Extended Release Behavior Research Articles

A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Environmentally benign approach to formulate nanoclay/starch hydrogel for controlled release of zinc and its application in seed coating of Oryza Sativa plant

Improper use of conventional fertilizers has been linked to adverse effects on soil nutrient levels. To mitigate the negative impact of surface feeding fertilizers and reduce environmental pollution, a new type of seed coating material has been developed to provide nutrients in close proximity to the growing seed. In this study, a biodegradable seed coating film encapsulating micronutrients was fabricated by incorporating montmorillonite into a starch matrix using the melt processing technique. The dispersion of montmorillonite within the starch matrix was examined using X-ray diffraction (XRD), infrared spectroscopy (IR), and thermal gravimetric analysis (TGA). The results revealed polar interactions among starch, silicate layers, and the hydrogel. The XRD analysis demonstrated a shift in the diffraction peak (001) of the Zinc/montmorillonite/starch/glycerol nanocomposite film from 6.2° to 4.9°, indicating the successful intercalation of Zinc, starch, and glycerol. Furthermore, the inclusion of nanoclay improved the thermal stability of the resulting polymer composite and enhanced its ion exchange capacity, water retention, and micronutrient retention. The time-dependent release of zinc micronutrient from the montmorillonite/starch/glycerol composite film was investigated in Zn-deficient soil extract over a 20-day period. The composite film demonstrated extended release behavior of Zn2+. Subsequently, rice seeds were coated with the zinc-containing composite film using a dip-coating method, and their performance in Zn-deficient soil was evaluated. The results indicated that zinc-coated seeds exhibited improved germination percentage, vegetative growth, and yield compared to uncoated seeds.

In vitro and preclinical assessment of factorial design based nanoethosomal transdermal film formulation of mefenamic acid to overcome barriers to its use in relieving pain and inflammation

Mefenamic acid (MA) is a non-steroidal anti-inflammatory drug with analgesic activity. Marketed MA tablets or capsules often result in gastrointestinal disorders, such as upset and bleeding. MA also has poor solubility and short half-life (2 h), which requires frequent dosing, leading to higher incidence of side effects. The objective was to develop a statistically optimized nanoethosome (NE) formulation of MA loaded into transdermal films, as an alternative to oral delivery, to offer an extended release behavior. Box-Behnken design was used to analyze the effect of phospholipid concentration, ethanol concentration, and ultrasonication time. On three variables, particle size, entrapment efficiency, and steady state flux. Optimized MA-loaded nanoethosome formulation was prepared using a thin layer evaporation technique. Further, the nanoethosomal-loaded transdermal film was evaluated for in-vitro release, ex-vivo permeation, and in-vivo pharmacokinetics studies. The optimized formula indicated particle size of 97 nm with 80% of entrapment efficiency. Enhanced skin permeation of MA was more than 3.4 folds higher for nanoethosomes loaded films in comparison to pure drug transdermal films The estimated steady state flux was 2 and 15 mcg/cm2 min. The bioavailability studies indicated that mean AUC0-48 increased by 4-folds after transdermal delivery of optimized nanoethosomal film with no side effects.

Design of amphiphilic PCL-PEG-PCL block copolymers as vehicles of Ginkgolide B and their brain-targeting studies

The amphiphilic PEG-b-PCL block copolymers were synthesized by ring-opening polymerization. The specific and selective antagonists of platelet activating factor, Ginkgolide B (GB), was successfully encapsulated in the synthesized PEG-PCL nanoparticles (NPs) with high Encapsulation Efficiency and Drug Loading. The synthesis of different PEG-PCL copolymers were confirmed with FTIR and 1H NMR spectra. The morphology and particles size distribution of cargo-free PEG-PCL NPs were studied by transmission electron microscope (TEM) analysis and Malvern laser particle analyzer. The bio-distribution and pharmacodynamics studies of GB were studied with Wistar mice as the animal models via tail injecting of GB-PEG-PCL NPs. Results from Malvern laser particle analyzer and TEM analysis illustrated that the cargo-free NPs showed narrow distribution and well separated particles size of about 60 nm in diameter. The in vitro experiment of GB-PEG-PCL NPs exhibited an extended release behavior. The bio-distribution data suggested that Tween-80 covered GB-PEG-PCL NPs showed a brain-targeting behavior. The pharmacodynamics results confirmed that the GB-PEG-PCL NPs had an obvious cerebral protection effect.

Sustained viral gene delivery from a micro-fibrous, elastomeric cardiac patch to the ischemic rat heart.

