Bridging the structure gap between pellets in artificial dissolution media and in gastro-intestinal tract in rats

Changes in structure of oral solid dosage forms (OSDF) elementally determine the drug release and its therapeutic effects. In this research, synchrotron radiation X-ray micro-computed tomography was utilized to visualize the 3D structure of enteric coated pellets recovered from the gastrointestinal tract of rats. The structures of pellets in solid state and in vitro compendium media were measured. Pellets in vivo underwent morphological and structural changes which differed significantly from those in vitro compendium media. Thus, optimizations of the dissolution media were performed to mimic the appropriate in vivo conditions by introducing pepsin and glass microspheres in media. The sphericity, pellet volume, pore volume and porosity of the in vivo esomeprazole magnesium pellets in stomach for 2 h were recorded 0.47, 1.55 × 108 μm3, 0.44 × 108 μm3 and 27.6%, respectively. After adding pepsin and glass microspheres, the above parameters in vitro reached to 0.44, 1.64 × 108 μm3, 0.38 × 108 μm3 and 23.0%, respectively. Omeprazole magnesium pellets behaved similarly. The structural features of pellets between in vitro media and in vivo condition were bridged successfully in terms of 3D structures to ensure better design, characterization and quality control of advanced OSDF.

Polymer blend: a new approach for eliminating curing effect of aqueous dispersion coatings

The aim of present work was to investigate blends of Eudragit® NE 30D with Aquacoat® ECD using different ratios to eliminate curing effect associated with individual polymers. Propranolol HCl 10% w/w was layered onto sugar cores using 5% w/w HPMC as a binder. Drug-layered-cores were coated either with pure or blends of Aquacoat® ECD: Eudragit® NE 30D in a fluidized bed coater to obtain 20% w/w coating level. Talc 35% w/w was used as anti-tacking agent. The pellets were characterized for in vitro dissolution studies, morphology, water uptake-weight loss, osmolality and adhesion of coating after curing at 60 °C or 60 °C/75% RH for 24 h. The findings revealed that Aquacoat® ECD coated pellets showed curing effect due to further gradual coalescence of polymeric particles which resulted into better film formation upon curing. In contrast, the curing effect of Eudragit® NE 30D coated pellets was caused by decrease in adhesion of coatings after curing which provided entirely different swelling behavior of uncured (localized swelling) and cured (uniform swelling) pellets. The undesired curing effect of individual polymers was eliminated by using their blends in appropriate ratio.

Study on the Preparation of Lansoprazole Enteric-coated Pellets Orally Disintegrating Tablets / 中国药师

Objective:To prepare lansoprazole enteric-coated pellets and compress them into orally disintegrating tablets , and e-valuate the acid resistance in the acid stage and the in vitro dissolution in the buffer stage .Methods:Lansoprazole enteric-coated pel-lets were prepared by fluid bed coating technology , and the effects of the ratio of methacrylic acid copolymer dispersion to ethyl acrylate–methyl methacrylate copolymer dispersion , the concentration of triethyl citrate and the main pressure on the acid resistance in the acid stage and the in vitro dissolution in the buffer stage were evaluated .The similarity of the self-prepared orally disintegrating tablets and the reference preparation was evaluated by using f 2 similarity factor method .Results:The average particle size of microcrystalline cellulose core was 150-180 μm, the ratio of methacrylic acid copolymer dispersion to ethyl acrylate –methyl methacrylate copolymer dispersion was adjusted to 8:2, the enteric-coated weight was 30％, 20％triethyl citrate was used and the main pressure was controlled within the range of 10-16 kN.Lansoprazole enteric-coated pellets had sufficiently flexibility and stability against the compression force . The enteric coating did not break , showing good acid resistance .The dissolution similarity factor of the self-prepared orally disintegra-ting tablets and the reference preparation was greater than 50.Conclusion: Lansoprazole enteric-coated pellets orally disintegrating tablets have good acid resistance and high similarity for the in vitro dissolution, which can be further amplified .

