Novel modified nanoporous silica for oral drug delivery: loading and release of clarithromycin

Nanoporous silica SBA-15 was prepared to evaluate its application as an oral drug delivery system. A series of surface-functionalized nanopore materials as efficient clarithromycin delivery carriers was investigated. An efficient pH-responsive carrier system was constructed by hydrogen bond interaction between carboxyl and hydroxyl groups in the clarithromycin and the amine group in modified SBA-15. HPLC analyses of clarithromycin were run on a C₁₈ column using a mobile phase comprised of potassium dihydrogen phosphate, acetonitrile and methanol (30:40:30, v/v/v). Active molecules such as clarithromycin could be stored and released from the pore voids of SBA-15 by changing the pH. The amount of clarithromycin stored in the pores of nanoporous silica based on TREN [tris(2-aminoethyl) amine]-modified SBA-15 rods was up to 46 ± 4.8 wt% at pH 8. In addition, when the pH was below 4, clarithromycin was steadily released from the pores of SBA-15 (up to 97 wt% in simulated gastric medium).     

Modified nanoporous silicas for oral delivery of the water insoluble organotin compound: loading and release of methylphenyltin dichloride as an anti-tumor drug model

Different nanoporous silica materials, MCM-41, MCM-48 and SBA-15, were modified by pyridine and their applications for oral drug delivery system were evaluated. These pyridine functionalized nanoporous silicas were loaded with a water insoluble diorganotin(IV) dichloride complex as an antitumor drug model and its release from them were investigated by changing pH. An efficient pH-responsive carrier system was constructed by coordination of the pyridine group in modified nonoporous materials to tin complex. In vitro, releasing of loaded tin complex was studied in three different kinds of fluids, including a simulated gastric medium and a simulated body fluid. The loading and releasing of the diorganotin(IV) dichloride from various modified nanoporous silicas and also a non-porous silica (SiO₂) were investigated, and the results were compared. In addition, the effect of some factors such as pH, time of loading and releasing were investigated through this study.     

Spray dried calcium gelled arabinoxylan microspheres: A novel carrier for extended drug delivery

Arabinoxylan (AX) microspheres were formulated by ionotropic gelation for extended drug delivery. AX from Plantago ovata was tested for gelation with aluminium, barium, calcium, magnesium, and iron(III) chloride. Only calcium was found to lead to weak gelation with AX. The conventional needle extrusion produced fragile AX beads with calcium and hence the spray drying process was adopted for the preparation of metronidazole hydrochloride (MH) loaded AX microspheres. MH loading in AX microspheres was 30.8 mass %, 31.9 mass %, and 29.3 mass % in formulations gelled with 0.05 g, 0.1 g, and 0.15 g of calcium chloride per 100 mL of solution, respectively. Scanning electron microscopy revealed the crystallinity reduction of MH in microspheres. The surface of drug loaded calcium gelled AX microsphere was rougher than that of an ungelled one. Interactions of calcium with AX and the amorphous nature of the drug in the microspheres were evidenced by infrared spectroscopy and X-ray diffraction studies. Calcium-induced gelation can extend the drug release to over 90 min in 0.1 M HCl despite the hydrophilic nature of AX and the high solubility of metronidazole.     

Synthesis of PHB-based carrier for drug delivery systems with pH-controlled release

Synthetic route to prepare model PHB-amine conjugate containing hydrolysable imine bond is reported. Short-chain PHB crotonate is converted into PHB glyoxylate via clean and efficient ozonolysis followed by reductive decomposition of peroxidic products with dimethylsulfide. Aldehyde-functionalized PHB is obtained quantitatively without polymer backbone degradation while PHB-amine conjugate is synthesized with very high yield. Release properties of such-prepared conjugate is confirmed in hydrolysis experiment revealing pH-dependent kinetics of amine release. Simplicity of the protocol in conjunction with unique properties of PHB carrier are believed to be powerful tool for development of novel drug conjugates.     

A tumor mRNA-dependent gold nanoparticle-molecular beacon carrier for controlled drug release and intracellular imaging

We demonstrate a tumor mRNA-dependent drug carrier for controlled release of doxorubicin (Dox) and intracellular imaging based on gold nanoparticle-molecular beacon. Fluorescent Dox is released effectively and induces apoptosis in breast cancer cells but not in normal cells. Significantly, the release of Dox is correlated positively with the quantities of tumor mRNA, which is according to various stages of tumor progression, and so can decrease effectively side effects of Dox.     

