Controlled Release Rate Research Articles

Formulation and Evaluation of Extended Release Floating Matrix Tablet of Eperisone Hydrochloride by Direct Compression Method

Increased complications and costs of marketing of innovative drugs focused greater attention to the development of sustained release (SR) or controlled release (CR) drug delivery systems. Delivery systems extended release or controlled release rate can achieve predictable and reproducible, the extended duration of activity for the short time of life - drugs, reduced toxicity and dose reduction request, the optimized therapy and better patient compliance. It is controlled primarily by the type and the proportion of the polymers used in the preparation. Eperisone hydrochloride is a centrally acting muscle relaxant acting through poly and mono-synaptic reflexes in the spinal cord, exhibits vasodilator effect, increases blood flow and inhibits the pain reflex pathway. The objective of present work was to develop and evaluated oral extended release floating matrix tablet of eperisone HCl prepared by the method of direct compression, using hydroxy propyl methyl cellulose (HPMC K15, HPMC K4) and PVP K30 as matrix formation polymers. Sodium bicarbonate and citric acid was used as gas generating agents. The FTIR spectra of the eperisone HCl and other excipients alone and in combination show the compatibility of the drug and excipients. Nine formulations of different polymer percentages were formulated (F1-F9). Pre-compression parameters were evaluated. The influence of matrix forming agents and binary mixtures of them on eperisone HCl release was investigated. The formulated tablets were characterized by thickness and diameter, drug content, hardness, friability, uniformity of weight, In vitro buoyancy studies and dissolution rate studies. The formulated tablets had acceptable physicochemical characters. The data obtained from the in-vitro dissolution studies of optimized batch F7 were fitted in different models. The optimized formulation F7 showed 99.45±0.45% drug content and floating lag times of 65±4 sec. Drug release mechanism was found to be first order kinetics. Eperisone HCl floating tablets exhibited increased gastric residence time, there by improved bioavailability and therapeutic effect of the drug. Keywords: Sustained release, Eperisone hydrochloride, Direct compression, Pre and post compression parameters

Diosgenin-loaded niosome as an effective phytochemical nanocarrier: physicochemical characterization, loading efficiency, and cytotoxicity assay.

The use of phytochemicals to prevent or suppress tumours is known as chemoprevention. Numerous plant-derived agents have been reported to have anticancer potentials. As one such anticancer phytochemical, diosgenin has several applications which are nevertheless limited due to its low solubility in water. We loaded diosgenin into niosome to increase its solubility and hence efficiency. Diosgenin-niosome (diosgenin loaded into niosome) was prepared by thin-film hydration method and characterised by optical microscopy, dynamic light scattering (DLS), scanning electron microscopy (SEM), and UV-visible spectrophotometry. Also, loading efficiency, in vitro drug release, and cytotoxicity assay were performed on HepG2 cell line. Diosgenin-niosome has a nanometric size with a normal size distribution and spherical morphology. The loading efficiency of diosgenin was about 89% with a sustainable and controllable release rate. Finally, the viability of free diosgenin was 61.25%, and after loading into niosomes, it was improved to 28.32%. The results demonstrated that niosomes increase the solubility of naturally derived hydrophobic chemicals and thus enhance their anticancer effect. Graphical abstract.

Stimuli-Responsive Graphene Nanohybrids for Biomedical Applications.

Stimuli-responsive materials, also known as smart materials, can change their structure and, consequently, original behavior in response to external or internal stimuli. This is due to the change in the interactions between the various functional groups. Graphene, which is a single layer of carbon atoms with a hexagonal morphology and has excellent physiochemical properties with a high surface area, is frequently used in materials science for various applications. Numerous surface functionalizations are possible for the graphene structure with different functional groups, which can be used to alter the properties of native materials. Graphene-based hybrids exhibit significant improvements in their native properties. Since functionalized graphene contains several reactive groups, the behavior of such hybrid materials can be easily tuned by changing the external conditions, which is very useful in biomedical applications. Enhanced cell proliferation and differentiation of stem cells was reported on the surfaces of graphene-based hybrids with negligible cytotoxicity. In addition, pH or light-induced drug delivery with a controlled release rate was observed for such nanohybrids. Besides, notable improvements in antimicrobial activity were observed for nanohybrids, which demonstrated their potential for biomedical applications. This review describes the physiochemical properties of graphene and graphene-based hybrid materials for stimuli-responsive drug delivery, tissue engineering, and antimicrobial applications.