Effects of Panax Notoginseng Saponins Enteric-coated Pellets on Hemorheology in Rabbits / 中国药师

Objective:To discuss the effects of panax notoginseng saponins (PNS) enteric-coated pellets on hemorrheology in rabbits.Methods:The rabbits were divided into the normal control group,the model control group,Xueshuangtong injection (lyophilization) group(15 mg·kg-1·d-1 ,im),PNS enteric-coated pellets groups respectively at high(45 mg·kg-1·d-1,ig),medium(30 mg·kg-1·d-1,ig) and low (15 mg·kg-1·d-1,ig) dose.The model was established by intragastric administration of high-fat diet.The whole-blood viscosity,plasma viscosity,erythrocyte aggregational index,crythrocyte index of rigidity and erythrocyte electro-phoresis rate in the groups were detected using hemorheological methods.Results:The above indices of hemorheology in the model control group were all significantly higher than those in the normal control group (P0.05).Compared with Xueshuangtong injection (lyophilization) group,PNS enteric-coated pellets group at medium dose could significantly reduce the whole blood middle shear viscosity(P<0.05).Conclusion:PNS enteric-coated pellets can reduce the whole-blood viscosity,plasma viscosity,erythrocyte aggregational index,crythrocyte index of rigidity and erythrocyte electro-phoresis rate,and effectively promote blood circulation and remove stasis,inhibit thrombosis formation and increase blood supply for heart and cerebral vessels.

Preparation and Drug Release in vitro of (R)-Rabeprazole Sodium Enteric-coated Pellets / 中国药师

Objective:To prepare enteric-coated pellets of ( R)-rabeprazole sodium and investigate the drug release behavior in vitro. Methods:The pellets of ( R)-rabeprazole sodium were prepared by a fluid bed coating technology, and HPMC and Eudragit L30D-55 was used as the material of isolation layer and enteric coating, respectively. The similarity of in vitro drug release was com-pared between the reference preparation and the self-prepared preparation. Similar factor ( f2 ) was used to evaluate the similarity of re-lease curves. Results:The coating formula of ( R)-rabeprazole sodium enteric-coated pellets was as follows: the weight of HPMC E5 and Eudragit L30D-55 was 12. 0% and 45. 0%, respectively, and the plasticizer was 8. 0% of the weight of the polymers. The f2 of the reference preparation and the self-prepared preparation was more than 50, which indicated the release behavior was similar. Con-clusion:The release behavior of ( R)-rabeprazole sodium enteric-coated pellets is quite promising, and the preparation technology can be used in the industrial production.

Preparation of lansoprazole biphasic release pellet capsules / 国际药学研究杂志

Objective To prepare lansoprazole biphasic release pellet capsules. Methods The pellets carrying lansoprazole were directly prepared by centrifugal making-pill method,and the pellets of enteric coating and enteric pulsatile coating were adopted by fluidized bed coating method. Then the two kinds of pellets were filled by a fixed proportion to hollow capsules. In vitro dissolution method was used for the observation of the drug release behavior. Results The optimized formulation was as follows:the magnesium carbonate level was 15%,the L-HPC level was 20%in pellets carried drug,the isolation gown level was 9%-10%,the enteric coating level was above 41%in enteric coated pellets,the swelling agent level was 50-60%,the controlled layer level was 50%,the enteric coating level was above 41%in pulsatile enteric coated pellets,and the drying time was 4 h in the end. Conclusion The method is feasible for preparation of lansoprazole biphasic release pellet capsules by encapsulating enteric-coated pellets,and able to obtain good repeatability and stable quality.

Preparation of lansoprazole biphasic release pellet capsules / 国际药学研究杂志

Objective To prepare lansoprazole biphasic release pellet capsules. Methods The pellets carrying lansoprazole were directly prepared by centrifugal making-pill method, and the pellets of enteric coating and enteric pulsatile coating were adopted by fluidized bed coating method. Then the two kinds of pellets were filled by a fixed proportion to hollow capsules. In vitro dissolution method was used for the observation of the drug release behavior. Results The optimized formulation was as follows: the magnesium carbonate level was 15%, the L-HPC level was 20% in pellets carried drug, the isolation gown level was 9%-10%, the enteric coating level was above 41% in enteric coated pellets, the swelling agent level was 50-60%, the controlled layer level was 50%, the enteric coating level was above 41% in pulsatile enteric coated pellets, and the drying time was 4 h in the end. Conclusion The method is feasible for preparation of lansoprazole biphasic release pellet capsules by encapsulating enteric-coated pellets, and able to obtain good repeatability and stable quality.

