Controlled release of levofloxacin sandwiched between two plasma polymerized layers on a solid carrier

Targeted delivery and controlled local release of drugs has a number of advantages over conventional systemic drug delivery approaches. Novel platforms for local delivery from solid drug carriers are needed to satisfy the requirements of various medical applications, in particular for the incorporation and release of hydrophilic drugs from a solid carrier material. We have utilized the plasma polymerization of n-heptylamine for the generation of two thin coated layers that serve two distinct purposes. First, an n-heptylamine plasma polymer layer is applied onto the surface of the solid carrier material in order to facilitate spreading of the drug, which is applied by solvent casting; levofloxacin in ethanol was used for this study. A second n-heptylamine plasma polymer coating then serves as a thin barrier coating to control the release. We show that the rate of release can be adjusted via the thickness of the plasma polymer overlayer. We also show that this modality of controlled release of levofloxacin completely inhibits Methicillin-resistant Staphylococcus aureus (MRSA) colonization and biofilm formation on and near the coated biomaterial surface.     

Studies of Guar Gum Compression-Coated 5-Aminosalicylic Acid Tablets for Colon-Specific Drug Delivery

The aim of this study was to develop colon-specific delivery systems for 5-aminosalicylic acid (5-ASA) using guar gum as a carrier. Core tablets containing 5-ASA were prepared by wet granulation with starch paste and were compression coated with coating formulations containing different quantities of guar gum (300, 200, 150, and 125 mg). In vitro drug release studies were carried out in simulated gastric and intestinal fluids and in pH 6.8 buffer containing rat cecal contents. The application of 175 mg of coating formulation containing 150 mg of guar gum over 5-ASA core tablets resulted in the release of less than 2% drug in simulated gastric and intestinal fluids and about 93% of 5-ASA in pH 6.8 buffer containing rat cecal contents. Differential scanning calorimetric (DSC) studies showed the absence of any interaction between 5-ASA and the excipients on storage at 45°C for 12 weeks. The study confirmed that selective delivery of 5-ASA to the colon can be achieved using guar gum as a carrier in the form of a compression coating over the drug core.     

Studies of guar gum compression-coated 5-aminosalicylic acid tablets for colon-specific drug delivery

The aim of this study was to develop colon-specific delivery systems for 5-aminosalicylic acid (5-ASA) using guar gum as a carrier. Core tablets containing 5-ASA were prepared by wet granulation with starch paste and were compression coated with coating formulations containing different quantities of guar gum (300, 200, 150, and 125 mg). In vitro drug release studies were carried out in simulated gastric and intestinal fluids and in pH 6.8 buffer containing rat cecal contents. The application of 175 mg of coating formulation containing 150 mg of guar gum over 5-ASA core tablets resulted in the release of less than 2% drug in simulated gastric and intestinal fluids and about 93% of 5-ASA in pH 6.8 buffer containing rat cecal contents. Differential scanning calorimetric (DSC) studies showed the absence of any interaction between 5-ASA and the excipients on storage at 45°C for 12 weeks. The study confirmed that selective delivery of 5-ASA to the colon can be achieved using guar gum as a carrier in the form of a compression coating over the drug core.     

Development of polysaccharide-based colon targeted drug delivery systems for the treatment of amoebiasis

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30-40% drug release during the initial 4-5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18-24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Development of Polysaccharide-Based Colon Targeted Drug Delivery Systems for the Treatment of Amoebiasis

ABSTRACT

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30–40% drug release during the initial 4–5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18–24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Evaluation of two polymeric blends (EVA/PLA and EVA/PEG) as coating film materials for paclitaxel-eluting stent application

The ethylene vinyl acetate copolymer (EVA)/Poly (lactic acid) (PLA) blend and EVA/Poly (ethylene glycol) (PEG) blend were applied as the drug carrier materials for a bi-layer drug-loaded stent coating film, which consisted of a paclitaxel (PTX)-loaded layer and a drug-free EVA layer. The changes of weight and appearance of the drug-free polymeric blend films with increasing time were examined by X-ray diffraction analysis (XRD), gel permeation chromatography (GPC) tests and scanning electronic microscopy (SEM), and the results showed the degradation of PLA and the leaching of PEG from the films. The effects of PLA, PEG and drug contents on in vitro drug release were investigated, and the results demonstrated that the addition of PLA promoted the drug release while the addition of PEG almost did not. Franz cells diffusion test results indicated that the bi-layer structure successfully endowed the stent coating with the release of drug in a unidirectional fashion. The release profiles of films incorporated PTX and the mechanical performance of the film could be customized by readily adjusting the contents of the blend components. Therefore, the polymeric blends could be useful drug carrier materials for drug-loaded stent coating capable of releasing drug in a highly tunable manner.     

