The most common biomineral produced in the contemporary ocean is calcium carbonate, including the polymorph calcite produced by coccolithophores. The surface waters of the ocean are supersaturated with respect to calcium carbonate. As a result, particulate inorganic carbon (PIC), such as calcite coccoliths, is not expected thermodynamically to dissolve in waters above the lysocline (~4500–6000 m). However, observations indicate that up to 60–80% of calcium carbonate is lost in the upper 500–1000 m of the ocean. This is hypothesized to occur in microenvironments with reduced saturation states, such as zooplankton guts. Using a new application of the highly precise14C microdiffusion technique, we show that following a period of starvation, up to 38% of ingested calcite dissolves in copepod guts. After continued feeding, our data show the gut becomes increasingly buffered, which limits further dissolution; this has been termed the Tums hypothesis (after the drugstore remedy for stomach acid). As less calcite dissolves in the gut and is instead egested in fecal pellets, the fecal pellet sinking rates double, with corresponding increases in pellet density. Our results empirically demonstrate that zooplankton guts can facilitate calcite dissolution above the chemical lysocline, and that carbon export through fecal pellet production is variable, based on the feeding history of the copepod.
Many solid-dose oral drug products are engineered to release their active ingredients into the body at a certain rate. Techniques for measuring the dissolution or degradation of a drug product in vitro play a crucial role in predicting how a drug product will perform in vivo. However, existing techniques are often labor-intensive, time-consuming, irreproducible, require specialized analytical equipment, and provide only “snapshots” of drug dissolution every few minutes. These limitations make it difficult for pharmaceutical companies to obtain full dissolution profiles for drug products in a variety of different conditions, as recommended by the US Food and Drug Administration. Additionally, for drug dosage forms containing multiple controlled-release pellets, particles, beads, granules, etc. in a single capsule or tablet, measurements of the dissolution of the entire multi-particle capsule or tablet are incapable of detecting pellet-to-pellet variations in controlled release behavior. In this work, we demonstrate a simple and fully-automated technique for obtaining dissolution profiles from single controlled-release pellets. We accomplished this by inverting the drug dissolution problem: instead of measuring the increase in the concentration of drug compounds in the solution during dissolution (as is commonly done), we monitor the decrease in the buoyant mass of the solid controlled-release pellet as it dissolves. We weigh single controlled-release pellets in fluid using a vibrating tube sensor, a piece of glass tubing bent into a tuning-fork shape and filled with any desired fluid. An electronic circuit keeps the glass tube vibrating at its resonance frequency, which is inversely proportional to the mass of the tube and its contents. When a pellet flows through the tube, the resonance frequency briefly changes by an amount that is inversely proportional to the buoyant mass of the pellet. By passing the pellet back-and-forth through the vibrating tube sensor, we can monitor its mass as it degrades or dissolves, with high temporal resolution (measurements every few seconds) and mass resolution (700 nanogram resolution). As a proof-of-concept, we used this technique to measure the single-pellet dissolution profiles of several commercial controlled-release proton pump inhibitors in simulated stomach and intestinal contents, as well as comparing name-brand and generic formulations of the same drug. In each case, vibrating tube sensor data revealed significantly different dissolution profiles for the different drugs, and in some cases our method also revealed differences between different pellets from the same drug product. By measuring any controlled-release pellets, particles, beads, or granules in any physiologically-relevant environment in a fully-automated fashion, this method can augment and potentially replace current dissolution tests and support product development and quality assurance in the pharmaceutical industry.
more » « less- NSF-PAR ID:
- 10201475
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
more » « less
Abstract Additive manufacturing (AM) appears poised to provide novel pharmaceutical technology and controlled release systems, yet understanding the effects of processing and post‐processing operations on pill design, quality, and performance remains a significant barrier. This paper reports a study of the relationship between programmed concentration profile and resultant temporal release profile using a 3D printed polypill system consisting of a Food and Drug Administration (FDA) approved excipient (Pluronic F‐127) and therapeutically relevant dosages of three commonly used oral agents for treatment of type 2 diabetes (300–500 mg per pill). A dual‐extrusion hydrogel microextrusion process enables the programming of three unique concentration profiles, including core–shell, multilayer, and gradient structures. Experimental and computational studies of diffusive mass transfer processes reveal that programmed concentration profiles are dynamic throughout both pill 3D printing and solidification. Spectrophotometric assays show that the temporal release profiles could be selectively programmed to exhibit delayed, pulsed, or constant profiles over a 5 h release period by utilizing the core–shell, multilayer, and gradient distributions, respectively. Ultimately, this work provides new insights into the mass transfer processes that affect design, quality, and performance of spatially graded controlled release systems, as well as demonstrating the potential to create disease‐specific polypill technology with programmable temporal release profiles.
