Zwitterionic gold nanorods: low toxicity and high photothermal efficacy for cancer therapy.

Novel "zwitterionic" gold nanorods (Au NRs) were constructed through a facile ligand exchange process between cetyltrimethylammonium bromide (CTAB)-Au NRs and the zwitterionic block polymer {poly(2-methacryloyloxyethyl phosohorylcholine)-b-poly(lipoic methacrylate) (pMPC-b-pLA)}. In vitro, they exhibited low dark cytotoxicity and a high therapeutic efficacy to cancer cells. Their blood circulation half-life in vivo (t1/2, ∼10 h) was 20-fold longer than that of CTAB-Au NRs (t1/2, <30 min). After intravenous administration, they accumulated in tumour sites via an enhanced permeability and retention (EPR) effect and enabled destruction of human xenograft tumours in mice after exposure of the tumour location to NIR laser irradiation at 808 nm. These studies showed that the "zwitterionic" Au NRs had low toxicity and high photothermal efficacy both in vitro and in vivo due to the suprahydrophilic, biocompatible zwitterionic polymer coating layer. They may have the potential to be a promising NIR PTT agent in the biomedical field.

Hyaluronan-cisplatin conjugate nanoparticles embedded in Eudragit S100-coated pectin/alginate microbeads for colon drug delivery.

Hyaluronan-cisplatin conjugate nanoparticles (HCNPs) were chosen as colon-targeting drug-delivery carriers due to the observation that a variety of malignant tumors overexpress hyaluronan receptors. HCNPs were prepared by mixing cisplatin with a hyaluronan solution, followed by dialysis to remove trace elements. The cells treated with HCNPs showed significantly lower viability than those treated with cisplatin alone. HCNPs were entrapped in Eudragit S100-coated pectinate/alginate microbeads (PAMs) by using an electrospray method and a polyelectrolyte multilayer-coating technique in aqueous solution. The release profile of HCNPs from Eudragit S100-coated HCNP-PAMs was pH-dependent. The percentage of 24-hour drug release was approximately 25.1% and 39.7% in pH 1.2 and pH 4.5 media, respectively. However, the percentage of drug released quickly rose to 75.6% at pH 7.4. Moreover, the result of an in vivo nephrotoxicity study demonstrated that Eudragit S100-coated HCNP-PAMs treatment could mitigate the nephrotoxicity that resulted from cisplatin. From these results, it can be concluded that Eudragit S100-coated HCNP-PAMs are promising carriers for colon-specific drug delivery.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Design and in vitro performance evaluation of purified microparticles of pravastatin sodium for intestinal delivery.

The purpose of research was to develop a mucoadhesive multiparticulate sustained drug delivery system of pravastatin sodium, a highly water-soluble and poorly bioavailable drug, unstable at gastric pH. Mucoadhesive microparticles were formulated using eudragit S100 and ethyl cellulose as mucoadhesive polymers. End-step modification of w/o/o double emulsion solvent diffusion method was attempted to improve the purity of the product, that can affect the dose calculations of sustained release formulations and hence bioavailability. Microparticles formed were discrete, free flowing, and exhibited good mucoadhesive properties. DSC and DRS showed stable character of drug in microparticles and absence of drug polymer interaction. The drug to polymer ratio and surfactant concentration had significant effect on mean particle size, drug release, and entrapment efficiency. Microparticles made with drug: eudragit S100 ratio of 1:3 (F6) exhibited maximum entrapment efficiency of 72.7% and ex vivo mucoadhesion time of 4.15 h. In vitro permeation studies on goat intestinal mucosa demonstrated a flux rate (1,243 µg/cm(2)/h) that was 169 times higher than the flux of pure drug. The gastric instability problem was overcome by formulating the optimized microparticles as enteric-coated capsules that provided a sustained delivery of the highly water-soluble drug for 12 h beyond the gastric region. The release mechanism was identified as fickian diffusion (n = 0.4137) for the optimized formulation F6. Conclusively, a drug delivery system was successfully developed that showed delayed and sustained release up to 12 h and could be potentially useful to overcome poor bioavailability problems associated with pravastatin sodium.

pH-enzyme di-dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma.

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(®) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release.

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.

Genetic and cellular toxicology of dental resin monomers.

