Osmotically controlled oral drug delivery

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Preparation and characterization of novel sinomenine microcapsules for oral controlled drug delivery

Background: Developing a sustained release drug to cure arthritis is needed. Sinomenine (SIN) is abstracted from sinomenium acutum and widely used in the treatment of various rheumatism and arrhythmia with few side effects. The primary aim of this study is to develop SIN microcapsules with polyelectrolyte multilayers for controlled drug release. Method: SIN microcrystals were encapsulated with chitosan, gelatin, and alginate by layer-by-layer technique, such as (gelatin/alginate)₄ and (chitosan/alginate)₆. The size distribution, zeta-potential, stability, and morphology of the microcapsules were characterized by a particle size analyzer, zetasizer, ultraviolet spectroscopy, and transmission electron microscope, respectively. The in vitro controlled release pattern of SIN was studied using a diffusion cell assembly at physiological pH of 6.8 or 1.4. Results: Light stability of these microcapsules was improved after microencapsulation. Compared with release rate of the SIN microcapsules coated by the poly(dimethyldiallyl ammonium chloride)/alginate and gelatin/alginate multilayers, release rate of the SIN microcapsules coated with chitosan/alginate multilayers was fast. Release rate progressively decreased with the increase of chitosan/alginate bilayer number and the decrease of pH value of release medium. Conclusion: These novel SIN microcapsules may be developed into oral controlled drug delivery for rheumatism and arthritis.     

Synthesis strategies for disulfide bond-containing polymer-based drug delivery system for reduction-responsive controlled release

Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most significant signal of the difference between the normal tissue and the tumor cells, besides the media pH and temperature. In recent years, the reduction-responsive DDSs have attracted more and more attention for delivery of anti-cancer drugs, based on such physiological signal. Among them, disulfide bond-containing polymers have been designed as the main tool for the purpose. The recent progress in the synthesis strategies for the disulfide bond-containing polymer-based DDS is focused in the present review.     

Thermosensitive Y-shaped micelles of poly(oleic acid-Y-N-isopropylacrylamide) for drug delivery

A novel thermosensitive amphiphilic copolymer comprised of two hydrophobic poly(oleic acid) (POA) segments and one hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) segment was designed and synthesized. The structure of the copolymer was confirmed as Y-shaped by FTIR, 1H NMR, and SEC-MALLS analysis. A cytotoxicity study shows that the P(OA-Y-NIPAAm) copolymer exhibits good biocompatibility. The copolymer may self-assemble into micelles in water, with the hydrophobic POA segments at the cores of micelles and the hydrophilic PNIPAAm segments as the outer shells. The resulting micelles demonstrate temperature sensitivity with a lower critical solution temperature (LCST) of 31.5 degrees C and a critical micelle concentration (CMC) of 12.6 mg L(-1). Transmission electron microscopy (TEM) shows that the micelles exhibit a nanospheric morphology within a narrow size range of approximately 10-30 nm. A study of controlled release reveals that the self-assembled micelles have great potential as drug carriers.     

内盐凝胶的制备及对烟酰胺的控释

以甲基丙烯酸二甲基氨基乙酯(DMAE-MA)、衣康酸(IA)、亚甲基双丙基酰胺(BIS)和过硫酸钾(KPS)为原料在室温下制备内盐凝胶。研究了原料配方对凝胶形成的影响、内盐凝胶的吸水动力学及溶胀机制、凝胶的pH值敏感性以及对烟酰胺的负载与负载凝胶在不同pH值介质中的释放行为,并用红外光谱对凝胶结构进行了表征。结果表明,n(IA)/n(DMAEMA)>1后将降低单体的转化率,不利于凝胶的形成;内盐凝胶不具有高吸水性,其吸水溶胀机制符合Fickian扩散;在pH值为12的缓冲溶液中溶胀率比在pH值为3的缓冲溶液中高;凝胶对烟酰胺的负载率可以超过200%。在25℃下,烟酰胺在pH值为3的介质中释放比在pH值为12的介质中释放快。     

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.     

Stimulus-responsive liquids for encapsulation storage and controlled release of drugs from nano-shell capsules

Drug-delivery systems with a unique capability to respond to a given stimulus can improve therapeutic efficacy. However, development of such systems is currently heavily reliant on responsive polymeric materials and pursuing this singular strategy limits the potential for clinical translation. In this report, with a model system used for drug-release studies, we demonstrate a new strategy: how a temperature-responsive non-toxic, volatile liquid can be encapsulated and stored under ambient conditions and subsequently programmed for controlled drug release without relying on a smart polymer. When the stimulus temperature is reached, controlled encapsulation of different amounts of dye in the capsules is achieved and facilitates subsequent sustained release. With different ratios of the liquid (perfluorohexane): dye in the capsules, enhanced controlled release with real-time response is provided. Hence, our findings offer great potential for drug-delivery applications and provide new generic insights into the development of stimuli drug-release systems.     

