Oral Drug Delivery Carrier Research Articles

Design and development of vitamin C-encapsulated proliposome with improved in-vitro and ex-vivo antioxidant efficacy

Vitamin C, as an antioxidant additive in pharmaceutical and food products, is susceptible to environmental conditions, and new design strategies are needed to enhance its stability. The aim of this study is to prepare vitamin C proliposome using film deposition on the carrier by applying different factors, and optimise the characteristics of the obtained powder using the design expert® software. The optimised formulation demonstrated acceptable flowability with 20% vitamin C loading. This formulation released about 90% vitamin C within 2 h and showed higher (1.7-fold) in-vitro antioxidant activity. Ex-vivo antioxidant activity was 1.9 and 1.6 times higher in brain and liver cells, respectively. A 27% reduction in malondialdehyde (MDA) level of liver cell was obtained comparing free vitamin C. Therefore, this study results suggest that the vitamin C-encapsulated proliposome powder might be an appropriate carrier for oral drug delivery of vitamin C with better antioxidant efficacy.

Polymer-coated mesoporous silica nanoparticles for controlled release of the prodrug sulfasalazine

MCM-41 and SBA-15 silicas with particle sizes around 100 nm and 400 nm, respectively, were synthesized. The initial silica materials were modified with amino groups by post-synthesis method. Incipient wetness impregnation was applied for loading of prodrug sulfasalazine. The non-loaded and drug loaded mesoporous silica samples were characterized by XRD, TEM, SEM, N2 physisorption, thermal analysis, and ATR FT-IR spectroscopy. The nanoparticles were post-coated twice by two different layers of polymers (Eudragit RL and Eudragit S), one of them being a pH sensitive one (Eudragit S). The functionalized and polymer coated mesoporous systems are suitable oral drug delivery carriers providing an opportunity to modify the release properties of the loaded drug.

Preparation of glutinous rice starch/polyvinyl alcohol copolymer electrospun fibers for using as a drug delivery carrier

Glutinous rice starch (GRS) is commonly produced in the Northeast of Thailand. GRS is a biopolymer which is widely used in the food industry but not yet commonly applied within the pharmaceutical industry as an alternative resource. GRS exhibits a branch chain structure which is not feasible to fabricate as nanofiber. Therefore, combining GRS with polyvinyl alcohol (PVA) in hybrid form can be a potential platform to produce GRS-PVA nanofibers. Smooth nanofibers of 2% (w/v) GRS combined with 8% (w/v) PVA were fabricated by an electrospinning process. A scanning electron microscope (SEM) revealed an average diameter size of the GRS-PVA nanofibers equal to 191 ± 25 nm. A highly water soluble model drug, Chlorpheniramine maleate (CPM), was incorporated into the GRS-PVA electrospun fibers to prove a drug delivery carrier concept and drug release control of the nanofibers. The GRS-PVA nanofibers exhibited a biphasic CPM release in which approximately 60% of the drug immediately released in 10 min, and it reached 90% drug release in 120 min. This study demonstrated a potential application of GRS combining with PVA as an oral drug delivery carrier. Therefore, it can be a promised step that expands the application GRS in pharmaceuticals and related areas.

PH-responsive lignin-based complex micelles: Preparation, characterization and application in oral drug delivery

We developed a simple and practical method to prepare pH-responsive lignin-based complex micelles in green solvents using purified alkali lignin. Alkali lignin (AL) was quaternized and further self-assembled into lignin-based complex micelles with sodium dodecyl benzenesulfonate (SDBS) in an ethanol/water mixture. The FT-IR and 1H NMR spectra indicated the successful grafting of quaternary ammonium groups on AL. TEM images showed that the complex micelles were uniform spherical nanoparticles. The complex micelles also exhibited rich phase behaviors responding to pH changes. Ibuprofen (IBU) was used as a drug model and more than 74.44% could be encapsulated via hydrophobic interactions. The in vitro release behavior of IBU was pH-dependent and exhibited controlled release properties. Therefore, more than 75% of IBU could be preserved in simulated gastric fluid (SGF, pH 1.2), and over 90% could be released smoothly in simulated intestinal fluid (SIF, pH 7.4). This work suggests a novel strategy for fabricating an oral drug delivery carrier and is of significance for the value-added utilization of lignin.

