Preparation and in-vitro drug release of Baizhu Huanglian pellets containing colon-targeting capsules / 药学实践杂志

Objective Colon-targeting capsules based on gastric pellets and enteric pellets were prepared from Baizhu Huanglian prescription. The formulation composition and preparation process were optimized and the in-vitro release characteristics were investigated. Methods Optimum formulation composition and process parameters of Baizhu Huanglian pellets were screened out by single factor experiment and orthogonal design. The pellets core were prepared by extrusion-spheronization technique and coated in the fluid bed using bottom spray coating technique. To investigate the effect of coating level of the isolation layer, the proportion of polymer, the amount of plasticizer and weight gain of enteric coating on the release behavior of the enteric pellets. The pellets release behavior was fitted by model as well. Results The prescription of gastric pellets was drug loading 50%, PVPP 5%, MCC to lactose 1∶2 and wetting agent 40%. The process parameters were extrusion frequency 20 Hz, rounding speed 500 r/min and rounding time 5 min. The prescription of enteric pellets was drug loading 27%, PVPP 5%, MCC to lactose 5∶2, wetting agent 30% and adhesive 20%. The process parameters were extrusion frequency 20 Hz, rounding speed 700 r/min and rounding time 7 min. For enteric coating layer, the coating mixture of EUDRAGIT®L30D-55 to EUDRAGIT® FS30D was 1∶2. The amount of plasticizer was 10%. The increased weight of coating layer was 15%. The release time of enteric pellets in-vitro was up to 24 hours. The release behavior of the pellets conforms to the Higuchi model. Conclusion The colon targeting capsule of Baizhu Huanglian pellets were successfully prepared and showed the characteristics of sustained release and colon targeting.

Development of andrographolide colon-targeting release pellets based on quality by design (QbD) approach / 中草药

Objective: To optimize andrographolide pellet by using a quality by design (QbD) approach. Methods: Usingthe cumulative in vitro release as evaluation index, the single-factor investigation and hazard analysis were used to study the core and coating process of andrographolide colon-targeting pellets, and the central composite design-response surface method was used to optimize and predict the three key factors of plasticizer dosage, aging time, and coating weight gain. Results: The optimum coating process parameters were as following: plasticizer dosage of 3 g, coating weight gain of 20%, and aging time of 1 h. The process had been verified that the optimal formulation process had a cumulative in vitro release of 6.9% in the acid phase (0.1 mol/L HCl)-buffered salt phase (pH 6.0) and a cumulative in vitro release of more than 90% in the pH 7.2 buffered salt phase. Conclusion: It is feasible to apply the QbD concept optimization in the study of andrographolide colon-targeting pellets.

Design and preparation of a novel colon-targeted tablet of hydrocortisone

ABSTRACT The objective of this research was to design a new colon-targeted drug delivery system based on chitosan. The properties of the films were studied to obtain useful information about the possible applications of composite films. The composite films were used in a bilayer system to investigate their feasibility as coating materials. Tensile strength, swelling degree, solubility, biodegradation degree, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscope (SEM) investigations showed that the composite film was formed when chitosan and gelatin were reacted jointly. The results showed that a 6:4 blend ratio was the optimal chitosan/gelatin blend ratio. In vitro drug release results indicated that the Eudragit- and chitosan/gelatin-bilayer coating system prevented drug release in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). However, the drug release from a bilayer-coated tablet in SCF increased over time, and the drug was almost completely released after 24h. Overall, colon-targeted drug delivery was achieved by using a chitosan/gelatin complex film and a multilayer coating system.

Preparation and in Vitro/in Vivo Evaluation of Indomethacin Multi-dosage Mini Tablets for Colon Target Delivery / 医药导报

