Insights on novel particulate self-assembled drug delivery beads based on partial inclusion complexes between triglycerides and cyclodextrins

Most of the newly designed drug molecules are lipophilic in nature and often encounter erratic absorption and low bioavailability after oral administration. Finding ways to enhance the absorption and bioavailability of these lipophilic drugs is one of the major challenges that face pharmaceutical industry nowadays. In view of that, the purpose of this review is to shed some light on a novel particulate self-assembling system named “beads” than can act as a safe carrier for delivering lipophilic drugs. The beads are prepared simply by mixing oils with cyclodextrin (CD) aqueous solution in mild conditions. A unique interaction between oil components and CD molecules occurs to form in situ surface-active complexes which are prerequisites for beads formation. This review mainly focuses on the fundamentals of beads preparation through reviewing present, yet scarce, literature. The key methods used for beads characterization are discussed in details. Also, the potential mechanisms by which beads increase the bioavailability of lipophilic drugs are illustrated. Finally, the related research areas that needs to be addressed in future for optimizing this promising delivery system are briefly outlined.     

Improvement of tetracaine antinociceptive effect by inclusion in cyclodextrins

Local anesthetics (LA) are among the most important pharmacological compounds used to attenuate or eliminate pain. However, systemic toxicity is still a limitation for LA application, especially for ester-type drugs, such as tetracaine (TTC) that presents poor chemical stability (due to hydrolysis by plasma esterases). Several approaches have been used to improve LA pharmaceutical properties, including the employment of drug-delivery systems. Here we used beta-cyclodextrin (β-CD) or hydroxypropyl-beta-cyclodextrin (HP-β-CD) to develop two new TTC formulations (TTC:β-CD and TTC:HP-β-CD). The inclusion complexes formation, in a 1:1 stoichiometry, was confirmed by differential scanning calorimetry, X-ray diffraction, UV-VIS absorption and fluorescence. Nuclear magnetic resonance (DOSY experiments) revealed that TTC association with HP-β-CD is stronger (K_a?=?1200?mol/L^?1) than with β-CD (K_a?=?845?mol/L^?1). Moreover, nuclear Overhauser effect (NOE) experiments provided information on the topology of the complexes, where TTC aromatic ring is buried inside the CD hydrophobic cavity. In vitro tests with 3T3 fibroblast cells culture revealed that complexation decreased TTC cytotoxicity. In addition, the total analgesic effect of TTC, tested in rats through the infraorbital nerve test, was improved in 36% with TTC:β-CD and TTC:HP-β-CD. In conclusion, these formulations presented potential for future clinical use, by reducing the toxicity and increasing the antinociceptive effect of tetracaine.     

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes

Objectives Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories. Key findings Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin‐based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug‐to‐cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation ‘push’ and may reduce the bioavailability of the system. Conclusions A mechanism‐based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates.     

Interaction of Omeprazole with a Methylated Derivative of β-Cyclodextrin: Phase Solubility,NMR Spectroscopy and Molecular Simulation

Purpose Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of β-cyclodextrin, methyl-β-cyclodextrin (MβCD). A comparison with results obtained from the most commonly used natural cyclodextrin, β-cyclodextrin (βCD) is also presented in most cases. Materials and Methods The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D ¹H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. Results The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. ¹H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MβCD than in βCD cavity, in agreement with a larger apparent stability constant (K _S) obtained for the inclusion complex with MβCD. Conclusions MβCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.     

NMR studies of the inclusion complex between β-cyclodextrin and paroxetine

A ¹H and ¹³C NMR study on the inclusion complex of paroxetine with β-cyclodextrin was carried out in order to define the stoichiometry of the association and its strength. Proton and carbon chemical shift measurements of paroxetine and β-cyclodextrin were performed at several molar ratios and temperatures, allowing the determination of a 1:1 stoichiometry and an association constant value of the order of 2 × 10³ for the paroxetine–β-cyclodextrin complex. Overhauser effects in the rotating frame were also measured, and the experimental interproton distance constraints have been used for molecular model building of the complex. The obtained model indicates that the benzodioxolyl moiety of paroxetine is deeply inserted in the cavity of the cylindrical structure of β-cyclodextrin, while the fluoro-phenyl ring lays above the wider rim.     