Potential core-shell designed scaffolds with a gelatin-based shell in achieving controllable release rates of proteins for tissue engineering approaches.

The biomaterials design as core-shell structures opens a new door to the release of susceptible biomolecules in a controllable manner and enables to place natural biomaterials as shell layers to impart the effective biofunctional features at surfaces. In this study, core-shell designed scaffolds were prepared using coaxial electrospinning with hybrid of gelatin (GT)/polycaprolactone (PCL) at different weight ratios as their shell and protein solution as their core, followed by cross-linking to impart controllable release rates, tunable mechanical properties, and enhanced cytocompatibility. SEM, FM, and TEM confirmed the successful production of uniform core-shell nanofibers and homogeneous protein distribution. Results showed that an increase in GT proportion in the shell resulted in a decrease in fiber diameter, an increase of Young's modulus, and an intense burst release of BSA 0.2% which could be controlled through cross-linking. The mechanical tests revealed that the GT/PCL combining and cross-linking improved mechanical properties which correlated with an increase in spreading and proliferation of HUVECs. A slight burst release was also detected from BSA 0.05% and EGF encapsulated GT73P-cross-linked scaffold which demonstrated their applicability for a controlled release of dilute proteins. We were able to successfully incorporate two types of protein with different concentrations without supporting polymer into the GT shell to provide scaffolds possessing tunable mechanical properties and controllable release rates through blending with PCL at different ratios and/or cross-linking. These findings are promising to promote delivery systems of angiogenic growth factors that are needed a sustained release with different rates at each angiogenesis stage. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.

Inulin: A promising carrier for controlled and targeted drug delivery system

The delivery of a drug to the preferred site of action is referred to as drug targeting. The benefits of drug targeting are a reproducible and controlled release rate of the therapeutic compound, which forestalls overdose. Due to the potential to treat colonic diseases with minimum side effects, colon targeting has become of high interest over the last decades. Inulin was investigated for its potential as encapsulation material regarding its enzymatic degradability and its drug release behaviour. Inulin is a polysaccharide with a widespread range of therapeutic uses such as a carrier in a drug delivery vehicle, as a diagnostic/analytical tool or as a dietary fibre with additional health benefits. In the main, much research has focused on inulin as a drug delivery carrier for colon-specific drug delivery. The justification for this is its potential to survive in the stomach’s acidic environment. This unique stability and strength are utilized in many ways to deliver drugs safely to the colon, where they can be easily absorbed through the gut epithelium into the blood. There are also some proofs that inulin’s prebiotic features also lead to health benefits, mainly for patients with inflammatory bowel disease or in the prevention of colonic cancer. Inulin based hydrodynamic research will be useful to discover the potential of inulin.

Insight of Stability of Procyanidins in Free and Liposomal Form under an in Vitro Digestion Model: Study of Bioaccessibility, Kinetic Release Profile, Degradation, and Antioxidant Activity.

Small unilamellar and multilayered liposomes loaded with polymeric (epi)catechins up to pentamers were produced. The bioaccessibility, kinetic release profile, and degradation under in vitro gastrointestinal conditions were monitored by UHPLC-DAD-QTOF-MS/MS. The results show that all of the procyanidins underwent depolymerization and epimerization into small molecular oligomers and mainly to (epi)catechin subunits. Moreover, all of the liposome formulations presented higher bioaccessibility and antioxidant activity in comparison to their respective counterparts in non-encapsulated form. Similar results were obtained with procyanidins from cocoa extract-loaded liposomes. Namely, the bioaccessibility of dimer, trimer, and tetramer fractions from cocoa-loaded liposomes were 4.5-, 2.1-, and 9.3-fold higher than those from the non-encapsulated cocoa extract. Overall, the procyanidin release profile was dependent on their chemical structure and physicochemical interaction with the lipid carrier. These results confirmed that liposomes are efficient carriers to stabilize and transport procyanidins with the aim of enhancing their bioaccessibility at a controlled release rate.