Monomers are released from dental resin materials, and thus cause adverse biological effects in mammalian cells. Cytotoxicity and genotoxicity of some of these methacrylates have been identified in a vast number of investigations during the last decade. It has been well-established that the co-monomer triethylene glycol dimethacrylate (TEGDMA) causes gene mutations in vitro. The formation of micronuclei is indicative of chromosomal damage and the induction of DNA strand breaks detected with monomers like TEGDMA and 2-hydroxyethyl methacrylate (HEMA). As a consequence of DNA damage, the mammalian cell cycle was delayed in both G1 and G2/M phases, depending on the concentrations of the monomers. Yet, the mechanisms underlying the genetic and cellular toxicology of resin monomers have remained obscure until recently. New findings indicate that increased oxidative stress results in an impairment of the cellular pro- and anti-oxidant redox balance caused by monomers. It has been demonstrated that monomers reduced the levels of the natural radical scavenger glutathione (GSH), which protects cell structures from damage caused by reactive oxygen species (ROS). Depletion of the intracellular GSH pool may then significantly contribute to cytotoxicity, because a related increase in ROS levels can activate pathways leading to apoptosis. Complementary, cytotoxic, and genotoxic effects of TEGDMA and HEMA are inhibited in the presence of ROS scavengers like N-acetylcysteine (NAC), ascorbate, and Trolox (vitamin E). Elevated intracellular levels of ROS can also activate a complex network of redox-responsive macromolecules, including redox-sensitive transcription factors like nuclear factor kappaB (NF-kappaB). It has been shown that NF-kappaB is activated probably to counteract HEMA-induced apoptosis. The induction of apoptosis by TEGDMA in human pulp cells has been associated with an inhibition of the phosphatidylinositol 3-kinase (PI3-K) cell-survival signaling pathway. Although the details of the mechanisms leading to cell death, genotoxicity, and cell-cycle delay are not completely understood, resin monomers may be able to alter the functions of the cells of the oral cavity. Pathways regulating cellular homeostasis, dentinogenesis, or tissue repair may be modified by monomers at concentrations well below those which cause acute cytotoxicity.

[Some interactions of natural and synthetic anionic polymers with biologically active substances]. / Wybrane interakcje naturalnych i syntetycznych polimerów anionowych z substancjami leczniczymi.

Anionic polymers are nowadays extensively used in drug form technology, especially in drug delivery and drug targeting. Development of proper drug and macromolecular excipient composition allows controlled drug delivery in the term of the drug concentration in blood or other tissues, and in the term of the action-time. Between anionic polymers most frequently carbopols, eudragits, alginates and pectins are used. Application of anionic polymers in drug form technology is an up to date problem. According to new synthesis methods and new anionic polymers, new drug delivery systems would be researched. Most selective and safe devices should be developed, concerning biodegradation aspects.

Biodegradation behavior of gellan gum in simulated colonic media.

The objective of this investigation was to test the biodegradability of gellan gum in the presence of galactomannanase in order to explore its suitability for the development of colon-specific controlled delivery systems. Gellan beads containing azathioprine (AZA) were prepared by ionotropic gelation in the presence of Ca2+ ions and were coated with an enteric polymer, Eudragit S-100. The effects of the simulated colonic fluid (SCF, pH 7.4 phosphate buffer) containing 15 mg/mL of galactomannanase on the in vitro release profiles of uncoated and enteric-coated beads were investigated, and the morphological changes in the structure of uncoated beads were assessed by scanning electron microscopy (SEM). In addition, 1% solution of deacetylated gellan gum was prepared and several aliquots of the resulting solution were evaluated rheologically to determine the concentration- and time-dependent effects of galactomannanase. Based on the percent drug released at 2 h, approximately 10% greater amount of drug was released in the SCF containing galactomannanase when compared with the enzyme-free dissolution medium. Results of rheological studies demonstrated that effects of galactomannanase on the viscosity of gellan gum solution are concentration-dependent rather than time-dependent. A significant decrease in the viscosity was noted in the presence of galactomannanase at a concentration of 15 mg/ mL, indicating that the polysaccharide degraded in an enzymatic reaction. SEM micrographs showed a distinct disruption of the polymeric network in the SCF. Overall, the results suggest that gellan gum undergoes significant degradation in the presence of galactomannanase which in turn facilitates the drug release from beads in the SCF in a controlled manner, thus approving the suitability of gellan gum as a carrier for controlled colonic delivery.

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine.

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol 888ATO, Eudragit RS, Methocel K100M, Polyox WSR301 and Precirol ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol and hydrophilic Methocel produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.

Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology on insulin delivery characteristics.

