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.     

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.     

In vivo evaluation of a colonic delivery system using isotope techniques

AIM: To evaluate, using isotope techniques, the in vivo effectiveness of a pH-dependent colonic delivery system. Methods: In order to dispose of differently labelled substrates for measurement of orocaecal transit time, inulin-14C-carboxylic acid was evaluated as an alternative substrate to inulin and lactose-13C-ureide. Secondly, the time of release of 13C- and 15N-urea from the colonic delivery system was compared with the orocaecal transit time, measured using inulin and inulin-14C-carboxylic acid. This study was repeated after a 2-week lactulose intake period. RESULTS: The orocaecal transit time determined using inulin-14C-carboxylic acid (398 min) was not significantly different from the orocaecal transit time determined using inulin (420 min) or lactose-13C-ureide (396 min). Before lactulose intake, the 13CO2 excretion time was 358 min and the orocaecal transit times determined with the inulin-14C-carboxylic acid and inulin breath test were 376 and 375 min respectively. After lactulose, the 13CO2 excretion time was 383 min and orocaecal transit times were 354 min for inulin-14C-carboxylic acid and 392 min for inulin. A highly significant correlation was found. Good agreement was found between the urinary 15N excretion and the appearance of 13CO2 in breath. CONCLUSION: Isotope techniques provide an excellent non-invasive tool for the in vivo evaluation of a colonic delivery system.     

In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 ± 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 ± 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T_max of 8 h comparing to that of theophylline solution with T_max of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2626–2635, 2009     

新型茶碱口服结肠靶向给药系统的体内动力学

目的研究以时间为释药开关的结肠靶向给药系统。方法以非pH依赖型聚丙烯酸树脂Eu dragit NE 3 0D为膜材 ,制备茶碱薄膜衣片 ;用HPLC法进行体内血药浓度分析 ;以γ 闪烁照相研究该制剂体内胃肠道的转运情况。结果本制剂与参比制剂主要药代动力学参数分别为 :tlag( 8 67± 1 0 4 )h、( 0 67± 1 1 5 )h ;Cmax( 5 2 5± 1 2 1 )mg/L、( 4 0 9± 1 2 5 )mg/L ;AUC0 2 6 ( 2 7 5 0±7 2 0 )mg·h/L、( 3 9 0 4± 1 0 4 3 )mg·h/L ;体内γ 闪烁照相研究表明 ,体外 6 5h释放的制剂口服8 0h后到达升结肠处开始释药 ,且体内释药与体外释药有一定的相关性。结论本制剂能达到结肠靶向释药的设计要求     

In vitro and in vivo evaluation of guar gum-based matrix tablets of rofecoxib for colonic drug delivery

The present study was carried out to develop and evaluate guar gum-based matrix tablets of rofecoxib for their intended use in the chemoprevention of colorectal cancer. Matrix tablets containing 40% (RXL-40), 50% (RXL-50), 60% (RXL-60) or 70% (RXL-70) of guar gum were prepared by wet granulation technique, and were subjected to in vitro drug release studies. Guar gum matrix tablets released only 5 to 12% of rofecoxib in the physiological environment of stomach and small intestine. The matrix tablets RXL-40 disintegrated completely within 10 h in a dissolution medium without rat caecal contents (control study), and hence not studied further. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets RXL-50 were acted upon by colonic bacterial enzymes releasing the entire quantity of drug wherein there was no appreciable difference when compared to that released in control study. The matrix tablets RXL-60 released another 88% of rofecoxib whereas matrix tablets RXL-70 released only 57% of rofecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The guar gum matrix tablets RXL-70 were subjected to in vivo evaluation in human volunteers to find their ability of targeting rofecoxib to colon. The delayed Tmax, prolonged absorption time (ta), decreased Cmax and decreased ka indicated that rofecoxib was not released significantly in stomach and small intestine, but was delivered to colon resulting in a slow absorption of the drug and making it available for local action in human colon.     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

In vitro and in vivo consideration of novel environmentally responsive ophthalmic drug delivery system