Development of pH-sensitive pectinate/alginate microspheres for colon drug delivery

The purposes of this study were to develop and evaluate calcium pectinate/alginate microspheres (PAMs) and to exploit their pH-sensitive properties for colon-targeted delivery of encapsulated cisplatin. PAMs were prepared using an electrospraying method. The PAMs, as cores, were then coated with Eudragit S100 using a polyelectrolyte multilayer coating technique in aqueous solution. The morphology of the microspheres was observed under scanning electron microscopy. In vitro drug release studies were performed in simulated gastrointestinal fluid, and the results indicated that approximately 5 % of the cisplatin was released from the Eudragit S100-coated PAMs, and 51 % of the cisplatin was released from the uncoated PAMs at 1 h. The release of cisplatin from the Eudragit S100-coated PAMs was more sustained in simulated gastric fluid than in simulated intestinal fluid due to the increased solubility of the coating polymer in media with pH >7.0. Drug release from the Eudragit S100-coated PAMs was best described by the Higuchi’s square root model. From these results, it was concluded that Eudragit S100-coated PAMs are a potential carrier for delivery of cisplatin to the colon.     

Delivery of a Therapeutic Protein for Bone Regeneration from a Substrate Coated with Graphene Oxide

The therapeutic efficacy of drugs often depends on the drug delivery carrier. For efficient delivery of therapeutic proteins, delivery carriers should enable the loading of large doses, sustained release, and retention of the bioactivity of the therapeutic proteins. Here, it is demonstrated that graphene oxide (GO) is an efficient carrier for delivery of therapeutic proteins. Titanium (Ti) substrates are coated with GO through layer‐by‐layer assembly of positively (GO‐NH₃⁺) and negatively (GO‐COO^?) charged GO sheets. Subsequently, a therapeutic protein (bone morphogenetic protein‐2, BMP‐2) is loaded on the GO‐coated Ti substrate with the outermost coating layer of GO‐COO^?(Ti/GO‐). The GO coating on Ti substrate enables loading of large doses and the sustained release of BMP‐2 with preservation of the structure and bioactivity of the drug. The extent of in vitro osteogenic differentiation of human bone marrow‐derived mesenchymal stem cells is higher when they are cultured on Ti/GO‐ carrying BMP‐2 than when they are cultured on Ti with BMP‐2. Eight weeks after implantation in mouse models of calvarial defects, the Ti/GO‐/BMP‐2 implants show more robust new bone formation compared with Ti, Ti/GO‐, or Ti/BMP‐2 implants. Therefore, GO is an effective carrier for the controlled delivery of therapeutic proteins, such as BMP‐2, which promotes osteointegration of orthopedic or dental Ti implants.     

Resistant starch as a carrier for oral colon-targeting drug matrix system

In this study, a novel tablet of protein drug matrix for colon targeting was developed using resistant starch as a carrier prepared by pre-gelatinization and cross-linking of starch. The effects of pre-gelatinization and cross-linking on the swelling and enzymatic degradation of maize starch as well as the release rate of drug from the matrix tablets were examined. Cross-linked pre-gelatinized maize starches were prepared by double modification of pre-gelatinization and cross-linked with POCl₃, and bovine serum albumin was used as a model drug. For in vitro drug release assays, the resistant starch matrix tablets were incubated in simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid, respectively. The content of resistant starch and swelling property of maize starch were increased by pre-gelatinization and cross-linking, which retarded its enzymatic degradation. Drug release studies have shown that the matrix tablets of cross-linked pre-gelatinized maize starch could delivery the drug to the colon. These results indicate that the resistant starch carrier prepared by pre-gelatinization and cross-linking can be used for a potential drug delivery carrier for colon-targeting drug matrix delivery system.     

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.     

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.     