药物控释芯片

综述了微机电系统（MEMS）在药物传递系统中的应用,着重介绍药物控释芯片、全塑料元件水动力微型药物释放系统和基于人工肌肉原理智能植入式智能药物释放系统三类作用原理不同的药物传递系统芯片,详细介绍这些不同种类芯片的作用原理、微制造过程及应用。     

Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system

Context: Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach.

Objective: Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material.

Materials and methods: Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM.

Results: LSH tablets exhibited dynamic swelling–deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (<10%) at pH 1.2 and higher release at pH 6.8 and 7.4. SEM showed elongated channels in swollen then freeze-dried tablets.

Discussion: The drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion.

Conclusions: These finding indicates that LSH holds potential to be developed as sustained release material for tablet.     

Oral-based controlled release formulations using poly(acrylic acid) microgels

Aim: To investigate the release of hydrophobic and hydrophilic substances from tablets containing Pemulen and Carbopol as excipients. Method: The dissolution patterns of a hydrophobic (diazepam) and a hydrophilic active substance (midodrine-HCl) from different tablet formulations containing a nonmodified polyacrylic microgel (Carbopol 981 F) or a hydrophobically modified polyacrylic microgel (Pemulen®) have been studied. Possible differences in dissolution in phosphate buffer (pH 6.8) and in 0.1 M HCl between tablets produced using wet granulation and direct compression were also investigated. Results: Tablets produced by wet granulation had a greater effect on the release of active substance from the tablets. No major differences were observed in the release patterns of the hydrophilic substance midodrine-HCl from wet granulated tablets based on Carbopol and Pemulen. However, the release pattern of the more hydrophobic drug substance, diazepam, differed considerably between the two polymers. Wet granulation gave reproducible release patterns. The release patterns from the polymers differed considerably at pH 6.8 but were similar at low pH. Conclusions: The release of the diazepam from the hydrophobic polymer Pemulen was very slow, and the release was close to zero order.     

离子交换膜控制释放药物技术进展

主要针对离子交换膜控制释放药物体系,来阐述该体系的三大传质机理,以及药物、聚合物性质和外界环境对释药过程的影响.同时汇总了近几年文献所展示的一些释放体系及其释放结果,并陈述了基于能斯特普朗克方程和唐南平衡理论建立的两种离子交换膜释放药物的数学模型.     

Performing Logical Operations with Stimuli‐Responsive Building Blocks

Chemical logic gates can be fabricated by synthesizing molecules that have the ability to detect external stimuli (e.g., temperature or pH) and provide logical outputs. It is, however, challenging to fabricate a system that consists of many logic gates using this method: complex molecules can be difficult to synthesize and these logic gates typically cannot be integrated together. Here, we fabricated different types of logic gates by assembling a combination of different types of stimuli‐responsive hydrogels that change their size under the influence of one type of stimulus. Importantly, the preparation of these stimuli‐responsive hydrogels is widely reported and technically simple. Through designing the geometry of the systems, we fabricated the YES, NOT, OR, AND, NOR, and NAND gates. Although the hydrogels respond to different types of stimuli, their outputs are the same: a change in size of the hydrogel. Hence, we show that the logic gates can be integrated easily (e.g., by connecting an AND gate to an OR gate). In addition, we fabricated a standalone system with the size of a normal drug tablet (i.e., a “smart tablet”) that can analyze (or diagnose) different stimuli and control the release of a chemical (or drug) via the logic gates.     

Coated biodegradable casein nanospheres: a valuable tool for oral drug delivery

Abstract

Biodegradable casein nanospheres for the sustained release of bioactive molecules in the gastro-intestinal tract were prepared by precipitation polymerization using sodium methacrylate (NaMA) and N,N′-methylene bis-acrylamide (MEBA) as pH-responsive monomer and cross-linker. Three materials with different casein amount were obtained and characterized by scanning electron microscopy, dimensional analysis, water uptake, cytotoxicity and enzymatic degradation experiments. Nanospheres biodegradability was tuned by coating with polyacrylic acid. Coated and uncoated materials were investigated as delivery vehicles for diclofenac sodium salt. For un-coated samples, the release raise 100% in 30?h, while for coated specimens these values were lower than 70%, due to the diffusional constraints of polymer layer.     

Factors influencing the erosion rate and the drug release kinetics from organogels designed as matrices for oral controlled release of a hydrophobic drug

Abstract

This article proposes solid-like systems from sunflower oil structured with a fibrillar network built by the assembly of 12-hydroxystearic acid (12-HSA), a gelator molecule for an oil phase. The resulting organogels were studied as oral controlled release formulations for a lipophilic drug, Efavirenz (EFV), dissolved in the oil. The effects of the gelator concentration on the thermal properties of the organogels were studied by Differential Scanning Calorimetry (DSC) and showed that drug incorporation did not change the sol–gel–sol transitions. The erosion and drug release kinetics from organogels under conventional (filling gelatin capsules) or multiparticulate (beads obtained by prilling) dosage forms were measured in simulated gastric and intestinal fluids. EFV release profiles were analyzed using model-dependent (curve-fitting) and independent approaches (Dissolution Efficiency DE). Korsmeyer–Peppas was the best fitting release kinetic model based on the goodness of fit, revealing a release mechanism from organogels loaded with EFV different from the simple drug diffusion release mechanism obtained from oily formulations. From organogels, EFV probably diffuses through an outer gel layer that erodes releasing oil droplets containing dissolved EFV into the aqueous medium.     

