Release Medium Research Articles

Preparation and evaluation of reduction-responsive micelles based on disulfide-linked chondroitin sulfate A-tocopherol succinate for controlled antitumour drug release.

The study was to construct reduction-responsive chondroitin sulfate A (CSA)-conjugated TOS (CST) micelles with disulfide bond linkage, which was used for controlled doxorubicin (DOX) release and improved drug efficacy in vivo. CST and non-responsive CSA-conjugated TOS (CAT) were synthesized, and the chemical structure was confirmed by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, fluorescence spectrophotometer and dynamic light scattering. Antitumour drug DOX was physically encapsulated into CST and CSA by dialysis method. Cell uptake of DOX-based formulations was investigated by confocal laser scanning microscopy. In vitro cytotoxicity was studied in A549 and AGS cells. Furthermore, antitumour activity was evaluated in A549-bearing mice. CST and CAT can form self-assembled micelles, and have low value of critical micelle concentration. Notably, DOX-containing CST (D-CST) micelles demonstrated reduction-triggered drug release in glutathione-containing media. Further, reduction-responsive uptake of D-CST was observed in A549 cells. In addition, D-CST induced stronger cytotoxicity (P < 0.05) than DOX-loaded CAT (D-CAT) against A549 and AGS cells. Moreover, D-CST exhibited significantly stronger antitumour activity in A549-bearing nude mice than doxorubicin hydrochloride and D-CAT. The reduction-responsive CST micelles enhanced the DOX effect at tumour site and controlled drug release.

Effect of Carbon Chain Length, Ionic Strength, and pH on the In Vitro Release Kinetics of Cationic Drugs from Fatty-Acid-Loaded Contact Lenses.

This paper explores the use of fatty acids in silicone hydrogel contact lenses for extending the release duration of cationic drugs. Drug release kinetics was dependent on the carbon chain length of the fatty acid loaded in the lens, with 12-, 14- and 18-carbon chain length fatty acids increasing the uptake and the release duration of ketotifen fumarate (KTF) and tetracaine hydrochloride (THCL). Drug release kinetics from oleic acid-loaded lenses was evaluated in phosphate buffer saline (PBS) at different ionic strengths (I = 167, 500, 1665 mM); the release duration of KTF and THCL was decreased with increasing ionic strength of the release medium. Furthermore, the release of KTF and THCL in deionized water did not show a burst and was significantly slower compared to that in PBS. The release kinetics of KTF and THCL was significantly faster when the pH of the release medium was decreased from 7.4 towards 5.5 because of the decrease in the relative amounts of oleate anions in the lens mostly populated at the polymer–pore interfaces. The use of boundary charges at the polymer–pore interfaces of a contact lens to enhance drug partition and extend its release is further confirmed by loading cationic phytosphingosine in contact lenses to attract an anionic drug.

Mechanisms of bentonite colloid aggregation, retention, and release in saturated porous media: Role of counter ions and humic acid

In the subsurface environment, colloids play an important role in pollutant transport by acting as the carriers. Understanding colloid release, transport, and deposition in porous media is a prerequisite for evaluating the potential role of colloids in subsurface contaminant transport. In this work, the aggregation, retention, and release of bentonite colloid in saturated porous sand media were investigated by kinetic aggregation and column experiments, the correlation and mechanism of these processes were revealed by combining colloid filtration theory, interaction energy calculation and density functional theory. The results showed that the retention and release of colloids were closely related to the dispersion stability and filtration effect. Multivalent cations with higher mineral affinity reduced the colloid stability, and the dispersion stability and mobility of the colloid were greatly improved by humic acid due to the enhancement of electrostatic repulsion and steric hindrance effects. The primary minimum interaction was found to contribute more to irreversible colloid retention in a Ca2+ system, while the secondary energy minimum was found to be responsible for colloid release with the occurrence of transient solution chemistry. The deposited colloid aggregates could be redistributed and released when the solution chemistry became favorable towards dispersion. These findings provide essential insight into the environmental colloid fate as well as a vital reference for the risk of colloid-driven transport of contaminants in the subsurface aquifer environment.