Evaluation of Bioavailability and Bioequivalence of Rabeprazole Sodium Enteric-coated Pellets Capsules in Humans / 中国药师

Objective: To evaluate the bioavallability and bioequivalence of rabeprazole sodium enteric-coated pellets capsules. Methods:A randomized crossover design was performed in 32 healthy male volunteers. A single oral dose of 20 mg rabeprazole sodium enteric-coated pellets capsules ( test preparation) or enteric-coated shell capsules ( the reference capsules) was administrated under fed conditions. The wash period was 7 days. The blood samples were collected at different time points. The concentration of rabeprazole in plasma was determined by an LC-MS/MS method. The pharmacokinetic parameters were calculated by DAS 3. 0 software and the bio-equivalence was evaluated. Results:The maln pharmacokinetic parameters of the two formulations were shown as follows:T1/2 of (2. 20 ± 0. 83)h and(1. 951 ± 0. 515)h,Tmax of (3. 88 ± 1. 11)h and(4. 64 ± 1. 504)h,Cmax of (401. 06 ± 170. 75)ng·ml-1 and(394. 63 ± 215.64)ng·ml-1,AUC0→t of (918.42 ±427.39)ng·h·ml-1 and (994.49 ±520.73)ng·h·ml-1, and AUC0→∞ of(937.30 ± 445.13)ng·h·ml-1 and(1 011.69 ±534.77)ng·h·ml-1. The analysis showed that the maln pharmacokinetic parameters of the two formulations had no significant differences(P>0. 05) except for Tmax(P<0. 05). The relative bioavallability of rabeprazole sodium enteric-coated pellets capsules was (99. 80 ± 7. 20) %. Conclusion:Compared with the reference capsules, rabeprazole sodium enter-ic-coated pellets capsules show the property of higher dispersion degree, milder influence from food, more rapid release and absorption. The enteric-coated pellets capsules and the reference capsules are bioequivalence.

Determination related substances of rabeprazole sodium enteric-coated pellets by HPLC / 中国生化药物杂志

Objective To establish an HPLC method for the determination of related substances of rabeprazole sodium.Methods The determination was performed on a Xtimate C18 column.The mobile phase consisted of 2 g/L ammonium acetate-acetonitrile (95:5)and 2 g/L ammonium-methanol(15:85), with linear gradient elution and the flow rate of 1.0 mL/min.Detection wavelength was 290 nm.Results Related substances were completely separated from the main constituent.The limit of detection of rabeprazole was 0.25 ng and the limit of quantification was 0.75 ng,which were 0.01% and 0.03% of test sample and met the detection.With the selected solvents, principal component could be extracted efficiently and good stability.The sample solution was not stable at room temperature.Conclusion The method is simple, rapid and accurate, and can be used to control the quality of rabeprazole sodium enteric-coated pellets.

Formulation optimization of metoprolol succinate sustained release pellets using central composite design-response surface methodology / 军事医学

Objective To optimize the formulation of metoprolol succinate ( MS) controlled release pellets by central composite design-response surface methodology .Methods MS sustained-release pellets were prepared using sugar pellet cores as starter beads , ethyl cellulose as coating materials and MS itself as a pore former .The formulation of MS sustained-release pellets was optimized by a central composite design with two factors at five levels .These two factors ( two independ-ent variables) were the pore former level and coating level , and the evaluated indexes ( namely dependent variables ) included the in vitro cumulative release percentages of MS at 1, 4, 8, 12 and 16 h, respectively.Results and Conclusion The results of mathematical equation fitting suggested that the second-order quadratic model was the optimal fitting equa-tion.According to the response surfaces , the optimum values at the pore former level and coating level weve ranged from 16%to 18%and 20% to 25%, respectively .The in vitro cumulative release percentage of MS from the pellets at 1 h reached 9.15%,which consequently eliminated the lag phase in the initial release period and exhibited a good sustained-release effect.Central composite design-response surface methodology can be applied to optimizing the coating formulation for MS sustained release pellets .

