Bioavailability Of Therapeutic Agents Research Articles

Recent Patents and Applications of Nanoemulsion and Nanoemulgel for Topical Drug Delivery

Nanocarriers like nanoemulsions and nanoemulgels have emerged as revolutionary platforms in the realm of topical drug delivery, addressing many limitations of traditional dosage forms. Conventional methods often struggle with challenges such as poor skin penetration, inconsistent drug targeting, and potential local toxicity, which can undermine therapeutic outcomes and patient adherence. Nanoemulsions, with their submicron-sized droplets, offer a promising solution by enhancing the delivery and bioavailability of therapeutic agents, especially those that are poorly soluble. Nanoemulgels further elevate this potential by providing a versatile vehicle for lipophilic drugs, overcoming the limitations of traditional formulations. These advanced formulations not only improve drug penetration through the skin but also expand the range of active compounds viable for clinical use. Their ability to target specific skin regions more effectively reduces adverse reactions and increases therapeutic efficacy. This article delves into the physicochemical properties, preparation techniques, and latest advancements in nanoemulsions and nanoemulgels. By exploring recent clinical trials and patents, the review provides valuable insights into the development and optimization of these cutting-edge topical drug delivery systems, offering a promising avenue for enhancing dermatological treatments and patient outcomes.

Investigation of a novel bilayered PCL/PVA electrospun nanofiber incorporated Chitosan-LL37 and Chitosan-VEGF nanoparticles as an advanced antibacterial cell growth-promoting wound dressing

Chronic wounds have become a growing concern as they can have a profound impact on individuals, potentially resulting in mortality. It is crucial to prevent and manage bacterial infections, particularly drug-resistant ones. Antimicrobial peptides, such as LL-37, can firmly eliminate pathogens. Additionally, the process of angiogenesis, facilitated by growth factors like VEGF, is essential for tissue repair and wound healing. To enhance the stability and bioavailability of therapeutic agents, targeted delivery strategies utilizing Chitosan-based carriers have been employed. Electrospun biopolymers in advanced wound dressings have revolutionized wound care by providing a more effective and efficient solution for promoting tissue regeneration and speeding up the healing process. The present investigation utilized Chitosan nanoparticles to encapsulate the recombinant LL37 peptide and VEGF. An in-depth investigation was carried out to analyze the biophysical and morphological traits of the LL37-CSNPs and VEGF-CSNPs. The first support layer consisted of PCL electrospun nanofiber, followed by the electrospinning of PVA/CsLL37, PVA/CsVEGF, and PVA/CsLL37/CsVEGF onto the PCL layer. An in vitro examination assessed the fabricated nanofibers’ morphological, mechanical, and biological characteristics. The antimicrobial effects were tested on methicillin-resistant Staphylococcus aureus (MRSA). The in vivo experiments assessed the antibacterial and wound-healing capabilities of the nanofibers. The findings validated the continuous release of LL37 and VEGF. The composite material PCL/PVA/CsLL37/CsVEGF demonstrated potent bactericidal and antioxidant characteristics. The cytotoxic assay demonstrated the biocompatibility of the fabricated nano mats and their potential to accelerate fibroblast cell proliferation. The efficacy of PVA/CsLL37/CsVEGF in promoting wound healing was confirmed through an in vivo wound healing assay. Furthermore, the histological analysis provided evidence of faster epidermal formation and improved antibacterial activity in wounds covered with PVA/CsLL37/CsVEGF. Adding LL37 and VEGF to the composite material improves the immune response and promotes blood vessel formation, accelerating wound healing and decreasing inflammation.