In the present study, novel environmentally responsive ophthalmic drug delivery system composed of two gelling polymers with different phase transition mechanisms was developed in order to obtain sustained drug release in ocular cavity. Combination of polyacrylic acid (carbopol 934P) and xanthan gum was investigated as ophthalmic vehicle and assessed for its in vitro and in vivo performance. Different ratios of these polymers were used to prepare environmentally responsive ophthalmic drug delivery system by simple mixing procedure. Developed formulation was assessed for physical tests such as appearance/clarity, pH, gelation; and performance characteristics such as drug content, rheological measurement, in vitro release, antimicrobial efficiency, in vivo studies for eye irritation, residence time estimation. Prepared formulation showed agreeable appearance/clarity, acceptable pH and good gelation property. In vitro and in vivo studies demonstrated adequate drug content, desired rheological behavior and reasonable in vitro and in vivo drug release property. In conclusion, the optimum concentration of polymers results in increased residence time and sustained drug release. On the basis of these findings, environmentally responsive system based on combination of carbopol and xanthan gum may be considered as a promising tool for ophthalmic delivery.     

醋柳黄酮自微乳化给药系统的体内外评价

本文的目的在于对醋柳黄酮自微乳化给药系统进行评价,该给药系统用于提高难溶性药物醋柳黄酮的口服生物利用度。评价指标包括自微乳化时间、粒径及多分散指数、形态学特征、体外分散性、稳定性、在体小肠吸收及生物利用度。结果表明,该自微乳化给药系统在3 min内即形成微乳,平均粒径低于40 nm,多分散指数低于0.2,电镜下观察粒子形态为球形;20 min时体外累积释放百分率(以槲皮素计)接近90%,显著高于普通胶囊剂;加速试验条件下放置6个月,自微乳化给药系统的所有指标均未发生明显改变;该自微乳化给药系统的在体小肠吸收速率常数(以槲皮素计)显著高于醋柳黄酮乙醇溶液(P<0.05);以醋柳黄酮的混悬液为参比制剂,自微乳化给药系统的大鼠灌胃给药相对生物利用度(以槲皮素计)为518%。     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans

Microballoons (MB) possessing a spherical cavity enclosed within a hard polymer shell have been developed as a dosage form characterized by excellent buoyancy in the stomach. MB were prepared by the emulsion solvent diffusion method using enteric acrylic polymers dissolved in a mixture of dichloromethane and ethanol. Riboflavin-containing MB were administered orally to each of three healthy volunteers. The pharmacokinetics of riboflavin was investigated by analysis of the urinary excretion. Prolongation of the urinary excretion of riboflavin could be obtained by ingestion of water as well as "fed" conditions. This phenomenon was attributable to the buoyancy properties of MB in the stomach and an increase in the gastric residence time (GRT). The excretion half-life time (t(1/2)) following administration of MB (particle size: 500-1000 microm) exhibiting high buoyancy was longer than that of MB (particle size: <500 microm) displaying low buoyancy. Therefore, the intragastric floating properties of MB are potentially beneficial as far as a sustained pharmacological action is concerned. MB prepared by mixing it with hydroxypropylmethylcellulose (HPMC) in different ratio, results in improved riboflavin-release properties. These MB were evaluated in vivo by analysis of the urinary excretion of riboflavin. As a result, strong correlations were observed between the buoyancy and excretion half-life (t(1/2)) and between the riboflavin release from the MB and total urinary excretion.     

Design of a potential colonic drug delivery system of mesalamine

The aim of the present investigation was to develop a site-specific colonic drug delivery system, built on the principles of the combination of pH and time sensitivity. Press-coated mesalamine tablets with a coat of HPMC E-15 were over-coated with Eudragit S100. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2, 6.0, 7.2 and 6.4 mimicking different regions of gastrointestinal tract. The optimized batch (F2) showed less than 6% of drug release before reaching colonic pH 6.4 and complete drug release was obtained thereafter within 2 hr. A short-term dissolution stability study demonstrated statistical insignificant difference in drug release.     

