Calcium pectinate capsules for colon-specific drug delivery

The calcium pectinate (CaP) capsule, a novel, colon-specific delivery system, was designed and developed using 5-fluorouracil (5-FU) as a model drug. Technically, CaP capsules were prepared by dipping a glass or stainless steel rod successively into pectin and calcium chloride solutions, followed by subsequent air-drying and coating. In vitro studies showed that the release of 5-FU from CaP capsules markedly increased in the presence of rat cecal contents, and the release characteristic was mainly associated with some capsule parameters such as calcium content, shell thickness, and coat amount. Gamma scintigraphic studies demonstrated that CaP capsules could pass through the stomach and small intestine intact and could release drug in colon. The 5-FU releasing characteristics acquired both from in vitro biomimic dissolution experiments and from healthy volunteers indicated that the newly developed CaP capsule possessed the ideal colon-specific drug delivery characteristic.     

Design and development of SMEDDS for colon-specific drug delivery

Abstract

Context: Lipoidal systems have particularly shown potential for specific accumulation in areas with inflamed tissue increasing the selectivity of local drug delivery.

Objective: Formulation and evaluation of self-microemulsifying drug delivery system (SMEDDS) for colon-specific drug delivery for effective treatment of colonic diseases.

Method: Ternary phase diagram was used to optimize level of oil, surfactant and co-surfactant to optimize SMEDDS and were evaluated for percent transmittance, emulsification time, in vitro release, myeloperoxidase (MPO) activity and intestinal accumulation. The spray dried SMEDDS were filled in capsules which were enteric coated with Eudragit S-100 at 10% weight gain to ensure SMEDDS delivery at colon. The spray dried SMEDDS were also evaluated for IR, DSC, XRD, SEM and stability study.

Result: In ternary phase diagram, Capmul MCM C8 and Capmul PG12 NF with surfactant (Tween 20) and co-surfactant (PG) in ratio 2:1 and 3:1, respectively, showed maximum emulsification area. These liquid SMEDDS show maximum transmittance, globule size of 90–30?nm. The spray-dried SMEDDS with diluents show good flow property. The units of MPO activity show lower level as compared to pure drug and control group, histopathology results supports better healing with SMEDDS. This was attributed to accumulation of SMEDDS in inflammatory area as compared to drug which was further proved by accumulation study. Enteric-coated capsule containing SMEDDS are able to deliver drug, specifically at the colonic region.

Conclusion: Higher accumulation of lipoidal drug in inflammatory area and specific release of liposomes by enteric-coated capsules provide better option for the treatment of colonic disease.     

Statistical evaluation of influence of xanthan gum and guar gum blends on dipyridamole release from floating matrix tablets

The present investigation explored the use of xanthan gum and guar gum for development of floating drug delivery system of dipyridamole using factorial design approach. The content of polymer blends (X(1)) and ratio of xanthan gum to guar gum (X(2)) were selected as independent variables. The diffusion exponent (n), release rate constant (k), percentage drug release at 1 hr (Q(1)) and 6 hr (Q(6)) were selected as dependent variables. Tablets of all batches had desired buoyancy characteristics. Multiple regression analysis with two way ANOVA revealed that both the factors had statistically significant influence on the response studied (p<0.05). Results of Tukey test showed the relative contribution of each level of different factors for the response studied. It was concluded that the ratio of xanthan to gaur gum had equal or dominant role as controlling factor on kinetics of drug release compared to content of polymer blends.     

Organic redox-initiated polymerization process for the fabrication of hydrogels for colon-specific drug delivery

Organic-redox initiated polymerization technique based on the co-initiators system comprising benzoyl peroxide and N-phenyldiethanolamine was used at ambient temperature to fabricate pH-responsive hydrogels. The effects of changes in the concentration of the co-initiators system, the ratio in which the co-initiators combined, the type of the polymerization solvent, the pH of the hydrating medium, the concentration of the cross-linking agent based on azo-bond and the pH-sensitive cross-linking agent on the properties of the hydrogels were investigated. Increasing the concentration of the co-initiators system, decreasing the concentration of the two types of cross-linking agents, and replacing DMSO by ethanol as the polymerization solvent resulted in hydrogels with increased equilibrium swelling ratio and increased molecular weight between cross-links at pH 7.4. Increasing the concentration of N-phenyldiethanolamine while keeping the concentration of benzoyl peroxide constant gave hydrogels with increased equilibrium swelling ratios. The equilibrium swelling ratios of the hydrogels at pH 2.0 were not affected by the factors investigated. The polymerization technique may be suitable for the design of drug delivery systems containing thermolabile bioactive agents like peptides and proteins.     