PH responsive N-succinyl chitosan/Poly (acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil.

There has been significant progress in the last few decades in addressing the biomedical applications of polymer hydrogels. Particularly, stimuli responsive hydrogels have been inspected as elegant drug delivery systems capable to deliver at the appropriate site of action within the specific time. The present work describes the synthesis of pH responsive semi-interpenetrating network (semi-IPN) hydrogels of N-succinyl-chitosan (NSC) via Schiff base mechanism using glutaraldehyde as a crosslinking agent and Poly (acrylamide-co-acrylic acid)(Poly (AAm-co-AA)) was embedded within the N-succinyl chitosan network. The physico-chemical interactions were characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscope (FESEM). The synthesized hydrogels constitute porous structure. The swelling ability was analyzed in physiological mediums of pH 7.4 and pH 1.2 at 37°C. Swelling properties of formulations with various amounts of NSC/ Poly (AAm-co-AA) and crosslinking agent at pH 7.4 and pH 1.2 were investigated. Hydrogels showed higher swelling ratios at pH 7.4 while lower at pH 1.2. Swelling kinetics and diffusion parameters were also determined. Drug loading, encapsulation efficiency, and in vitro release of 5-fluorouracil (5-FU) from the synthesized hydrogels were observed. In vitro release profile revealed the significant influence of pH, amount of NSC, Poly (AAm-co-AA), and crosslinking agent on the release of 5-FU. Accordingly, rapid and large release of drug was observed at pH 7.4 than at pH 1.2. The maximum encapsulation efficiency and release of 5-FU from SP2 were found to be 72.45% and 85.99%, respectively. Kinetics of drug release suggested controlled release mechanism of 5-FU is according to trend of non-Fickian. From the above results, it can be concluded that the synthesized hydrogels have capability to adapt their potential exploitation as targeted oral drug delivery carriers.

Nanostructured mucoadhesive microparticles to enhance oral drug bioavailability

Abstract To enhance oral drug bioavailability, we propose mucoadhesive, nanostructured microparticles (PLGA/PEG NM) as a drug-delivery vehicle. The PLGA/PEG NM herein retain nanofibrous structures within microparticles, and possess a seven-fold increase in specific surface area than conventional spherical microparticles, allowing for synergistic improvement of a mucoadhesive property. In vivo evaluations demonstrated that PLGA/PEG NM showed prolonged retention in the gastrointestinal tract, as compared to control microparticles. When PLGA/PEG NM was loaded with losartan, an oral anti-hypertension drug, drug’s bioavailability increased by two-fold in comparison to a bolus losartan solution. Therefore, the PLGA/PEG NM are a promising carrier for oral drug delivery.

Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery

The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS–PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery.

Cytotoxicity and Acute Gastrointestinal Toxicity of Bacterial Cellulose-Poly (acrylamide-sodium acrylate) Hydrogel: A Carrier for Oral Drug Delivery

Background: Preliminary safety evaluation of polymer intended to use as drug delivery carrier is essential. Methods: In this study polyacrylamide grafted bacterial cellulose (BC/AM) hydrogel was prepared by microwave irradiation initiated free radical polymerization. The synthesized hydrogel was subjected to in vitro cytotoxicity and acute gastrointestinal toxicity studies to evaluate its biological safety as potential oral drug delivery carrier. Results: The results indicate that hydrogel was non cytotoxic and did not show any histopathological changes in GI tract after a high dose of oral administration. Conclusion: The results revealed that hydrogel composed of bacterial cellulose and polyacrylamide is safe as oral drug delivery carrier.

Application of mesoscale simulation to explore the aggregate morphology of pH-sensitive nanoparticles used as the oral drug delivery carriers under different conditions

The pH-sensitive nanoparticles are selected as the potentially promising oral protein and peptide drug carriers due to their excellent performance. With the poly (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate (PLGA/HP55) nanoparticle as a model nanoparticle, the structure-property relationship of nanoparticles with different conditions is investigated by dissipative particle dynamics (DPD) simulations in our work. In the oral drug delivery system, the poly (lactic-co-glycolic acid) (PLGA) is hydrophobic polymer, hydroxypropyl methylcellulose phthalate (HP55) is pH-sensitive enteric polymer which used to protect the nanoparticles through the stomach and polyvinyl alcohol (PVA) is hydrophilic polymer as the stabilizer. It can be seen from DPD simulations that all polymer molecules form spherical core-shell nanoparticles with stabilizer PVA molecules adsorbed on the outer surface of the PLGA/HP55 matrix at certain compositions. The DPD simulation study can provide microscopic insight into the formation and morphological changes of pH-sensitive nanoparticles which is useful for the design of new materials for high-efficacy oral drug delivery.