Coated pellets:the emerging direction of oral modified-release solid dosage forms / 国际药学研究杂志

Oral modified-release multiple-unit dosa ge forms such as coated pellets have always been more effective therapeutic alternative to conventional single-unit dosage forms. Coated pellets ranging in size,typically,between 0.5-1.0 mm,are produced primarily for the purpose of oral controlled-release dosage forms having gastro-resistant or sustained-release properties or the capability of site-specific drug delivery. With regards to the final dosage form,the multi-particulates are usually formulated into single-unit dosage forms such as filling them into hard gelatin capsules or compressing them into tablets. As drug-delivery systems become more sophisticated,the role of pellets in the design and development of dosage forms is increasing. The safety and efficacy of the formulation is higher than that of other dosage forms. This review provides an update on this research area and discusses the phenomena and mechanisms of the multi-particulate system concluding multiple-unit pellet system and pellet-containing tablets.

Preparation and in vtro Release of Dexketoprofen Enteric-coated Pellets / 中国药师

Objective:To prepare dexketoprofen enteric-coated pellets and explore the drug release rate respectively in 0. 1 mol· L-1 hydrochloric acid and phosphate buffered saline(PBS,pH 6. 8). Methods:Dexketoprofen enteric-coated pellets were prepared u-sing fluid-bed coating technology, the blank sugar pellets were coated with drug layer, isolation layer and enteric layer in order. Drug-loading rate as the index, the optimal concentrations of HPMC and drug were screened. Such indicators as adhesion, pellet uniform and surface color as the indices, the coating process was optimized by orthogonal experiment. Drug release in PBS of the enteric-coated pel-lets and the common enteric-coated tablets were compared. Results:The prepared pellets showed the properties of uniform drug load-ing, high drug-loading rate, complete round shape and lustrous appearance. The concentration of HPMC and drug was 5% and 15%, respectively. The optimal coating process was as follows:the material temperature was 36℃, the atomization pressure was 1. 0 bar and the airbrush rate was 0. 8 ml·min-1 . The drug release of the pellets in hydrochloric acid was below 10% in 2 hours, while the release in PBS was greater than that of the common enteric-coated tablets. Conclusion: The prepared enteric-coated pellets are feasible in technology, and exhibit satisfactory acid endurance and drug release in vitro.

Coated pellets:The emerging direction of oral modified-Release solid dosage forms / 国际药学研究杂志

Oral modified-release multiple-unit dosage forms such as coated pellets have always been more effective therapeutic alternative to conventional single-unit dosage forms. Coated pellets ranging in size, typically, between 0.5-1.0 mm, are produced primarily for the purpose of oral controlled-release dosage forms having gastro-resistant or sustained-release properties or the capability of site-specific drug delivery. With regards to the final dosage form, the multi-particulates are usually formulated into single-unit dosage forms such as filling them into hard gelatin capsules or compressing them into tablets. As drug-delivery systems become more sophisticated, the role of pellets in the design and development of dosage forms is increasing. The safety and efficacy of the formulation is higher than that of other dosage forms. This review provides an update on this research area and discusses the phenomena and mechanisms of the multi-particulate system concluding multiple-unit pellet system and pellet-containing tablets.

Development of mesalazine pellets coated with methacrylic-derived polymer / Desenvolvimento de pelotas mesalazina revestidos com metacrílico derivado de polímero

Mesalazine (5-ASA) is the standard drug for the treatment of inflammatory bowel disease (IBD) due to its local effect on intestinal and colonic mucosa. The effective and safe treatment of this disease requires more efficient delivery of the active substance to its site of action. The focus of this study was the use of multiparticulate systems, a modified release form in which the drug is divided into several functional subunits of release in the form of granules or pellets. When these forms are administered, they are rapidly disintegrated, distributing their content throughout the gastrointestinal tract. The aim of this study was to develop and evaluate a multiparticulate system consisting of pellets coated with polymer for pH-dependent release, derived from methacrylic acid and incorporated into the tablet dosage form of mesalazine as a model drug. The extrusion-spheronisation technique was used, resulting in smooth and spherical pellets with uniform size distribution, which were coated in fluidized bed using Opadry® Enteric 94K28327 containing Eudragit® S100 as the agent regulating drug release. The dissolution profile of coated pellets showed good control of drug release from the polymer at the two levels of coating evaluated (8 percent and 10 percent), but only the 10 percent coated pellets were statistically similar to Asalit® 400 mg.

