloride, citric acid or Eudragit^® E, respectively, were applied to immediate release theophylline pellets which were subsequently coated with shellac. Drug release from the resulting pellet formulations was measured. The mechanism of interaction between the modifying subcoat ingredients and the shellac coating was investigated using FT-IR spectroscopy. All formulations with modifying subcoat prolonged drug release. Whereas the effect of calcium chloride was a result of ionic interactions with shellac, the effect of citric acid was a reduction of the degree of dissociation of shellac. The influence of Eudragit^® E can be explained by the solubility characteristics of this basic polymer. The application of modifying subcoats is an easy and effective means to achieve sustained release from shellac-coated dosage forms. The choice of a suitable substance and the adjustment of its concentration allow tailor made sustained release profiles.     

阿莫西林脉冲释药微丸的研制

目的:制备阿莫西林脉冲释药微丸。方法:取空白丸芯分别以含药层、溶胀层(羧甲基淀粉钠)和控释层(乙基纤维素水分散体)顺序依次进行包衣制备阿莫西林脉冲释药微丸。采用紫外法和篮法考察溶胀层(12%、16%、20%)和控释层包衣增重(24%、28%、32%)及不同介质(水、盐酸、pH6.8磷酸盐缓冲液)对药物释放的影响。结果:溶胀层和控释层包衣增重对脉冲控释微丸的释药时滞和释放速率具有显著影响,药物释放情况不受介质pH值的影响;溶胀层和控释层包衣增重分别为16%、28%时制备的微丸时滞时间约为4h,时滞后4h累积释药率达到80%。结论:所制备的阿莫西林脉冲释药微丸具有体外脉冲释放作用。     

SM-1小粒径肠溶微丸的制备及体外评价

目的制备SM-1小粒径肠溶微丸,并优化其处方,以达到肠溶和便于小动物给药的目的。方法采用流化床空白丸芯上药法,在丸芯表面依次包覆含药层、羟丙基甲纤维素（HPMC）隔离层和丙烯酸树脂（EudragitL30D-55）肠溶层。以载药量、耐酸性及释放度为指标,对SM-1肠溶微丸的处方进行优化。结果隔离层增重8%,肠溶层增重15%的肠溶微丸粒径〈450μm（40目筛）,圆整度良好,载药量约为20%;在pH为2.0的盐酸溶液中2 h内肠溶衣层薄层完好,药物释放度〈4%;在pH为6.8的PBS溶液中,45 min内释放度均〉70%。结论采用流化床制备SM-1肠溶微丸工艺可行,重现性好,具有良好的肠溶特性,粒径〈380μm,可用于小动物给药。     

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.     

An approach to a cold chain free oral cholera vaccine: in vitro and in vivo characterization of Vibrio cholerae gastro-resistant microparticles

The present work describes the formulation of Eudragit^® L30 D-55 microparticles (MP) alone or with mucoadhesive agents, alginate or Carbopol^®, as an approach for the development of an oral cholera vaccine. In the first part, a spray drying technique was optimized for microparticle elaboration, obtaining a microparticle size ranging from 7 to 9 μm with high encapsulation efficiencies. Moreover, gastro resistant properties and Vibrio cholerae (VC) antigenicity were maintained, but for Eudragit^®-Carbopol^® microparticles which showed low antigenicity values, ≈25%. Next, a stability study was performed following ICH Q1 A (R2) guidelines, i.e. 25 °C-60% relative humidity (RH) for 12 months, and 30 °C-65% RH and 40 °C-75% RH for 6 months. Upon storage, microparticle size changed slightly, 1 μm for Eudragit^®-alginate MPs and 0.36 μm for Eudragit^®MP. However, gastro resistance and antigenicity values were kept in an acceptance range. In the third stage of this work, in vivo experiments were performed. The immune response evoked was measured by means of vibriocidal titer quantification, observing that Eudragit^®-alginate MPs were able to induce stronger immune responses, comparable to the free VC. Therefore, microencapsulation of VC by spray drying could be proposed as an approach to a cold chain free and effective oral cholera vaccine.     

The stability of insulin in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol

Abstract

Non-pareil cores were spray-coated with a chlorpheniramine maleate (an alkylamine antihistamine) layer and a Eudragit^R N overcoat in a Wurster air-suspension apparatus. In vitro dissolution studies demonstrated that drug release was a function of polymer membrane thickness. Polyethylene glycol 6000, as a hydrophillic additive, increased the in vitro release of chlorphenir amine maleate from the pellets. Pellets coated with 8 0% Eudragit^R N, 0 0% talc and 0% polyethylene glycol 6000 were found to display desirable controlled release characteristics for chlorpheniramine maleate over the 8-h testing period, which were also comparable with that of Dykatuss^R capsules. The controlled release pellets exhibited first-order release characteristics for chlorpheniramine maleate. Reproducibility of the manufacturing conditions employed in the study were confirmed thus ensuring reproducibility of drug release characteristics between batches of chlorpheniramine maleate pellets. Drug release from the pellets was shown to be independent of the dissolution method and medium used. Pellets displayed no significant change in drug release characteristics relative to the initial drug release data when stored for 12 weeks at room temperature (20+2) and for 8 weeks at a low temperature (5 + 1 °C). However, pellets stored at 37 °C with 80% relative humidity and at 40 + 2 showed a slower in vitro drug release after 8-week storage and therefore failed to maintain their initial drug release profile.     

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques. Centrifugal granulator and fluidized-bed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively. The prepared pellets were evaluated for physicochemical characterization, subjected to differential scanning calorimetry (DSC) and in vitro release of different pH. Different release models and scanning electron microscopy (SEM) were utilized to analyze the release mechanism of Harnual^® and home-made pellets. By comparing the dissolution profiles, the ratio and coating weight gain of Eudragit^® NE30D and Eudragit^® L30D55 which constitute the inside membrane were identified as 18:1 and 10%–11%. The coating amount of outside membrane containing Eudragit^® L30D55 was determined to be 0.8%. The similarity factors (f₂) of home-made capsule and commercially available product (Harnual^®) were above 50 in different dissolution media. DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual^® and self-made pellets before and after dissolution. According to Ritger-Peppas model, the two dosage form had different release mechanism.