Poly(ε-benzyloxycarbonyl-L-lysine)-grafted branched polyethylenimine as efficient nanocarriers for indomethacin with enhanced oral bioavailability and anti-inflammatory efficacy.

The use of polyethylenimine (PEI) as an oral drug delivery carrier is limited because it is not biodegradable and the use of higher molecular weight PEI leads to improved efficiency but also increased cytotoxicity. The design of functionalized PEIs with low cytotoxicity and high efficiency is crucial for developing a successful oral drug delivery system. In our study, poly(ε-benzyloxycarbonyl-L-lysine) (PZLL)-grafted branched PEI (PEI-g-PZLL) was reported as an oral nanocarrier for indomethacin (IND). The low cytotoxicity and biodegradability, well-defined self-assembled nano-sized polymeric micelles, high loading capacity and loading efficiency, amorphous state of the encapsulated IND, as well as the enhanced oral bioavailability of IND, makes the copolymer PEI-g-PZLL a promising nanocarrier for the oral administration of IND and possibly other poorly water-soluble drugs.

Evaluation of mesoporous carbon aerogels as carriers of the non-steroidal anti-inflammatory drug ibuprofen

Towards the development of novel drug carriers for oral delivery of poorly soluble drugs mesoporous aerogel carbons (CAs), namely CA10 and CA20 with different pore sizes (10 and 20nm, respectively), were evaluated. The non-steroidal anti-inflammatory lipophilic compound ibuprofen was incorporated via passive loading. The drug loaded carbon aerogels were systemically investigated by means of High-Resolution Transmission Electron Microscopy (HR-TEM), Nitrogen physisorption studies, X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), X-ray photon electron spectroscopy (XPS) and ζ-potential studies. In vitro release studies were performed in simulated intestinal fluids reflecting both fasted (FaSSIF) and fed (FeSSIF) state conditions. Cytotoxicity studies were conducted with human intestinal cells (Caco-2). Drug was in an amorphous state in the pores of the carbon carrier as shown from the physicochemical characterization studies. The results showed marked differences in the release profiles for ibuprofen from the two aerogels in the media tested whereas in vitro toxicity profiles appear to be compatible with potential therapeutic applications at low concentrations.

Preparation of pH-sensitive micelles from miktoarm star block copolymers by ATRP and their application as drug nanocarriers

In this study, novel pH-sensitive micelles were prepared from miktoarm star block copolymer, mPEG-b-P(MMA-co-MAA)2, by the atom transfer radical polymerization (ATRP) technique and dialysis method. Molecular structures and characteristics of the micelles were confirmed by 1H nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) spectroscopy, gel permeation chromatography (GPC), dynamic light scattering (DLS), and transmission electron microscopy (TEM). The self-assembled micelles have a very low critical micelle concentration, indicating a high colloidal stability in aqueous solution. Methotrexate (MTX) was selected as the model drug of poor solubility. A relatively high drug loading capacity was found, and the in vitro release studies revealed that about 26% of the drug was released in simulated gastric fluid (SGF, pH1.2) over 48h compared to the maximum drug release of about 98% in simulated intestinal fluid (SIF, pH7.4). Thus, the pH-sensitive micelles might serve as promising carriers for oral drug delivery of hydrophobic drugs with controlled release behavior.

Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs

pH-sensitive polymer poly (polylactide-co-methacrylic acid)–b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and 1H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)–b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.

