Microemulsion-Based Mucoadhesive Buccal Wafers: Wafer Formation, In Vitro Release, and Ex Vivo Evaluation.

Microemulsion has the potentials to enhance dissolution as well as facilitate absorption and permeation of poorly water-soluble drugs through biological membranes. However, its application to govern a controlled release buccal delivery for local treatment has not been discovered. The aim of this study is to develop microemulsion-based mucoadhesive wafers for buccal delivery based on an incorporation of the microemulsion with mucoadhesive agents and mannitol. Ratio of oil to surfactant to water in the microemulsion significantly impacted quality of the wafers. Furthermore, the combination of carbopol and mannitol played a key role in forming the desired buccal wafers. The addition of an extra 50% of water to the formulation was suitable for wafer formation by freeze-drying, which affected the appearance and distribution of carbopol in the wafers. The amount of carbopol was critical for the enhancement of mucoadhesive properties and the sustained drug release patterns. Release study presented a significant improvement of the drug release profile following sustained release for 6 h. Ex vivo mucoadhesive studies provided decisive evidence to the increased retention time of wafers along with the increased carbopol content. The success of this study indicates an encouraging strategy to formulate a controlled drug delivery system by incorporating microemulsions into mucoadhesive wafers.

Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method.

PURPOSE: This study is to design a sustained release solid dispersion using swellable polymer by melting method. METHODS: Polyethylene glycol 6000 (PEG 6000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were used in solid dispersion for not only enhancing drug dissolution rate but also sustaining drug release. HPMC 4000 is a common swellable polymer in matrix sustained release dosage form, but could not be used in preparation of solid dispersion by melting method. However, the current study utilized the swelling capability of HPMC 4000 accompanied by the common carrier PEG 6000 in solid dispersion to accomplish the goal. RESULTS: While PEG 6000 acted as a releasing stimulant carrier and provided an environment to facilitate the swelling of HPMC 4000, this swellable polymer could act as a rate-controlling agent. This greatly assisted the dissolution enhancement by changing the crystalline structure of drug to more amorphous form and creating a molecular interaction. CONCLUSIONS: These results suggested that this useful technique can be applied in designing a sustained release solid dispersion with many advantages.

Polymer conjugate-based nanomaterials for drug delivery.

The structure of polymeric amphiphiles with both hydrophilic and hydrophobic groups forming self-assembled nanoparticles have attracted increasing attention in studies of delivery systems of therapeutic agents. An amphiphilic carrier for self-assembly in an aqueous solution is preferable because of its structure with a hydrophobic core and hydrophilic outer shell, which can be applied to many biotechnological and pharmaceutical fields with numerous types of drugs. An amphiphilic carrier for self-assembly also represents the most appealing delivery system owing to its exceptional advantages in selectively delivering drugs to tumor cells and thus, reduction of side effects. This paper reviews two types of self-assembled nanoparticles/micelles of conjugated polymeric amphiphiles: (1) self-assembled micelles/nanoparticles of amphiphilic conjugates followed by drug loading and (2) self-assembled micelles/nanoparticles of polymer-drug conjugates where a conjugation reaction occurs between the polymer and drug. The development of the research has been addressed in this review with up-to-date references. In conclusion, the challenges and remaining difficulties for the future development are discussed.

Development of Blueberry-Derived Extracellular Nanovesicles for Immunomodulatory Therapy.

Over the past decade, there has been a significant expansion in the development of plant-derived extracellular nanovesicles (EVs) as an effective drug delivery system for precision therapy. However, the lack of effective methods for the isolation and characterization of plant EVs hampers progress in the field. To solve a challenge related to systemic separation and characterization in the plant-derived EV field, herein, we report the development of a simple 3D inner filter-based method that allows the extraction of apoplastic fluid (AF) from blueberry, facilitating EV isolation as well as effective downstream applications. Class I chitinase (PR-3) was found in blueberry-derived EVs (BENVs). As Class I chitinase is expressed in a wide range of plants, it could serve as a universal marker for plant-derived EVs. Significantly, the BENVs exhibit not only higher drug loading capacity than that reported for other EVs but also possess the ability to modulate the release of the proinflammatory cytokine IL-8 and total glutathione in response to oxidative stress. Therefore, the BENV is a promising edible multifunctional nano-bio-platform for future immunomodulatory therapies.

Controlled release systems containing solid dispersions: strategies and mechanisms.

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan.

The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na2CO3, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pH(M)) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na2CO3 was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na2CO3 was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm⁻¹ and the disappearance of carbonyl group at 1598 cm⁻¹. Furthermore, Na2CO3 efficiently modulated pH(M) by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pH(M).

Design and mechanism of on-off pulsed drug release using nonenteric polymeric systems via pH modulation.