Preparation of biocompatible system based on electrospun CMC/PVA nanofibers as controlled release carrier of diclofenac sodium

Nanofibers of naturally modified polymer such as carboxymethyl cellulose (CMC) blended with poly(vinyl alcohol) (PVA) at different ratios was obtained by electrospinning technique. The blended solutions of CMC and PVA loaded with and without diclofenac sodium (DS) were electrospun using environmentally benign electrospinning technique in the absence of organic solvents. Scanning electron microscopy (SEM), Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) were used to investigate the surface morphology functional groups, as well as the thermal stability of DS loaded CMC/PVA nanofibers mat. The mechanical properties of the as prepared electrospun nanofibers was also evaluated. The entrapment efficiency and the in vitro release of DS loaded CMC/PVA nanofibers were characterized using UV-Vis spectroscopy. The obtained results displayed that the blended nanofibers have shown a smooth morphology, no beads formation when the concentration of CMC was equal or below 5% and beads formation above 5%. FTIR data demonstrated that there were good interactions between CMC and PVA possibly via the formation of hydrogen bonds. The electrospun blended CMC/PVA nanofibers exhibit good mechanical properties. From the in vitro release data, it was found that with the presence of CMC, the release of DS from the nanofibers mats became sustained controlled. Due to the biocompatibility and low cost of the two blended polymers (CMC and PVA), the blended nanofibers system can be considered as one of the promising materials for the preparation of excellent drug carrier.     

Synthesis and characterization of thermosensitive copolymers for oral controlled drug delivery

Poly(N-isopropylacrylamide) (PNIPAAm) copolymers were synthesized in order to obtain co-polymers with a phase transition temperature slightly higher than the physiological temperature, as required by a new drug delivery concept described in a previous paper. Six hydrophilic comonomers bringing about a rise of the phase transition temperature were evaluated. The synthesized copolymers were characterized and the influence of the type and of the amount of the used comonomer on the phase transition temperature was discussed. Among the comonomers, Acrylamide (AAm), N-methyl-N-vinylacetamide (MVA), N-vinylacetamide (NVA), and N-vinyl-2-pyrrolidinone (VPL) were found to be capable to raise the phase transition temperature to a value slightly higher than 37 °C and to have adequate phase transition behavior. The selected four copolymers were subjected to an additional purification step that should make them fit to use as a controlling agent in drug delivery systems.     

The effects of irradiation on controlled drug delivery/controlled drug release systems

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.     

Hollow spherical mesoporous phosphosilicate nanoparticles as a delivery vehicle for an antibiotic drug

Mesoporous phosphosilicate nanoparticles of hollow sphere architecture have been prepared hydrothermally for the first time under acidic pH conditions and this material is found to be efficient in encapsulating an antibiotic drug and its controlled release at physiological pH for possible cargo delivery applications.     

A novel magnetic triple-responsive composite semi-IPN hydrogels for targeted and controlled drug delivery

In this work, Fe₃O₄/poly(3-acrylamidephenylboronic acid-co-(2-dimethylamino) ethyl methacrylate) (Fe₃O₄/P(AAPBA-co-DMAEMA)) hydrogels possessing magnetic and triple-responsive properties and semi-interpenetrated by β-cyclodextrin-epichlorohydrin (β-CD-EPI) were prepared via radical polymerization. The characteristics of the materials have been investigated by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM). The swelling measurements and the application of Fe₃O₄/P(AAPBA-co-DMAEMA)/(β-CD-EPI) hydrogels in controlled release of drug were also investigated. It was found that the magnetic hydrogels exhibit swelling behaviors affected by pH, temperature, glucose concentration and magnetic field, and have porous morphologies, superparamagnetism. Moreover, the hydrogels possess targeting and could control the release of quercetin by adjusting pH value, temperature, glucose concentration and magnetic field.     

Synthesis of biocompatible nanocomposite hydrogels as a local drug delivery system