Objective Enzyme triggered multi unit colon targeting mini tablet of indomethacin were prepared,in order to improve the target treatment of colon disease.Methods Different proportion of enteric layer and chitosan layer were screened to optimize the prescription.The colon targeting mini tablets were prepared by direct compression method.The drug release properties were investigated in different release medium.Rats were used to investigate the distribution of tissue in vivo.The Beagle dogs were used to study the pharmacokinetics and bioavailability.Results The optimum chitosan layer prescription:coating liquid concentration was 2％,plasticizer three citric acid ethyl ester (TEC) was 15％,an anti sticking agent amount of talc was 30％,coating weight was 5％;Enteric layer prescription:coating liquid solid content was 20％,plasticizer content of TEC was 5％,anti sticking agent talc powder dosage was 40％,coating weight was 3％.The chitosan multi unit colon targeted preparation seldom released in rat stomach and small intestine,released slowly in colon.The pharmacokinetics parameters in Beagle dogs were:Cmax =(3.25 + 0.672) mg·L-1,tmax =(2.00 + 0.014) h,AUC(0.∞) =(10.2 +0.871) mg·L-1 ·h,MRT (0-∞) =(2.82 + 0.180) h,CL =(2.46 + 0.202) L·h-1 ·kg-1.The release time of mini tablets for colon targeted was significantly prolonged and preserved stable blood concentration.Conclusion The enzyme triggered multi unit colon targeting mini tablet of indomethacin showed good target to colon and sustained release effect,providing an important reference for the development of preparation of indomethacin for the treatment of colon disease.

Preparation of Astragalus polysaccharide colon targeting pellets / 中国药学杂志

OBJECTIVE: To study the preparation process of pH-dependent delayed colon targeting pellets of astragalus polysaccharide. METHODS: Colon targeting agents of APS pellets were produced by extrusion-spheronization and fluid bed coating method and the best preparation technology was chosen by response surface optimization method. RESULTS: The ratio of pill core: APS powder-avicel-tannic acid-carboxymethylcellulose sodium was 25:15:8:2, the wetting agent was water, the rate of extrusion was 60 r·min-1, the rate of spheronization was 1 400 r·min-1, and the time of spheronization was 4 min. The best fluid bed coating condition was as follows the fan frequency was 29.50 Hz, the pressure of spray gun was 0.70 kg·cm-2, the rate of coating flow was 3 mL·min-1, and the colon coating weight was 15%. The release degree of pill for simulated gastric fluid in 2 h was 0%, The release degree of pill for artificial intestinal fluid in 3 h was less than 5%. The release degree of pill for artificial colon fluid in 2 h was release completely. CONCLUSION: The preparation method can be qpplied to the preparation of APS pellets, it's simplicity of operator and had good reproducibility, it can be applied to the industrial production.

Enteric coated HPMC capsules plugged with 5-FU loaded microsponges: a potential approach for treatment of colon cancer

The work was aimed at developing novel enteric coated HPMC capsules (ECHC) plugged with 5 Florouracil (5-FU) loaded Microsponges in combination with calcium pectinate beads. Modified quasi-emulsion solvent diffusion method was used to formulate microsponges based on 32 factorial design and the effects of independent variables (volume of organic solvent and Eudragit RS100 content) on the dependent variables (Particle size, %EE & % CDR) were determined. The optimized microsponges (F4) were characterized by SEM, PXRD, TGA and were plugged along with calcium pectinate beads in HPMC capsules and the HPMC capsules were further coated with enteric polymer Eudragit L 100 (Ed-L100) and/ or Eudrgit S 100 (Ed-S 100) in different proportions. In vitro release study of ECHC was performed in various release media sequentially SGF for 2 h, followed by SIF for the next 6 h and then in SCF (in the presence and absence of pectinase enzyme for further 16 h). Drug release was retarded on coating with EdS-100 in comparison to blend of EdS-100: EdL-100 coating. The percentage of 5-FU released at the end of 24 h from ECHC 3 was 97.83 ± 0.12% in the presence of pectinase whereas in control study it was 40.08 ± 0.02% drug. The optimized formulation was subjected to in vivo Roentgenographic studies in New Zealand white rabbits to analyze the in vivo behavior of the developed colon targeted capsules. Pharmacokinetic studies in New Zealand white rabbits were conducted to determine the extent of systemic exposure provided by the developed formulation in comparison to 5-FU aqueous solutions. Thus, enteric coated HPMC capsules plugged with 5-FU loaded microsponges and calcium pectinate beads proved to be promising dosage form for colon targeted drug delivery to treat colorectal cancer.

