Multiparticulate chitosan-dispersed system for drug delivery

A multiparticulate chitosan-dispersed system (CDS), which is composed of the drug reservoir and the drug release-regulating layer, was developed for drug delivery. The drug release-regulating layer is a mixture of water-insoluble polymer and chitosan powder. The drug is released from CDS pellets in all regions of the gastrointestinal tract (from the stomach to the colon). CDS pellets containing chitosan powder were designed to dissolve chitosan powder partly in the release-regulating layer in the stomach and release part of drug. After passing through the stomach, the drug is released from CDS pellets at a constant speed in the small intestine. In the large intestine, CDS pellets were designed to disintegrate the remaining chitosan powder at an accelerated speed and the remaining drug in CDS pellets is released. The drug release rate can be controlled with the thickness of the chitosan-dispersed water-insoluble layer. Furthermore, for colon-specific drug delivery, an additional outer enteric coating is necessary to prevent drug release from CDS pellets in the stomach, because the chitosan-dispersed water-insoluble layer dissolves gradually under acidic conditions. The resulting enteric-coated CDS (E-CDS) pellets were found to permit colon-specific drug delivery. In this study, the multiparticulate CDS was adopted not only for colon-specific drug delivery but also for sustained drug release.     

Controlled Drug Delivery Systems: Current Status and Future Directions

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.     

Phenotype-related drug sensitivity analysis of single CTCs for medicine evaluation

Due to the heterogeneous and variable drug sensitivity of tumor cells, real-time monitoring of a patient''s drug response is desirable for implementing personalized and dynamic therapy. Although considerable efforts have been directed at drug screening in living cells, performing repeated drug sensitivity analysis using patient-derived primary tumor cells at the single-cell level remains challenging. Here, we present an efficient approach to assess phenotype-related drug sensitivity at the single-cell level using patient-derived circulating tumor cells (CTCs) based on a drug sensitivity microfluidic chip (DS-Chip). The DS-Chip consists of a drug gradient generator and parallel cell traps, achieving continuous single CTC capture, drug gradient distributions, drug stimulation, fluorescent probe labeling and three-color fluorescence imaging. Based on the established DS-Chip, we investigated the drug sensitivity of single cells by simultaneously monitoring epithelial–mesenchymal transition (EMT) biomarkers and apoptosis in living cells, and verified the correlation between EMT gradients and drug sensitivity. Using the new approach, we further tested the optimal drug response dose in individual CTCs isolated from 5 cancer patients through fluorescence analysis of EMT and apoptosis. The DS-Chip allows noninvasive and real-time measurements of the drug sensitivity of a patient''s tumor cells during therapy. This developed approach has practical significance and can effectively guide drug selection and therapeutic evaluation for personalized medicine.

Due to the heterogeneous and variable drug sensitivity of tumor cells, real-time monitoring of a patient''s drug response is desirable for implementing personalized and dynamic therapy.     

Highly efficient drug delivery with gold nanoparticle vectors for in vivo photodynamic therapy of cancer

A highly efficient drug vector for photodynamic therapy (PDT) drug delivery was developed by synthesizing PEGylated gold nanoparticle conjugates, which act as a water-soluble and biocompatible "cage" that allows delivery of a hydrophobic drug to its site of PDT action. The dynamics of drug release in vitro in a two-phase solution system and in vivo in cancer-bearing mice indicates that the process of drug delivery is highly efficient, and passive targeting prefers the tumor site. With the Au NP-Pc 4 conjugates, the drug delivery time required for PDT has been greatly reduced to less than 2 h, compared to 2 days for the free drug.     

Colon targeting of fluticasone propionate inclusion complex: a novel approach in inflammatory bowel disease

Purpose of the present research was to present fluticasone propionate, a glucocorticoid, as a novel formulation exhibiting improved aqueous solubility, and targeting the drug directly to colon for the treatment of inflammatory bowel disease. Inclusion complex of the drug with hydroxypropyl betacyclodextrin were prepared by solvent evaporation and subsequently the granules of the inclusion complex were coated with Eudragit S100, in order to achieve colon targeting. Inclusion complex was characterized by FTIR, DSC, XRD and ¹H-NMR studies. In vitro drug release from coated granules and the drug transport across excised rat colon using modified Ussing chamber were also attempted. The drug was found to be present in amorphous form, when included in HPβCD cavities. Furthermore, intrinsic dissolution of the drug was found to increase by ~18 times. Coated granules exhibited no drug release in 0.01 N HCl as dissolution medium, indicating gastro-resistance, while 92 % of the drug was released in 120 min, in phosphate buffer (pH 7.4) as dissolution medium. The drug transport studies with rat colon led to more drug transport and concentration in target tissue, when presented as inclusion complex. The formulation releases the drug with improved aqueous solubility in colonic region, and thus concentrating the drug at the target tissue itself.     