The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on-off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pH(M)). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pH(M), so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release ("off" release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on-off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on-off release behavior of the drug and fumaric acid from coated tablets.

The Use of Natural Materials in Film Coating for Controlled Oral Drug Release.

BACKGROUND: Although synthetic materials have been used in film coating processes for drug delivery for many years, substantial studies on natural materials have also been conducted because of their biodegradable and unique properties. METHODS: Because of the ability to form and modify films for controlled oral drug delivery, increasing attention has been shown to these materials in the design of film coating systems in recent research. RESULTS: This review aims to provide an overview of natural materials focusing on film coating for oral delivery, specifically in terms of their classification and their combinations in film coating formulations for adjusting the desired properties for controlled drug delivery. CONCLUSIONS: Discussing natural materials and their potential applications in film coating would benefit the optimization of processes and strategies for future utilization.

Investigation of Crystallization and Salt Formation of Poorly Water-Soluble Telmisartan for Enhanced Solubility.

The crystal changes and salt formation of poorly water-soluble telmisartan (TEL) in various solvents were investigated for enhanced solubility, stability and crystallinity. Polymorphic behaviors of TEL were characterized by dispersing in distilled water, acetone, acetonitrile, DMSO, or ethanol using Method I: without heat and then dried under vacuum at room temperature; and Method II: with heat below boiling temperature, cooled at 5 °C, and then dried under vacuum at 40 °C. For salt formation (Method III), the following four powdered mixtures were prepared by dispersing in solution of hydrochloric acid (HCl) (pH 1.2), TEL/HCl; in simulated gastric fluid (pH 1.2 buffer), TEL/simulated gastric fluid (SGF); in intestinal fluid (pH 6.8 buffer), TEL/simulated intestinal fluid (SIF); or in NaOH (pH 6.8), TEL/NaOH, respectively, and then dried under a vacuum at room temperature. The structures of powdered mixtures were then studied using a field emission scanning electron microscope (FESEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), FTIR, ¹H nuclear magnetic resonance (¹H-NMR), and LC⁻MS. The solubility of TEL in powdered forms was performed in pH 6.8, pH 1.2, and distilled water. No polymorphic behaviors of TEL were observed in various solvents as characterized by FESEM, DSC, PXRD, and FTIR. However, the structural changes of powdered mixtures obtained from Method III were observed due to the formation of salt form. Moreover, the solubility of salt form (TEL/HCl) was highly increased as compared with pure TEL. There were no significant changes of TEL/HCl compared with TEL in the content assay, PXRD, DSC, and FTIR during stressed storage conditions at 40 °C/75% relative humidity (RH) for 4 weeks under the closed package condition. Therefore, the present study suggests the new approach for the enhanced stability and solubility of a poorly water-soluble drug via salt form.

A Detailed Protein-SELEX Protocol Allowing Visual Assessments of Individual Steps for a High Success Rate.

As a nucleic acid alternative to traditional antibody, aptamer holds great potential in various fields of biology and medicine such as targeted gene therapy, drug delivery, bio-sensing, and laboratory medicine. Over the past decades, the conventional Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method has undergone dramatic modifications and improvements owing to developments in material sciences and analytical techniques. However, many of the recently developed strategies either require complex materials and instruments or suffer from low efficiency and high failure rates in the selection of desired aptamers. Accordingly, the development of aptamers against new or novel targets is still a major obstacle for aptamer-based research and application. Here, an improved protein-SELEX procedure is presented for simplified and highly efficient isolation of aptamers against protein targets. Approaches are described that ensure a high success rate in aptamer selection by simplifying polymerase chain reaction procedures, introducing denature gel, utilizing an electro-elution-based single-stranded DNA separation strategy, as well as an enzyme-linked immunosorbent assay-based highly sensitive binding assay. In addition, a simplified sample preparation method for MiSeq-based next-generation sequencing is also introduced. While a recombinant protein as a bait protein for SELEX is discussed here, this protocol will also be invaluable for researchers wishing to develop aptamers against targets other than proteins such as small molecules, lipids, carbohydrates, cells, and micro-organisms for future gene therapy and/or diagnostics.

Biodistribution and in vivo performance of fattigation-platform theranostic nanoparticles.