Development and In Vitro Characterization of Liposomes Coated with Thiolated Poly(Acrylic Acid) for Oral Drug Delivery

Mucoadhesive drug delivery systems offer promising opportunities for oral drug delivery. The aim of this study was to investigate the feasibility of preparing liposomes that are coated with the multifunctional polymer poly(acrylic acid)-cysteine (PAA-Cys). Cationic multilamellar vesicles (MLV) as well as cationic submicron-sized liposomes (ssLip) were prepared and coated with PAA-Cys. Size, zeta potential, amount of free thiol groups, aggregation behavior, drug-loading, and drug release of these novel carriers were evaluated. A switch of the initial positive zeta potential to a negative value after coating indicated the successful coating procedure. In both size ranges, MLV and ssLip, the amount of free thiol groups was comparable to that in a PAA-Cys solution of the same concentration. Drug loading of the hydrophilic marker fluorescence-isothiocyanate 4 kDa (FD4) was higher in PAA-Cys liposomes in comparison to noncoated liposomes, but lower in comparison to liposomes coated with unmodified poly(acrylic acid) (PAA). Only a minor ssLip or no increase MLV of the drug-loading was observed when using carboxyfluorescein (CF). These effects were attributed to interactions between the markers and the poly(acrylates). Coating of liposomes with PAA-Cys and PAA did not influence the release profile of FD4 and CF, whereas the release profile was affected by the molecular mass of the marker and the liposome size. In conclusion, the feasibility of coating liposomes with PAA-Cys was demonstrated, and it could be shown that this novel carrier system fulfills the basic requirements for an intended use in oral drug delivery.     

Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery

The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5?mm and a thickness of 0.8?mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route.     

An asymmetric coating composed of gelatin and hydroxyapatite for the delivery of water insoluble drug

An asymmetric coating composed of gelatin and hydroxyapatite on Ti6Al4V alloy implant was prepared to control the release of water-insoluble drug ibuprofen and improve the surface properties of the implant. The asymmetric coating developed into a thin dense outer layer and a thick porous inner layer using a dip-coating method and a succedent phase-inversion process. The drug loading ranged from 10 to 30% (w/w), and depended on the immersion time and drug concentration in the quenching solution. The in vitro release from this system was always at an approximately zero-order rate and at least lasted for 30 days. The in vitro studies in SBF revealed that the coating could induce the formation of apatite, and was fully covered after 14 days soaking in SBF solution. This asymmetric coating had better bioactivity of inducing the formation of apatite in vitro, compared with pure gelatin coating and bare Ti6Al4V implant.     

中空层状羟基磷灰石微球对溶菌酶的吸附与缓释研究

利用锂钙硼玻璃在磷酸盐溶液中的原位转化反应制备表面多孔且具有中空层状结构的羟基磷灰石(HA)微球,以溶菌酶为蛋白的药物模型,研究了中空层状结构的羟基磷灰石微球对溶菌酶的吸附及缓释特性,结果显示,中空微球对不同浓度的溶菌酶溶液,具有不同的吸附机理,当溶菌酶溶液的浓度低于0.8mg/mL时,溶菌酶的吸附主要发生在微球的外表面,符合Langmuir模型,释放速率较快,48h内基本释放完全;当溶菌酶溶液的浓度高于0.8mg/mL时,溶菌酶扩散进入微球内部及球壁的微孔中,使得吸附量显著增加,满足Henry吸附模型,溶菌酶的释放周期明显增加,可持续释放800h,微球对蛋白具有很好的缓释效果。     

In vitro drug release and in vivo human X-ray studies of ileo-cecal targeting budesonide fast disintegrating tablet

Crohn's disease is a type of inflammatory bowel disease that frequently affects the ileo-cecal region of the gastrointestinal tract. For effective treatment of this disease, a site-targeting drug in the ileo-cecal region is essential. Budesonide (BD) is a synthetic, non-halogenated glucocorticoid and is the drug of choice for the treatment of Crohn's disease. The present study is an attempt to develop the dosage form of a BD tablet to achieve targeted drug release in the ileo-cecal region. The BD tablets are coated with Eudragit FS 30 D, which is a polymer that specifically dissolves at and above pH 6.8. The in vitro drug release and in vivo tablet disintegration (using X-ray radiography) were carried out. The coating process was optimized successfully. The in vitro performance of the tablet with coating thickness showed that the tablet did not disintegrate till 4.5 hours, which represents the transit time to the ileo-cecal region. In vivo studies also established that the tablet lasted till 4.5 hours. The tablet containing 0.5%?superdisintegrant and 10%?coating thickness was able to deliver BD effectively to the ileo-cecal region, thus making it a promising drug delivery system for the treatment of Crohn's disease.     