环境敏感性水凝胶在药物控释系统中的应用

论述了温度敏感性水凝胶、pH敏感性水凝胶及温度/pH双重敏感性水凝胶的结构、性质及在药物控释体系中的应用.     

Calcium alginate nanocarriers as possible vehicles for oral delivery of insulin

In the present investigation, alginate nanoparticles have been prepared and characterised by various techniques such as FTIR, SEM, particle size analysis and surface charge measurements. It was found from both the SEM and particle size analysis that average size of the particle was about 40?nm. The particles were loaded with insulin and the release kinetics of insulin was studied in PBS medium. The results indicated that when percent loading increases from 11.7 to 38.9, the released amount of insulin increased from 18% to 60% of the loaded drug. The effect of composition of nanoparticles, pH and temperature of the release medium was examined on the amount of released insulin. It was observed when that amount of alginate in the feed mixture was varied from 1.0 to 2.0?g, the prepared nanoparticles showed a decreasing tendency to release insulin. Similarly, upon increasing the concentration of crosslinker in the range 0.5–1.1?mM, the release of insulin constantly decreased. The chemical stability of the loaded drug was assessed especially under highly acidic conditions of artificial gastric juice and it was noticed that even in harsh acidic environment (pH 1.2) the insulin remains chemically stable. The invitro blood compatibility of nanoparticles was also investigated and it was found that for a definite composition of nanoparticles, protein adsorption and percent haemolysis were minimum which suggested for an optimum blood compatibility of alginate nanoparticles of definite composition. Thus, it can be conclusively stated that the calcium alginate nanoparticles prepared by emulsion crosslinking method show potential to be developed as oral formulation for insulin delivery.     

Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Berberine hydrochloride (BBH), an important bioactive compound from Chinese Medicines with poor water solubility. Pseudoternary phase diagrams were constructed using oil, surfactant and co-surfactant types to identify the efficient self-microemulsification region. SMEDDS was characterized by morphological observation, droplet size, zeta-potential determination, stability, in vitro release and in vivo bioavailability study. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 40% (w/w) of ethyl linoleate and oleic acid (2:1), 35% (w/w) Tween-80 and 25% (w/w) glycerol. The SMEDDS of BBH could exhibit good stability. In vitro release test showed a complete release of BBH from SMEDDS was in 5 h. In vivo results indicated that the peak plasma concentration (C_max) and the area under the curve (AUC_{0→12 h}) of SMEDDS of BBH were higher than the commercial tablet by 163.4% and 154.2%, respectively. The relative bioavailability of SMEDDS of BBH was enhanced about 2.42-fold compared with the commercial tablet in rats. The study confirmed that the SMEDDS formulation could be used as a possible alternative to traditional oral formulations of BBH to improve its bioavailability.     

水滑石作为药物载体--萘普生的插层和缓释

水滑石(LDHs)是由带正电荷类水镁石层和层间的可交换阴离子组成的阴离子型粘土化合物,由于它的生物适应性,能够以它为主体,以药物为客体,插层组装成超分子结构复合物.抗炎药萘普生采用共沉淀法一步插层进入LDHs,用X射线衍射、红外光谱及热分析方法表征了超分子结构,表明层间距离扩大了,即萘普生已经插层组装成功,并且以单层、垂直作用在层间.萘普生柱撑水滑石的药物释放度在模拟肠液(pH7.4的缓冲液)条件下测定,结果表明萘普生柱撑水滑石释放速度降低,具有缓释作用,说明药物--无机混合物材料能够用作有效的药物传输系统.     

可控降解抗感染材料的体外释药机制研究

在前期合成并表征了可控降解抗感染材料环丙沙星聚氨酯（CFPU）的基础上,建立高效液相色谱法（HPLC）测定其体外降解释放抗菌药物环丙沙星的含量;通过制作累积药物释放曲线,考察不同降解介质及其浓度对药物释放的影响;并对累积药物释放曲线进行拟合,研究其体外可控降解的药物释放机制。结果表明建立的HPLC法简单准确可靠。该材料的降解具有生物响应性,且符合一级动力学;药物释放是以Ritger-Pappas方程（0.45     

Potential applications of carbomer in oral mucoadhesive controlled drug delivery system: a review

Carbomers are extensively being used in controlled drug delivery systems (CDDS). They are also finding numerous applications in oral mucoadhesive drug delivery because of their ability to interact with the mucus glycoprotein and to remain localized to a specific site. The present review aims at giving an insight into the potential application of carbomers in mucoadhesive CDDS. This review deals with the physicochemical properties of carbomers and various mechanisms of mucoadhesion. The mechanism for the release of the drug, both water soluble and water insoluble, is discussed. The use of carbomers in oral delivery of peptides or protein-based drugs is also covered.