吲哚美辛－β－环糊精包合物贴片的制备及其药物动力学研究

以水凝胶为底基，制备了吲哚美辛－β－环糊精包合物贴片；并进行了透皮吸收及其药物动力学研究。实验表明，环糊精可明显增加吲哚美辛的透皮吸收；本品给药后血药水平较平稳，持续时间长，具有一定缓释效果；该剂型可避免胃肠道副反应；相对于非包合物贴片，生物利用度较高。     

布洛芬-羟丙基-β-环糊精及布洛芬-β-环糊精微观结构的原子力显微镜表征

采用原子力显微镜(AFM)表征布洛芬-羟丙基-β-环糊精(IBU-HP-β-CyD)及布洛芬-β-环糊精(IBU-β-CyD)微观结构。测定条件为：钨丝探针(力常数0.06 N·m^-1)，扫描范围10.5 nm×10.5 nm，轻敲模式下成像，室温下逐点采集数据，G3DR软件处理数据。结果表明，β-CyD与HP-β-CyD空穴外径为1.53 nm，布洛芬的苯环直径为0.62 nm，布洛芬的苯环及其疏水基团插入HP-β-CyD与β-CyD空穴，形成1∶1的包合物。红外光谱、X-射线衍射和相溶解度佐证了AFM测定结果。     

Preparation and characterization of mosapride citrate inclusion complexes with natural and synthetic cyclodextrins

The aim of this work was to investigate the inclusion complexes between mosapride citrate and SBE₇β-CD in comparison with the natural β-CD to enhance its bioavailability by improving the solubility and dissolution rate. The complexation efficiency value of SBE₇β-CD was higher than that for β-CD. Solid binary systems of mosapride citrate with CDs were prepared by physical mixing, kneading and freeze-drying techniques at molar ratio of 1:1(drug:CD). Physicochemical characterization of the prepared systems was studied using X-ray diffractometry, differential scanning calorimetry, Fourier-transform infrared spectroscopy and scanning electron microscopy (SEM). Amorphous drug was detectable to large extent in inclusion complexes prepared using the freeze-drying technique. From the dissolution study of different inclusion complexes in simulated saliva solution (pH 6.8), we could concluded that irrespective of the preparation technique, the systems prepared using SBE₇β-CD showed better performance than the corresponding ones prepared using β-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the SBE₇β-CD     

那格列奈—2-羟丙基-β-环糊精包合物的制备及其理化性质

目的考察2-羟丙基-β-环糊精(HPCD)对那格列奈的增溶作用;研究那格列奈-HPCD包合物的制备工艺;考察包合物的光谱表征及包合物胶囊的体外释放行为。方法考察不同pH值、不同浓度的HPCD对那格列奈的增溶作用;通过研磨法和冷冻干燥法制备包合物;采用X-射线衍射及差示扫描热量法2种技术手段确证包合物的形成;在不同介质中考察不同方法制备的包合物的溶出度。比较不同环糊精用量比例的包合物、混合物及普通原料药的溶出度。结果不同pH条件下HPCD对那格列奈的增溶作用不同;差热分析及X-射线衍射证明了那格列奈与HPCD形成了包合物;那格列奈-HPCD包合物的水溶性好,在水介质中溶出度较高,在那格列奈与HPCD摩尔比为1∶2的情况下,冷冻干燥法制备的包合物,在pH 1.0的条件下体外溶出度达到100%,研磨法制备的包合物溶出度大于85%,而原料药溶出度仅为20%,显示出了那格列奈包合后的优势。结论包合物的光谱表征同那格列奈有明显不同;经包合后那格列奈的溶解度明显增大;用包合物制的胶囊体外溶出速度快,溶出度高。     

Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug

Abstract

Orally fast disintegrating tablets (FDTs or ODTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Although the FDT area has passed its infancy, as shown by a large number of commercial products on the market, there are still many aspects to improve in the FDT formulations. Despite advances in the FDT technologies, formulation of hydrophobic drugs is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in FDT formulations, β cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests.     

