Fast Drug Delivery Research Articles

Multi-material 3D printed eutectogel microneedle patches integrated with fast customization and tunable drug delivery

Microneedle patches are emerging multifunctional platforms for transdermal diagnostics and drug delivery. However, it still remains challenging to develop smart microneedles integrated with customization, sensing, detection and drug delivery by 3D printing strategy. Here, we present an innovative but facile strategy to rationally design and fabricate multifunctional eutectogel microneedle (EMN) patches via multi-material 3D printing. Polymerizable deep eutectic solvents (PDES) were selected as printing inks for rapid one-step fabrication of 3D printing functional EMN patches due to fast photopolymerization rate and ultrahigh drug solubility. Moreover, stretchable EMN patches incorporating rigid needles and flexible backing layers were easily realized by changing PDES compositions of multi-material 3D printing. Meanwhile, we developed multifunctional smart multi-material EMN patches capable of performing wireless monitoring of body movements, painless colorimetric glucose detection, and controlled transdermal drug delivery. Thus, such multi-material EMN system could provide an effective platform for the painless diagnosis, detection, and therapy of a variety of diseases.

Oral fast-dissolving risperidone loaded electrospun nanofiber drug delivery systems for antipsychotic therapy

Risperidone is an antipsychotic drug classified as BCS Class II with low solubility at physiological pH and orally used in the treatment of schizophrenia. Electrospinning is one of the newest fabrication methods used for the development of fast soluble drug delivery systems. In this study, an orally disintegrating film (ODF) formulation of risperidone was developed with green electrospinning technique. Different molecular weight polyethylene oxide (PEO) as a polymer and xylitol or Kollidon VA64 as a disintegration agent were used for the preparation of formulations. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR) analyses were conducted as part of pre-formulation studies to identify possible incompatibilities in formulation components. We characterized ODFs based on their mechanical properties, shape and diameter of nanofibers, disintegration behavior, and in vitro dissolution profiles. A few wrinkles appeared on the surface of fibers prepared with xylitol, but a smooth surface was evident on Kollidon VA64 fibers. Disintegration studies performed in the simulated oral environment showed that ODFs disintegrate in as little as 1 s. The dissolution behavior of developed ODFs and commercial products was compared with a dissolution study in distilled water. The chosen formulations had acceptable mechanical properties with much faster dissolution compared to the commercially available product. In this study, risperidone ODF formulation was successfully produced and characterized. The study showed that risperidone-loaded nanofibers could provide a promising alternative to conventional oral dosage forms like tablets and capsules.

Comparison of Hydroxypropyl Methylcellulose and Alginate Gel Films with Meloxicam as Fast Orodispersible Drug Delivery.

The aim of the study was the preparation and comparison of two types of orodispersible gel films (ODF) by the solvent casting method. Natural polymers: sodium alginate (ALG) or hydroxypropyl methylcellulose (HPMC) were used as the gel film formers, and Kollidon or microcrystalline cellulose was used as the disintegrant. Meloxicam (MLX), the drug used to treat rheumatic diseases for children and adults, was proposed as the active pharmaceutical ingredient (API). The influence of the polymer and disintegrant on the properties of ODF was investigated. The evaluation of prepared gel films was based on appearance description, mass uniformity measurement, disintegration time, API content, film wettability, and water content. Also, the dissolution test was prepared in a basket apparatus using artificial salvia (pH = 6.8) as the medium. The obtained API release profiles were analyzed for the similarity factors (f2) with the DDSolver software. The results showed that independently of the polymer or disintegrant, using the solvent casting method, gel films have a similar appearance and active substance content close to the theoretical value and water content of less than 10%. Only the type of polymer influences the release profiles of MLX. However, the disintegration time was longer than 30 s, which makes the films non-fast-dissolving drug delivery systems. This means that for the ODF system, further evaluation is required, and some changes in the composition of the film have to be done.