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery

Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of molecules warrants additional study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was observed at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chemistry work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-week intervals. No mortality was observed. Forty-eight hours following the last administration, blood chemistry revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathological data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.     

Development and evaluation of pulsatile drug delivery system using novel polymer

The aim of the present investigation was to develop a pulsatile drug delivery system based on an insoluble capsule body filled with theophylline microspheres and sealed with a swellable novel polymer plug isolated from the endosperm of seeds of higher plant Delonix regia family-Fabaceae. Theophylline microspheres were prepared by solvent evaporation method using Eudragit S 100. The swellable plugs of varying thickness and hardness were prepared by direct compression, which were then placed in the capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed most to offer convenience to the chronic patients of asthma. Formulated dosage forms were evaluated for an in vitro drug release study, which showed that the release might be consistent with a release time expected to deliver the drug to the colon depending on the thickness and hardness of the hydrogel plug. Thus, thickness and hardness of the novel polymeric plug plays an important role in controlling the drug release from the formulated drug delivery system.     

Cytosolic drug delivery using pH- and light-sensitive liposomes

A growing body of literature describes the development and applications of novel targeting and/or contents release triggering schemes to improve the therapeutic index of drugs encapsulated within liposomes. This review focuses on literature appearing between January 1995-December 1997 that report 1) antibody and receptor-mediated targeting approaches for improving drug localization and 2) acid, enzymatic, thermal or photochemical triggering processes that destabilize membranes and improve drug bioavailability via cytoplasmic delivery of liposomal contents.     

In vivo evaluation of a nasal insulin delivery system based on thiolated chitosan

The aim of this study was the preparation and in vivo evaluation of a nasal insulin delivery system based on thiolated chitosan. 2-Iminothiolane was covalently attached to chitosan. The resulting conjugate (chitosan-TBA) exhibited 304.9 +/- 63.5 micromol thiol groups per gram polymer. Microparticles were prepared via a new precipitation-micronization technique. The microparticulate delivery system comprised insulin, reduced glutathione and chitosan-TBA (Chito-TBA/Ins) or unmodified chitosan (Chito/Ins) and control microparticles were composed of insulin and mannitol (Mannitol/Ins). Due to a hydration process the size of Chito-TBA/Ins and Chito/Ins microparticles increased in phosphate buffer pH 6.8 2.6- and 2.2-fold, respectively. Fluorescent-labeled insulin-loaded chitosan-TBA microparticles showed a controlled release over 4 h. Chito-TBA/Ins administered nasally to rats led to an absolute bioavailability of 6.9 +/- 1.5%. The blood glucose level decreased for more than 2 h and the calculated absolute pharmacological efficacy was 4.9 +/- 1.4%. Chito/Ins, in comparison, displayed a bioavailability of 4.2 +/- 1.8% and a pharmacological efficacy of 0.7 +/- 0.6%. Mannitol/Ins showed a bioavailability of 1.6 +/- 0.4% and no reduction of the blood glucose level at all. According to these findings microparticles comprising chitosan-TBA seem to have substantial higher potential for nasal insulin administration than unmodified chitosan.     

肽类和蛋白质类药物肺部给药的体内外评价方法

目的介绍肽类和蛋白质类药物肺部给药的体内外评价方法。方法对肽类和蛋白质药物肺部给药研究中的给药方法、药动学评价、药效学评价、肺部沉积、体外评价及安全性评价方法进行综述。结果根据研究的不同阶段选择合适的动物给药模型,采用特异性强、灵敏度高的分析方法是肽类和蛋白质药物肺部给药系统体内评价的关键。肺内沉积是对剂型和给药装置递送效果的综合考察。具有良好体内外相关性的体外评价方法的建立与安全性评价在肺部给药制剂开发中具有十分重要的意义。结论肽类和蛋白质类药物肺部给药的体内外评价方法与其他给药途径有较大区别,在研究和开发中应根据需要选取适当的方法。