Supramolecular Tuning of H2S Release from Aromatic Peptide Amphiphile Gels: Effect of Core Unit Substituents.

H2S is a gasotransmitter with several physiological roles, but its reactivity and short half-life in biological media make its controlled delivery difficult. For biological applications of the gas, hydrogels have the potential to deliver H2S with several advantages over other donor systems, including localized delivery, controlled release rates, biodegradation, and variable mechanical properties. In this study, we designed and evaluated peptide-based H2S-releasing hydrogels with controllable H2S delivery. The hydrogels were prepared from short, self-assembling aromatic peptide amphiphiles (APAs), functionalized on their N-terminus with S-aroylthiooximes (SATOs), which release H2S in response to a thiol trigger. The APAs were studied both in solution and in gel forms, with gelation initiated by addition of CaCl2. Various substituents were included on the SATO component of the APAs in order to evaluate their effects on self-assembled morphology and H2S release rate in both the solution and gel phases. Transmission electron microscopy (TEM) images confirmed that all H2S-releasing APAs self-assembled into nanofibers above a critical aggregation concentration (CAC) of ∼0.5 mg/mL. Below the CAC, substituents on the SATO group affected H2S release rates predictably in line with electronic effects (Hammett σ values) according to a linear free energy relationship. Above the CAC, circular dichroism, infrared, and fluorescence spectroscopies demonstrated that substituents influenced the self-assembled structures by affecting hydrogen bonding (β-sheet formation) and π-π stacking. At these concentrations, electronic control over release rates diminished, both in solution and in the gel form. Rather, the release rate depended primarily on the degree of organization in the β-sheets and the amount of π-π stacking. This supramolecular control over release rate may enable the evaluation of H2S-releasing hydrogels with different release rates in biological applications.

Nanoencapsulation of functional food ingredients.

Many functional food ingredients are poorly soluble in water, susceptible to chemical degradation, and incompatible with surrounding food matrix. Other issues are related to limited oral bioavailability, unpleasant sensory properties, and poor release profiles. Nanoencapsulation of functional food ingredients can help increase their water solubility/dispersibility in foods and beverages, improve their bioavailability by exhibiting good dose-dependent functionalities, mask undesired flavors/tastes to reduce the adverse effect on mouth-feel, enhance shelf-life and compatibility during production, storage, transportation and utilization of food products, and control release rate or specific delivery environment for better performance on their functionalities. This chapter provides an overview of different delivery systems for different functional food ingredients, the types of materials suitable for wall materials or building blocks of nanocapsules, the fabrication methods to assemble different delivery systems and release these active ingredients under different physiological conditions.

Increases in controlled-release oxycodone utilisation following the subsidy of oxycodone with naloxone formulations: An Australian population-based study.

Despite increasing use of oxycodone/naloxone controlled-release (CR) in Australia, little is known about how it has affected the overall oxycodone CR market since its subsidy in 2011. We used Pharmaceutical Benefits Scheme dispensing claims (2006-2016) and interrupted time series analysis to examine changes in the quarterly rates of dispensing of oral oxycodone CR formulations (oxycodone/naloxone CR and single-ingredient oxycodone CR) and new oxycodone CR treatment episodes. We also performed a retrospective cohort study in a sample of people initiating a new oxycodone CR treatment episode in 2009, 2012/2013, and 2016 to compare opioid utilisation patterns over time. The subsidy of oxycodone/naloxone CR was associated with a 1.6-fold increase in the growth rate of oxycodone CR dispensing, resulting from rapid uptake of low strength (≤5mg) oxycodone/naloxone CR. In our cohort of initiators, the number of new oxycodone CR treatment episodes increased 2.1-fold between 2009 and 2016; in 2016, 91.4% of new treatment episodes involved oxycodone/naloxone CR. Comparing 2016 with 2009, we observed an increase in people initiating with a tablet strength less than or equal to 5-mg (risk difference [RD]=21.1%, 95% CI, 19.9%-22.4%) in people initiating with no other opioid dispensing 90days prior to initiation (RD=5.2%, 3.8%-6.6%) and with no further opioid dispensing 90days after initiation (RD=8.8%, 7.4%-10.2%). After its subsidy, the uptake of low-dose oxycodone/naloxone CR was greater than expected if it were substituting the single-ingredient oxycodone CR, resulting in an expansion of the oxycodone CR market.

Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma

A dual-targeting drug delivery system for paclitaxel (PTX) was developed by functionalizing novel polyester-based nanoparticles (NPs) with peptides possessing special affinity for low-density lipoprotein receptor (LDLR), overcoming the limitations of the current chemotherapeutics, to transport drug from blood to brain, and then target glioma cells. Employing novel biodegradable block co-polymers (P and 2P), PTX loaded and peptide-functionalized nanoparticles were prepared by a modified nano-co-precipitation method, carried out in one step only without emulsifier, allowing to obtain spherical nanometric (<200 nm), monodisperse (PDI ∼ 0.1), Poly (Ethylene Glycol) (PEG)-coated and high PTX loaded NPs with a slow and controlled release rate for a prolonged period of time. Peptide functionalization, confirmed by fluorimetric assay and HPLC amino acids analysis, enhanced the cellular uptake of functionalized-PTX-NPs by human primary glioblastoma cell line (U-87 MG) and Bovine Brain Endothelial Cells (BBMVECs), compared with non-functionalized-PTX-NPs. To confirm dual-targeting effect, transendothelial transport experiments in an in vitro BBB model and in vitro anti-tumoral activity against U-87 MG revealed that peptide-functionalized-PTX-NPs significantly increased the transport ratio of PTX across the BBB along with an improved anti-proliferative efficiency. Pharmacokinetics and biodistribution studies in rats, carried out by in vivo experiments with 125I radiolabelled dual-targeting PTX-NPs, confirmed the stealthy behavior of NPs and indicated slightly lower levels of penetration into brain tissue in comparison with peptides known to be able to cross the BBB. These promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

적층 제조 기술을 이용한 지능형 약물 전달 시스템의 개발

A programmable drug delivery system can control the release rate of a drug. It can minimize side effects while maximizing therapeutic effects. In this research, we investigated the feasibility of producing a programmable drug delivery system using 3D printing technology. A capsule with a micro-orifice and a drug-laden hydrogel was designed. The designed system was then fabricated by the printing process using polycaprolactone and hydrogel. The printed drug delivery system was immersed in PBS at 37°C and the number of molecules released was measured thorough colorimetric analysis. The effect of diameter and length of the micro-orifice and concentration of the hydrogel on drug release characteristics was then determined. The initial burst release rate was found to be increased with increasing orifice size. Increasing the length of the orifice linearly delayed the start time of drug release. At length of 600 μm and 1,200 μm, drug release was initiated after 36 h and 72 h for, respectively. When the concentration of hydrogel was increased, drug release rate tended to decrease. These results successfully confirmed that a drug delivery system with controlled release rate and initiation time could be manufactured using 3D printing technology.

Risperidone Controlled Release Microspheres Based on Poly(Lactic Acid)-Poly(Propylene Adipate) Novel Polymer Blends Appropriate for Long Acting Injectable Formulations.