Design, Development and Optimization of Solid Lipid Nanoparticles of Rizatriptan for Intranasal delivery: Invitro & Invivo assessment

Solid lipid nanoparticles were at the frontline of the rapid development of nanotechnology, with several potential applications in drug administration. Because of their unique size-dependent properties, solid lipid nanoparticles have the potential to produce innovative treatments. The capacity to incorporate drugs into nanocarriers allows for the creation of a revolutionary drug delivery prototype that might be utilized for targeting novel drugs to the brain. RZT benzoate intra nasal formulation would be a practical, non-invasive, & alternative method of fast drug delivery to the brain for migraine treatment. Poloxamer-containing solid lipid nanoparticles having mucoadhesive characteristics improve drug absorption by increasing contact duration at the nasal mucosa. Shape, surface morphology, particle size, FTIR, DSC, X-ray diffraction tests, drug entrapment, total drug content, and in vitro drug release studies were all performed on RZT-loaded solid lipid nanoparticles created utilizing a modified solvent diffusion method. There was a wide range in particle size from 124.9 to 467.2 nm for these lipid nanoparticles, all of which were spherical and smooth on the outside. There was a maximum in vitro drug release of 92.6% in 24 h, a drug content of 45–55%, and a maximum entrapment efficacy of 78.6 percent. When administered through the nose, RZT benzoate may be more bioavailable than when taken orally, overcoming the first-pass impact and allowing for a long-term therapy plan for acute migraine.

Applicability of Hyperdimensional Computing to Seizure Detection

Hyperdimensional (HD) computing is a form of brain-inspired computing which can be applied to numerous classification problems. In past research, it has been shown that seizures can be detected from electroencephalograms (EEG) with high accuracy using local binary pattern (LBP) encoding. This paper explores applicability of binary HD computing to seizure detection from intra-cranial EEG (iEEG) data from the Kaggle seizure detection contest based on using both LBP and power spectral density (PSD) features. In the PSD method, three novel approaches to HD classification are presented for both selected features and all features. These are referred as <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">single classifier long hypervector</i> , <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">multiple classifiers</i> , and <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">single classifier short hypervector</i> . To visualize the quality of classification of test data, a <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">hypervector distance</i> plot is introduced that plots the Hamming distance of the query hpervectors from one class hypervector <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">vs.</i> that from the other. Simulation results show that: <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1)</i> . LBP method offers an average 80.9% test accuracy, 71.9% sensitivity, 81.4% specificity and 76.6% test AUC whereas the PSD method can achieve an average of 91.0% test accuracy, 81.8% sensitivity, 92.0% specificity and 86.9% test AUC. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2)</i> . The average seizure detection latency is 2.5s for LBP method and is 4.5s for the PSD methods. This average latency, less than 5s, is a relevant parameter for fast drug delivery, indicating that both LBP and PSD methods are able to detect the seizures in a timely manner. The performance using selected PSD features is better than that using all features. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3)</i> . It is shown that the dimensionality of the hypervector can be reduced to 1, 000 bits for LBP and PSD methods from 10, 000. Futhermore, for some approaches of selected features, the dimensionality of the hypervector can be reduced to 100 bits.

Numerical simulation of intracellular drug delivery via rapid squeezing.