Facile preparation of layered double hydroxide (LDH)-alginate beads as sustainable system for the triggered release of diclofenac: Effect of pH and temperature on release rate

This paper concerns the facile preparation of alginate beads encapsulating layered double hydroxide (LDH) intercalated with diclofenac sodium as drug delivery systems. To better evaluate the effect of LDH carrier, alginate beads loaded with free diclofenac were also prepared. Composites hydrogel beads were ionotropically crosslinked in CaCl2 solution at 4 °C. Thermal and barrier properties were evaluated and correlated with the presence of the inorganic phase. Swelling behavior was investigated over time. Release kinetics of diclofenac at different pH and temperatures were evaluated. The diclofenac release behavior appeared to be affected by the presence of LDH, the pH of release medium and the temperature allowing for fabricating a sustainable composite characterized by a triggered drug release rate. Finally, empirical relationships correlating the drug diffusion as a function of temperature and pH were extrapolated.

Design of thermosensitive polymer‐coated magnetic mesoporous silica nanocomposites with a core‐shell‐shell structure as a magnetic/temperature dual‐responsive drug delivery vehicle

AbstractA stimuli‐responsive nanocomposite with a core‐shell‐shell structure consisting of iron oxide (Fe3O4) nanoparticles as core, mesoporous silica as middle shell, and poly(N‐isopropyl acrylamide‐co‐acrylic acid) (P[NIPAAm‐co‐AAc]) as an exterior shell with thermo‐responsivity properties was synthesized to be used as a magnetic/temperature responsive drug delivery system. The structure, morphology, and size of P(NIPAAm‐co‐AAc)‐coated mesoporous silica embedded magnetite nanoparticles (P(NIPAAm‐co‐AAc)@mSiO2@Fe3O4) were characterized by XRD, FTIR, and TEM analyses. Also, the heating ability of mesoporous silica‐coated Fe3O4 nanoparticles, and P(NIPAAm‐co‐AAc)@mSiO2@Fe3O4 nanocomposites was investigated under the exposure of an alternating magnetic field (AMF). The results indicated that the prepared nanocomposites could generate enough heat for hyperthermia applications. Moreover, the magnetic/temperature‐responsive drug release behavior of P(NIPAAm‐co‐AAc)@mSiO2@Fe3O4 nanocomposites loaded with fluorouracil (5‐FU) was studied under the exposure of the AMF (frequency = 120 kHz, and amplitude = 22 kA m−1), as well as two different temperatures (37°C and 45°C). The results showed that only 7.8% of the drug could be released after 20 h at 37°C (below the LCST of the copolymer). In contrast, by increasing the temperature of release medium up to 45°C (above the LCST of the copolymer), the amount of released drug was increased up to 47%. Moreover, by exposing the prepared nanocomposite to a safe AMF, a burst release of drug was observed, indicating the excellent responsivity of the carrier to an external magnetic field. These results proved that the obtained nanocomposite has a great performance to be used as a magnetic/temperature‐sensitive drug carrier for advanced drug delivery applications.

Theoretical study of diffusional release of a dispersed solute from a hollow cylindrical polymeric matrix

An exact solution for the release kinetic of a solute from inside a hollow cylindrical polymeric matrix into an infinite medium has been developed, when the initial concentration of the solute (A) is greater than the solubility limit (Cs). A combination of analytical and numerical methods was used to calculate the solute concentration profile and the release rate. The model was developed for two different strategies: 1) the release medium is flowing through the hollow cylinder in which boundary layer may be neglected, 2) the release medium inside the hollow cylinder is stagnant and the boundary layer should be considered. The results indicated that the release profiles were close to the constant release rate after a typical burst release. Also, the release profile from a solid cylindrical matrix and a hollow cylinder was compared. The results indicated that the hollow cylindrical matrix is a promising carrier when zero-order release is desirable. The present model demonstrates the potential of the hollow cylindrical matrix as a suitable geometry for sustained drug delivery systems.