Xylan-based temperature/pH sensitive hydrogels for drug controlled release

Xylan-based temperature/pH sensitive hydrogels were prepared by the crosslinking copolymerization of xylan with N-isopropylacrylamide (NIPAm) and acrylic acid (AA) using N,Ń-methylenebis-acrylamide (MBA) as a cross-linker and 2,2-dimethoxy-2-phenylacetophenone as a photoinitiator via ultraviolet irradiation. The influence of the NIPAm, AA and MBA amount on properties of xylan-based hydrogels was discussed. The morphology and interactions of hydrogels were characterized by SEM and FTIR. The lower critical solution temperature (LCST) of hydrogels was investigated by DSC. The results indicated that the LCST of hydrogels emerged at around 34°C and increased with increasing the AA content. The drug encapsulation efficiency of as-prepared hydrogels reached to 97.60% and the cumulative release rate of acetylsalicylic acid was 90.12% and 26.35% in the intestinal and gastric fluid, respectively. Xylan-based hydrogels were proved to be biocompatible with NIH3T3 cell by MTT assay and showed the promising application as drug carriers for the intestinal-targeted oral drug delivery.

Spray-dried Eudragit® L100 microparticles containing ferulic acid: Formulation, in vitro cytoprotection and in vivo anti-platelet effect

This paper aimed to obtain new spray-dried microparticles containing ferulic acid (FA) prepared by using a methacrylic polymer (Eudragit® L100). Microparticles were intended for oral use in order to provide a controlled release, and improved in vitro and in vivo biological effects. FA-loaded Eudragit® L100 microparticles were obtained by spray-drying. Physicochemical properties, in vitro cell-based effects, and in vivo platelet aggregation were investigated. FA-loaded Eudragit® L100 microparticles were successfully prepared by spray-drying. Formulations showed suitable encapsulation efficiency, i.e. close to 100%. Microparticles were of spherical and almost-spherical shape with a smooth surface and a mean diameter between 2 and 3μm. Fourier-transformed infrared spectra demonstrated no chemical bond between FA and polymer. X-ray diffraction and differential scanning calorimetry analyses indicated that microencapsulation led to drug amorphization. FA-loaded microparticles showed a slower dissolution rate than pure drug. The chosen formulation demonstrated higher in vitro cytoprotection, anti-inflammatory and immunomodulatory potential and also improved in vivo anti-platelet effect. These results support an experimental basis for the use of FA spray-dried microparticles as a feasible oral drug delivery carrier for the controlled release of FA and improved cytoprotective and anti-platelet effects.

Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape

Mesoporous silica nanoparticles (MSNs) have been proven to be effective drug carriers for oral delivery. However, little attention has been paid to their in vivo biodistribution and toxicity after oral administration. The effect of particle shape on their in vivo behavior is also unknown. In this study, we systematically studied the acute toxicity and biodistribution of three types of MSNs with aspect ratios (ARs) of 1, 1.75 and 5 after oral administration. The effect of particle shape as a key physicochemical parameter of MSNs was discussed. With the increase of AR, MSNs showed decreased in vivo biodegradation, systematic absorption and excretion, especially decreased liver distribution and urinal excretion. During the period of urinal excretion, MSNs induced a shape-dependent renal damage including hemorrhage, vascular congestion and renal tubular necrosis. These findings will enrich the knowledge to rationally engineer bionanomaterials, and bring new insights into nanotoxicity. From the Clinical EditorAdvances in nanotechnology have resulted in improvement in drug delivery, of which mesoporous silica nanoparticles have been used as carriers for oral drugs. Nonetheless, studies on their absorption, distribution, metabolism, excretion (ADME) and toxicity still need to be performed. In this article, authors evaluated the effects of particle size and shape on in vivo behavior. The findings would shine light on future design of future drug delivery systems.

Synthesis and characterization of pH-responsive N-naphthyl-N,O-succinyl chitosan micelles for oral meloxicam delivery.

The aim of this study was to synthesize pH responsive chitosan and to evaluate the influence of drug-loaded micelle methods on loading efficiency, particle size and micelle stability. N-naphthyl-N,O-succinyl chitosan (NSCS) was successfully synthesized and meloxicam (MX) was loaded into the inner core of the NSCS micelles by physical entrapment methods (dialysis, O/W emulsion, dropping and evaporation) with a regular spherical shape (particle size 84-382nm). MX-loaded micelles by evaporation method showed the highest entrapment efficiency. The stability of the drug-loaded micelles depended on not only the methods but also the initial of drug. NSCS micelles are less toxic on Caco-2 cells. In acidic medium at 0-2h, percentage cumulative release of MX from MX-loaded micelles was similar to free drug. When the pH was adjusted to pH 6.8, the MX release was increased significantly. Therefore, this NSCS micelle would be desirable to develop MX carrier for oral drug delivery.