Intracellular drug delivery by rapid squeezing is one of the most recent and simple cell membrane disruption-mediated drug encapsulation approaches. In this method, cell membranes are perforated in a microfluidic setup due to rapid cell deformation during squeezing through constricted channels. While squeezing-based drug loading has been successful in loading drug molecules into various cell types, such as immune cells, cancer cells, and other primary cells, there is so far no comprehensive understanding of the pore opening mechanism on the cell membrane and the systematic analysis on how different channel geometries and squeezing speed influence drug loading. This article aims to develop a three-dimensional computational model to study the intracellular delivery for compound cells squeezing through microfluidic channels. The Lattice Boltzmann method, as the flow solver, integrated with a spring-connected network via frictional coupling, is employed to capture compound capsule dynamics over fast squeezing. The pore size is proportional to the local areal strain of triangular patches on the compound cell through mathematical correlations derived from molecular dynamics and coarse-grained molecular dynamics simulations. We quantify the drug concentration inside the cell cytoplasm by introducing a new mathematical model for passive diffusion after squeezing. Compared to the existing models, the proposed model does not have any empirical parameters that depend on operating conditions and device geometry. Since the compound cell model is new, it is validated by simulating a nucleated cell under a simple shear flow at different capillary numbers and comparing the results with other numerical models reported in literature. The cell deformation during squeezing is also compared with the pattern found from our compound cell squeezing experiment. Afterward, compound cell squeezing is modeled for different cell squeezing velocities, constriction lengths, and constriction widths. We reported the instantaneous cell center velocity, variations of axial and vertical cell dimensions, cell porosity, and normalized drug concentration to shed light on the underlying physics in fast squeezing-based drug delivery. Consistent with experimental findings in the literature, the numerical results confirm that constriction width reduction, constriction length enlargement, and average cell velocity promote intracellular drug delivery. The results show that the existence of the nucleus increases cell porosity and loaded drug concentration after squeezing. Given geometrical parameters and cell average velocity, the maximum porosity is achieved at three different locations: constriction entrance, constriction middle part, and outside the constriction. Our numerical results provide reasonable justifications for experimental findings on the influences of constriction geometry and cell velocity on the performance of cell-squeezing delivery. We expect this model can help design and optimize squeezing-based cargo delivery.

Intramuscular adrenaline for out-of-hospital cardiac arrest is associated with faster drug delivery: A feasibility study

BackgroundEarly adrenaline administration is associated with return of spontaneous circulation (ROSC) and survival in out-of-hospital cardiac arrest (OHCA). Animal data demonstrate a similar rate of ROSC when early intramuscular (IM) adrenaline is given compared to early intravenous (IV) adrenaline. AimTo evaluate the feasibility of protocolized first-dose IM adrenaline in OHCA and it’s effect on time from Public Safety Access Point (PSAP) call receipt to adrenaline administration when compared to IO and IV administration. MethodsThis is a before-and-after feasibility study of adult OHCAs in a single EMS service following adoption of a protocol for first-dose IM adrenaline. Time from PSAP call to administration and outcomes were compared to 674 historical controls (from January 1, 2013–February 8, 2021) who received at least one dose of adrenaline by IV or IO routes. ResultsDuring the study period, first-dose IM adrenaline was administered to 99 patients (December 1, 2019–February 8, 2021). IM adrenaline was given a median of 12.2 min (95% CI 11.4–13.1 min) after the PSAP call receipt compared to 15.3 min for the IV route (95% CI 14.6–16.0 min) and 15.3 min for the IO route (95% CI 14.9–15.7 min) with a time savings of 3 min (95% CI 2–4 min). Rates of survival to hospital discharge appeared similar between groups: 10% for IM, 8% for IV and 7% for IO. However, results related to survival were underpowered for statistical comparison. ConclusionsWithin the limitations of a small sample size and before-and-after design, first-dose IM adrenaline was feasible and reduced the time to adrenaline administration.

Smart magnetocaloric coatings for implants: Controlled drug release for targeted delivery

Among the medical applications of the magnetocaloric effect (MCE) a technology of targeted drug delivery (TDD) is of great interest. The remote, noninvasive drug delivery to human organs or tissues is one of the actual challenges at present. Delivery devices, which provide a controlled, reproducible and reliable drug release, can have a significant impact on the treatment of different diseases. An ideal device for the fast drug delivery should contain a great amount of medication, should not practically release the drug in the off state, be able to repeatedly switch to the on state without mechanical damage, not require the implanted electronics, and be able to release a controlled dose of drug as stated in the physician’s prescription.This paper describes a composite material to coat implants and other drug carriers, which enables to control the quantity and the period of medication release. The paper also offers the results of thermodynamic model’s analysis of these medical devices based on the properties of ‘polymer/magnetic material’ composite systems. The results of magnetic and nonmagnetic nanoparticles deposition on the fragments of abdominal meshes are also presented.