O trabalho teve como objetivo o desenvolvimento de novas cápsulas com revestimento entérico HPMC (ECHC) conectadas com microesponjas carregadas com fluoruracila (5-FU) em combinação com grânuos de pectinato de cálcio. O método de difusão de solvente modificado quasi-emulsão foi usado para formular microesponjas com base no planejamento fatorial 32 e determinaram-se os efeitos das variáveis independentes (volume de solvente orgânico e conteúdo Eudragit RS100) sobre as variáveis dependentes (tamanho de partícula, EE% e % CDR). As microesponjas otimizadas (F4) foram caracterizadas por SEM, PXRD, TGA e ligadas aos grânulos de pectinato de cálcio em cápsulas de HPMC e estas foram, ainda, revestidas com polímero entérico Eudragit L 100 (Ed-L100) e/ou Eudrgit S 100 (Ed S 100) em diferentes proporções. No estudo de liberação in vitro de ECHC foi realizada em vários meios de liberação sequencial SGF durante 2 h, seguido de SIF para as próximas 6 h, e, em seguida, em SCF (na presença e na ausência de enzima pectinase por mais 16 h). A liberação do fármaco foi retardada em revestimento com a EDS-100, em comparação com mistura de EDS-100: EDL-100, de revestimento. O percentual de 5-FU liberado de ECHC 3 ao final de 24 h foi 97,83 ± 0,12% em presença de pectinase, enquanto que para o controle foi de 40,08 ± 0,02% do fármaco. A formulação otimizada foi submetida a estudos Roentgenográficos in vivo, em coelhos brancos Nova Zelândia, para analisar o comportamento das cápsulas desenvolvidas direcionadas ao cólon. Os estudos de farmacocinética em coelhos brancos da Nova Zelândia foram conduzidos para determinar a extensão da exposição sistêmica propiciada pela formulação desenvolvida, em comparação com solução aquosa de 5-FU. Assim, cápsulas entéricas de HPMC revestidas e conectadas com microesponjas carregadas com 5-FU e grânulos de pectinato de cálcio se mostraram promissoras como formulação para liberação do fármaco no cólon no tratamento do câncer colorretal.

Pharmacokinetic and Intestinal Absorption Study on Rats of Emodin in Colon-Targeted Huchang Qingdu Pellets / 中国中医药信息杂志

Objective To establish an HPLC method for concentration determination of emodin in plasma and colon tissues after gavage withHuchang Qingdu Pellets;To explore pharmacokinetic properties and colon tissue distribution ofHuchang Qingdu Pellets in rats.Methods Wistar rats were randomly divided into Pellets group and ordinary capsule group. Blood was taken after gavage withHuchang QingduPellets or capsule content in given time points (1, 2, 3, 4, 5, 6, 8, 12, 24 h) from rat venous sinus and analyzed. Rats were put to death, and gastric and colon tissues were isolated and extracted for analysis. Chromatographic conditions:Phenomenex C18 column (4.6 mm × 150 mm, 10μm), the mobile phase of methanol-0.1% acetic acid solution (80∶20), flow rate of 1 mL/min, the detection wavelength of 254 nm.Results Emodin was in good linear range of 0.102-20.40μg/mL. The regression equations were:plasma solutionA=76 825C + 3567.8,r=0.999 4 (n=6);intestinal tissue solutionA=75 931C + 3384.2,r=0.999 0 (n=6). Day-to-day precision and within-day precision were less than 4%. The recovery rate was more than 90%. Pharmacokinetic parameters of T1/2 and Tmax of emodin in rat blood and intestinal tissues increased compared with the ordinary capsule group;Cmax and AUC0-24 were obviously improved compared with the ordinary capsule group.ConclusionHuchang Qingdu Pellets do have controlled release and colon targeting effect.

Determination of rosmarinic acid in common selfheal fruit-spike effective components of colon target tablets / 国际中医中药杂志

Objective To establish HPLC method to determine the content and the recovery of rosmarinic acid in common selfheal fruit-spike effective component of colon target tablets.Methods HPLC column was Diamonsil C18,200 mm×4.6 mm,5μm, wavelength was 330 nm, mobile phase methanol was 0.1% formic acid aqueous solution (45:55), flow rate was 1.0 ml/min, and the sample size was 20μl.Results The fine linear relation was shown at the rosmarinic acid methanol concentration of 2.99-119.6μg/ml, with 72 h in stable state. The method has fine precision, the spotting recovery was 95%-105%, andRSD was less than 2%. Conclusion The method has high specificity, meeting the demands for content determination.