Loading and sustained release of sodium alginate membranes on pyridirubicin chloride

To develop diversified drug carriers for local treatment of cancer, three types of alginate membranes were fabricated by spin-coating, freeze drying and electrospinning. The uniaxial tensile test is shown that spin-coated membranes possess the maximum tensile strength. All the three types of membranes present excellent adsorption performance toward pyridirubicin chloride (THP) and the electrospinning membranes exhibit the maximum adsorption mass of 144.13 mg g−1. The pseudo-first order, pseudo-second order, and intra-particle diffusion equation were used to evaluate the kinetic data and the drug adsorption process followed the pseudo-first-order model well. The drug releasing mechanism was studied by using different release medium, and it shows that the release process was undertaken by ions exchange reaction. The result shows that the three types of membranes are promising materials for the local treatment of cancer such as local cancers of the pancreas and trachea.

Preparation of Polylactic Acid/Glycolic Acid Copolymer Nanoparticles and Its Effect in the Treatment of Diabetes

Insulin (INS) is easily degraded when administered orally and loading it into polylactic acid/glycolic acid (PLGA) polymer nanoparticles can enhance the efficacy of the drug. The W/O/W double emulsion solvent volatilization method was adopted to prepare INS-loaded PLGA nanoparticles. The preparation formula of nanoparticles was determined according to the type, concentration, and PLGA concentration of the emulsifier. Then, the morphology, particle size, and drug encapsulation efficiency of nanoparticles were characterized. Phosphate buffered solution (PBS) with pH = 7.4 was utilized as the release medium, and the prepared nanoparticles were analyzed for in vitro release performance. In addition, the rat diabetes model was constructed, and subcutaneous injection of nanoparticle in vitro release solution was performed to observe its hypoglycemic effect, which was used for the treatment of diabetic patients. Patients were rolled into experimental group and control group. The changes of the patients’ HbA1c, blood lipids (total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)), C peptide, and aminopeptidase N (APN) were observed before and after treatment. Through the test, the appearance of the prepared nanoparticles was round, the average particle size was 416.7 nm, and the INS encapsulation efficiency was (36.82±2.26)%. After 36 h, the cumulative release of INS reached (60.58 ±1.45)%, and then the release rate gradually slowed down. The drug release tended to be balanced after 72 h, and the best hypoglycemic effect was achieved after subcutaneous administration 3 h (P &lt; 0.01). The blood glucose level of the rat diabetes model was greatly decreased after 3 h injection of 36.8 IU/kg PLGA polymer nanoparticles (P &lt; 0.05), and the blood glucose dropped to the lowest at 8 h (P &lt; 0.01), which was only (38.8 ± 3.72)% of the initial blood glucose. HbA1C of diabetic patients increased remarkably after treatment (P &lt; 0.05), TG, TC, and LDL-C in blood lipids decreased, and HDL-C increased, without statistically considerable differences (P &gt; 0.05). The serum APN level increased greatly (P &lt; 0.01). In short, the prepared PLGA polymer nanoparticles can effectively reduce blood glucose, help diabetic patients to relieve the toxicity of high glucose in the body, and improve the secretion function of INS.