Microfluidic interface boosted synthesis of covalent organic polymer capsule

Microcapsules have been widely used in drug carriers, nano/microreactors, artificial organelles for their empty space and functional shell. Microcapsules synthesized from spherical liquid-liquid interface show ultrathin shell and large cavities. However, spherical liquid-liquid interfaces generated by stirring or sonicating are difficult in controlling the droplet size and preventing their coalescence, which results in inhomogeneous capsules. Here, we demonstrate a microfluidic interfacial synthetic method to produce microcapsules using the hot covalent organic polymers (COPs) coupled with Schiff-base reaction. A very high throughput of uniform and individual microdroplets about ~1400 min−1 was generated under high flow rate for COP capsules fabrication. Acidic catalyst promoted amine and aldehyde condensation that reacted less than 1 ​s assured the polymerization occurred at the liquid-liquid interface regardless of the diffusion intensification in microfluidic system. COP capsules with shell thickness around 50 ​nm were flexible enough to response to slight interior capillary force and exterior filtration force to form origami structure and sealed flat membrane, respectively. Each of the interfacial synthesized capsule expressed large capacity by encapsulating 1.41 ​× ​10−2 ​μg SiO2 nanoparticles as theoretically calculated. Thus, these properties make the COP capsules promising in, but not limited to, fast drug delivery and microreactors.

Model-based analysis on systemic availability of co-administered cannabinoids after controlled vaporised administration.

The most important two medicinal cannabinoids are Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown. To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users. The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study. Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered. The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the 'real-world' setting.

Simultaneous investigation of the liquid transport and swelling performance during tablet disintegration.

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body.

Amino acid‐derived Poly(L‐Lysine) (p(LL)) microgel as a versatile biomaterial: Hydrolytically degradable, drug carrying, chemically modifiable and antimicrobial material

Here, a microgel of poly(L‐Lysine) (p(LL)) from an amino acid, L‐Lysine, was synthesized by microemulsion technique using AOT as surfactant in gasoline. The prepared p(LL) microgel was shown to be hydrolytically degradable at pH values of 5.4, 7.4, and 9 in phosphate buffer solution (PBS). The protonated p(LL) microgel was loaded with model drugs such as naproxen and riboflavin and found to release about 80% of loaded naproxen in 180 minutes and 70% of loaded riboflavin in about 120 minutes suggesting the potential of p(LL) microgels to act as fast drug delivery vehicles. Furthermore, p(LL) microgels were chemically modified with 1‐bromoethane (BE), 1‐bromooctane (BO), and 1‐bromoethylamine (BEA) to render antimicrobial capabilities. It was found that protonated p(LL) microgels had 29 ± 1 mm inhibition zone diameter for Pseudomonas aeruginosa ATCC 10145. Furthermore, minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) values for Staphylococcus aureus ATCC 6538 were also calculated as 1 and 2.5 mg/mL concentrations, respectively, for protonated p(LL) microgels.

The Effect of Ethanol on Gelation, Nanoscopic, and Macroscopic Properties of Serum Albumin Hydrogels.

Serum albumin has shown great potential in the development of new biomaterials for drug delivery systems. Different methods have been proposed to synthesis hydrogels out of serum albumin. It has been observed that ethanol can also act as a trigger for serum albumin denaturation and subsequent gelation. In this study, we focus on basic mechanisms of the albumin gelation process at 37 °C when using the chemical denaturant ethanol. The temperature of 37 °C was chosen to resemble human body temperature, and as under physiological conditions, albumin is in a non-denatured N conformation. As established in our previous publication for the triggers of pH and temperature (and time), we here explore the conformational and physical properties space of albumin hydrogels when they are ethanol-induced and show that the use of ethanol can be advisable for certain gel properties on the nanoscopic and macroscopic scale. To this end, we combine spectroscopic and mechanically (rheology) based data for characterizing the gels. We also study the gels′ binding capacities for fatty acids with electron paramagnetic resonance (EPR) spectroscopy, which implies observing the effects of bound stearic acids on gelation. Ethanol reduces the fraction of the strongly bound FAs in bovine serum albumin (BSA) hydrogels up to 52% and induces BSA hydrogels with a maximum storage modulus of 5000 Pa. The loosely bound FAs in ethanol-based hydrogels, besides their relatively weak mechanical properties, introduce interesting new materials for fast drug delivery systems and beyond.