The Application of Factorial Experimental Design in Capsule Coating for Potential Colon Targeting of an Antiamebic Drug.

Aim: The application of factorial experimental design to evaluate the effect of particle size, capsule surface coating and binder concentration on the in vitro controlled release profile of metronidazole from encapsulated granules. Methodology: Metronidazole granules were prepared by the wet granulation technique and encapsulated in hard gelatin capsule shells. Eudragit® L-100 and Landolphia owariensis latex served as primary and secondary coatings respectively on 50 or 75% of capsule surface. The three formulation factors (% capsule surface coating, matrix former concentration and particle size) were subjected to a 2x3x4 factorial design experiment using the software (JMP 4.0.4, SAS Inc. USA). Gradient drug release studies were conducted in three media; firstly in media of pH 1.2 for 2 h, pH 6.8 for 3 h and finally pH 7.4 until exhaustion of drug release. The drug release data were subjected to kinetic treatment to establish operational release kinetics such as zero order, first order, Higuchi, Hixon Crowell and Kitazawa, while the power law enabled the prediction of mechanism of drug release. Results: Results showed that % capsule surface coated with Landolphia owariensis latex and particle size significantly (p<0.05) contributed to time of drug release (T7.4) at pH 7.4. In tandem with this, maximum amount of drug released (D7.4) at pH 7.4 was significantly (p<0.05) affected by particle size alone. A few batches were characterized by anomalous transport while over 80% were associated with super case 11 type of release. Conclusion: We therefore conclude that, factorial experimental design identified Landolphia owariensis latex coating and particle size of granules as being chiefly responsible for drug release variations.

Formulation, in vitro drug release and in vivo human X-ray investigation of polysaccharide based drug delivery systems for targeting 5-fluorouracil to the colon

The purpose of this research study was to develop 5-fluorouracil compression coated tablets by using biodegradable polysaccharide polymer locust bean gum (LBG) and hydroxyl propyl methyl cellulose (HPMC) as coating materials. The fast disintegrating core tablets containing 50 mg of 5-fluorouracil were compression coated with LBG and HPMC in different ratios (8:1, 7:2 and 6:3) with a coat weight of 300, 400 and 500 mg. In vitro dissolution data indicated that the formulation (CLH63) with a coat weight of 500 mg containing LBG and HPMC in the ratio 6:3 gave the best release profile (0% in first 5 hour and 96.18% in 24 hours). DSC and FTIR results indicated no possibility of interaction between drug and polymers or other excipients. In vivo human X-ray studies revealed that formulation CLH63 was able to resist breakdown in the stomach and small intestine. The disintegration of the tablet occurred in the colon between 8 to 16 hours of post dose. By the present study, it can be concluded that the LBG and HPMC based compression coated tablets of 5-fluorouracil will be useful strategy for colonic delivery of 5-fluorouracil without being released in upper gastrointestinal region for the safe and effective management of colon cancer.

O propósito desta pesquisa foi desenvolver comprimidos revestidos de fluoruracila utilizando polissacarídio biodegradável polymer locust bean gum (LBG) e hidroxipropilmetil celulose (HPMC) como materiais de revestimento. Os comprimidos de desintegração rápida contendo 50 mg de fluoruracila foram revestidos por compressão com LBG e HPMC em diferentes proporções (8:1, 7:2 e 6:3), com peso de cobertura de 300, 400 e 500 mg. Os dados da dissolução in vitro indicaram que a formulação (CLH63) com peso de cobertura de 500 mg contendo LBG e HPMC na proporção de 6:3 forneceu o melhor perfil de liberação (0% nas primeiras 5 horas e 96,18% em 24 horas). Os resultados de DSC e de FTIR não indicaram interação entre o fármaco e os polímeros ou outros excipientes. Os estudos de raios X in vivo revelaram que a formulação CLH63 foi capaz de resistir à quebra no estômago e no intestino delgado. A desintegração do comprimido ocorreu no cólon, entre 8 e 16 horas após a administração da dose. Pelo presente estudo, concluiu-se que os comprimidos de fluoruracila revestidos com LBG e HPMC por compressão se constituirão em estratégia útil na liberação de fluoruracila no cólon, para o tratamento seguro e efetivo do câncer de cólon, sem que o fármaco seja liberado na região gastrointestinal superior.

