Development of an Accelerated Rotator-based Drug Release Method for the Evaluation of Bupivacaine Multivesicular Liposomes.

PURPOSE: A multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an in vitro release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes. METHODS: Three IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24 h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations. RESULTS: The rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24 h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4. CONCLUSIONS: An accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations.

Recent strategies for constructing hierarchical multicomponent nanoparticles/metal-organic framework hybrids and their applications.

Hybrid nanoparticles with unique tailored morphologies and compositions can be utilized for numerous applications owing to their combination of inherent properties as well as the structural and supportive functions of each component. Controlled encapsulation of nanoparticles within nanospaces (NPNSs) of metal-organic frameworks (MOFs) (denoted as NPNS@MOF) can generate a large number of hybrid nanomaterials, facilitating superior activity in targeted applications. In this review, recent strategies for the fabrication of NPNS@MOFs with a hierarchical architecture, tailorability, unique intrinsic properties, and superior catalytic performance are summarized. In addition, the latest and most important examples in this sector are emphasized since they are more conducive to the practical applicability of NPNS@MOF nanohybrids.

Colorectal and bladder prokinetic activity of [Lys5, MeLeu9, Nle10]-NKA(4-10) after intranasal or sublingual delivery in dogs.

The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, [Lys5, MeLeu9, Nle10]-NKA(4-10), was examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 µg/kg IN or 2.0-6.7 mg/kg SL increased colorectal peak pressure and area under the curve. Peak bladder pressure was also increased at the same doses, and this was accompanied by highly efficient voiding at normal physiological bladder pressure. The onset of these effects was rapid (≤2.5 min), and the primary contractions lasted ∼25 min, returning to baseline in <60 min. Slight hypotension lasting a few minutes and causing <10% change from baseline was detected after higher doses and was statistically significant after only 100 µg/kg IN. In conscious dogs, there was a dose-related increase in voiding responses and reduction in the latency to urinate and defecate after 300 and 1000 µg/kg IN; emesis was also observed at these doses. SL administration of 6.7 mg/kg induced urination within 10 min, but not defecation or emesis. These findings support the feasibility of developing a convenient dosage form of small peptide NK2 receptor agonists as on-demand defecation or urination therapies.

Convective Solvent Transport Pathways for Absorption of Drugs from Topical Formulation.

Physicochemical and formulation factors influencing penetration of drugs from topical products into the skin and mechanisms of drug permeation are well investigated and reported in the literature. However, mechanisms of drug absorption during short-term exposure have not been given sufficient importance. In this project, the extent of absorption of drug molecules into the skin from aqueous and ethanolic solutions following a 5-min application period was investigated. The experiments demonstrated measurable magnitude of absorption into the skin for all the molecules tested despite the duration of exposure being only few minutes. Among the two solvents used, absorption was greater from aqueous than ethanolic solution. The results suggest that an alternative penetration pathway, herein referred to as the convective transport pathway, is likely responsible for the rapid, significant uptake of drug molecules during initial few minutes of exposure. Additionally, absorption through the convective transport pathways is a function of the physicochemical nature of the formulation vehicle rather than the API.

Impact of particle flocculation on the dissolution and bioavailability of injectable suspensions.

Injectable suspensions occasionally exhibit variations in dissolution and bioavailability, which may impact the clinical outcome of the drug product. Here, variation in the injection method (i.e., applied shear) for triamcinolone acetonide (TA) injectable suspension (40 mg/mL) altered the flocculation state of the particles and subsequently their dissolution. Notably, TA suspensions contained primary particles of approximately 2 µm and secondary flocculates of tens of microns. The conversion between flocculated and deflocculated particles was rapid, reversible and highly shear dependent. As such, changing shear rates during laser diffraction (LD) measurement like stirring rate, sonication, and sample introduction method (micropipette vs 25-gauge needle) may result in variability in particle size distributions (PSD) that have the potential to alter drug dissolution. Furthermore, a non-sink, discriminatory in vitro release testing (IVRT) method was developed, which combined in-situ fiber optic UV with LD to simultaneously monitor the dissolution and changing PSD of the suspension. The simultaneously measured dissolution and PSD data showed that flocculated and deflocculated particles followed different dissolution pathways. Importantly, deflocculated particles dissolved up to six times faster than the flocculated particles. Similar shear-induced changes during injection could occur in a clinical setting and have implications for drug bioavailability.

A study on time-concentration superposition of dilatational modulus and foaming behavior of sodium alkyl sulfate.

The oscillatory dilatational flow of interfacial rheology is a useful tool to unveil the motion of molecules and the interaction between adsorbed molecules at the interfacial layers. Despite its usefulness, it is difficult to analyze the dilatational moduli because they are functions of both the frequency and concentration. In this study, we adopted superposition behavior to investigate the diffusive transport of sodium alkyl sulfate surfactant based on the interfacial rheology under oscillatory dilatational flow. We found that the time-concentration superposition is valid for dynamic dilatational moduli. The shifting factors for superposition on time-axis exponentially decrease as concentration increases due to the molecular exchange between interface and bulk. It is found that the concentration dependence of the shift factors decreases as the size of the hydrophilic and hydrophobic groups increases. It is worth noting that the concentration dependence of the shift factors is related to the foaming speed of the surfactant solutions: As the concentration-dependence of shifting factors increases, the foaming speed increases. It is expected that the time-concentration superposition can be a new tool to study the dynamic dilatational rheology.