Frontiers of Plant-derived Exosomes from Research Methods to Pharmaceutical Applications in Plant-based Therapeutics

Exosomes have emerged as critical mediators of intercellular communication and various physiological processes between cells and their environment. These nano-sized vesicles have been extensively investigated and confirmed to exhibit multifunctionality in animal systems. In particular, they participate in intercellular signaling, influence disease progression, and exhibit biological activity. However, Plant-Derived Exosomes (PDEs), especially therapeutic PDEs, have received relatively limited attention in the past few decades. Recent studies have demonstrated that PDEs are involved in signaling molecule transport in addition to intercellular communication, as they serve as functional molecules in the cellular microenvironment. This characteristic highlights the immense potential of PDEs for a wide array of applications, including antioxidation, anti-inflammation, tumour cell elimination, immune modulation, and tissue regeneration. In addition, PDEs hold substantial promise as efficient drug carriers, enhancing the stability and bioavailability of therapeutic agents and consequently enabling targeted delivery to specific cells or tissues. Therefore, PDEs may serve as effective tools for drug delivery and the treatment of various diseases. This comprehensive review provides an overview of recent studies on therapeutic PDEs, focusing on their extraction, isolation, characterization methods, biological activities, and application prospects. It summarises the research progress of exosome-like nanovesicles derived from medicinal plants, with a specific emphasis on traditional Chinese medicine, and highlights their importance in disease treatment and nanoparticle delivery. The main objective is to accelerate the clinical translation of these nanovesicles while providing novel approaches and methodologies for the research and development of innovative drugs.

Olanzapine Liquisolid Tablets Using Kolliphor EL with Improved Flowability and Bioavailability: In vitro and In vivo Characterization.

Liquisolid tablets are an innovative approach to enhance the dissolution rate and, thereby, the bioavailability of therapeutic agents with poor aqueous solubility. The objective of the current research was to compare the bioavailability of the optimized formulation of the olanzapine (OLZ) liquisolid tablet with that of the marketed tablet (MT) by conducting pharmacokinetic and behavioral assessment studies. Ten formulations were designed using Kolliphor EL as a non-volatile solvent, and the respective tablets were prepared by the direct compression method. Pre-compression studies of powders of all the formulations showed good/excellent flow properties and compressibility. The drug release profiles of liquisolid tablets were determined and compared with those of MT. Based on the in vitro results, K250 was considered as an optimized formulation and selected for further in vivo studies. AUC0-∞ value of K250 formulation was found to be 357.2 ± 35.5 ng.h.mL-1, which was higher than that of the MT (258.4 ± 29.9 ng.h.mL-1). The reduction in locomotor activity was enhanced remarkably in K250 compared with MTs at p < 0.05. The time periods taken to fall in the rotarod test were approximately equal in the experimental groups, which indicated the absence of extrapyramidal side effects. There was a remarkable decrease in the number of boxes covered in the open field test. Kolliphor EL was found to be a potential non-volatile solvent that can be used to produce liquisolid tablets of OLZ with improved flow, compressibility, dissolution, and bioavailability.

Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications.

The blood–brain barrier (BBB) protects the central nervous system (CNS) from invasive pathogens and maintains the homeostasis of the brain. Penetrating the BBB has been a major challenge in the delivery of therapeutic agents for treating CNS diseases. Through a physical acoustic cavitation effect, focused ultrasound (FUS) combined with microbubbles achieves the local detachment of tight junctions of capillary endothelial cells without inducing neuronal damage. The bioavailability of therapeutic agents is increased only in the area targeted by FUS energy. FUS with circulating microbubbles is currently the only method for inducing precise, transient, reversible, and noninvasive BBB opening (BBBO). Over the past decade, FUS-induced BBBO (FUS-BBBO) has been preclinically confirmed to not only enhance the penetration of therapeutic agents in the CNS, but also modulate focal immunity and neuronal activity. Several recent clinical human trials have demonstrated both the feasibility and potential advantages of using FUS-BBBO in diseased patients. The promising results support adding FUS-BBBO as a multimodal therapeutic strategy in modern CNS disease management. This review article explores this technology by describing its physical mechanisms and the preclinical findings, including biological effects, therapeutic concepts, and translational design of human medical devices, and summarizes completed and ongoing clinical trials.

Nuclear imaging approaches facilitating nanomedicine translation.