Biodegradable and elastomeric patches have been applied to the surface of infarcted hearts as temporary mechanical supports to effectively alter adverse left ventricular remodeling processes. In this report, recombinant adeno-associated virus (AAV), known for its persistent transgene expression and low pathogenicity, was incorporated into elastomeric polyester urethane urea (PEUU) and polyester ether urethane urea (PEEUU) and processed by electrospinning into two formats (solid fibers and core-sheath fibers) designed to influence the controlled release behavior. The extended release of AAV encoding green fluorescent protein (GFP) was assessed invitro. Sustained and localized viral particle delivery was achieved over 2 months invitro. The biodegradable cardiac patches with or without AAV-GFP were implanted over rat left ventricular lesions three days following myocardial infarction to evaluate the transduction effect of released viral vectors. AAV particles were directly injected into the infarcted hearts as a control. Cardiac function and remodeling were significantly improved for 12 weeks after patch implantation compared to AAV injection. More GFP genes was expressed in the AAV patch group than AAV injection group, with both α-SMA positive cells and cardiac troponin T positive cells transduced in the patch group. Overall, the extended release behavior, prolonged transgene expression, and elastomeric mechanical properties make the AAV-loaded scaffold an attractive option for cardiac tissue engineering where both gene delivery and appropriate mechanical support are desired.

Fabrication of self-assembled chitosan-dispersed LDL nanoparticles for drug delivery with a one-step green method

Self-assembled nanoparticles (NPs) composed of chitosan (CS) and low density lipoprotein (LDL) of hen eggs were prepared by a one-step green synthesis of mixing CS solution and LDL suspension. The formulated CS-LDL NPs were then applied to encapsulate doxorubicin hydrochloride (DOX) with the encapsulation efficiency of 51.7%. The average particle size and ζ-potential of DOX-loaded CS-LDL NPs (CS-LDL-DOX NPs) were 179nm and +48.3mV, respectively. The encapsulated DOX showed less cytotoxicity than free DOX after 24-h incubation with gastric cancer SGC7901 cells, which may be due to extended release. Cellular uptake of CS-LDL-DOX NPs was significant higher than that of free DOX due to the endocytosis of tumor cells. Thus CS-LDL-DOX NPs showed a potential in reducing cytotoxicity of DOX by extended release behavior and preferential uptake compared to free DOX. In addition, flow cytometry and terminal-deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay demonstrated that CS-LDL-DOX NPs induced the apoptosis of cancer cells. Autophagy was involved in effects caused by CS-LDL-DOX NPs through blocking AKT/mTOR signaling, which was demonstrated by the analyses of the expression of LC3, p62, AKT, p-AKT, mTOR and p-mTOR.

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release.

Evaluation of chitosan–anionic polymers based tablets for extended-release of highly water-soluble drugs

The objective of this study is to develop chitosan–anionic polymers based extended-release tablets and test the feasibility of using this system for the sustained release of highly water-soluble drugs with high drug loading. Here, the combination of sodium valproate (VPS) and valproic acid (VPA) were chosen as the model drugs. Anionic polymers studied include xanthan gum (XG), carrageenan (CG), sodium carboxymethyl cellulose (CMC-Na) and sodium alginate (SA). The tablets were prepared by wet granulation method. In vitro drug release was carried out under simulated gastrointestinal condition. Drug release mechanism was studied. Compared with single polymers, chitosan–anionic polymers based system caused a further slowdown of drug release rate. Among them, CS–xanthan gum matrix system exhibited the best extended-release behavior and could extend drug release for up to 24 h. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies demonstrated that polyelectrolyte complexes (PECs) were formed on the tablet surface, which played an important role on retarding erosion and swelling of the matrix in the later stage. In conclusion, this study demonstrated that it is possible to develop highly water-soluble drugs loaded extended-release tablets using chitosan–anionic polymers based system.