A mesalazina (5-ASA) tem se apresentado como fármaco padrão para o tratamento da doença inflamatória intestinal (DII) devido ao seu efeito local na mucosa intestinal e colônica. A terapia efetiva e segura desta doença requer a chegada da substância ativa ao seu local de ação com maior eficiência. Nessa busca, tem se destacado o uso de Sistemas Multiparticulados, forma farmacêutica de liberação modificada, em que o fármaco está dividido em várias subunidades funcionais de liberação, sob a forma de grânulos ou péletes, que quando administrados, são rapidamente desintegrados distribuindo seu conteúdo por todo trato gastrintestinal. Este trabalho teve como objetivo desenvolver e avaliar péletes revestidos com polímero de liberação pH-dependente, derivado do ácido metacrílico, tendo como fármaco modelo a mesalazina. A técnica de extrusão-esferonização foi utilizada obtendo-se péletes lisos e esféricos com distribuição granulométrica uniforme, que foram revestidos em leito fluidizado utilizando Opadry® Enteric 94K28327 contendo Eudragit® S100 como agente regulador da liberação do fármaco. O perfil de dissolução dos péletes revestidos demonstrou bom controle na liberação do fármaco por parte do polímero nos dois níveis de revestimento avaliados (8 e 10 por cento), porém, apenas os péletes revestidos a 10 por cento demonstraram semelhança estatística com o medicamento de referência Asalit® 400 mg.

Combined system of sinomenine hydrochloride sustained-release pellets / 中国药科大学学报

Aim: To establish a linear additive model for the predication of in vitro sinomenine hydrochloride release from the combination of immediate release, enteric-coated and sustained-release pellets based on the release profiles of each pellet type. Methods: Immediate release pellets were manufactured by extrusion/spher-onization technology. The operation of bottom-spraying in the fluid-bed equipment was conducted to enteric-coating using Eudragit~(R) L-30D-55 and sustained-release coating using Surelease~(R) . In vitro sinomenine hydrochloride release profiles of both uncoated and coated pellets were fitted to the chosen mathematical equations offered by the curve fitting toolbox of Matlab~(R) before a linear additive model was created based upon the best-to-fitting equations. The proportion of each pellet type in the combined format to generate the desired 24 h sinomenine hydrochloride release profile was solved by Matlab~(R). The predicted and assayed sinomenine hydrochloride release from the polled pellets was compared. Results: It was shown that the actual sinomenine hydrochloride release profiles of each pellet type were approximate to those of predicted ones. A linear additive model of the appropriate mathematical equations of each pellet was proven to be capable of controlling in vitro release of sinomenine hydrochloride multiple-unit pellets. Conclusion: A multiple-unit combined system of the selected pellets, as a novel sustained-release system, was successfully prepared. In vitro release performance of the calculated combination of each pellet type could be guaranteed by this approach in designing sustained-release drug delivery system.

Preparation of Oxymatrine Enteric-coated Pellets / 中国药房

OBJECTIVE: To prepare Oxymatrine enteric-coated pellets.METHODS: The coating conditions such as the rotation speed,the coating temperature as well as the pressure of spray gun were optimized through single factor experiment;the properties of different coating solutions of resins were compared to optimize the coating material.The enteric-coated pellets were prepared by bed coating technology.The coating effect was evaluated by the dissolution in vitro. RESULTS: The optimal coating conditions were as follows: the rotation speed of the coating pan was 50 r?min-1,the coating temperature was 30 ℃,the pressure of spray gun was 0.10 MPa;the coating material was polyacrylic resin(Huzhou Ⅲ).The in vitro dissolution of the enteric-coated pellets prepared by the bed coating technology met the requirements specified in the Chinese Pharmacopeia(2005 edition).CONCLUSION: By using the bed coating technology,the enteric-coated pellets with good dissolution in vitro can be obtained.