Nanomedicine approaches can effectively modulate the biodistribution and bioavailability of therapeutic agents, improving their therapeutic index. However, despite the ever-increasing amount of literature reporting on preclinical nanomedicine, the number of nanotherapeutics receiving FDA approval remains relatively low. Several barriers exist that hamper the effective preclinical evaluation and clinical translation of nanotherapeutics. Key barriers include insufficient understanding of nanomedicines' in vivo behavior, inadequate translation from murine models to larger animals, and a lack of patient stratification strategies. Integrating quantitative non-invasive imaging techniques in nanomedicine development offers attractive possibilities to address these issues. Among the available imaging techniques, nuclear imaging by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly attractive in this context owing to their quantitative nature and uncontested sensitivity. In basic and translational research, nuclear imaging techniques can provide critical quantitative information about pharmacokinetic parameters, biodistribution profiles or target site accumulation of nanocarriers and their associated payload. During clinical evaluation, nuclear imaging can be used to select patients amenable to nanomedicine treatment. Here, we review how nuclear imaging-based approaches are increasingly being integrated into nanomedicine development and discuss future developments that will accelerate their clinical translation.

Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment.

Focused Ultrasound (FUS) in combination with gaseous microbubbles has emerged as a potential new means of effective drug delivery to the brain. Recent research has shown that, under burst-type energy exposure with the presence of microbubbles, this modality can transiently permeate the blood-brain barrier (BBB). The bioavailability of therapeutic agents is site-specifically augmented only in the zone where the FUS energy is targeted. The non-invasiveness of this approach makes FUS-induced BBB opening a novel and attractive means to perform localized CNS therapeutic agent delivery. Over the past decade, FUS-BBB opening has been preclinically confirmed to successfully enhance CNS penetration of therapeutic agents including chemotherapeutic agents, therapeutic peptides, monoclonal antibodies, and nanoparticles. Recently, a number of clinical human trials have begun to explore clinical utility. This review article, explores this technology through its physical mechanisms, summarizes the existing preclinical findings (including current medical device designs and technical approaches), and summarizes current ongoing clinical trials.

Design, optimization and pharmacodynamic comparison of dorzolamide hydrochloride soluble ocular drug insert prepared by using 32 factorial design

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. The current study aimed to enhance ocular bioavailability of dorzolamide hydrochloride, a potent antiglaucoma drug by preparing novel ophthalmic drug delivery system like soluble ophthalmic drug inserts (SODI).Various batches of dorzolamide hydrochloride Soluble Ocular Drug Insert were prepared using Polyvinyl Alcohol, Poloxamer 407 as polymer with Propylene Glycol as plasticizer by solvent casting method. The drug inserts were prepared by using 32 factorial designs (version 10). Solvent casting method was used to prepare drug inserts which were further evaluated for various parameters like drug interaction studies, physicochemical characteristics, in vitro release studies, transcorneal permeation study by using excised goat cornea. The optimized batch F2 showed 98.50 ± 0.05% drug release at the end of 6 h and has desired physicochemical properties. The gamma radiation sterilized batch F2 was subjected to sterility test as per Indian Pharmacopeia 2014 and accelerated stability studies as per International Conference on Harmonization stability testing of new drug substances and products guideline, ex vivo and Pharmacodynamic studies. The comparative pharmacokinetic result shows that Dorzolamide Hydrochloride SODI is more effective than the marketed formulation. The promising pharmacokinetic results and possibility of commercial applicability justifies the need of product in market.