This study was aimed at characterizing superparamagnetic nanoparticles surface-functionalized with gelatin-oleic acid (GOAS-MNPs) and loaded with paclitaxel by assessing the pharmacokinetics and biodistribution of paclitaxel in tissues and the in vivo efficacy of antitumor activity after the administration of the drug. Initially, instrumental analysis was performed to examine the particle size distribution, surface charge, and morphology of the paclitaxel-loaded GOAS-MNPs. Furthermore, we evaluated their magnetic properties and performed T2-weighted magnetic resonance imaging (MRI) on cells. We intravenously administered Taxol® and paclitaxel-loaded GOAS-MNPs and compared the pharmacokinetics, biodistribution, and antitumor efficacies of the two formulations. Determination of the pharmacokinetics and the biodistribution of paclitaxel-loaded NPs showed that this formulation increased the systemic circulation time of paclitaxel and regulated its transport to tissues. The in vivo antitumor efficacy of the paclitaxel-loaded NPs was better than that of Taxol® at the same dose. Furthermore, the paclitaxel-loaded GOAS-MNPs were found to be effective as contrast agents for enhanced MRI in cancer cells. Thus, GOAS-MNPs could be an effective diagnostic system for cancer and for the delivery of paclitaxel with better therapeutic effects and a significant reduction in toxicity.

Fattigation-platform theranostic nanoparticles for cancer therapy.

A new conceptual nanoparticle consisting of a silica-coated iron oxide magnetic core and a fattigation-based biocompatible shell with oleic acid and hydrophilic protein (gelatin). The prepared particle can be a useful theranostics platform material for diagnostic imaging and as a drug delivery system. Oleic acid and gelatin were conjugated on the silica-coated magnetic nanoparticle surface to provide three primary functionalities: 1) enhancing biocompatibility and solubility in aqueous solution and providing the ability to incorporate hydrophobic chemical drugs into the shell for delivery, 2) improving treatment-response magnetic monitoring as a diagnostic agent with low nanotoxicity, and 3) increasing anticancer efficacy owing to the controlled release of the incorporated drug in cells and in an animal model. We prepared magnetic-silica nanoparticles with super-paramagnetic properties, which are utilized as a T2-weighted magnetic resonance imaging agent. After formation of an oleic acid-gelatin shell, the prepared materials exhibited high loading capacity for a hydrophobic anticancer drug (paclitaxel). Our particle platform system exhibited higher therapeutic efficacy and lower toxicological effects in vitro and in an in vivo cancer model than a clinically available chemo-drug (Taxol®). Our findings strongly suggest that this nanoparticle system can serve as a platform for cancer therapy by the incorporation of chemical drugs.

Fattigation-platform nanoparticles using apo-transferrin stearic acid as a core for receptor-oriented cancer targeting.

A major hurdle in cancer treatment is the precise targeting of drugs to the cancer site. As many cancer cells overexpress the transferrin receptor (TfR), the transferrin (Tf)-TfR interaction is widely exploited to target cancer cells. In this study, novel amphiphilic apo-Tf stearic acid (TfS) conjugates were prepared and characterized by Fourier transform infrared (FTIR) spectroscopy, matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and trinitrobenzenesulfonic acid (TNBS) assay. The prepared TfS conjugates were readily self-assembled in water to form nanoparticles (NPs), consisting of TfS as a core of NPs, whose sizes and zeta potentials were determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a particle size analyzer. Hydrophilic water-soluble doxorubicin (DOX) was chosen as a model drug. DOX-loaded TfS NPs (NP+DOX), prepared by the adsorption of DOX on the NP surface via the incubation method, were analyzed for their cell targeting and killing efficiencies in TfR-overexpressing A549 and HCT116 cell lines by MTT assay, confocal microscopy, and fluorescence assisted cell sorting (flow cytometry). The data showed that NP+DOX exhibited improved cancer cell targeting and killing properties compared to that reported for free DOX. Further, the cytotoxic efficiency of NP+DOX was comparable to that of PEGylated liposomal product, Doxil®, while its cellular uptake was higher than that of Doxil®. Thus, this novel receptor-based TfS NP drug delivery system has great potential to target TfR-overexpressing cancer cells without off-target effects.

Sonication-Assisted Nanoprecipitation in Drug Delivery.

Sonication-assisted nanoprecipitation provides an effective tool for nanomedicine engineering in therapeutic improvement. In the scope of this review, original works in interdisciplinary areas of using sonication with precipitation method for nanoparticulate drug delivery systems and its applications in management of different diseases are discussed. The use of sonication-assisted nanoprecipitation has been proved to improve drug bioavailability, which attracts tremendous interests as an effective strategy for drug delivery. However, many challenges still remain. To overcome these barriers, different approaches such as precipitation method, rational design, optimization and modification have been investigated. Accordingly, current knowledge of sonication-assisted nanoprecipitation proposes a broad perspective and optimization for the applications of nanotechnology in drug delivery.

Strategies of Engineering Nanoparticles for Treating Neurodegenerative Disorders.