Development of alginate microspheres as nystatin carriers for oral mucosa drug delivery

To develop more effective antifungal mucoadhesive systems for the treatment of oral candidiasis, three types of microspheres, alginate (AM1), chitosan coated (CCM) and hydrogel (AM2) containing nystatin (Nys) were successfully elaborated by emulsification/internal gelation method. Physicochemical properties of microspheres resulted in 85–135μm mean sizes, spherical shaped with narrow distribution. Optimal encapsulation efficiency and negative zeta potentials were observed. AM2 showed a consistent decrease in viscosity with increasing shear rate (Herschel–Bulkley). Optimal mucoadhesive properties and swelling behaviour where evidenced. Nys release from AM1 and CCM followed a concentration gradient pattern, contrary AM2 followed a complex release mechanism. All systems exhibited a marked fungicidal activity against Candida albicans strains. In vivo studies demonstrated that Nys was not found in systemic circulation assuring the safety of the treatment. Nys amounts retained in the mucosa were more than enough to ensure an effective fungicidal action without tissue damage. Based on the obtained results, AM2 could be proposed as the vehicle with the best properties for the buccal vehiculization of Nys.

Preparation and evaluation of mucoadhesive beads/discs of alginate and algino-pectinate of piroxicam for colon-specific drug delivery via oral route.

Targeted drug delivery to colon would ensure direct treatment at the disease site, decrease in dose administration and reduction side effects improved drug utilization. The purpose of this research was to decrease gastric side effects of piroxicam by formulating microspheres of alginate and algino-pectinate beads of the drug. Ionotropic gelation was used to entrap piroxicam into alginate and algino-pectinate mucoadhesive microspheres as a potential drug carrier for oral delivery of piroxicam. Microparticles with different drug to polymers ratio were prepared and characterized by encapsulation efficiency, particle size, DSC (differential scanning calorimetric), mucoadhesive property, gastroretentive time and drug release studies. The best drug to polymer ratio of microparticles was 1:2.5 (F1) with Na-Alg and 1:7.5 (F4) with Alg-Na with pectin, respectively. The microparticles F1 and F4 showed 28.80%, 50.01% loading efficiency, 82.57%, 82.31% production yield and 945.4, 899.91 µm mean particle size. DSC showed stable character of piroxicam in drug-loaded microparticles and revealed amorphous form. It was found that microparticles (Na-Alg) prepared had faster release and microparticles (Alg-Na and pectin mixture) prepared had slower release than untreated piroxicam (P < 0.05). Microparticles (mixture of Na-Alg and pectin) exhibited very good percentage of mucoadhesion and flowability properties. Mucoadhesion strength and retention time study showed better retention of piroxicam microparticles in intestine. Besides, there was a significant higher retention of mucoadhesive microparticles in upper GI tract. Algino-pectinate mucoadhesive formulations exhibited promising properties of a sustained release form for piroxicam and provided distinct tissue protection in stomach.

Bacterial cellulose/acrylamide pH-sensitive smart hydrogel: development, characterization, and toxicity studies in ICR mice model.

The objective of this study is to synthesize and evaluate acute toxicity of the bacterial cellulose (BC)/acrylamide (Am) hydrogels as noncytotoxic and biocompatible oral drug delivery vehicles. A novel series of solubilized BC/Am hydrogels were synthesized using a microwave irradiation method. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), swelling ratio, porosity, drug release, and in vitro and in vivo biocompatibility experiments. FTIR spectra revealed that the BC crystallinity and gel fraction decreased as the NaOH concentration increased from 2% to 10% w/v, whereas the optical transparency, pH sensitivity, and porosity were enhanced with increasing alkali concentration. Theophylline was used as a model drug for drug loading and release studies. The percentage of drug released was higher at pH 7.4 compared to pH 1.5. In vitro cytotoxicity and hemolytic tests indicated that the BC/Am hydrogel is noncytotoxic and hemocompatible. Results of acute oral toxicity tests on ICR mice suggested that the hydrogels are nontoxic up to 2000 mg/kg when administered orally, as no toxic response or histopathological changes were observed in comparison to control mice. The results of this study demonstrated that the pH-sensitive smart hydrogel makes it a possible safe carrier for oral drug delivery.