The present study evaluates the preparation of risperidone controlled release microspheres as appropriate long-acting injectable formulations based on a series of novel biodegradable and biocompatible poly(lactic acid)–poly(propylene adipate) (PLA/PPAd) polymer blends. Initially, PPAd was synthesized using a two-stage melt polycondensation method (esterification and polycondensation) and characterized by 1H-NMR, differential scanning calorimetry (DSC), and powder X-ray diffraction (XRD) analyses. DSC and XRD results for PLA/PPAd blends (prepared by the solvent evaporation method) showed that these are immiscible, while enzymatic hydrolysis studies performed at 37 °C showed increased mass loss for PPAd compared to PLA. Risperidone-polyester microparticles prepared by the oil–water emulsification/solvent evaporation method showed smooth spherical surface with particle sizes from 1 to 15 μm. DSC, XRD, and Fourier-transformed infrared (FTIR) analyses showed that the active pharmaceutical ingredient (API) was dispersed in the amorphous phase within the polymer matrices, whereas in vitro drug release studies showed risperidone controlled release rates in all PLA/PPAd blend formulations. Finally, statistical moment analysis showed that polyester hydrolysis had a major impact on API release kinetics, while in PLA/PPAd blends with high PLA content, drug release was mainly controlled by diffusion.

Fabrication of PAA-PETPTA Janus Microspheres with Respiratory Function for Controlled Release of Guests with Different Sizes.

Poly(acrylic acid)-poly(ethoxylated trimethylolpropane triacrylate) (PAA-PETPTA) Janus microspheres with "respiratory" function for controlled release were prepared by polymerization of acrylic acid-ethoxylated trimethylolpropane triacrylate (AA-ETPTA) Janus microdroplets in a continuous oil phase in a simple capillary-based microfluidic device with the assistance of UV radiation. The flow rate ratios of AA and ETPTA phases and surfactant content in the continuous oil phase have a significant effect on the structure of the Janus microspheres. PAA part in the Janus microspheres has respiratory function for loading and release due to the different stimuli responses to different pHs. The hollow structure of PETPTA part with different sizes of opening serves as the host materials for PAA and could control release rate further due to the different opening sizes. The obtained PAA-PETPTA Janus microspheres showed high rhodamine B (RhB) loading of 860 mg g-1 and different controlled-release behavior in water with different pHs. The release rate increases with the increase of pH and the contact area of PAA part with water. The maximum controlled-release time for RhB was about 3 h in water with pH of 5. In addition, the Janus microspheres also showed controlled-release behavior for larger size guests, e.g., 150 nm polystyrene beads, which indicated a wide range of application. The loading and release behaviors for guests, for instance, for RhB, have almost no change even after six times of reuse, which indicated a high stability.

Hot melt granulation method for the preparation of floating matrix tablets of Tolperison Hydrochloride

Tolperisone HCl is a centrally muscles relaxant drug. It is a highly water-soluble drug. It has a biological half-life of 1.5–2.5 h. It has absorption window in the small intestine and unstable in intestinal pH 4 to 7. Gastroretentive drug delivery systems have shown to be of better significance in controlling release rate for drug having site specific absorption. The aim of the present investigation was to develop effervescent floating matrix tablets of Tolperisone Hydrochloride. Cetyl alcohol was selected to prepare hot melt granules (HMG) of Tolperisone HCl. Effervescent floating matrix tablet was prepared using cetyl alcohol as lipophilic surfactant and HPMC K100M as hydrophilic polymers. The HMG based floating matrix tablets were optimized by 32 full factorial design to study the effect of independent variables, i.e. amount of cetyl alcohol (X1) and amount of HPMC K100M (X2) on dependent variables like % swelling index (Y1), time required to 50% drug released(t50)(Y2) and time required for 90% drug release (t90)(Y3). From the regression analysis, it was observed that selected two independent variables show significant effect on response variables. From the results obtained, F10 formulation (58.10 mg of cetyl alcohol, 147.18 mg of HPMC K100M) was selected as optimized batch which showed optimum floating lag time (14 s), drug content (102.78 ± 2.15%), %swelling index (182.63 ± 2.15 at 12 h), t50 (310.2 min) and t90(649.8 min). Thus, the effervescent floating matrix tablets based on HMG is suitable to get site specific delivery and controlled release of Tolperisone HCl.