The importance of impurity analysis in pharmaceutical products: an integrated approach

To purify a material and remove the excess impurities one should first recognize that whether they are actually present and what their nature is. In the past, this was not always done. But presently drug analysis and pharmaceutical impurities are the subjects of constant review in the public interest. The International Conference on Harmonisation (ICH) guidelines achieved a great deal in harmonizing the definitions of the impurities in new drug substances. It is necessary to perform all the investigations on appropriate reference standards of drug and impurities to get meaningful specifications. In order to meet the challenges to ensure high degree of purity of drug substances and drug products, a scheme is proposed for profiling drug impurity. Finally, analytical methods based on analytical instrumentation must be employed to quantitate drug substance and its impurities. Important aspects and suggestions related to drug analysis and pharmaceutical impurities are discussed.     

Preparation and in vitro release profiles of drug-eluting controlled biodegradable polymer coating stents

In the present study, the different drug-eluting controlled biodegradable polymer coatings were fabricated on stainless steel stents. The coatings were not only uniform and smooth but also had excellent mechanical property. The drug release profiles of drug-eluting stents were studied in detail in this study. Depending on the drug type, different drug-eluting stents exhibited different drug release profile. There were two basic release profiles for different drug-eluting stents, i.e., two-phase release profile with burst release or linear release profile without burst release. Incorporating heparin in the rapamycin or curcumin eluting stents can improve the average drug release rate of both and the burst release of rapamycin. The average drug release rate increased with the increase of drug loading but was not proportional to increase of the ratio of drug/polymer. Fabricating the control release layer on rapamycin-eluting stent surface can prevent the burst release of rapamycin and prolong the release period of rapamycin. All results showed that the drug release profile of drug-eluting stents depends on many parameters including drug type, ratio of drug/polymer, and drug carrier properties.     

Molecularly Precise Dendrimer–Drug Conjugates with Tunable Drug Release for Cancer Therapy

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer–drug conjugates. Current dendrimer–drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer–drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.     

Core–Shell Hollow Microspheres of Magnetic Iron Oxide@Amorphous Calcium Phosphate: Synthesis Using Adenosine 5′‐Triphosphate and Application in pH‐Responsive Drug Delivery

Drug nanocarriers with magnetic targeting and pH‐responsive drug‐release behavior are promising for applications in controlled drug delivery. Magnetic iron oxides show excellent magnetism, but their application in drug delivery is limited by low drug‐loading capacity and poor control over drug release. Herein, core–shell hollow microspheres of magnetic iron oxide@amorphous calcium phosphate (MIO@ACP) were prepared and investigated as magnetic, pH‐responsive drug nanocarriers. Hollow microspheres of magnetic iron oxide (HMIOs) were prepared by etching solid MIO microspheres in hydrochloric acid/ethanol solution. After loading a drug into the HMIOs, the drug‐loaded HMIOs were coated with a protective layer of ACP by using adenosine 5′‐triphosphate (ATP) disodium salt (Na₂ATP) as stabilizer, and drug‐loaded core–shell hollow microspheres of MIO@ACP (HMIOs/drug/ACP) were obtained. The as‐prepared HMIOs/drug/ACP drug‐delivery system exhibits superparamagnetism and pH‐responsive drug‐release behavior. In a medium with pH 7.4, drug release was slow, but it was significantly accelerated at pH 4.5 due to dissolution of the ACP shell. Docetaxel‐loaded core–shell hollow microspheres of MIO@ACP exhibited high anticancer activity.     

Design and evaluation of cyclodextrin-based drug formulation

The pharmaceutically useful cyclodextrins (CyDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in design and evaluation of CyD-based drug formulation, focusing on their ability to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site.     