Evaluation of soluble fentanyl microneedles for loco-regional anti-nociceptive activity.

The use of opioids for treating acute and chronic pain condition is a common clinical practice. When delivered systemically, the analgesic activity is mediated through the central pathway, which although effective, leads to various adverse effects such as dependence, abuse and respiratory depression. Fentanyl is an opioid analgesic that is available as injection and transdermal patch products for the management of acute and chronic pain. These products require stringent regulatory controls and label warnings on disposal due to the abuse potential associated. This research project evaluated the regional antinociceptive efficacy of fentanyl delivered from soluble microneedles. The microneedle patches were formulated with relatively less drug loading as compared to patches intended for systemic delivery and were tested for their antinociceptive activity in rats by measuring the paw withdrawal latency when exposed to a thermal stimulus. The results indicate that regional delivery of fentanyl mediated through soluble microneedles provides an effective antinociceptive activity. The onset of analgesic activity was faster with microneedle patch (0.5 h) when compared to the adhesive dermal patch (6 h). This study thus demonstrates the effectiveness of microneedle mediated pain management for immediate pain relief.

Characterization and in vivo efficacy of a heptapeptide ODT formulation for the treatment of neurogenic bladder dysfunction.

The objective of this study was to develop oral disintegrating tablet (ODT) formulations of a heptapeptide, [Lys5,MeLeu9,Nle10]-NKA(4-10), for the treatment of neurogenic bladder dysfunction. A design of experiment approach was applied to determine the optimal ratio of chosen excipients: gelatin (X1), glycine (X2), and sorbitol (X3). These formulations were optimized for efficacy studies to produce ODTs exhibiting rapid disintegration times (Y1) and appropriate structural integrity (Y2) using JMP® 12.0.1 software. Based on theoretically predicted values from 12 experimental runs, the optimal ODT formulation was determined to be 3% (w/v) gelatin, 2% (w/v) glycine, and 1% (w/v) sorbitol in deionized water. Using this formulation, blank and drug-loaded ODTs containing 1.5 mg or 5 mg of [Lys5,MeLeu9,Nle10]-NKA(4-10) were manufactured by a lyophilization process. The peptide-loaded tablets disintegrated in less than 30 s and released 97% of the peptide within 15 min. The peptide was stable for 90 days under 25 °C/60% relative humidity (RH) and 40 °C/75% RH. In vivo efficacy of the peptide-loaded ODTs was confirmed in a rat acute spinal cord injury model under isovolumetric bladder pressure recording conditions, concluding that sublingual administration of peptide-containing ODTs evoke a rapid dose-related neurokinin 2-mediated increase in bladder pressure.

Novel Biodegradable Polymer with Redox-Triggered Backbone Cleavage Through Sequential 1,6-Elimination and 1,5-Cyclization Reactions.

In the past decade, the self-immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self-immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox-sensitive polymer that can systemically degrade via sequential 1,6-elimination and 1,5-cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles.

Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology.

The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization.

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG750) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG750. PolyQPA-mPEG750 was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by (1)H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG750 underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG750 polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.

Microfluidic device for sheathless particle focusing and separation using a viscoelastic fluid.

Continuous sheathless particle separation with high efficiency is essential for various applications such as biochemical analyses and clinical diagnosis. Here, a novel microfluidic device for highly efficient, sheathless particle separation using an elasticity-dominant non-Newtonian fluid is proposed. Our device consists of two stages: sheathless three-dimensional focusing (1 st stage) and separation (2nd stage). It is designed based on the principle of a viscoelasticity-induced particle lateral migration, which promises precise separation of particles in a microfluidic device. Particles of 5- and 10-µm diameters were all focused at the centerline of a circular channel at the 1st stage and successfully separated at the 2nd stage with an efficiency of ∼99.9% using size-based lateral migration of particles induced by the viscoelasticity of the medium. We also demonstrated the capability of our device for separation of blood cells into multiple fractions. The tunability of separable particle size could be achieved by changing the viscoelastic property of the medium and flow rate.

Nitroreductase-triggered activation of a novel caged fluorescent probe obtained from methylene blue.

A near-infrared fluorescent probe based on methylene blue (p-NBMB) was developed for the detection of nitroreductase. Conjugating methylene blue with a p-nitrobenzyl moiety enables it to be activated by nitroreductase-catalyzed 1,6-elimination, resulting in the release of an active methylene blue fluorophore.

Redox-sensitive polymeric nanoparticles for drug delivery.

Bioresponsive polymeric nanoparticles have been extensively pursued for the development of tumor-targeted drug delivery. A novel redox-sensitive biodegradable polymer with "trimethyl-locked" benzoquinone was synthesized for the preparation of paclitaxel-incorporated nanoparticles. The synthesized redox-sensitive nanoparticles released paclitaxel in response to chemically triggered reduction.