High Dependence on Medicare and Foundation Grant Assistance Among Patients with Hematologic Malignancies Receiving Novel Oral Therapeutics

Introduction: Oral novel therapeutics place a high financial burden on patients. A specialty pharmacy at Karmanos Cancer Institute (KCI) was established which streamlines prior authorization, determines patient cost-sharing, then automatically applies for additional financial assistance (through co-pay cards or foundation grant funding as needed) prior to setting final patient cost-sharing and drug delivery. We evaluated patterns of cost and need for additional funding since this program was established. Methods: We used the KCI Specialty Pharmacy dataset for a retrospective review of patients who received prescriptions for hematologic malignancies between March 2018 - May 2019. Oral therapeutics &amp;gt;$10,000/month average wholesale price were considered high cost. We evaluated patients by drug prescribed and insurance type (Medicare, Medicaid, Private) and gathered information on insurer cost, final patient cost-sharing, cost covered by foundation grant assistance (if needed), and cost covered by manufacturer co-pay cards (if needed). We also calculated time in days from prescription written date to date of prior authorization, as well as prescription written date to date of delivery to the patient for all new first-time prescriptions. Results: 214 prescriptions among 100 patients were available for analysis. 2 of these patients switched insurance types. Drugs that were evaluated included imatinib, dasatinib, bosutinib, nilotinib, ponatinib, ruloxitinib, venetoclax, acalabrutinib, ibrutinib, ixazomib, midostaurin, gilteritinib, everolimus (for relapsed Hodgkin lymphoma), vorinostat, and enasidenib. The majority of patients had Medicare +/- supplemental insurance (52%), followed by private insurance (33%), and Medicaid (17%). Among all patients, 35% required additional financial assistance (for 75 claims). Most of these were through foundation grant funding (26% of all patients, 59 claims) and the remaining through manufacturer co-pay cards (9% of all patients, 16 claims). Medicaid patients did not require additional financial aid and have low cost-sharing given cost-sharing subsidies provided by Medicaid. Most of the patients requiring financial assistance were Medicare patients receiving foundation grant funding (Table). There were 10% of patients who did not receive additional assistance, but had high cost-sharing exceeding $100/prescription (range $295-$3514). Claims costs for all prescriptions totaled just over $2,000,000. The majority of the cost was paid by insurers with more than half covered by Medicare, ~$52,950 paid by foundation grant assistance, ~$8,486 paid by manufacturer co-pay cards, and $23,818 by patient cost-sharing. There were 105 first-time prescriptions to evaluate. When comparing the times required for prior authorization and delivery of drugs to patients, median times were similar by insurance type (Table), and most prescriptions received prior authorization approval within 1 day and were delivered within 7 days. Conclusions: Financial assistance was needed for 35% of all patients on novel therapeutics, mostly through foundation grant assistance. Medicare covered half of total 2 million dollar cost. Medicare patients bear the most burden, with 40% requiring foundation grant assistance, and 19% acquiring high co-pays. The KCI Specialty Pharmacy attained a total of ~$61,433 in financial assistance, and provided an efficient process for fast authorization and drug delivery which did not vary by insurance type or need for grants. Disclosures Smith: Genentech Advisory Council: Other: Pharmacy Consultant.