Recent Aspect of Cyclodextrin-Based Drug Delivery System

The pharmaceutically useful cyclodextrins (CyDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. These CyDs can serve as multi-functional drug carriers, through the formation of inclusion complex or the form of CyD/drug conjugate. In addition, the combined use of different CyDs and/or pharmaceutical excipients is capable of alleviating the undesirable properties of drug molecules, improving efficacy and reducing side effects. This contribution outlines the potential use of CyDs in the design and evaluation of CyD-based drug formulation, focusing on their ability to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to targeted site.     

Bioinspired Core–Shell Nanoparticles for Hydrophobic Drug Delivery

A large range of nanoparticles have been developed to encapsulate hydrophobic drugs. However, drug loading is usually less than 10 % or even 1 %. Now, core–shell nanoparticles are fabricated having exceptionally high drug loading up to 65 % (drug weight/the total weight of drug‐loaded nanoparticles) and high encapsulation efficiencies (>99 %) based on modular biomolecule templating. Bifunctional amphiphilic peptides are designed to not only stabilize hydrophobic drug nanoparticles but also induce biosilicification at the nanodrug particle surface thus forming drug‐core silica–shell nanocomposites. This platform technology is highly versatile for encapsulating various hydrophobic cargos. Furthermore, the high drug loading nanoparticles lead to better in vitro cytotoxic effects and in vivo suppression of tumor growth, highlighting the significance of using high drug‐loading nanoparticles.     

Non-ionic and cationic micelle nanostructures as drug solubilization vehicles: spectrofluorimetric and electrochemical studies

The use of colloidal organized media, such as micelles, to solubilize tetracaine hydrochloride (TC.HCl), a local anaesthetic drug, in aqueous solution has been studied by means of fluorescence spectroscopy at 298.15 K. Because tetracaine molecule is a fluorescent probe, changes in the fluorescence emission spectra of the drug when it is solubilized by the micelles enable the study of the micelles–drug association process through the calculation of the association constants. Two kinds of micelles have been selected to solubilize the drug: non-ionic micelles and cationic micelles. Complementary conductometric experiments were also done to determine the critical aggregation concentration of the surfactants in the presence of the drug. The micelle–drug association process has been also analyzed by deconvoluting the fluorescent of the drug into several Gaussian components, each of which assigned to the solubilization of the drug within different microenvironment inside and outside the cationic and/or non-ionic micelles.     

The process of structure-based drug design

The field of structure-based drug design is a rapidly growing area in which many successes have occurred in recent years. The explosion of genomic, proteomic, and structural information has provided hundreds of new targets and opportunities for future drug lead discovery. This review summarizes the process of structure-based drug design and includes, primarily, the choice of a target, the evaluation of a structure of that target, the pivotal questions to consider in choosing a method for drug lead discovery, and evaluation of the drug leads. Key principles in the field of structure-based drug design will be illustrated through a case study that explores drug design for AmpC beta-lactamase.     

基于天然高分子基元的阻隔层对磁性载药聚乳酸微球的控释作用

利用层层组装技术构建了基于天然高分子壳聚糖和海藻酸钠的阻隔层, 并研究了该阻隔层对磁性载药聚乳酸微球的药物释放作用. 实验结果表明, 阻隔层能够有效抑制模型药物的突释, 具有延缓药物释放的效果. 具有阻隔层的磁性载药体系具有药物释放平缓和生物相容性高等特点, 是理想的磁靶向载药体系.     

Transdermal drug transfer from a polymer device: study of the polymer and the process

Special polymer devices containing a drug are able to deliver the drug to the patient through transdermal delivery. Two points are of interest: the nature of the polymer device, and the process of drug delivery. The polymer device considered in this paper is able to maintain a constant drug concentration on the patient's skin surface. The process of drug delivery is studied through in vitro and in vivo tests. In vitro tests show that the skin plays the role of a membrane, with a steady state for the drug transfer following a non-steady state. The parameters of diffusion through the skin are thus calculated from this test. In vivo tests are described by a process of drug transfer consisting of two stages: the stages of absorption into, and elimination out of, the blood. The polymer device plays a major role, as it should maintain a constant concentration of drug on the skin.     

Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 1: A multifunctional system for controlled drug delivery

Biodegradable poly(d,l-lactide-co-glycolide) (PLGA) and bioactive hydroxyapatite (HAp) are selected for the formation of a multifunctional system with the specific core-shell structure to be applied as a carrier of a drug. As a result, both components of PLGA/HAp core-shells are able to capture one part of the drug. Polymeric shells consisting of small nanospheres up to 20nm in size act as a matrix in which one part of the drug is dispersed. In the same time, ceramic cores are formed of rod-like hydroxyapatite particles at the surface of which another part of the drug is adsorbed onto the interface between the polymer and the ceramics. The content of the loaded drug, as well as the selected solvent/non-solvent system, have a crucial influence on the resulting PLGA/HAp morphology and, finally, unimodal distribution of core-shells is obtained. The redistribution of the drug between the organic and inorganic parts of the material is expected to provide an interesting contribution to the kinetics of the drug release resulting in non-typical two-step drug release.     

Enhanced Drug Delivery by Dissolution of Amorphous Drug Encapsulated in a Water Unstable Metal–Organic Framework (MOF)

Encapsulating a drug molecule into a water‐reactive metal–organic framework (MOF) leads to amorphous drug confined within the nanoscale pores. Rapid release of drug occurs upon hydrolytic decomposition of MOF in dissolution media. Application to improve dissolution and solubility for the hydrophobic small drug molecules curcumin, sulindac, and triamterene is demonstrated. The drug@MOF composites exhibit significantly enhanced dissolution and achieves high supersaturation in simulated gastric and/or phosphate buffer saline media. This combination strategy where MOF inhibits crystallization of the amorphous phase and then releases drug upon MOF irreversible structural collapse represents a novel and generalizable approach for drug delivery of poorly soluble compounds while overcoming the traditional weakness of amorphous drug delivery: physical instability of the amorphous form.     

Strategies Using Gelatin Microparticles for Regenerative Therapy and Drug Screening Applications

Gelatin, a denatured form of collagen, is an attractive biomaterial for biotechnology. In particular, gelatin particles have been noted due to their attractive properties as drug carriers. The drug release from gelatin particles can be easily controlled by the crosslinking degree of gelatin molecule, responding to the purpose of the research. The gelatin particles capable of drug release are effective in wound healing, drug screening models. For example, a sustained release of growth factors for tissue regeneration at the injured sites can heal a wound. In the case of the drug screening model, a tissue-like model composed of cells with high activity by the sustained release of drug or growth factor provides reliable results of drug effects. Gelatin particles are effective in drug delivery and the culture of spheroids or cell sheets because the particles prevent hypoxia-derived cell death. This review introduces recent research on gelatin microparticles-based strategies for regenerative therapy and drug screening models.     

Functionalized mesoporous silica nanoparticles templated by pyridinium ionic liquid for hydrophilic and hydrophobic drug release application

Chemotherapy is the most common treatment for all cancer patients but this treatment poses many side effects due to lack of drug’s selectivity. To overcome this problem, utilizing a better and more effective delivery agent is the solution. Mesoporous silica nanoparticles (MSNs) emerged as a promising platform in development of drug delivery agent. This is due to its desirable properties such as tunable pores, large surface area, good biocompatibility and easy functionalization. Furthermore, these properties can be tuned through the utilization of alternative template such as pyridinium ionic liquid. Besides, by employing surface functionalization, the effectiveness of MSNs as drug delivery agent may also increase. This work reported the usage of 1-hexadecylpyridinium bromide ionic liquid as template for MSNs production and the surface of MSNs was then further functionalized via post – grafting method in order to obtain MSN – NH₂, MSN – SH and MSN – COOH as drug carrier, respectively. These functionalized MSNs were then used to study the drug loading and drug release of hydrophilic drug, gemcitabine and hydrophobic drug, quercetin. For quercetin, MSN-NH₂ had the highest drug loading percentage (72%) and slowest release (14%) in 48 h while for gemcitabine, it was found that MSN-COOH had the highest drug loading percentage (45%) and slowest release (15%) in 48 h. Based on the results, it is suggested that mesoporous silica nanoparticle with surface functionalization has suitable properties for controlled drug release which gives constant release behavior over a period of time to avoid repeated administration of drug where the drug is administered at a fixed dosage and regular time interval.