Abstract 5157: Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer

Abstract Prostate cancer is the most frequently diagnosed cancer and the second cause of cancer-related deaths in American men. Bioavailability of therapeutic agents is important for the treatment effectiveness. Previous studies have shown that the development of nanoparticles (NPs) drug delivery vehicles offers an opportunity for targeted drug delivery to tumor cells. Natural compounds such as curcumin have shown decreased bioavailability and stability when used as anticancer agents. Therefore, the purpose of this study is to synthesize the curcumin analog m-nitrochalcone (3bNchalc) encapsulated into poly (lactic-co-glycolic acid) (PLGA) NPs and determine the anticancer activity against prostate cancer cell lines. In our approach, 3bNChalc were encapsulated into PLGA NPs in the presence of PVA using the single emulsion-solvent evaporation method. 3bNChalc loading, encapsulation efficiency, and drug release was determined by spectrophotometric techniques. Physico-chemical properties such as zeta potential, particle size, polydispersity index (PDI), and morphology was measured using a combination of Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). Cell viability and proliferation of PC3 and 22RV1 prostate cancer cell lines treated with 3bNchalc NPs and control were assessed using the MTS assay. 3bNchalc PLGA NPs were found to have a particle size of 250 nm and smooth spherical shape. In addition, zeta potential and mobility values revealed that 3bNChalc PLGA NPs are negatively charged and they tend to repel each other avoiding the tendency to flocculate. Moreover, 22RV1 cells treated with 3bNchalc PLGA NPs showed decreased in viability and proliferation when compared to control. We demonstrated that 3bNChalc was successfully encapsulated into PLGA NPs. In addition, our results showed that 3bNchalc PLGA NPs decreased the viability of 22RV1 prostate cancer cells when compared to control, suggesting that PLGA improves the delivery of 3bNChalc inside the cell. Results of our study will impact broadly the field by developing more effective and less toxic PLGA NPs based therapies. Citation Format: Maylein C. Juan-Rivera, Maria M. Sánchez-Vázquez, Gamalier Maldonado, Geovanny Ruíz, Noralejandra Vázquez, Christian Vélez, Beatriz Zayas, Carlos Cabrera, Magaly Martínez-Ferrer, David Sanabria-Ríos. Preparation of curcumin analog nanoparticles and determination of their anticancer activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5157. doi:10.1158/1538-7445.AM2017-5157

Biodegradable Ocular Inserts for Sustained Delivery of Brimonidine Tartarate: Preparation and In Vitro/In Vivo Evaluation

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect compared with that of its non-coated or dual-side-coated counterpart.

The Role of Intestinal Carboxylesterase in the Oral Absorption of Prodrugs

The bioavailability of therapeutic agents can be improved by using prodrugs which have better passive diffusion than the active agents. Intestinal hydrolysis is an important reaction in the bioconversion of prodrugs, and may be the rate-limiting factor in their absorption. Carboxylesterase (CES) is ubiquitous in most organs and is located in the endoplasmic reticulum. Single-pass perfusion experiments in rat intestine have shown that CES is the main enzyme involved in intestinal first-pass hydrolysis. In man, intestinal CESs belong to the CES2 gene family and their activity is nearly constant along the jejunum and ileum. The predominant human intestinal CES, hCE2, preferentially hydrolyzes prodrugs in which the alcohol group of a pharmacologically active molecule has been modified by the addition of a small acyl group. In preclinical animal models, CES2 isozymes are also the major intestinal enzymes although they have different substrate specificities to human CES2, while CES1 isozymes and other unidentified enzymes are also present. It is therefore difficult to predict human intestinal absorption from animal experiments. Caco-2 cells mainly express the human CES1 isozyme, hCE1, which shows quite different substrate specificity from hCE2, making Caco-2 cells unsuitable for prediction of human intestinal absorption of prodrugs. However, we have developed a novel experimental method for predicting the human intestinal absorption of prodrugs using Caco-2 cells in which CES-mediated hydrolysis has been inhibited. The expression of hCE2 shows inter-individual variation and is regulated by several mechanisms, such as gene polymorphism and epigenetic processes. There are no reports suggesting that severe toxicity is associated with prodrugs due to genetic polymorphism of the CES2 gene.

Mucoadhesion: a review of characterization techniques

Importance of the field: Mucoadhesive drug delivery vehicles attract much attention owing to benefits such as extended residence time of the drug at the site of application, a relatively rapid uptake of a drug into the systemic circulation, and enhanced bioavailability of therapeutic agents. Mucoadhesion, defined as the ability to adhere to the mucus gel layer covering organs that are exposed to the outer surface of the body yet are not covered with skin, such as the mouth and the respiratory tract, is a key element in the design of these drug delivery systems.Areas covered in this review: This review focuses on the numerous experimental methods that have been proposed over the years for mucoadhesion characterization. These techniques are categorized into directs methods, which measure the force or time required to detach the mocoadhesive from a mucus, and indirect methods, which asses the interactions between the mucoadhesive and mucin type glycoproteins.What the reader will gain: The comprehensive description of the available techniques could facilitate the selection of a characterization method that meets the requirements of a specific study. Moreover, a comparison between the results obtained in different laboratories is given whenever possible.Take home message: The challenge of adopting a universal test method that could be used to compare data from different research groups and rank new mucoadhesion candidates has not yet been met.

Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.

Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.