Microfluidic Production of Polymeric Core-Shell Microspheres for the Delayed Pulsatile Release of Bovine Serum Albumin as a Model Antigen

For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee’s compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(dl-lactide-co-glycolide) (PLGA) with various dl-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines.

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation’s ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

The GH-IGF-1 Axis in Circadian Rhythm

Organisms have developed common behavioral and physiological adaptations to the influence of the day/night cycle. The CLOCK system forms an internal circadian rhythm in the suprachiasmatic nucleus (SCN) during light/dark input. The SCN may synchronize the growth hormone (GH) secretion rhythm with the dimming cycle through somatostatin neurons, and the change of the clock system may be related to the pulsatile release of GH. The GH—insulin-like growth factor 1 (IGF-1) axis and clock system may interact further on the metabolism through regulatory pathways in peripheral organs. We have summarized the current clinical and animal evidence on the interaction of clock systems with the GH—IGF-1 axis and discussed their effects on metabolism.

A Novel Pulsatile Release Film Coated Tablet of Zaltoprofen Loaded SNEDDS

The aim of the present study was to formulate pulsatile release film coated tablet of zaltoprofen for the treatment of rheumatoid arthritis. Initially solubility of zaltoprofen was enhanced by formulating self emulsifying fast disintegrating tablet of zaltoprofen. Core fast disintegrating tablet of zaltoprofen was coated with ethyl cellulose and eudragit L100 in various proportions as coating polymer. Ethanol was used as coating solvent and dibutyl phthalate as plasticizer. Film coated tablet with different coating levels were formulated and were evaluated for parameters like lag time, rupture time, in vitro dissolution etc. Amongst the nine different formulations P-4 formulation containing 3:1 ratio of ethyl cellulose and eudragit L100 with 5% coating level gives desired lag time with best drug dissolution profile. Formulated film coated tablet of zaltoprofen can be useful for chronotherapeutic treatment of rheumatoid arthritis.

Recording and neural circuit-based manipulation of the maternal oxytocin pulses in mice

For mammals, successful parturition and breastfeeding are critical to the survival of offspring. Pulsatile release of the hormone oxytocin mediates uterine contraction during parturition and milk ejection during lactation. These oxytocin pulses are generated by unique activity patterns of the central neuroendocrine oxytocin neurons located in the paraventricular and supraoptic hypothalamus. However, the maternal activities of oxytocin neurons remain elusive because most classical electrophysiological studies in anesthetized rats have lacked the genetically defined cell identity of oxytocin neurons. We herein introduce viral genetic approaches in mice to characterize the maternal pulsatile activities of oxytocin neurons by fiber-photometry-based chronic in vivo Ca2+ imaging. We also demonstrate the pharmaco-genetic manipulation of oxytocin pulses during lactation via activating a prominent pre-synaptic structure of oxytocin neurons defined by retrograde trans-synaptic tracing. Collectively, our study opens a new avenue for the neuroscience of maternal neuroendocrine functions.

A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing

Effective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.

A REVIEW ON RECENT ADVANCEMENT IN PULSATILE DRUG DELIVERY SYSTEMS

Delivery systems with a pulsatile-release method are particularly involved in designing medicines for which traditional managed drug-release systems with the continuous release are not suitable. This medication also has a high first-pass impact or special conditions for chrono-pharmacology. These medications also have a high first-pass or unique chronopharmacological effect. The pulsatile release profile is characterised by a duration of no release (lag time) followed by a fast and full release of the drug. Pulsatile drug delivery systems may be classified into site-specific systems in which the drug is released inside the gastrointestinal system (e. g. colon) or time-controlled devices wherein the drug is released after a well-defined time period. Site-regulated release is typically controlled by environmental factors, such as pH or enzymes found in the intestinal tract, whereas drug release from time-controlled processes is controlled mainly by the delivery system and, preferably, not by the environment. This review covers various single-and multiple-unit oral pulsatile drug-delivery systems with an emphasis on time-controlled drug-release systems.

Trimetazidine Dihydrochloride Pulsatile–Release Tablets for the Treatment of Morning Anginal Symptoms: Dual Optimization, Characterization and Pharmacokinetic Evaluation

Objective: This research work aimed to target the early morning peak symptoms of chronic stable angina through formulating antianginal drug, Trimetazidine (TMZ) in a pulsatile-release tablet. Methods: The core formulae were optimized using 22.31 factorial design to minimize disintegration time (DT) and maximize drug release after 5 minutes (Q5min). Different ratios of Eudragit S100 and Eudragit L100 were used as a coating mixture for the selected core with or without a second coating layer of hydroxypropyl methyl cellulose (HPMC E50). The different formulation variables were statistically optimized for their effect on lag time and drug release after 7 hours (Q7h) using Box-Behnken design. The optimized formula (PO) was subjected to stability study and pharmacokinetic assessment on New Zealand rabbits. Results: The optimal core (F8) was found to have 1.76 min disintegration time and 61.45% Q5min PO showed a lag time of 6.17 h with 94.80% Q7h and retained good stability over three months. The pharmacokinetic study confirmed the pulsatile–release pattern with Cmax of 206.19 ng/ml at 5.33 h (Tmax), as well as 95.85% relative bioavailability compared to TMZ solution. Conclusion: Overall pulsatile-release tablets of TMZ succeeded in releasing the drug rapidly after a desirable lag time, providing a promising approach for early morning anginal symptoms relief.

High-Fat Diet Alters LH Secretion and Pulse Frequency in Female Mice in an Estrous Cycle-Dependent Manner

Reproductive fitness in females is susceptible to obesogenic diets. Energy balance and reproduction are tightly regulated, in part, by hypothalamic neurons in the arcuate nucleus (ARC), and high-fat diet (HFD) can steadily increase estradiol levels in rodents. Estradiol regulates the reproductive axis via negative feedback mechanisms in ARC neurons by modulating pulsatile release of the gonadotropin luteinizing hormone (LH). However, it is unclear how the circulating estradiol milieu of adult females interacts with a state of high-caloric fat intake to alter LH pulse dynamics. Here, we used serial tail-tip blood sampling to measure pulsatile LH release at different estrous cycle stages in mice fed a HFD. Starting at 21 days of age, female C57BL/6J mice were freely fed with either regular chow diet (RD) or 60% kcal HFD for 12 weeks. Blood samples were collected once at diestrus, and then again at estrus. LH was measured in 10-minute intervals for 3 hours and analyzed for pulse frequency, amplitude, and mean and basal LH levels. Compared with RD-fed controls, mice fed HFD displayed significantly increased pulse frequency at diestrus, but not at estrus. HFD-fed mice also had lower mean and basal LH levels compared with RD-fed controls, but only during estrus. These data suggest that circulating estradiol can variably contribute to the impact that HFD has on LH pulsatile release and also provide insight into how obesity impacts women’s reproductive health when ovarian estradiol levels drastically change, such as during menopause or with hormone replacement therapy.