Development of Rizatriptan Mouth Dissolving Films: A Fast Absorbing Drug Delivery System for Effective Treatment of Migraine

The aim of this investigation was to develop Rizatriptan (RIZ) mouth dissolving films (MDFs)and evaluate the effect of formulation variables like film thickness, plasticizers, film formers and solubilizing agents on physicomechanical, chemical and drug release properties of MDFs. MDFs were prepared (using wet film applicator, a commercially scalable technique) using Hydroxy propyl methyl cellulose (HPMC) of different viscosity grades (E3, E5 and E15) as film former, PEG 400 and glycerol as plasticizers. FTIR studies showed no RIZ-excipient interactions in the MDF formulations. Photomicrographs together with DSC and X-RD studies confirmed the absence of RIZ recrystallization within the MDFs. MDFs of higher film thickness were brittle with low tensile strength values indicating an inverse relationship between film thickness and tensile strength. Whereas, increase in polymer viscosity increased the tensile strength of MDFs and about a 2.6fold increase in tensile strength was obtained with HPMC E15 MDFs compared to E3. In vitro drug release studies revealed that higher film thickness and polymer viscosities delayed the RIZ release from MDFs and the release was in the order of E3>E5>E15. Addition of solubilizing agents (PVP K30 and SLS) to the E3 formulations resulted in 2 and 1.43 fold faster RIZ release compared to formulations without them. Overall, F11 formulation (1% w/w RIZ+7.5% w/w HPMC E3+0.04% w/w PVP K30+0.5% w/w PEG 400) showed faster disintegration (within 8sec) and RIZ release rates (complete release was obtained in 60sec) compared to other formulations. The MDFs showed 98102% RIZ content even after 6months time period indicating that the RIZ was stable in MDF formulations.

Acetaminophen loaded nanofibers as a potential contact layer for pain management in Burn wounds

Application of drugs at local site is beneficial with less side effects. This study dealt with the development of nanofibers (NFs) based drug delivery system for local pain management in burn wounds with acetaminophen as model drug which has been proven to be an effective pain killer in mid to moderate burn wounds. The electrospinning process parameters were optimized by using Taguchi method. The optimized NFs were then selected for further characterization i.e. Fourier Transform Infra-Red Spectroscopy (FTIR), Scanning Electron Microscope (SEM), x-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC). The NFs final diameter varied from 185 to 375 nm. The optimized NFs showed good liquid absorption properties (∼11 g g−1) with fast release of drug (∼80% in 60 min). The equilibrium drug release data was best followed by Ritger-Peppas kinetic model and showed case II transport mechanism. FTIR analysis confirmed that the drug was successfully incorporated within the NFs. DSC and XRD confirmed that the addition of drug increased the crystallinity of NFs but reduced the liquid absorption to some extent. The desired fast drug delivery along with good liquid absorption and moist environment of the fabricated NFs could be promising solution to manage pain in burn wounds at local site.

Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin™) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 μm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1nu showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 1010 ± 2.5 × 1010 and 3.8 × 109 ± 1.6 × 109 p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.

Highly Selective Photodynamic Therapy with a Short Drug-Light Interval Using a Cytotoxic Photosensitizer Porphyrus Envelope for Drug-Resistant Prostate Cancer Cells

Background: Photodynamic therapy (PDT) is a less invasive cancer treatment using photochemical reactions induced by light irradiation to a photosensitizer (PS). Highly selective PDT with fast accumulation of the PS in target site might be a promising treatment option for drug-resistant prostate cancer facing high incidence rate of elderly men who have no effective treatment options and require a minimally invasive treatment. Hemagglutinating virus of Japan envelope (HVJ-E) allows selective and fast drug delivery to the drug-resistant prostate cancer cells via rapid cell membrane fusion. PS named porphyrus envelope (PE) has been developed by insertion of lipidated protoporphyrin IX (PpIX lipid) into HVJ-E. In this study, we investigated the optimal conditions for PE preparation and laser irradiation for highly selective PDT using PE with a short drug-light interval. Materials and Methods: Human hormon refractory prostate cancer cell line PC-3 and human normal prostate epithelial cell line PNT2 were cultured. PpIX lipid uptake and cytotoxicity of PDT in the cells incubated with PE for 10 min were evaluated by measuring fluorescence intensity and by using a cell counting reagent 24 h after PDT, respectively. Results: PpIX lipid uptake and cytotoxicity of PDT were increased with PpIX lipid concentration. Cytotoxicity of PDT using PE was more than 9 times as strong as that with PpIX lipid and PpIX induced by 5-aminolevulinic acid. Much stronger cytotoxicity was induced in PC-3 cells than PNT2 cells with the ratio of cell death rate for cancer to normal cells up to 4.64 ± 0.09. Conclusions: Fast PS delivery with HVJ-E allows highly selective PDT with a short drug-light interval. Therefore, PDT using PE has a potential to shorten treatment period and reduce side effects of PDT.