Hydrogels of poly(methacrylic acid-g-ethylene glycol) were prepared using different reaction water contents in order to vary the network mesh size, swelling behavior and insulin loading/release kinetics. Gels prepared with greater reaction solvent contents swelled to a greater degree and had a larger network mesh size. All of the hydrogels were able to incorporate insulin and protected it from release in acidic media. At higher pH (7.4), the release rates increased with reaction solvent content. Using a closed loop animal model, all of the insulin loaded formulations produced significant insulin absorption in the upper small intestine combined with hypoglycemic effects. In these studies, bioavailabilities ranged from 4.6% to 7.2% and were dependent on reaction solvent content.

Preparation of alginate/chitosan microcapsules and enteric coated granules of mistletoe lectin.

The aqueous extract of European mistletoe (Viscum album, L.) has been used in cancer therapy. The purified mistletoe lectins, main components of mistletoe, have demonstrated cytotoxic and immune-system-stimulating activities. Korean mistletoe (Viscum album L. coloratum), a subspecies of European mistletoe, has also been reported to possess anticancer and immunological activities. A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. coloratum agglutinin, VCA) with Mr 60 kDa was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously due to the low stability of lectin in the gastrointestinal (GI) tract. In the present study, we investigated the possibility of alginate/chitosan microcapsules as a tool for oral delivery of mistletoe lectin. In addition, our strategy has been to develop a system composed of stabilizing cores (granules), which contain mistletoe lectin, extract or powder, coated by a biodegradable polymer wall. Our results indicated that successful incorporation of VCA into alginate/chitosan microcapsules has been achieved and that the alginate/chitosan microcapsule protected the VCA from degradation at acidic pH values. And coating the VCA with polyacrylic polymers, Eudragit, produced outstanding results with ideal release profiles and only minimal losses of cytotoxicity after manufacturing step. The granules prepared with extract or whole plant produced the best results due to the stability in the extract or whole plant during manufacturing process.

Studies in preparation and evaluation of pH-independent sustained-release matrix tablets of verapamil HCl using directly compressible Eudragits.

The objective of the present study was to investigate the impact of formulation factors on the properties of a 12h modified-release formulation of verapamil HCl. A 2(3) full factorial design was employed to investigate the influence of amount of Eudragit RS PO/RL PO (X1, a matrixing agent), HPMC K4M (X2, an auxiliary matrixing agent cum binder) and PEG 4000 (X3, channelling agent cum plasticizer). The tablets were prepared by direct compression and they were evaluated for in vitro dissolution studies in 0.1 N HCl. The time required for 90% of the drug release (t90) and similarity factor (f2) were used as responses for the selection of most appropriate batches. Swelling and fluid penetration studies were carried out in 0.1 N HCl. Time required for 90% of the drug release (t90) was calculated by using an appropriate kinetic model for each batch. An ideal drug release profile (i.e., 25% in the first hour and a constant drug release thereafter) was considered as a reference release profile for calculation of f2. Multiple regression analysis was adopted to evolve refined models for t90. The required release pattern was shown by batches containing a low level of Eudragit RS PO/RL PO (30% w/w), low level of HPMC K4M (10% w/w), and high level of PEG 4000 (15% w/w). Response surface plots are shown for t90. These formulations showed slower drug release in alkaline medium (pH 7.2). Succinic acid and KH2PO4 were incorporated in the matrix in order to obtain pH-independent drug release. Swelling of tablets and fluid penetration in the matrix were found to be influenced by the selected independent variables. This study demonstrates that the desired drug release pattern can be obtained by adopting a systematic formulation approach.

Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit.

The aim of the present work was to prepare and evaluate the sustained release of potassium chloride formulations. Eudragit RS and/or RL loaded with potassium chloride microspheres were prepared by a solvent evaporation method. The effect of sustained release of Eudragit microspheres was evaluated by an in vitro dissolution test and in vivo oral absorption study, and the results were compared to a commercial product (Slow-K). The results showed that Eudragit microspheres loaded with potassium chloride can be easily prepared and satisfactory results obtained considering the size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-90% and 27%, respectively. Moreover, the Eudragit RS (30-45 mesh) and Eudragit RS/RL (20-30 mesh) microspheres showed a similar sustained release effect of commercial product via in vitro dissolution and in vivo oral absorption study.

Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum.

Patients failing to obtain benefit from nicotine polacrilex gum in their efforts to quit smoking may be inadvertently blocking nicotine absorption. Effective nicotine absorption depends on the mildly alkaline saliva that is produced when buffering agents in the polacrilex are released along with nicotine as the polacrilex is chewed. We found that intermittent mouth rinsing with coffee or cola, but not distilled water, substantially reduced salivary pH and nicotine absorption. Because many commonly consumed substances were also found to be highly acidic, we recommend that patients do not ingest any substance during or immediately before nicotine polacrilex use.