Basic coating polymers for the colon-specific drug delivery in inflammatory bowel disease

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit® E or AEA® in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100-200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.     

Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-β) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p?相似文献   

Development of delayed-release proliposomes tablets for oral protein drug delivery

Context: One among many attempts to improve oral protein drug delivery was utilizing the colloidal drug carriers particularly liposomes.

Objective: The purpose was to develop proliposomes of bovine serum albumin (BSA) in the form of granules and delayed-release tablets by using simple tablet manufacturing process.

Materials and methods: BSA proliposomes granules were prepared by spraying 7:3 (w/w) – lecithin:cholesterol solution mixture onto BSA-mannitol granules rotating in a glass coating pan. BSA proliposomes granules were directly compressed into tablets and subsequently coated with Eudragit^® L100 film. The physical properties and stability in gastrointestinal fluids of delayed-release BSA proliposomes tablets as well as reconstituted liposomes were assessed.

Results: The BSA proliposomes tablets disintegrated readily and the obtained reconstituted BSA liposomes exhibited multilamellar vesicles, the size and entrapment efficiency of which were around 2–3 µm and 10–14%, respectively. The delayed-release BSA proliposomes tablets were found to be relatively stable in United States Pharmacopoeia (USP) simulated gastric and intestinal fluids. Increase in amount of BSA in granules resulted in the increase in entrapment efficiency and loading capacity.

Discussion: The Fourier transform infrared spectroscopy (FTIR) results indicated increase in α-helix structure of BSA entrapped in liposomes. ³¹P phosphorous nuclear magnetic resonance spectroscopy (³¹P-NMR) spectrum indicated interaction between BSA molecules and phosphoric acid polar groups of bilayers membrane.

Conclusion: The delayed-release BSA proliposomes tablets developed could completely be reconstituted into liposomes with sufficient resistance to the hostile environment in gastrointestinal tract.     

In vitro evaluation of compression-coated glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu2+)-loaded microparticles for colonic drug delivery

Glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu(2+))-loaded Zn-pectinate microparticles in the form of hydroxypropyl cellulose (HPC) compression-coated tablets were prepared and their in vitro behavior tested. GHK-Cu(2+) delivery to colon can be useful for the inhibition of matrix metalloproteinase, with the increasing secretion of tissue inhibitors of metalloproteinases (TIMPS),which are the major factors contributing in mucosal ulceration and inflammation in inflammatory bowel disease. The concentration of peptide was determined spectrophotometrically. The results obtained implied that surfactant ratio had a significant effect on percent production yield (1.25 to 1.75 w/w; 72.22% to 80.84%), but cross-linking agent concentration had not. The entrapment efficiency (EE) was found to be in the range of 58.25-78.37%. The drug-loading factor significantly increased the EE; however, enhancement of cross-linking agent concentration decreased it. The release of GHK-Cu(2+) from Zn-pectinate microparticles (F1-F8) in simulated intestinal fluid was strongly affected by cross-linking agent concentration and drug amount (50 mg for F1-F6; 250 mg for F7-F8), but not particularly affected by surfactant amount. Release profiles represented that the microparticles released 50-80% their drug load within 4 h. Therefore, the optimum microparticle formulation (F8) coated with a relatively hydrophobic polymer HPC to get a suitable colonic delivery system. The optimum colonic delivery tablets prepared with 700 mg HPC-SL provided the expected delayed release with a lag time of 6 h. The effects of polymer viscosity and coat weight on GHK-Cu(2+) release were found to be crucial for the optimum delay of lag time. The invention was found to be promising for colonic delivery.     