Thermosensitive hydrogel of hydrophobically-modified methylcellulose for intravaginal drug delivery

Hydrogels with the advantages of prolonging drug release and administration convenience are necessary for intravaginal drug delivery to prevent sexual transmission of human immunodeficiency virus and other vaginal infections. In this study, the thermosensitive hydrogel of methylcellulose modified by stearic acid (MCS) were evaluated in the presence of NaCl and phosphates, which exhibited sol-to-gel transition performance at body temperature or even lower. The in vitro cytotoxicity and in vivo mucosal irritation were investigated and the results showed that MCS hydrogel possessed good biocompatibility similar with hydroxyethyl cellulose (HEC) gel. Significantly, the release studies revealed that MCS hydrogel could control tenofovir sustained release for 10 h without burst release, longer than that from HEC gel or poloxamer 407 hydrogel. Therefore, MCS thermosensitive hydrogel would be a promising carrier for intravaginal delivery of antiviral drugs for long time controlled release.     

Drug delivery devices based on macroporous silica spheres

A new kind of silica materials was proposed as carriers for drug delivery. The materials are characterized by the presence of hierarchical macro/mesopores, penetrable macropores and large pore volumes. The unique structure renders them ideal carriers for efficient and sufficient loading of drugs to establish controlled delivery systems. A series of such materials were synthesized and derivatized with octyl or octadecyl to investigate their drug delivery behavior. Nimodipine, as a model drug, was entrapped into the carriers by repeated soaking, filtration and evaporation. It is found that the drug-loading amount increased with increasing mesopore sizes of the carriers. The loading amount can reach as high as 350 wt% (drug/carrier). The in vitro release studies demonstrate that both enhanced release and sustained release can be achieved on the proposed materials. Moreover, the release speed can be controlled by the macropore sizes and surface characteristics of the materials.     

A novel enzymatically-mediated drug delivery carrier for bone tissue engineering applications: combining biodegradable starch-based microparticles and differentiation agents

In many biomedical applications, the performance of biomaterials depends largely on their degradation behavior. For instance, in drug delivery applications, the polymeric carrier should degrade under physiological conditions slowly releasing the encapsulated drug. The aim of this work was, therefore, to develop an enzymatic-mediated degradation carrier system for the delivery of differentiation agents to be used in bone tissue engineering applications. For that, a polymeric blend of starch with polycaprolactone (SPCL) was used to produce a microparticle carrier for the controlled release of dexamethasone (DEX). In order to investigate the effect of enzymes on the degradation behavior of the developed system and release profile of the encapsulated osteogenic agent (DEX), the microparticles were incubated in phosphate buffer solution in the presence of α-amylase and/or lipase enzymes (at physiological concentrations), at 37°C for different periods of time. The degradation was followed by gravimetric measurements, scanning electron microscopy (SEM) and Fourier transformed infrared (FTIR) spectroscopy and the release of DEX was monitored by high performance liquid chromatography (HPLC). The developed microparticles were shown to be susceptible to enzymatic degradation, as observed by an increase in weight loss and porosity with degradation time when compared with control samples (incubation in buffer only). For longer degradation times, the diameter of the microparticles decreased significantly and a highly porous matrix was obtained. The in vitro release studies showed a sustained release pattern with 48% of the encapsulated drug being released for a period of 30 days. As the degradation proceeds, it is expected that the remaining encapsulated drug will be completely released as a consequence of an increasingly permeable matrix and faster diffusion of the drug. Cytocompatibility results indicated the possibility of the developed microparticles to be used as biomaterial due to their reduced cytotoxic effects.     

Preparation and characterization of hollow Fe3O4/SiO2@PEG–PLA nanoparticles for drug delivery

In this study we present a novel targeted anticancer drug delivery, which was size controlled Fe₃O₄/SiO₂ hollow microspheres (HMS) as magnetic core and poly (ethylene glycol)-poly–(d,l-lactide) (PEG–PLA) surface coating (HMS@PEG–PLA). And investigations were to test a new convenient method, which is one-step precipitation polymerization on HMS, forming magnetic hollow polymer microspheres. The HMS@PEG–PLA which have hollow structure and uniform size were characterized by Transmission Electron Microscopy (TEM). Vibrating Sample Magnetometer (VSM) showed a characteristic of super paramagnetic with saturation magnetization value of about 19.78 emu/g. In vitro cytotoxicity of Fe₃O₄/SiO₂@PEG–PLA (HMS@PEG–PLA) hollow microspheres were of low toxicity, so it can be used as a drug carrier, and cisplatin (CDDP) as the model drug release behavior was researched. The results have exhibited preferable release properties.