In vitro and in vivo evaluation of ketotifen fumarate-loaded silicone hydrogel contact lenses for ocular drug delivery

The purpose of this work was to evaluate the usefulness of silicone hydrogel contact lenses loaded with ketotifen fumarate for ocular drug delivery. First, silicone contact lenses were prepared by photopolymerization of bitelechelic methacrylated polydimethylsiloxanes macromonomer, 3-methacryloxypropyltris(trimethylsiloxy)silane, and N,N-dimethylacrylamide using ethylene glycol dimethacrylate as a cross-linker and Darocur 1173 as an initiator followed by surface plasma treatment. Then, the silicone hydrogel matrices of the contact lenses were characterized by equilibrium swelling ratio (ESR), tensile tests, ion permeability, and surface contact angle. Finally, the contact lenses were loaded with ketotifen fumarate by pre-soaking in drug solution to evaluate drug loading capacity, in vitro and in vivo release behavior of the silicone contact lenses. The results showed that ESR and ion permeability increase, and the surface contact angle and tensile strength decreased with the increase of DMA component in the silicone hydrogel. The drug loading and in vitro releases were dependent on the hydrogel composition of hydrophilic/hydrophobic phase of the contact lenses. In rabbit eyes, the pre-soaked contact lenses sustained ketotifen fumarate release for more than 24?h, which leads to a more stable drug concentration and a longer mean retention time in tear fluid than that of eye drops of 0.05%.     

In vitro and in vivo evaluation of ketotifen fumarate-loaded silicone hydrogel contact lenses for ocular drug delivery

The purpose of this work was to evaluate the usefulness of silicone hydrogel contact lenses loaded with ketotifen fumarate for ocular drug delivery. First, silicone contact lenses were prepared by photopolymerization of bitelechelic methacrylated polydimethylsiloxanes macromonomer, 3-methacryloxypropyltris(trimethylsiloxy)silane, and N,N-dimethylacrylamide using ethylene glycol dimethacrylate as a cross-linker and Darocur 1173 as an initiator followed by surface plasma treatment. Then, the silicone hydrogel matrices of the contact lenses were characterized by equilibrium swelling ratio (ESR), tensile tests, ion permeability, and surface contact angle. Finally, the contact lenses were loaded with ketotifen fumarate by pre-soaking in drug solution to evaluate drug loading capacity, in vitro and in vivo release behavior of the silicone contact lenses. The results showed that ESR and ion permeability increase, and the surface contact angle and tensile strength decreased with the increase of DMA component in the silicone hydrogel. The drug loading and in vitro releases were dependent on the hydrogel composition of hydrophilic/hydrophobic phase of the contact lenses. In rabbit eyes, the pre-soaked contact lenses sustained ketotifen fumarate release for more than 24?h, which leads to a more stable drug concentration and a longer mean retention time in tear fluid than that of eye drops of 0.05%.     

In vitro evaluation of dendrimer prodrugs for oral drug delivery

Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-lact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2)=180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2)=4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen.     

pH-sensitive polymers for cytoplasmic drug delivery

The pH-sensitive drug delivery systems could be triggered by a mild acidic environment, such as that occurring in solid tumors, inflammatory tissues and intracellular endosomal compartments. Moreover, the cytoplasmic delivery of internalized macromolecules (such as oligonucleic acid, siRNA, DNA, proteins and polymer–antibody complex) will be possible. Synthetic polymers – such as polyanions (acrylic acid derivatives) and polycations (poly ethylenimine and chitosan complexes) – are among the most popular compounds studied for intracellular trafficking of drugs. As research is progressing in the area of cytoplasmic delivery, many novel and innovative applications making use of the unique properties of pH-sensitive polymers are expected in the future.     

In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 ± 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 ± 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T_max of 8 h comparing to that of theophylline solution with T_max of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2626–2635, 2009     

In vitro evaluation of drug release from self micro-emulsifying drug delivery systems using a biodegradable homolipid from Capra hircus

Self micro-emulsifying drug delivery systems (SMEDDS) are specialized form of delivery systems in which drugs are encapsulated in a lipid base with or without a pharmaceutically acceptable surfactant. In this work, SMEDDS were formulated with a biodegradable homolipid from Capra hircus and Tween 65, and contained lipophilic drug-piroxicam, hydrophilic drug-chlorpheniramine maleate and hydrolipophilic drug-metronidazole. The SMEDDS formulated were evaluated for their drug release and drug content. The drug release studies were conducted in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and distilled water, representing different pH values. Particle size of the SMEDDS was determined by light microscopy. The results of this study indicated that drug release was affected by the particle size of the SMEDDS. It was found that piroxicam release from the SMEDDS formulated with homolipids from Capra hircus was highest in SIF compared to the other drugs. This method of drug delivery could prove to be a versatile and reliable alternative to conventional drug delivery approaches.     