瓜尔胶与甲基丙烯酸缩水甘油酯的接枝共聚合

以硝酸铈铵(CAN)为引发剂,采用溶液聚合法,制备了瓜尔胶与甲基丙烯酸缩水甘油酯的接枝共聚物(GGgGMA).研究了反应条件对接枝率的影响,在反应温度为50℃,瓜尔胶浓度为5g/L,硝酸铈铵占瓜尔胶单体质量分数为12%,甲基丙烯酸缩水甘油酯用量为4 mL,反应时间为6h时,接枝率达最大值,并对接枝共聚物用红外光谱FT-...     

Multiparticulate systems containing 5-aminosalicylic acid for the treatment of inflammatory bowel disease

Background: In recent years, many achievements have been realized in the therapy of inflammatory bowel disease (IBD) although its etiology remains unknown. Thus IBD treatment is symptomatic and targets general inflammatory mechanisms. Oral formulations containing 5-aminosalicylic acid (5-ASA) have become the standard therapy for mild-to-moderate IBD.

Objective: This article is a review of recently published research dealing with new 5-ASA dosage forms. Thus promising candidates for IBD treatment evaluated in vitro are reported; systems tested in vivo in trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats are mentioned; and 5-ASA formulations used in clinical studies are presented. Moreover, all oral dosage forms containing 5-ASA or its prodrugs are reviewed; their characteristics and utilization in IBD treatment are discussed.

Conclusion: In several clinical studies, it has been shown that multiparticulates such as pellets offer more advantages as compared with single unit forms, that is, coated tablets. Prolonged presence close to the site of the action, improved drug bioavailability, and easier administration of large drug doses belong to the benefits of pellets.     

Preparation of grafted microspheres CPVA-g-PSSS and studies on their drug-carrying and colon-specific drug delivery properties

Sodium 4-styrene sulfonate (SSS) was graft-polymerized on the surfaces of crosslinked polyvinyl alcohol (CPVA) microspheres in a manner of surface-initiated graft-polymerization by using cerium salt-hydroxyl group redox initiation system, obtaining the grafted microspheres CPVA-g-PSSS. The chemical structure and physicochemical characters of CPVA-g-PSSS microspheres were fully characterized with infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and zeta potential determination. The aim of this work is to constitute a novel colon-specific drug delivery system via molecular design by using CPVA-g-PSSS microspheres as the drug-carrying material and by taking metronidazole (MTZ) as the model drug. The drug-carrying ability and mechanism of the grafted microspheres CPVA-g-PSSS for MTZ were investigated. Finally, in-vitro release tests for the drug-carrying microspheres were conducted. The experimental results show that in an acidic medium, the grafted microspheres CPVA-g-PSSS exhibit strong adsorption ability for MTZ by driving of electrostatic interaction, and have an adsorption capacity of 112 mg/g, displaying the high efficiency of drug-carrying. The in-vitro release behavior of the drug-carried microspheres is highly pH-sensitive. In the medium of pH = 1, the drug-carrying microspheres do not release the drug, whereas in the medium of pH = 7.4, a sudden delivery phenomenon of the drug will occur, displaying an excellent colon-specific drug delivery behavior.     

Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery

Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p > 0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power.     

Feasibility of xanthan gum–sodium alginate as a transdermal drug delivery system for domperidone

The present investigation comprises the formulation and in vitro evaluation of domperidone loaded transdermal drug delivery system (TDDS) for controlled release. The polymer membranes were prepared using xanthan gum (XG) and sodium alginate (SA) by varying the blends compositions viz., 10:0, 8:2, 6:4, 5:5, 4:6, 2:8, and 0:10 (XG/SA, wt/wt, %). The drug loaded membranes were evaluated for thickness, content uniformity, tensile behaviours, and in vitro drug release studies. Domperidone was found to be compatible with the prepared formulation as revealed by Fourier transform infrared (FTIR) spectroscopy studies. In vitro release studies were carried out in open glass diffusion cell for a period of 8 h and it showed controlled release of drug from the XG/SA matrix. The present study concludes that, the prepared transdermal films can be used to achieve controlled release of drug and improved bioavailability.     