-
more » « less
Abstract Oral drug products have become indispensable in modern medicine because of their exceptional patient compliance. However, poor bioavailability of ubiquitous low‐water‐soluble active pharmaceutical ingredients (APIs) and lack of efficient oral drug formulations remain as significant challenges. Nanocrystalline formulations are an attractive route to increase API solubility, but typically require abrasive mechanical milling and several processing steps to create an oral dosage form. Using the dual amphiphilic and thermoresponsive properties of methylcellulose (MC), a new thermogelling nanoemulsion and a facile thermal dripping method are developed for efficient formulation of composite particles with the MC matrix embedded with precisely controlled API nanocrystals. Moreover, a fast and tunable release performance is achieved with the combination of a fast‐eroding MC matrix and fast‐dissolving API nanocrystals. Using the versatile thermal processing approach, the thermogelling nanoemulsion is easily formulated into a wide variety of dosage forms (nanoparticle suspension, drug tablet, and oral thin film) in a manner that avoids nanomilling. Overall, the proposed thermogelling nanoemulsion platform not only broadens the applications of thermoresponsive nanoemulsions but also shows great promise for more efficient formulation of oral drug products with high quality and tunable fast release.
-
null (Ed.)Remotely activated drug release strategy with controllable dosage is the key factor of various targeting drug delivery methods as minimal invasive treatment. This article describes mass transport in liquid in microscale with a controllability of releasing amount, which is wirelessly excited by an external acoustic excitation. A liquid droplet (releasing agent, or drug in application) is trapped in the middle of a one-end open microtube which has a ratchet-structure on its inner wall. The droplet is trapped in the tube and neighbored by two gaseous air bubbles on both sides. In the presence of acoustic wave, the air bubbles oscillate and resonate. The air bubble near the tube opening segregates the liquid droplet into smaller ones and transport them on the ratchet-surface wall of the microtube. This mass transport occurs in both directions at similar rates: from the surrounding fluid to the trapped droplet and vice versa. As a result, the overall mass of droplet remains similar. Meanwhile, the other bubble positioned back in the tube sealing side enhances mixing between incoming mass from the surrounding and existing mass in the droplet. This mass transport is significant only when the inner wall of the tube has rachets. The exchanging mass between the surrounding and droplet is monotonically proportional to the excitation period, showing high controllability of mass transport. This mass transport phenomenon possibly provides a new mechanism of in vivo, on-demand, dose controllable drug delivery.more » « less
-
Lime kiln dust (LKD) is a fine particulate material by-product produced during the lime burning processes. Current reuse options are chiefly focused on reuse in the cement industry which are limited by the inherent porosity of this by-product. Due to the presence of calcium (Ca), magnesium (Mg) and other elements which can serve as micronutrients to the plants, LKD has the potential to be used as a replacement for conventional liming materials for both soil pHKCl increase and plant supplement with secondary major- (Ca and Mg) and micronutrients (Mn, Cu, Zn and Ni). The work described here outlines the investigation of physicochemical properties of pelletized LKD materials and their effect on soil pHKCl, available Ca and Mg content in the soil as well as straw and grain yields of spring barley. LKD were analyzed using X-ray diffraction, scanning electron microscopy with energy dispersive analysis, while detailed chemical analysis of both pelletized LKD and soil was performed using Atomic Absorption Spectroscopy. Pellet size and major element composition were used as chief indicators for the liming capacity of LKD. It was shown that low acidic soil (pHKCl 5.4) can be conditioned using fine (0.1–2 mm) pelletized LKD due to the high release rates while coarse pellets (5–8 mm) did not significantly increase available Ca and Mg content in soil and did not reach optimum pHKCl range even after 48 weeks. The highest application rate of LKD at 4 t/ha increased spring barley grain yield compared to control but the increase was not statistically significant. Thus, pelletized lime kiln dust could be a potential alternative to natural limestone or dolomite minerals as liming material for acid soils with the pellet size determining the liming kinetics.more » « less