Application of poly(amidoamine) dendrimer as transfer agent to synthesize poly(amidoamine)-b-poly(methyl acrylate) amphiphilc block copolymers: Self-assembly in aqueous media and drug delivery

Herein, second generation cystamine-cored poly(amidoamine) (PAMAM) dendrimer has been synthesized and used as transfer agent in atom transfer radical polymerization (ATRP) of poly(methyl acrylate) (PMA). Transfer reaction to dendrimer has been resulted in synthesis of PAMAM-b-PMA block copolymers with different degree of polymerization of PMA block. Synthesized block copolymers have been self-assembled in aqueous media to prepare cubic/hexagonal and spherical supramolecular structures with nanoscale particle size. Finally, the behavior of drug release from supramolecular structures as nanocarriers of the anticancer drug, doxorubicin (DOX), has been investigated under different conditions. Results showed that in block copolymers with shorter length of hydrophobic block, drug loading capacity was increased due to predominant interactions between dendrimer and drug molecules. Higher hydrophobic block length led to higher cumulative release of drug due to presence of hydrophobic interactions between PMA block and DOX molecules. Moreover, nanocarriers showed significant drug release in acidic media whereas no remarkable release was observed at pH = 7.4.

A pH-sensitive curcumin loaded microemulsion-filled alginate and porous starch composite gels: Characterization, in vitro release kinetics and biological activity

To improve the controlled release and stability of the loaded drug, the alginate–porous starch solution, as the gel matrix (GM), was prepared and added into curcumin-loaded microemulsion (CUR-ME) in a certain proportion, and then mixed with slow-gelling agents (CaCO3 + d-glucono-δ-lactone) to prepared curcumin-loaded microemulsion gel (CUR-ME-G). With increasing the proportion of GM from 25% (CUR-ME3G1) to 83% (CUR-ME1G5), the drug loading efficiency increased from 24% to 98% and the maximum drug loading capacity (14.9 mg/g) was found in CUR-ME1G3 with 75% GM. Moreover, a denser structure that entrapped all microemulsion droplets was formed with increasing the proportion of microemulsion according to the observation of scanning electron microscopy. This was also confirmed by Fourier transform infrared spectroscopy and Raman spectroscopy that no new peaks appeared in CUR-ME-G, while the hydrogen bonding interactions might exist between curcumin and sodium alginate. The in vitro release of the CUR-ME-G followed diffusion-controlled mechanism that was consistent with the first-order kinetic model. The release rate depended on the components of the CUR-ME-G and the pH value of the release medium. CUR-ME-G with curcumin concentration of 0.20% exhibited the best biological activity. CUR-ME-G might provide a potential application in the smart drug delivery systems.

Using 3D perfusion bioreactor system to studying cell biology of ovarian cancer.

e17558 Background: Epithelial Ovarian Cancer (EOC) is the most common cause of death among gynecological malignancies. This is a result of the high rate of recurrence and chemo-resistance in EOC patients. Therefore, the development of new therapeutics is crucial. A major factor contributing to this is the lack of therapeutic candidates is lack of translational accuracy in preclinical models. Recently, 3-dimensional (3-D) models have aided in accurately recreating tumor biology. We have developed an EOC 3-D perfused bioreactor system that recapitulates EOC tumor biology and incorporates tumor biomechanical regulation. This model allows for us to more accurately predict the clinical response of new drug candidates, which aids in elimination of ineffective candidates prior to clinical trials. Methods: EOC cell lines (luciferase-taggedSKOV-3 and OVCAR-8) were embedded in a relevant extracellular matrix (ECM) and injected into a perfused, polydimethylsiloxane (PDMS) bioreactor. Microchannels were embedded in matrigel so that the cell culture media with or without chemotherapy could flow through the perfused PDMS to provide nutrient delivery and gas exchange enhancing viability and function of surrounding cells. The bioreactors were connected to a peristaltic pump that allowed for the cell culture media to perfuse over a 7-day period. We monitored cell viability using bioluminescence imaging (BLI), immunohistochemistry (IHC), and lactate dehydrogenase (LDH) release in media. Results: BLI showed a linear increase in SKOV-3 and OVCAR-8 cell growth over 7 days. These results were confirmed by IHC measuring the number of nucleated cells per micron2. Graphical representation of the region of interest (ROI) showed a high correlation between IHC staining of nucleated cells and BLI score. IHC analysis of PAX8 staining was positive and proved that the perfusion bioreactor system maintains EOC biology over time. In addition, our results suggest that the bioreactor is a suitable model for drug preclinical testing in both cell lines as well as in patients’ samples. Conclusions: Our preliminary results using the 3D EOC perfused, PDMS bioreactor model showed increased EOC cell growth overtime, while maintaining original EOC histology. Moreover, our results suggest that this model could provide a novel platform to study therapeutic interventions in EOC. Our ultimate goal is to implement ovarian cancer microenvironment components (e.g. immune cells) into bioreactor system to study different drug treatments to better determine drug candidate’s translational efficacy.

