Silk fibroin (SF), a naturally occurring protein polymer, has several unique properties making it a favorable matrix for the incorporation and delivery of a range of therapeutic agents. SF is ...biocompatible, slowly biodegradable, and endowed with excellent mechanical properties and processability. Novel manufacturing techniques including mild all-aqueous processes have expanded its range of application even to sensitive protein and nucleic acid therapeutics. SF matrices were demonstrated to successfully deliver protein drugs and preserve their potency. Adjustments in SF crystallinity, concentration and structure, the design of the delivery systems as well as the molecular weight and structure of the embedded agents represent important variables when it comes to precisely tailor the release kinetics of SF matrices. Other strategies to fine-tune the release from SF matrices comprise the embedment of drug loaded micro- or nanoparticles or the coating of micro- or nanoparticles with SF films. So far, the main focus of SF drug delivery systems has been on tissue regeneration applications. For instance, growth factor loaded SF scaffolds were suggested for the tissue engineering of bone and cartilage, as well as for vascular and nerve regeneration devices and wound healing products. Moreover, SF matrices were proposed for oral, transmucosal and ocular drug delivery. This article reviews SF properties and fabrication processes that affect the release from SF drug delivery systems. For illustration, we discuss a variety of examples for the incorporation of drugs into SF systems and their release.
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Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers ...often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.
In hollow fiber membrane liquid-phase microextraction (LPME), target analytes are extracted from aqueous samples and into a supported liquid membrane (SLM) sustained in the pores in the wall of a ...small porous hollow fiber, and further into an acceptor phase present inside the lumen of the hollow fiber. The acceptor phase can be organic, providing a two-phase extraction system compatible with capillary gas chromatography, or the acceptor phase can be aqueous resulting in a three-phase system compatible with high-performance liquid chromatography or capillary electrophoresis. Due to high enrichment, efficient sample clean-up, and the low consumption of organic solvent, substantial interest has been devoted to LPME in recent years. This paper reviews important applications of LPME with special focus on bioanalytical and environmental chemistry, and also covers a new possible direction for LPME namely electromembrane extraction, where analytes are extracted through the SLM and into the acceptor phase by the application of electrical potentials.
To minimize environmental pharmaceutical micropollutants, treatment of human urine could be an efficient approach due to the high pharmaceutical concentration and toxic potential excreted in urine. ...This study investigated the degradation kinetics and mechanisms of sulfamethoxazole (SMX), trimethoprim (TMP) and N4-acetyl-sulfamethoxazole (acetyl-SMX) in synthetic fresh and hydrolyzed human urines by low-pressure UV, and UV combined with H2O2 and peroxydisulfate (PDS). The objective was to compare the two advanced oxidation processes (AOPs) and assess the impact of urine matrices. All three compounds reacted quickly in the AOPs, exhibiting rate constants of (6.09–8.53) × 109 M–1·s–1 with hydroxyl radical, and (2.35–16.1) × 109 M–1·s–1 with sulfate radical. In fresh urine matrix, the pharmaceuticals’ indirect photolysis was significantly suppressed by the scavenging effect of urine citrate and urea. In hydrolyzed urine matrix, the indirect photolysis was strongly affected by inorganic urine constituents. Chloride had no apparent impact on UV/H2O2, but significantly raised the hydroxyl radical concentration in UV/PDS. Carbonate species reacted with hydroxyl or sulfate radical to generate carbonate radical, which degraded SMX and TMP, primarily due to the presence of aromatic amino group(s) (k = 2.68 × 108 and 3.45 × 107 M–1·s–1) but reacted slowly with acetyl-SMX. Ammonia reacted with hydroxyl or sulfate radical to generate reactive nitrogen species that could react appreciably only with SMX. Kinetic simulation of radical concentrations, along with products analysis, helped elucidate the major reactive species in the pharmaceuticals’ degradation. Overall, the AOPs’ performance was higher in the hydrolyzed urine than fresh urine matrix with UV/PDS better than UV/H2O2, and varied significantly depending on pharmaceutical’s structure.
Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of ...pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis
. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF
) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF
could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF
sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF
desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.
•Comprehensive review of PDE-5 inhibitors, designer analogues as adulterants.•To date, more than 50 analogues are reported as adulterants.•Comprehensive review and list of analytical techniques ...developed for their analyses.•Compilation of important data for easy reference to identify known analogues.•Challenges in detecting and identifying unknown analogues and to curb adulteration.
The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography–mass spectrometry (GC–MS), liquid chromatography mass-spectrometry (LC–MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC–FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC–TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed.
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Amorphous solid dispersions (ASDs) are being employed frequently to improve bioavailability of poorly soluble molecules by enhancing the rate and extant of dissolution in drug product ...development process. These systems comprise of an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced stability. This review discussed the methodologies of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Rational selection of polymers, preparation techniques with its advantages and disadvantages and characterization of polymeric amorphous solid dispersions have discussed. Stability aspects have been described as per ICH guidelines which intend to depend on selection of polymers and preparation methods of ASD. The mechanism involved on improvement of bioavailability also considered. Regulatory importance of ASD and current evolving details of QBD approach were reviewed. Amorphous products and particularly ASDs are currently most emerging area in the pharmaceutical field. This strategic approach presents huge impact and advantageous features concerning the overall improvement of drug product performance in clinical settings which ultimately lead to drug product approval by leading regulatory agencies into the market.
By any measure, transdermal drug delivery (TDD) is a successful controlled release technology. Over the last 30+ years, a steady flux of transdermal products have received regulatory approval and ...reached the market. For the right compounds, TDD is an effective and preferred route of administration; for others, delivery across the skin makes no sense at all. Currently, the "rules" that govern (passive) TDD feasibility are clearly understood, and research activity is focused on novel approaches that strive to subvert skin's excellent barrier function, and broaden the range of active species amenable to percutaneous administration.
The tumor microenvironment provides unique challenges for the delivery of chemotherapeutic agents in doses that are effective while ensuring minimal systemic toxicity. The primary limitation of ...current therapeutics is a lack of specificity in delivery, as they target healthy and cancerous cells alike. The development of nanoscale carriers capable of delivering cancer therapies has the potential to overcome both systemic and tumor barriers and provide specific, targeted delivery. This review seeks to provide an overview of available nanoscale drug carriers by exploring the wide variety of developed nanostructures and the most commonly used moieties for targeted delivery. Additionally, the use of nanoscale carriers will be motivated by examining tumor physiology and the specific barriers present within both the tumor microenvironment and systemic delivery.
Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is ...capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.
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