BACKGROUND: Neurodegenerative disorders (NDs) are typically referred to Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis and prion disease. These are commonly debilitating and, unfortunately, have few therapeutic options. OBJECTIVE: In this review, we describe some emerging advances in nanoengineering strategies for the treatment of NDs. One of the main difficulties in fighting against NDs is to overcome the shielding of blood-brain barrier (BBB), which greatly limits the penetration of various therapeutic drugs, which sometimes leads to severe side effects. Nanotechnology, by engineering materials of a size scale usually within 1-100 nm, fortunately offers an alternative approach for novel, promising and innovative solutions. Nanoparticles are capable of not only penetrating the BBB but also releasing active ingredients at a specific site due to its surface functionalization. Therefore, nanoengineered delivery systems potentially facilitate the targeted delivery of neuronal therapeutic drugs and genes to the central nervous system. Furthermore, recently developed nanomaterials are considered as therapeutic agents themselves since they exhibit important roles in promoting the protection of healthy neurons or the regeneration of neurons to repair damaged tissues. CONCLUSION: There have been a variety of innovative approaches to designing therapeutic nanoparticles for NDs, and each has been associated with certain pros and cons.

Aptamer-mediated survivin RNAi enables 5-fluorouracil to eliminate colorectal cancer stem cells.

The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. Novel molecular therapeutic strategies able to overcome such limitations are urgently needed for future effective management of cancer. In this report, we show that EpCAM-aptamer-guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells. Thus, aptamer-mediated targeting of survivin in cancer stem cells in combination with chemotherapeutic drugs constitutes a new avenue to improve treatment outcome in oncologic clinics.

Transforming doxorubicin into a cancer stem cell killer via EpCAM aptamer-mediated delivery.

Chemotherapy-resistant cancer stem cells (CSCs) are a major obstacle to the effective treatment of many forms of cancer. To overcome CSC chemo-resistance, we developed a novel system by conjugating a CSC-targeting EpCAM aptamer with doxorubicin (Apt-DOX) to eliminate CSCs. Incubation of Apt-DOX with colorectal cancer cells resulted in high concentration and prolonged retention of DOX in the nuclei. Treatment of tumour-bearing xenograft mice with Apt-DOX resulted in at least 3-fold more inhibition of tumour growth and longer survival as well as a 30-fold lower frequency of CSC and a prolonged longer tumourigenic latency compared with those receiving the same dose of free DOX. Our data demonstrate that a CSC-targeting aptamer is able to transform a conventional chemotherapeutic agent into a CSC-killer to overcome drug resistance in solid tumours.

Nano-Precipitation: Preparation and Application in the Field of Pharmacy.

Over the last 30 years, nanoparticle-based medicine has received tremendous attention due to its advances with smart therapeutics and less toxicity. Few nanomedicine products have been approved for commercial use in the clinic (such as Doxil(®), Ambraxane(®)..). Nanomedicine research is still at its early stage and the preparation of nanoparticles must be carefully considered. Systems involving further increased supersaturation, either via solvent evaporation, temperature reduction or anti-solvent mixture, were suggested to be capable of inducing nanoprecipitation (NPT). Since this technique is straight-forward, fast and easy to duplicate in practice, it is highly preferred and recommended. In this review, the process of NTP was described and discussed in detail. Factors that affect the encapsulation efficiency, the nanoparticle size, the morphology and the stability of nanoparticles prepared by NTP were described. This process is one of the most preferable processes for preparing solid nano-protein due to their elegant techniques that preserve the bioactivity of proteins. Although the production of nanoparticles by this process has not been applied in the pharmaceutical industry due to the organic solvent issue, the production equipment for large-scale has been marketed.

Nanoparticulate Drug Delivery to Colorectal Cancer: Formulation Strategies and Surface Engineering.

The evolution of polymer-based nanoparticle as a drug delivery carrier has greatly contributed to the development of advanced nano and micro-medicine in the past few decades. The polymer-based nanoparticles of biodegradable and biocompatible polymers such as poly (lactide-co-glycolide) and chitosan which have been approved by Food & Drug Administration and/or European Medicine Agency can particularly facilitate the maintaining of specific properties for a real transition from laboratory to the clinical oral and parental administration. This review presents an overview of the strategies of preparing polymeric nanoparticles and using them for targeting colorectal cancer. Theranostics and surface engineering aspects of nanoparticle design in colonic cancer delivery are also highlighted.

Perspectives of Engineered Marine Derived Polymers for Biomedical Nanoparticles.

Marine environment exhibits an enormous diversity of organisms which contains an abundant source of polysaccharides. As polymer matrix carriers, marine-based polymers possess several valuable properties including high stability, non-toxicity, hydrophilicity, biodegradability, with low production cost. Despite notable biological activities of these natural polymers, there are certain limitations in exploring their functions in applications of nano-sized drug delivery systems. The review aims to demonstrate exceptional characteristics of marine-based polymers including fucoidan, alginate, carrageenan, hyaluronic acid, chondroitin sulfate, and chitosan as well as provide perspectives of current publications on their nanoparticle formulations for biomedical applications.