Nanocomposite biocompatible hydrogels (NCHG) were synthesised as model systems for in situ cured potentially local drug delivery devices for curing periodontal infections. The composite consists of the following components: nanoparticles (NPs), matrix gel, and chlorhexidine (CHX) as antibacterial drug. The NPs were obtained by free radical initiated copolymerization of the monomers, 2-hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA), in aqueous solution. The same monomers were used to prepare crosslinked matrices by photopolymerization. NCHGs were obtained by mixing NPs, monomers, and drug in an aqueous solution then crosslinked by photopolymerization. Mechanical properties, swelling behavior, and the kinetics of drug release have been investigated. It was found that compression strength values increased with increasing ratio of the crosslinker PEGDMA. Incorporation of NPs into the matrix resulted similar compression strength as the matrix hydrogel. The hydrated NCHGs swelled more slowly but admitted more water. The drug was incorporated in NPs by swelling in CHX aqueous solution or added to the solution of monomer mixture followed by photopolymerization. Studies of release kinetics revealed that on average 60% of the loaded drug was released. The most rapid release was observed over a 24 h period for matrix gels with low crosslinking density. For NCHGs, the release period exceeded 48 h. An unexpected result was observed for NCHGs without drug in the NPs. In this case, increasing release was observed for the first 24 h. Thereafter, however, the apparent quantity of detectable drug decreased dramatically.     

Structural characterization of novel phospholipid lipid nanoparticles for controlled drug delivery

Drug-phospholipid lipid nanoparticles (DPLNs) are prepared by incorporating drug-phospholipid complexes (DPCs) with a liquid lipid. DPLNs demonstrated interesting properties including increased encapsulation capacity, improved stability and controlled drug release profile. A comprehensive characterization of DPLNs was presented and then a schematic model was suggested according to the characterization results. Transmission electron microscopy and scanning electron microscope measurements showed the morphology of DPLNs. X-ray diffraction exhibited a predominantly amorphous structure for DPCs and totally amorphous for DPLNs. Laser confocal scanning microscopy revealed the relative position of DPCs and liquid lipid, showing that DPLNs formed a homogeneous system. Fluorescence spectra and electron spin resonance further confirmed the chemical environment inside the DPLNs in a non-invasive way.     

Design and preparation of pulsatile release tablet as a new oral drug delivery system.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.     

Preparation and characterization of a novel magnetized nanosphere as a carrier system for drug delivery using Plantago ovata Forssk. hydrogel combined with mefenamic acid as the drug model

The aim of the present study was to magnetize Plantago ovata Forssk. hydrogel and produce a nanosphere system to carrier mefenamic acid as the drug model. For this propose, P. ovata seeds hydrogel (POSH) was extracted and magnetized by Fe₃O₄ being functionalized using tetraethyl orthosilicate and trimethoxyvinysilane. Thereafter, mefenamic acid (MFA) was loaded on the carrier system. The final product, as the magnetic drug loaded nanosphere (Fe/POSH/MFA), was fully characterized through different techniques involving X-ray diffraction (XRD), scanning electron microscopy (SEM), vibrating-sample magnetometer (VSM), thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and FT-IR spectroscopy. The results confirmed the successful production of the drug loaded nanosphere system with particles magnetization of 25 emu/g over a range size of 40–50 nm. However, the size distribution less than 100 nm was measured through DLS analysis. The hydrogel showed a pH sensitivity swelling behavior representing the best efficacy at pH 7.4. The efficiency of the drug encapsulation was found to be 64.35%. The drug releasing was studied using a dialysis bag at pH = 7.4. The highest in vitro drug releasing was found to be 57.3 ± 0.6% after 72 h, as well. The findings of the current report account for the potential use of P. ovata hydrogel as an effective delivery system for encapsulation of water insoluble basic drugs, e.g., MFA in a magnetized carrier system.     

Self-assembled micelles of novel graft amphiphilic copolymers for drug controlled release

In this study, with the aim of designing an ideal anticancer drug carrier, we synthesized novel amphiphilic graft copolymers, P(Glu-alt-PEG)-graft-PCLA, based on poly(ethylene glycol) (PEG) segments and glutamic acid (Glu) units as the hydrophilic main chain, and poly(?-caprolactone-co-lactide) (PCLA) as hydrophobic branches. The chemical structure of the copolymers was characterized by (1)H MNR and FT-IR. The self-assembly of the copolymers to form micelles was studied by TEM, DLS and fluorescence spectroscopy. In vitro doxorubicin controlled release studies demonstrated that these graft copolymer micelles had high drug loading capacity and good controlled released properties, demonstrating their potential as a novel anticancer drug carrier. The drug loaded graft copolymer micelles exhibited efficient inhibition of HeLa cells in in vitro studies.     