Controlled-Release Matrixes for Drugs Based on Polyamide-Polyhydroxybutyrate Compositions

The transport properties of films based on poly(3-hydroxybutyrate) (PHB) and polyamide were studied. The factor responsible for the rate of controlled release of antiseptic from film compositions was the link between diffusion and PHB destruction. A model of this process and measurements of the coefficients of diffusion of an antiseptic are presented. The fundamental possibility of using these compositions as matrix systems for prolonged (more than one month) controlled delivery of a model pharmaceutical (the antiseptic furacillin) with constant and controllable release rates is discussed. The study matrixes could be used as wound coverings (dressings).

Simulation of Stimuli-Responsive and Stoichiometrically Controlled Release Rate of Doxorubicin from Liposomes in Tumor Interstitial Fluid.

To simulate the stimuli-responsive and stoichiometrically controlled doxorubicin (DOX) release from liposomes in in vivo tumor interstitial fluid (TIF), the effect of ammonia concentration and pH on the DOX release from liposomes in human plasma at 37°C was quantitatively evaluated in vitro and the release rate was calculated as a function of ammonia concentration and pH. Human plasma samples spiked with DOX-loaded PEGylated liposomes (PLD) or Doxil®, containing ammonia (0.3-50mM) at different pH values, were incubated at 37°C for 24h. After incubation, the concentration of encapsulated DOX in the samples was determined by validated solid-phase extraction (SPE)-SPE-high performance liquid chromatography. Accelerated DOX release (%) from liposomes was observed as the increase of ammonia concentration and pH of the matrix, and the decrease of encapsulated DOX concentration. The release rate was expressed as a function of the ammonia concentration and pH by using Henderson-Hasselbalch equation. The DOX release from PLD in TIF was expressed as a function ammonia concentration and pH at various DOX concentrations. Further, it was found that the DOX release from liposomes in a simulated TIF was more than 15 times higher than in normal plasma.

Manufacturing and Optimization the Nanofibres Tissue of Poly(N-vinyl-2-pyrrolidone) - Poly(e-caprolactone) Shell/Poly(N-vinyl-2-pyrrolidone)-Amphotericin B Core for Controlled Drug Release System

Controlled release of drugs is important to reduce the amount of medication in treatment of any diseases and improves life quality. Poly(e-caprolactone) (PCL) has a low biodegradation rate that is a disadvantage in the biomedical and pharmaceutical fields. Poly(N-vinyl-2-pyrrolidone) (PVP) is a water-soluble polymer that to overcome of PCL low biodegradation rate, electrospinning of PCL blended with PVP was used for shell of nanofibers with controllable degradation rates and drug release rates. Oral and vaginal mucosal infections mainly caused by candida albicans. It is usually a harmless commensal organism; however it is known as an opportunistic pathogen for almost immunologically week and immune compromised people. Amphotericin-B (AmB) is a strong polyene antifungal antibiotic that has a significantly efficacy on candida albicans. This study is manufactured and optimized the PVP-PCL shell/PVP-AmB core nanofiberous tissue by working distance and feed flow rate for controlled drug release. AmB with PVP was successfully inserted into the core. PVPPCL shell (50/50)/PVP-AmB core nanofiberous were electrospinning with two optimum distances working and two flow rates. The mechanical properties of coaxial nanofibers were analyzed by instron machine. Scanning electron microscopy and transmission electron microscopy was used for analysis morphology. Further, drug release test were done for coaxial nanofibers with AmB different morphologies. The effect of flow rate and working distance on morphology and mechanical properties were evaluated by statistical two-way analysis of the variance (ANOVA). The diameter averages of nanofibers were decreased significantly by increasing working distance. Moreover, the stress and strain were increased by increasing working distance. Coaxial nanofibers biodegradability rate and drug release of nanofibers were increased also by increasing working distance and flow rate of core. Nanofibers drug release mechanism was indicated by Korsmeyer-Peppas which they followed fick′s lows and Higuchi model significantly. Also, results presented that biodegradability and drug release rate accelerate with increasing the working distance and increasing the amount of PVP in core.