Formulation and evaluation of xanthan gum based aceclofenac tablets for colon targeted drug delivery / Formulação e avaliação de goma xantana baseados comprimidos Aceclofenac por câncer de cólon de entrega de drogas alvo

The objective of the present study is to develop a colon targeted drug delivery systems for Aceclofenac using xanthan gum as a carrier. In this study, multilayer coated system that is resistant to gastric and small intestinal conditions but can be easily degraded by colonic bacterial enzymes was designed to achieve effective colon delivery of Aceclofenac. The xanthan gum, the drug and the physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). All the formulations were evaluated for hardness, drug content uniformity and other physical properties. Release aspects of Aceclofenac in simulated gastrointestinal fluid and colonic fluid with enzymes were investigated. From these results, Eudragit coated system exhibited gastric and small intestinal resistance to the release of Aceclofenac. The rapid increase in release of Aceclofenac in SCF was revealed as due to the degradation of the xanthan gum membrane by bacterial enzymes. The designed system could be used potentially as a carrier for colon delivery of Aceclofenac by regulating drug release in stomach and the small intestine.

O presente estudo teve como objetivo o desenvolvimento de sistema de liberação cólon-alvo de aceclofenaco empregando goma xantana. Nesse trabalho, o revestimento de múltiplas camadas com característica de resistência às condições do intestino delgado além de gastrorresistência oferece como vantagem a rápida degradação desse sistema por enzimas bacterianas colônicas. Dessa forma, o planejamento de tal sistema possibilitou a liberação específica do aceclofenaco no cólon. A goma xantana e o fármaco, além da mistura física desses dois componentes, foram caracterizados por espectroscopia no infravermelho com transformada de Fourier (FTIR) e calorimetria diferencial exploratória (DSC). Todas as formulações foram avaliadas no que se refere à dureza, à uniformidade de conteúdo do fármaco além de outras propriedades físicas. Os perfis de liberação do aceclofenaco no fluido gástrico simulado e fluido colônico simulado contendo enzimas foram investigados. Os resultados revelaram que o sistema revestido com Eudragit® exibiu resistência gástrica e intestinal à liberação de aceclofenaco. O rápido aumento na liberação de aceclofenaco no fluido colônico simulado foi atribuido à degradação da goma xantana por enzimas bacterianas. O sistema apresenta aplicação potencial no desenvolvimento de produtos para a liberação cólon-alvo de aceclofenaco.

Advances in research on target-oriented drug delivery system of Chinese materia medica / 中草药

Target-oriented drug delivery systems(TODDS) of Chinese materia medicia(CMM) is ascribed as preparations in which active fractions or single ingredient extracted from CMM or natural medicines are directly delivered with the help of different carriers to target organs,target tissues,and target cells or intracellula.Recent advances of research on TODDSs of CMM classified according to carriers,such as liposomes,microspheres,nanocapsules,and emulsions are reviewed.In addition,due to the specific actions of CMM on intestinal diseases,oral colon targeting drug delivery system is considered substantials for TODDSs of CMM.Domestic researches on TODDS of CMM in its initial stage are limited to formulations using single natural active ingredient as raw material.While the fewer TODDSs using CMM active fractions or formula recipes are underway,which relates to the tremendous difficulties in both establishment of quality standard for CMM active fractions and technology for preparation of CMM.Nevertheless one of the important goals for the development on preparation of CMM is TODDS.

Study on Traditional Chinese Drug Colon Targeting System / 中成药

Objective:To study possibility of traditional Chinese drug preparation of controlled drug delivered to the colonic region. Methods: After the herbs was extracted and refined, micropills was produced with pectin selected as coating material and thallium monochloride was as internal standard substance. Results: The preparation was testified to attain schedule colon target. Conclusions: This research provided a way for traditional Chinese drug preparation of colon targeting.