A one-step in vitro continuous flow assessment of protein release from core-shell polymer microcapsules designed for therapeutic protein delivery

Developing accurate methods for the assessment of therapeutic protein release from polymer drug delivery systems (microcapsules, microspheres, nanoparticles, 3D-printed systems) is of paramount importance for new formulation development. The most straightforward method for protein release assessment is spectrophotometric analysis of the release medium surrounding the formulation. However, direct spectrophotometric analysis is inapplicable to formulations releasing interfering compounds (co-encapsulated drugs, additives) absorbing light in the same spectrum as proteins. Conventional protein release assays also require frequent release medium sampling and replacement, which reduces their accuracy. We propose a one-step method to assess protein release from core/shell microcapsules eliminating the need for sampling and allowing selective real-time protein quantitation in the release medium. To prevent spectral interferences, released protein is differentiated from interfering compounds by employing a colorimetric protein assay reagent, forming a colour complex selectively with the protein, as the release medium. To eliminate sampling, we employed a continuous flow closed loop set-up, where the release medium is constantly circulating between microcapsule-containing tank and spectrophotometer. A series of colorimetric protein assay reagents (bromocresol green, tetrabromophenol blue, eosin B, eosin Y, biuret) were evaluated in terms of their applicability as the release medium in described system. Only biuret reagent was found compatible with proposed method due to formation of color complex stable over extended period of time and low adsorption to microcapsules. Presented method allowed effective evaluation of albumin release from alginate-polyethersulfone microcapsules with accuracy equal to conventional ‘sample and separate’ technique. Albumin release followed first-order kinetics with plateau reached after 19 h.

Cochleate formulations of Amphotericin b designed for oral administration using a naturally occurring phospholipid

The purpose of this work was to formulate the poor soluble antifungal and antiparasitic agent Amphotericin B (AmB) in cost-effective lipid-based formulations suitable for oral use in developing countries, overcoming the limitations of poor water solubility, nephrotoxicity and low oral bioavailability. The antifungal agent was formulated, at different molar proportions, in cochleate nanocarriers prepared using an accessible naturally occurring phospholipid rich in phosphatidylserine (Lipoid PSP70). These nanoassemblies were prepared by condensation of negatively charged phospholipid membrane vesicles with divalent cations (Ca2+). Small-angle X-ray scattering studies revealed the Ca2+-triggered condensation of loosely packed multilamellar vesicles into tightly packed bilayers of strongly dehydrated multilamellar organization characterized by narrow Bragg peaks. Transmission electron microscopy and quasi-elastic light scattering studies demonstrated the formation of nanosized particles. AmB drug loading was above 55% in all formulations. Circular dichroism demonstrated the prevalence of monomeric and complexed forms of AmB over toxic aggregates. The stability of AmB in gastric medium was improved by loading in cochleates and its release in gastrointestinal media was retarded. Confocal microscopy studies revealed the in-vitro interactions of Lipoid PSP70-based cochleates with Caco2 intestinal cell monolayers. The results suggest that the low-cost AmB-loaded cochleates may increase the therapeutic range of this drug.