Nasal Delivery of Antioxidants by Cholesterol-incorporated Liposomes Extends the Neuroprotective Time Window in Cerebral Ischemia.

Antioxidants have the potential to prevent cerebral ischemia-reperfusion (IR)-associated secondary damage induced by reactive oxygen species (ROS); however, the short therapeutic time window of IR is a considerable obstacle. Nano-sized nasal delivery systems provide an effective means of delivering drugs through the BBB, but few such systems have been developed to extend the treatment time window in IR. In this work, a nanosized nasal delivery system for antioxidants was found to have the potential to extend the neuroprotective time window. The authors chose to use the antioxidant C-phycocyanin (C-Pc) to design a neuroprotective liposome with a long life, controllable release, and high neuronal uptake rate. Liposomes formulated with various cholesterol to phospholipid ratios were assessed thermodynamically, kinetically, and biologically. Thermodynamically stable, monodispersive, and release-controllable C-Pc liposomes were more effectively taken up by Neuro2a cells than free C-Pc and were biocompatible, maintaining the anti-oxidative properties of C-Pc. When optimal C-Pc liposomes were administered to middle cerebral artery occlusion (MCAO) rats 2 h after onset, infarct sizes were smaller and behavioral activities improved compared with the same metrics in free C-Pc-treated rats. Liposomal delivery still reduced infarct sizes and improved behavioral activity 6 h after onset, whereas free C-Pc did not.

Improved magnetic regulation of delivery profiles from ferrogels

While providing the ability to magnetically enhance delivery rates, ferrogels have not been able to produce the various types of regulated delivery profiles likely needed to direct complex biological processes. For example, magnetically triggered release after prolonged periods of payload retention have not been demonstrated and little has been accomplished towards remotely controlling release rate through alterations in the magnetic signal. Also, strategies do not exist for magnetically coordinating multi-drug sequences. The purpose of this study was to develop these capabilities through improved ferrogel design and investigating how alterations in the magnetic signal impact release characteristics. Results show that delivery rate can be remotely regulated using the frequency of magnetic stimulation. When using an optimized biphasic ferrogel design, stimulation at optimized frequencies enabled magnetically triggered deliveries after a delay of 5 days that were 690- to 1950-fold higher than unstimulated baseline values. Also, a sequence of two payloads was produced by allowing one payload to initially diffuse out of the ferrogel, followed by magnetically triggered release of a different payload on day 5. Finally, it was demonstrated that two payloads could be sequentially triggered for release by first stimulating at a frequency tuned to preferentially release one payload (after 24 h), followed by stimulation at a different frequency tuned to preferentially release the other payload (After 4 days). The strategies developed here may expand the utility of ferrogels in clinical scenarios where the timing and sequence of biological events can be tuned to optimize therapeutic outcome.

Mucoadhesive alginate pastes with embedded liposomes for local oral drug delivery

Oral cancers are extremely common among adults with increasing incidences due to human papillomavirus, while treatment modalities are limited. This study aims to develop a new oral mucoadhesive delivery system based on the combination of alginate and liposomes. The polymer provides adhesion properties and induces local release of the drug-loaded carriers, while the liposomes protect the drug from degradation and improve its absorption into the cells. Three hybrid alginate/liposomes delivery systems were investigated: a hybrid paste, which presented excellent adhesive capabilities, yet fast burst release of 90% after 2h; a hybrid hydrogel, demonstrating controllable release rates of 5%, 30% or 60% after 2h but poor mucoadhesive properties. These findings led to the development of a hybrid cross-linked paste. Polymer retention studies demonstrated that 80% of the crosslinked paste was retained on tongue tissue compared to 50% retention of the non-cross-linked pastes, verifying its superior mucoadhesion. The hybrid cross-linked paste presented controllable release rate of 20% after 2h. Alginate paste incorporating doxorubicin loaded liposomes presented similar release rates and were highly effective in promoting cancer cell death. Thus, our innovative formulation, including both desired characteristics of mucoadhesion and sustained liposomes release, is an important milestone in the development of a new potential treatment for oral cancer.