Nanostructured lipid carriers as novel carrier for parenteral delivery of docetaxel

The aim of this study was to design docetaxel-loaded nanostructured lipid carriers (DTX-NLC) to reduce toxicity and improve therapeutic efficacy. Docetaxel-loaded nanostructured lipid carriers (DTX-NLC) were prepared by the modified film ultrasonication–dispersion method. The DTX-NLC were characterized by particle size distribution, zeta potential and entrapment efficiency. In vitro cytotoxicity of DTX-NLC was evaluated by MTT assay against three human cancer cell lines and one murine malignant melanoma (B16). AnnexinV-FITC kit was used to measure the percentage of apoptosis induced by Duopafei^® or DTX-NLC. In vivo anti-tumor efficacy was evaluated in Kunming mice bearing murine malignant melanoma (B16). Compared with Duopafei^®, DTX-NLC revealed more cytotoxicity against A549 cells by inducing more apoptosis and more G2/M arrest. The inhibition rates of Duopafei^®, DTX-NLC (10 mg/kg) and DTX-NLC (20 mg/kg) were 42.74%, 62.69% and 90.36%, respectively, indicating that DTX-NLC could more effectively inhibit tumor growth. The results of the body weight variations of mice also showed that compared with Duopafei^®, DTX-NLC had lower toxicity during the therapeutic procedure. These results suggest that DTX-NLC may be a promising drug delivery system for cancer therapy. To our knowledge, this was the first report about DTX-NLC for murine malignant melanoma treatment.     

A general strategy for one-step fabrication of biocompatible microcapsules with controlled active release

Fabrication of biocompatible core-shell microcapsules in a controllable and scalable manner remains an important but challenging task.Here,we develop a one-step microfluidic approach for the highthroughput production of biocompatible microcapsules,which utilizes single emulsions as templates and controls the precipitation of biocompatible polymer at the water/oil interface.The facile method enables the loading of various oils in the core and the enhancement of polymer shell strength by polyelectrolyte coating.The resulting microcapsules have the advantages of controllability,scalability,biocompatibility,high encapsulation efficiency and high loading capacity.The core-shell microcapsules are ideal delivery vehicles for programmable active release and various controlled release mechanisms are demonstrated,including burst release by vigorous shaking,pH-triggered release for targeted intestinal release and sustained release of perfume over a long period of time.The utility of our technique paves the way for practical applications of core-shell microcapsules.     

Physicochemical and anti-bacterial performance characterization of clarithromycin nanoparticles as colloidal drug delivery system

The objective of the present study was to prepare clarithromycin (CLR) loaded biodegradable nanoparticles (NPS), with a view to investigate its physicochemical properties and anti-bacterial activity. PLGA was used as a biodegradable polymer and the particles were prepared by nano-precipitation method in 3 different drugs to polymer ratios. Evaluation of the physicochemical properties of the prepared nanoparticles was performed using encapsulation efficiency, nanoparticle production yield, dissolution studies, particle size analysis, zeta potential determination, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffractometry. The antimicrobial activity against Staphylococcus aureus was determined using serial dilution technique to achieve the minimum inhibitory concentration (MIC) of NPs. The particles were between 189 and 280 nm in size with narrow size distribution, spherical shape and 57.4-80.2% entrapment efficiency. Zeta potential of the NPs was fairly negative. The DSC thermograms and X-ray diffraction patterns revealed reduced drug crystallinity in the NPs. FT-IR spectroscopy demonstrated possible noncovalent interactions between the drug and polymer. In vitro release study showed an initial burst followed by a plateau during a period of 24 h. The NPs were more effective than intact CLR against S. aureus so that the former showed equal antibacterial effect at 1/8 concentration of the intact drug. In conclusion, the prepared CLR nanoparticles are more potent against S. aureus with improved MICs and appropriate physicochemical properties that may be useful for other susceptible microorganisms and could be an appropriate candidate for intravenous, ocular and oral and topical preparations.     

Periodic mesoporous organosilicas with co-existence of diurea and sulfanilamide as an effective drug delivery carrier

In this article we report the synthesis of new periodic mesoporous organosilicas (PMOs) with the co-existence of diurea and sulfanilamide-bridged organosilica that are potentially useful for controlled drug release system. The materials possess hexagonal pores with a high degree of uniformity and show long-range order as confirmed by the measurements of small-angle X-ray scattering (SAXS), N₂ adsorption isotherms, and transmission electron microscopy(TEM). FT-IR and solid state ²⁹Si MAS and ¹³C CP MAS NMR spectroscopic analyses proved that the bridging groups in the framework are not cleaved and covalently attached in the walls of the PMOs. It was found that the organic functionality could be introduced in a maximum of 10 mol% with respect to the total silicon content and be thermally stable up to 230 °C. The synthesized materials were shown to be particularly suitable for adsorption and desorption of hydrophilic/hydrophobic drugs from a phosphate buffer solution at pH 7.4.