Nanoengineering of Core-Shell Magnetic Mesoporous Microspheres with Tunable Surface Roughness.

Functional core-shell mesoporous microspheres with integrated functions, controlled structure, and surface properties and morphologies have received increasing attention due to their excellent physicochemical properties. Herein, core-shell magnetic mesoporous materials with cauliflower-like morphology and tunable surface roughness have been synthesized through a kinetics-controlled interface co-assembly and deposition of mesostructured nanocomposites on Fe3O4@RF microspheres (RF refers to resorcinol formaldehyde resin). The obtained microspheres, synthesized via this interface nanoengineering method, possess well-defined sandwich structure with a tunable rough morphology, uniform size (560-1000 nm), perpendicularly aligned mesopores (∼5.7 nm) in the outer shell, RF-protected magnetic responsive core, high surface area up to 382 m2/g, and large pore volume of 0.66 cm3/g. As a result of the unique surface features and magnetic properties, these microspheres exhibit excellent performance in stabilizing and oxygen-free manipulating aqueous solutions in petroleum ether by a magnetic field. They also exhibit superior cell uptake properties compared with traditional smooth core-shell magnetic mesoporous silica microspheres, opening up the possible applications in fast drug delivery in cancer therapy.

Ibuprofen and acetylsalicylic acid loaded electrospun PVP-dextran nanofiber mats for biomedical applications

The aim of this work is to investigate the suitability of electrospinning for biomedical applications and to produce fast-dissolving drug delivery through uniform dextran nanofiber nonwoven maps. To prepare oral fast-dissolving drug delivery nonwoven maps via electrospinning technology, ibuprofen (Ibu) and acetylsalicylic acid (ASA) as the model drugs, and polyvinylpyrrolidone (PVP), dextran T10 (Dext T10) and dextran T40 (Dext T40) as the filament-forming polymer and drug carrier were selected. Morphology of nanofiber samples was characterized by scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS). SEM images showed homogeneous dispersion of drugs into the polymer blends. The structure analysis made by attenuated total reflectance/Fourier transform infrared spectroscopy suggested that PVP/dextran and drug blended very well in the nanofibers. The amount of ibuprofen and acetylsalicylic acid in a nanofiber samples was determined using reverse-phase high-performance liquid chromatography. The results showed that the ibuprofen content in PVP/Dext T40-Ibu and PVP/Dext T10-Ibu nanofiber samples (431.7 ± 39.7 and 528.3 ± 24.7 µg/mL, respectively) is significantly higher than acetylsalicylic acid content in PVP/Dext T40-ASA and PVP/Dext T10-ASA nanofiber samples (145.5 ± 5.6 and 168.3 ± 7.3 µg/mL, respectively). Antibacterial properties of the fiber samples containing drug against Gram-negative (Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922) and Gram-positive bacteria (Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633) were examined. The PVP-drug containing nanofibers resulted in a superior antibacterial activity than PVP/dextran-drug containing nanofibers. PVP/Dext T10 and PVP/Dext T40 nanofibers have the potential to be used as solid dispersions to improve the dissolution profiles of poorly water-soluble drugs and/or fast disintegrating drug delivery systems.