Influence of cross-linking agent type and chitosan content on the performance of pectinate-chitosan beads aimed for colon-specific drug delivery

Pectinate-chitosan-beads aimed for colon theophylline delivery have been developed. The effect of zinc or calcium ions as cross-linking agent, and of chitosan concentration on the properties and colon-targeting performance of beads was investigated. Beads were characterized for morphology, entrapment efficiency and mucoadhesion properties. Zn-pectinate-chitosan beads formed a stronger gel network than the Ca-containing ones, enabling a greater entrapment efficiency, which further increased with chitosan content, probably due to polyelectrolyte complexes formation. Transport studies across Caco-2 cells evidenced a significant (p?>?0.05) drug permeation increase from all beads with respect to drug alone, attributable to the enhancer and/or mucoadhesion properties of the polymers, and Ca-pectinate-chitosan beads were more effective than the Zn-containing ones. Beads formulated as enteric-coated tablets demonstrated good colon-targeting properties, and no differences were observed in drug-release profiles from Zn- or Ca-pectinate-chitosan beads. Therefore, Ca-pectinate-chitosan beads emerged as the choice formulation, joining colon-targeting specificity with better permeation enhancer power.     

Miconazole chewing gum as a drug delivery system test of release promoting additives

The release of the antifungal drug miconazole from chewing gum formulations was evaluated in vitro and in vivo. It was proven that the addition of the anionic surfactant Panodan® 165 and polyethyleneglycol 6000 increased the release of miconazole. The anionic surfactant made the chewing gum tacky. The addition of polyethyleneglycol 6000 reduced the tacky properties of the chewing gum. 4 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. The salivary concentrations of miconazole were estimated, both by a reverse phase HPLC method and a plate microbioassay.     

On the solid-state ageing behaviour of the polysaccharide,guar gum

Dilute solution viscometry was used to explore the effect of solid-state ageing on the interactions that occur between guar gum and water. The resulting data set, derived from nearly 700 independent experiments, led to a value for the Flory–Huggins interaction parameter, χ, of 0.56 ± 0.12. This value, which appeared independent of ageing, is in good agreement with the majority of published data. The effect of ageing on molar mass was also explored, using Mark–Houwink–Sakurada (MHS) theory. Absolute molar mass values were found to depend sensitively on the choice of MHS constants, but the effect of ageing was unequivocal; under all conditions, it resulted in a pronounced decrease in molar mass. In concert, these results strongly suggest that, in guar, solid-state ageing reactions are largely associated with scission of the molecular backbone. This hypothesis was then tested by infra-red and Raman spectroscopy. Although infra-red spectroscopy did reveal some subtle differences between the spectra of guar and locust bean gum (LBG), a related polysaccharides with a different galactose:mannose ratio, no equivalent effects were seen in aged guar. However, clear differences between the Raman spectra of guar and LBG were seen, demonstrating that the technique is well capable of revealing changes in galactose:mannose ratios. Examination of aged guar samples revealed no comparable effects, reinforcing the notion that, in this polysaccharide, chain scission reactions dominate such that solid-state ageing does not lead to changes in the nature of its interaction with water.     

2-羟基-3-丁氧基丙基胍胶的制备及流变性能

以胍胶原粉(GG)为原料,正丁基缩水甘油醚(BGE)为疏水化试剂,氢氧化钠为催化剂,异丙醇为溶剂,制备了2-羟基-3-丁氧基丙基胍胶(HBPG)。通过FT-IR、XRD、TGA对HBPG结构性能进行了表征,并研究了HBPG水溶液和冻胶的流变性能。结果表明,HBPG结构中由于引入疏水基团,使其结晶度下降,热稳定性能提高,HBPG相比GG具有更好的增稠性能,且溶液稳定性能得到明显改善,HBPG制备的冻胶的流变性能优于GG,具有良好的耐温和剪切稳定性能。