Release of soil colloids during flow interruption increases the pore-water PFAS concentration in saturated soil

Groundwater flow through aquifer soils or packed bed systems can fluctuate for various reasons, which could affect the concentration of natural colloids and per- and polyfluoroalkyl substances (PFAS) in the pore water. In such cases, PFAS concentration could either decrease due to matrix diffusion of PFAS or increase by the detachment of colloids carrying PFAS. Yet, the effect of flow fluctuation on PFAS transport or release in porous media has not been examined. To examine the relative importance of either process, we interrupted the flow during an injection of groundwater spiked with perfluorobutanoic acid (PFBA), perfluorooctanoic acid (PFOA), and bromide as conservative tracer through clay-rich soil, so that diffusive transport would be prominent during flow interruption. After flow interruption, the PFAS concentration did not decrease indicating an insignificant contribution of matrix diffusion. The concentration increased, potentially due to enhanced release of colloid-associated PFAS. Analysis of samples before and after flow interruption by particle size analysis and SEM confirmed an increase in soil colloid concentration after the flow interruption. XRD analysis of soil and the colloids proved that PFAS were associated with specific sites of the colloids. Due to a higher affinity of PFOA to soil colloids, the total PFOA concentration in the effluent samples increased more than PFBA after the flow interruption process. The results indicate that colloids may have a disproportionally higher role in the transport of PFAS in conditions that release colloids from porous media. Thus, fluctuations in groundwater flow can increase this colloid facilitated mobility of PFAS.

Gelatin Beads/Hemp Hurd as pH Sensitive Devices for Delivery of Eugenol as Green Pesticide

In this paper gelatin beads reinforced with natural hemp hurd have been produced as pH sensitive devices for the release of eugenol, as green pesticide. The composites beads, with a mean diameter of about 1 mm, were obtained by polymer droplet gelation in sunflower oil. Thermal properties were evaluated showing no noticeable difference after the introduction of hemp hurd. Barrier properties demonstrated an improvement of hydrophobization. The introduction of 5% w/w of hemp hurd led to a reduction of sorption coefficient of about 85% compared to unloaded gelatin beads. Besides, the diffusion coefficient decreased, introducing 5% w/w of hemp hurd, from 8.91 × 10−7 to 0.77 × 10−7 cm2/s. Swelling and dissolution phenomena of gelatin beads were studied as function of pH. The swelling of gelatin beads raised as pH increased up to 2.3 g/g, 9.1 g/g and 27.33 g/g at pH 3, 7 and 12, respectively. The dissolution rate changed from 0.034 at pH 3 to 0.077 h−1 at pH 12. Release kinetics of eugenol at different pH conditions were studied. The released eugenol after 24 h is 98%, 91%, 81 and 63% w/w (pH 3), 87%, 62%, 37 and 32 wt% (pH 7) and 81%, 68%, 60 and 52 wt% (pH 12) for unloaded gelatin beads and gelatin beads with 1%, 3 and 5% of hemp hurd, respectively. The eugenol release behavior was demonstrated to be highly sensitive to the pH release medium, which allows to tune such devices as green pesticide release systems in soils with different level of acidity/basicity.

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis

BackgroundAtherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes.MethodsAdipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O2) or hypoxia (1%O2) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-β-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues.ResultsSpecific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-β-gal activity decreased in both animal groups.ConclusionsThese data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.

Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: In vitro and in vivo evaluation

The purpose of this work was to evaluate solid lipid nanoparticles (SLNs) as a long acting injectable drug delivery platform for intramuscular and subcutaneous administration. SLNs were developed with a low (unsaturated) and high (supersaturated) drug concentration at equivalent lipid doses. The impact of the drug loading as well as the administration route for the SLNs using two model compounds with different physicochemical properties were explored for their in vitro and in vivo performance. Results revealed that drug concentration had an influence on the particle size and entrapment efficiency of the SLNs and, therefore, indirectly an influence on the Cmax/dose and AUC/dose after administration to rats. Furthermore, the in vitro drug release was compound specific, and linked to the affinity of the drug compounds towards the lipid matrix and release medium. The pharmacokinetic parameters resulted in an increased tmax, t1/2 and mean residence time (MRT) for all formulations after intramuscular and subcutaneous dosing, when compared to intravenous administration. Whereas, the subcutaneous injections performed better for those parameters than the intramuscular injections, because of the higher blood perfusion in the muscles compared with the subcutaneous tissues. In conclusion, SLNs extend drug release, need to be optimized for each drug, and are appropriate carriers for the delivery of drugs that require a short-term sustained release in a timely manner.