In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery

Previously uncharacterized poly(N-isopropylacrylamide-acrylamide-allylamine)-coated magnetic nanoparticles (MNPs) were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Properties of these nanoparticles such as size, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. Spherical core-shell nanoparticles with a diameter of 100 nm showed significantly lower systemic toxicity than did bare MNPs, as well as doxorubicin encapsulation efficiency of 72%, and significantly higher doxorubicin release at 41°C compared with 37°C, demonstrating their temperature sensitivity. Released drugs were also active in destroying prostate cancer cells (JHU31). Furthermore, the nanoparticle uptake by JHU31 cells was dependent on dose and incubation time, reaching saturation at 500 μg/mL and 4 hours, respectively. In addition, magnetic resonance imaging capabilities of the particles were observed using agarose platforms containing cells incubated with nanoparticles. Future work includes investigation of targeting capability and effectiveness of these nanoparticles in vivo using animal models.From the Clinical EditorIn this paper, previously uncharacterized magnetic nanoparticles were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Various properties of these nanoparticles were evaluated in vitro for targeted drug delivery.     

pH-sensitive Eudragit nanoparticles for mucosal drug delivery

Drug delivery via vaginal epithelium has suffered from lack of stability due to acidic and enzymatic environments. The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. ES nanoparticles containing a model compound (sodium fluorescein (FNa) or nile red (NR)) were prepared by the modified quasi-emulsion solvent diffusion method. Loading efficiencies were found to be 26% and 71% for a hydrophilic and a hydrophobic compound, respectively. Both hydrophilic and hydrophobic model drugs remained stable in nanoparticles at acidic pH, whereas they are quickly released from nanoparticles upon exposure at physiological pH. The confocal study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release, with no cytotoxic activities. The pH-sensitive nanoparticles would be a promising carrier for the vaginal-specific delivery of various therapeutic drugs including microbicides and peptides/proteins.     

New pH-sensitive glycopolymers for colon-specific drug delivery

pH-sensitive hydrogels are suitable candidates for oral delivery of therapeutic peptides, proteins, and drugs, due to their ability to respond to environmental pH changes. New pH-sensitive glycopolymers have been developed by free-radical polymerization of methacrylic acid and 6-acryloyl-glucose-1, 2, 3, 4-tetraacetate, using 1, 6-hexandiol diacrylate and 1, 6-hexandiol propoxylate diacrylate as cross-linking agents. The hydrogels were characterized by differential scanning calorimetry and FTIR. Equilibrium swelling studies were carried out in enzyme-free simulated gastric and intestinal fluids (SGF and SIF, respectively). A model drug, olsalazine [3, 3'-azobis (6-hydroxy benzoic acid)] as an azo derivative of 5-aminosalicylic acid, was entrapped in these gels and the in vitro release profiles were established separately in both enzyme-free SGF and SIF. The drug-release profiles indicated that the amount of drug released depended on the degree of swelling. The hydrogels containing polar propoxylate groups were hydrolyzed rather easily.     

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery

Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of molecules warrants additional study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was observed at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chemistry work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-week intervals. No mortality was observed. Forty-eight hours following the last administration, blood chemistry revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathological data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.     

Novel pH-sensitive hydrogels for colon-specific drug delivery

The purpose of this study is to develop novel intestinal specific drug delivery systems with pH-sensitive swelling and drug release properties. Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Cubane-1,4-dicarboxylic acid (CDA), linked to two 2-hydroxyethyl methacrylate (HEMA) groups, was the cross-linking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate), and APAS in the presence of cubane cross-linking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1) and intestinal fluids (SIF, pH 7.4). The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug–polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1 and pH 7.4) at 37°C. Detection of the hydrolysis product by UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of HPAS as an azo derivative of 5-amino salicylic acid (5-ASA).     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

Montmorillonite Poly-L-Lactide Microcomposites of Procainamide for controlled drug delivery: In vitro and In vivo evaluation

The research work reported in this paper is extension of our previous findings related to intercalation of procainamide hydrochloride, an antiarrythmia drug in interlayer gallery of Na⁺-clay (montmorillonite). The microcomposite particles prepared from procainamide-montmorillonite hybrid and poly L-lactide were characterised by scanning electron microscope and atomic force microscopy analysis. In vitro drug release study in simulated intestinal fluid showed controlled release pattern up to ~72 h and significant reduction in the drug release in gastric environment. In vivo pharmacokinetics and biodistribution in rats showed that the plasma/tissue drug levels were within therapeutic window as compared with free drug. The data from toxicity biomarker estimations and clinical biochemistry/haematological parameters showed significant reduction in drug toxicity when formulated in montmorillonite/poly L-lactide as compared with free drug, which is of considerable value in achieving improved therapy with reduced side effects.     

New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug

This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250 g mol⁻¹). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10-14%) in a simulated gastric fluid (pH 1.2), and strongly (700-1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca²⁺ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14-20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350 min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2 h for alginate-g-PCL/Ca²⁺ beads against 1 h for alginate/Ca²⁺ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530 g mol⁻¹ in salt media allowed to retain the drug and to slow down its release considerably.     