维胺酯-β-环糊精包合物的研究

应用３因素８水平的均匀设计方法，优化出维胺酯－β－环糊精包合物最佳制备条件，所得包合物的包合率为９９．３％，其表观稳定常数为１３９４Ｍ－１．     

核黄素对双歧杆菌和蜡样芽孢杆菌增殖的影响

目的　探讨不同浓度核黄素对双歧杆菌、蜡样芽孢杆菌生长的影响。方法　应用常规细菌定量培养及革兰染色镜检技术 ,观察 1、0 5、0 2 5 g·L-1的核黄素对双歧杆菌和蜡样芽孢杆菌增殖生长的影响。结果　① 1g·L-1核黄素组 ,在 4 8h后双歧杆菌活菌数增加约 10～ 10 0倍 ;0 5和 0 2 5g·L-1核黄素组 ,在 72h内活菌数增加约 10～ 390倍 ,镜检示双歧杆菌链的长度亦增加。② 0 5g·L-1核黄素组 ,36h后蜡样芽孢杆菌活菌数增加 ;0 2 5 g·L-1核黄素组 ,在 72h内活菌数均增加 ,约 0 5～ 315倍 ,链长度增加 ,芽胞形成时间延迟。 (3) 4℃存放 ,悬液加核黄素 (0 5g·L-1)可提高双歧杆菌和蜡样芽孢杆菌 6mon内的存活率。结论　核黄素可促进双歧杆菌、蜡样芽孢杆菌的增殖 ,在一定范围内存在剂量依赖关系 ,并可提高悬液中双歧杆菌和蜡样芽孢杆菌的长期存活率     

Cyclodextrin based nanoparticles for smart drug delivery in colorectal cancer

The advancement of colorectal cancer (CRC) prevention, detection, and treatment is essential to ensure that survivors live longer and higher-quality lives. The field of cancer detection and therapy has undergone a revolution with the development of nanotechnology for targeted drug delivery. The significant problems with the delivery of cancer drugs are their solubility, stability, and nonspecific distribution. There is a challenge that the acidic and enzymatic environment in the digestive tract will modify or destroy the medication or the active pharmaceutical ingredient. To overcome the problems, nanoparticles have been widely employed during the past several years to increase the specificity, selectivity, and controlled release of drug delivery systems. The site-specific and targeted delivery leads to reduce toxicity and side effects. With respect to the capability and utilization of cyclodextrin-based nanoparticles in different aspects of the tumour microenvironment and gut microbiota, a survey of current research papers was conducted via looking through databases including GoogleScholar, PubMed, Web of Science, and Scopus. This review aims to summarize cutting-edge nanoparticulate-based technologies and therapies for CRC.     

Solid state studies of drug–cyclodextrin inclusion complexes in PEG 6000 prepared by a new method

The melting method was investigated as a possible method for producing drug–cyclodextrin (CD) inclusion compounds in a carrier. Various solid dispersions of -, β- and γ-CD in polyethylene glycol (PEG) 6000 with and without the addition of 5% w/w indomethacin or griseofulvin were prepared using the original components. Characterisations of the samples included X-ray powder diffraction, modulated-temperature differential scanning calorimetry and dissolution tests by the paddle method according to USP XXI standard. Evidence of a complex between indomethacin and β-CD in PEG 6000 was found. An indomethacin–γ-CD complex formed a well defined phase in the PEG carrier, with tetragonal structure and unit cell parameters a=23.885(35) Å and c=23.181(64) Å. No complexation of indomethacin with -CD, or with griseofulvin and β-CD could be detected. It is suggested that competition between PEG and the drug for the binding to different CDs along with varying patterns of water loss from the CDs influence the inclusion reaction. The formation of complexes was accompanied by a decrease in the relative crystallinity of the dispersions. Dissolution tests showed that the CDs have a delaying effect on the release of indomethacin from PEG 6000 in the order -CD<γ-CD≤β-CD.