Hyaluronic acid coating on the surface of curcumin-loaded ZIF-8 nanoparticles for improved breast cancer therapy: An in vitro and in vivo study

Despite developments in surgery and chemotherapy, effective treatment of breast cancer is still an urgent problem owing to recurrence and metastasis. By combining the advantages of curcumin (Cur), zeolitic imidazolate framework-8 nanoparticles (ZIF-8), and hyaluronic acid (HA) in breast cancer therapy, Cur-loaded and HA-coated ZIF-8 (Cur@ZIF-8@HA) were synthesized using a method based on the pH-dependent solubility of Cur and the electrostatic interactions between zinc ions and carboxyl groups of HA. Cur@ZIF-8 were also prepared as a control group. Comprehensive comparisons of the physicochemical properties and anticancer activities of Cur@ZIF-8@HA and Cur@ZIF-8 were conducted. The results indicated that the degradation of Cur during the synthesis of Cur@ZIF-8 was negligible. The obtained Cur@ZIF-8 and Cur@ZIF-8@HA were truncated cubes with hydrodynamic diameters of 174 and 217 nm, respectively. Cur@ZIF-8@HA possessed better stability during storage in different media, a slower drug release rate under neutral and acidic conditions, and a greater inhibitory effect on breast cancer than Cur@ZIF-8. For 4T1 cells, treatment using Cur@ZIF-8@HA induced more cellular uptake and higher cytotoxicity, accompanied by higher lactate dehydrogenase release, cell cycle arrest in G2/M and S phases, production of reactive oxygen species, and apoptosis. In 4T1 tumor-bearing mice models, Cur@ZIF-8@HA showed a stronger inhibitory effect on tumor growth and pulmonary metastasis. Therefore, Cur@ZIF-8@HA might hold great potential as an agent for the effective therapy of breast cancer.

Muscle Tissue as a Surrogate for In Vitro Drug Release Testing of Parenteral Depot Microspheres

Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

Development of Duloxetine Hydrochloride Tablets for Delayed and Complete Release Using Eudragit L 100

The purpose of the research was to optimize the preparation of duloxetine hydrochloride (duloxetine HCl) delayed release tablets. Duloxetine HCl produces a toxic substance called alpha-naphthol when duloxetine HCl is in contact with gastric fluid. Thus, duloxetine HCl when given orally needed a protective enteric coating that disable the delivery of duloxetine HCl in gastric fluid while enabling the drug delivery only in small intestine. Four different core tablets were prepared by direct compression technique, and the one which displayed quick disintegration and dissolution was chosen for enteric coating. The compressed tablets were enteric coated by dip coating technique. Since subcoating is required to safeguard the enteric coating, the core tablets were subcoated by using polymer HPMC K15M and then enteric coated with Eudragit L 100. The prepared tablets were assessed for the entire precompression and postcompression characteristics. FTIR study revealed the existence of all prominent peaks signifying its compatibility and authenticity. The in vitro studies showed that enteric-coated tablets were capable of restricting release in acidic media. The formulation F8 was optimised with 5% and 15% increase in weight of seal coat and enteric coat with good dissolution profile. Stability studies revealed that the optimized formulation was intact without any deterioration for 3 months. In conclusion, the optimized formulation could resist the drug release in acidic environment of gastrointestinal region and release the drug at a time once the tablet reaches the intestine.