New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug

This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250 g mol⁻¹). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10–14%) in a simulated gastric fluid (pH 1.2), and strongly (700–1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca²⁺ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14–20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350 min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2 h for alginate-g-PCL/Ca²⁺ beads against 1 h for alginate/Ca²⁺ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530 g mol⁻¹ in salt media allowed to retain the drug and to slow down its release considerably.     

In vitro evaluation of theophylline matrices using xyloglucan

Xyloglucan is a water soluble polysaccharide extracted from the beans of Tamarindus Indica. Very few publications are found related to its use for preparing oral sustained release swellable matrix. The purpose of this investigation was to prepare sustained release matrices using Xyloglucan and investigate the effects of polymer level, diluents type, pH and ionic strength of the dissolution medium, basket rotational speed, and swelling isotherms on drug release. Tablet formulations containing 50% theophylline as a drug model, Xyloglucan cold water soluble (20%, 30 and 40%) and different diluents (Avicel PH-101, lactose and dibasic calcium phosphate) were prepared. The formulation containing 30% Xyloglucan water soluble and Avicel was selected as best formulation because it gives controlled release profile and tested for swelling isotherms, drug release in different dissolution media, and different basket rotational speed. Percent drug release from formulations containing 50% theophylline, 30% Xyloglucan water soluble, and Avicel PH-101 was 34.2% at 6 hours, 35.6% with lactose, and 30.9% with Emcompress. ANOVA two-way analysis showed a change in drug release rate when polymer percent was increased at the 5% significance level. Different diluents, different dissolution media, and different basket rotational speeds did not significantly change the drug release. The mechanism of drug release appears to follow anomalous relaxation for swellable matrix.     

Cytotoxicity and biocompatibility evaluation of a poly(magnesium acrylate) hydrogel synthesized for drug delivery

We report the synthesis and characterization as well as cytotoxicity and biocompatibility studies of a poly(magnesium acrylate) hydrogel (PAMgA) developed for drug delivery applications. Two hydrogels with different mesh sizes, large and short, were synthesized (L-C PAMgA and S-C PAMgA). The hydrogels were characterized through swelling, FT-IR and DSC. Cytotoxicity in vitro was evaluated on cell line NIH-3T3 fibroblasts via direct contact and two indirect contact methods (MTT and flow citometry). Both PAMgA hydrogels exhibited low cytotoxicity with survival rates higher than 90%. To select their administration route, biocompatibility was evaluated after intraperitoneal, subcutaneous, and oral administration to mice of both hydrogels at different dose ranges. Swelling percentages obtained were 33.3 ± 4.2% and 166.7 ± 8.3% for L-C PAMgA and S-C PAMgA respectively, showing a great difference in both hydrogels. Among the administration routes assayed, the hydrogels were well tolerated after oral administration of a wide dose range (10-500 mg/kg), thereby indicating that both PAMgA hydrogels are excellent candidates for oral administration due to their in vitro biocompatibility and oral non-toxicity. These results together with the fact that their synthesis is simple and inexpensive make them good candidates for the design of oral drug delivery devices.     

Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor-specific drug delivery

When a nanoparticle is developed for systemic application, its surface is typically protected by poly(ethylene glycol) (PEG) to help prolonged circulation and evasion of immune clearance. On the other hand, PEG can interfere with interactions between nanocarriers and target cells and negatively influence the therapeutic outcomes. To overcome this challenge, we propose low molecular-weight chitosan (LMWC) as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in the weakly acidic pH of tumors. LMWCs with a molecular weight of 2-4 kDa, 4-6.5 kDa, and 11-22 kDa were produced by hydrogen peroxide digestion and covalently conjugated with poly(lactic-co-glycolic acid) (PLGA). Nanoparticles created with PLGA-LMWC conjugates showed pH-sensitive cell interactions, which enabled specific drug delivery to cells in a weakly acidic environment. The hydrophilic LMWC layer reduced opsonization and phagocytic uptake. These properties qualify LMWCs as a promising biomaterial for pH-sensitive stealth coating.     

Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery

pH-sensitive drug delivery systems can be engineered to release their contents or change their physicochemical properties in response to variations in the acidity of the surroundings. The present work describes the preparation and characterization of novel polymeric micelles (PM) composed of amphiphilic pH-responsive poly(N-isopropylacrylamide) (PNIPAM) or poly(alkyl(meth)acrylate) derivatives. On one hand, acidification of the PNIPAM copolymers induces a coil-to-globule transition that can be exploited to destabilize the intracellular vesicle membranes. In this work, PNIPAM-based PM were loaded with either doxorubicin or aluminium chloride phthalocyanine and their cytotoxicity was assessed in murine tumoral models. On the other hand, poly(alkyl(meth)acrylate) copolymers can be designed to interact with either hydrophobic drugs or polyions and release their cargo upon an increase in pH.