Inter-Grade and Inter-Batch Variability of Sodium Alginate Used in Alginate-Based Matrix Tablets

The purpose of this study is to characterize the inter-grade and inter-batch variability of sodium alginate used in the formulation of matrix tablets. Four different grades and three batches of one grade of sodium alginate were used to prepare matrix tablets. Swelling, erosion, and drug release tests of sodium alginate matrix tablets were conducted in a USP dissolution apparatus. Substantial differences in swelling and erosion behavior of sodium alginate matrix tablets were evident among different viscosity grades. Even different batches of the same grade exhibit substantial differences in the swelling and erosion behavior of their matrix tablets. The erosion behavior of sodium alginate matrix tablets can be partly explained by their rheological properties (both apparent viscosity and viscoelasticity) in solution. Sodium alginate with higher apparent viscosity and viscoelasticity in solution show slower erosion rate and higher swelling rate. Compacts prepared from grades or batches with higher viscosity and higher viscoelasticity show slower drug release. For grades or batches with similar apparent viscosities, apparent viscosities of sodium alginate solution at low concentration alone are not sufficient to predict the functionality of sodium alginate in matrix tablets. Viscoelastic properties of sodium alginate solutions at one high concentration corresponding to the polymer gel state, may be suitable indicia of the extended release behavior of sodium alginate matrix tablets.

Rubik-like magnetic nanoassemblies as an efficient drug multifunctional carrier for cancer theranostics

A practical and effective strategy for loading hydrophobic anticancer agents within the inside and outside oleic acid layer of Rubik-like magnetic nanoassemblies (MNAs) is established. In this strategy, four individual oleic acid-capped iron oxide nanocubes and dioleate-modified polyethylene glycol are assembled into cluster with high drug loading capability, high magnetism, as well as rapid and extended release behavior. After loading model drug paclitaxel (PTX), PTX-MNAs show greater antitumor activity both in vitro cell culture and in vivo animal trials compared with the same dose of free PTX (Taxol). With high uptake by tumor cells, MNAs exhibit in tumor imaging by magnetic resonance imaging. These outstanding properties are largely due to the drug delivery systems that take high drug-loading capability and high magnetism into consideration in a nano-dimension for maximizing the nanotheranostic functions and minimizing the toxic side effects. In summary, the Rubik-like magnetic nanoassemblies may have the potential to realize “all-in-one” nanotheranostic strategy to detect, diagnose, treat, and monitor tumors and therapeutic response in further pre-clinical and clinical studies.

Simultaneous interpenetrating silicone hydrogel based on radical/addition polymerization for extended release of ocular therapeutics

Hydrogels with interpenetrating network (IPN) can overcome thermodynamic incompatibility and obtain transparent materials with limited phase separation. In this report, hydroxyl-grafting polysiloxane (HPSO) was synthesized and transparent silicone hydrogels with interpenetrating network were simultaneously prepared based on radical polymerization of methacrylic monomer of 3-methacryloxypropyl tris(trimethylsiloxy)silane/N,N-dimethylacrylamide and addition polymerization of HPSO/isophorone diisocyanate. The silicone hydrogels were characterized by dehydration kinetics, tensile tester, light transmittance, ion permeability, oxygen permeability, and lysozyme deposition. The results show that increasing the proportion of hydrophobic network of HPSO in the IPN silicone hydrogel decreases equilibrium swelling ratio, ion permeability, Young’s modulus, and lysozyme deposition; on the contrary, increased tensile strength, elongation at break and oxygen permeability. Puerarin and ketoconazole were used as models to evaluate the drug loading and in vitro release behavior of the silicone hydrogels. It is revealed that the amount of loaded drugs in the hydrogel decreases with the increase of HPSO network in the hydrogels. All the silicone hydrogels exhibit extended release behavior, especially for ketoconazole, the in vitro release is divided into two phases corresponding to the rapid release at initial 24 h and relatively slow release from 125 to 360 h.

In Vitro and In Vivo Study of Poly(ethylene glycol) Conjugated Ibuprofen to Extend the Duration of Action

Ibuprofen–polyethylene glycol (PEG) conjugates (PEG-Ibu) were prepared and their potential as a prolonged release system was investigated. Two PEG-Ibu conjugates were synthesized from Ibuprofen and PEG with two different molecular weights by esterification in the presence of DCC and DMAP. The PEG-Ibu conjugates were characterized by FT-IR, 1H NMR, Mass spectroscopy and DSC analysis. The solubility study in aqueous system showed an increase in solubility of conjugates. The dissolution / hydrolysis studies showed a specific acid–base catalysis pattern dependent on the pH of the medium. This indicated a good chemical stability in aqueous buffer solution of acidic medium and the extended release behavior was found in both prodrugs after 9 hour. The results demonstrate that, in the same condition, the rate of hydrolysis for PEG4000-Ibu is slower than other. The Writhing induced by acetic acid experiment and paw edema test after oral administration showed that both conjugates had extended analgesic and anti-inflammatory effects compared with Ibuprofen. These results suggest that PEG-Ibu could be a promising NSAID prodrug with an extended pharmacological effect owing to delayed-release of parent drug.