Showing papers in "Pharmaceutical Research in 2013"
TL;DR: The in vitro investigation showed enhanced cellular uptake efficiency for PS NPs in both of Caco-2 and MDCK cells after TPGS surface coating, and in vivo investigation showed that the particle size and surface coating are the two parameters which can dramatically influence the NPs biodistribution after intravenous administration.
Abstract: Purpose
To investigate the effects of the particle size and surface coating on the cellular uptake of the polymeric nanoparticles for drug delivery across the physiological drug barrier with emphasis on the gastrointestinal (GI) barrier for oral chemotherapy and the blood–brain barrier (BBB) for imaging and therapy of brain cancer.
555 citations
TL;DR: Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed.
Abstract: Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.
492 citations
TL;DR: A critical review of the literature shows that most, if not all assays for anti- PEG antibodies are flawed and lack specificity, and the biological effects induced by anti-PEG antibodies lack the characteristics of a bona fide antibody reaction.
Abstract: An increasing number of pegylated therapeutic proteins and drug targeting compounds are being introduced in the clinic. Pegylation is intended to increase circulation time and to reduce an immunogenic response. Recently however a number of publications have appeared claiming that the polyethylene glycol (PEG) moiety of these products in itself may be immunogenic and that the induced anti-PEG antibodies are linked to enhanced blood clearance and reduced efficacy of the products. A critical review of the literature shows that most, if not all assays for anti-PEG antibodies are flawed and lack specificity. Also the biological effects induced by anti-PEG antibodies lack the characteristics of a bona fide antibody reaction. Standardization of the anti-PEG assays and the development of reference sera are urgently needed.
297 citations
TL;DR: In this paper, the intranasal delivery is proposed as a noninvasive option for delivering drugs to the central nervous system (CNS) with minimal peripheral exposure, which facilitates the delivery of large and/or charged therapeutics which fail to effectively cross the blood-brain barrier (BBB).
Abstract: One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.
250 citations
TL;DR: The in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics were described and the technologies and evaluation associated with the solidification process of the drug Nanocrystals suspensions were discussed in detail.
Abstract: The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.
175 citations
TL;DR: It is concluded that viable epidermis offers a significant permeability barrier that becomes rate limiting upon removal of stratum corneum, and microdermabrasion of skin using a mask may provide an effective way to increase skin permeability.
Abstract: Most methods to increase transdermal drug delivery focus on increasing stratum corneum permeability, without addressing the need to increase permeability of viable epidermis. Here, we assess the hypothesis that viable epidermis offers a significant permeability barrier that becomes rate limiting upon sufficient permeabilization of stratum corneum. We tested this hypothesis by using calibrated microdermabrasion to selectively remove stratum corneum or full epidermis in pig and human skin, and then measuring skin permeability to a small molecule (sulforhodamine) and macromolecules (bovine serum albumin, insulin, inactivated influenza vaccine) in vitro. We found that removal of stratum corneum dramatically increased skin permeability to all compounds tested. However, removal of full epidermis increased skin permeability by another 1–2 orders of magnitude. We also studied the effects of removing skin tissue only from localized spots on the skin surface by covering skin with a mask containing 125-μm holes during tissue removal. Skin permeabilized in this less-invasive way showed similar results. This suggests that microdermabrasion of skin using a mask may provide an effective way to increase skin permeability. We conclude that viable epidermis offers a significant permeability barrier that becomes rate limiting upon removal of stratum corneum.
168 citations
TL;DR: Experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.
Abstract: Although a number of studies have reported that cocrystals can form by heating a physical mixture of two components, details surrounding heat-induced cocrystal formation remain unclear. Here, we attempted to clarify the thermal behavior of a physical mixture and cocrystal formation in reference to a binary phase diagram. Physical mixtures prepared using an agate mortar were heated at rates of 2, 5, 10, and 30°C/min using differential scanning calorimetry (DSC). Some mixtures were further analyzed using X-ray DSC and polarization microscopy. When a physical mixture consisting of two components which was capable of cocrystal formation was heated using DSC, an exothermic peak associated with cocrystal formation was detected immediately after an endothermic peak. In some combinations, several endothermic peaks were detected and associated with metastable eutectic melting, eutectic melting, and cocrystal melting. In contrast, when a physical mixture of two components which is incapable of cocrystal formation was heated using DSC, only a single endothermic peak associated with eutectic melting was detected. These experimental observations demonstrated how the thermal events were attributed to phase transitions occurring in a binary mixture and clarified the relationship between exothermic peaks and cocrystal formation.
142 citations
TL;DR: In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described and the limitations and future directions of brain-targeted delivery systems are discussed.
Abstract: Major central nervous system (CNS) disorders, including brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke, are significant threats to human health. Although impressive advances in the treatment of CNS disorders have been made during the past few decades, the success rates are still moderate if not poor. The blood–brain barrier (BBB) hampers the access of systemically administered drugs to the brain. The development of nanotechnology provides powerful tools to deliver therapeutics to target sites. Anchoring them with specific ligands can endow the nano-therapeutics with the appropriate properties to circumvent the BBB. In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described. The limitations and future directions of brain-targeted delivery systems are also discussed.
139 citations
TL;DR: Activation of FXR by GW4064 suppressed weight gain in C57BL/6 mice fed with either HFD or high-fat and high-cholesterol diet and avoided diet-induced hyperinsulinemia and hyperglycemia through decreasing the transcript levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, two key enzymes in gluconeogenesis.
Abstract: Purpose
To examine the effect of farnesoid X receptor (FXR) activation by its synthetic agonist, 3-[2-[2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) on diet-induced obesity and hepatic steatosis.
138 citations
TL;DR: The prepared bandages can be used on various types of infected wounds with large volume of exudates and showed controlled swelling and degradation.
Abstract: β-chitin hydrogel/nZnO composite bandage was fabricated and evaluated in detail as an alternative to existing bandages. β-chitin hydrogel was synthesized by dissolving β-chitin powder in Methanol/CaCl2 solvent, followed by the addition of distilled water. ZnO nanoparticles were added to the β-chitin hydrogel and stirred for homogenized distribution. The resultant slurry was frozen at 0°C for 12 h. The frozen samples were lyophilized for 24 h to obtain porous composite bandages. The bandages showed controlled swelling and degradation. The composite bandages showed blood clotting ability as well as platelet activation, which was higher when compared to the control. The antibacterial activity of the bandages were proven against Staphylococcus aureus (S. aureus) and Escherichia coli (E.coli). Cytocompatibility of the composite bandages were assessed using human dermal fibroblast cells (HDF) and these cells on the composite bandages were viable similar to the Kaltostat control bandages and bare β-chitin hydrogel based bandages. The viability was reduced to 50–60% in bandages with higher concentration of zinc oxide nanoparticles (nZnO) and showed 80–90% viability with lower concentration of nZnO. In vivo evaluation in Sprague Dawley rats (S.D. rats) showed faster healing and higher collagen deposition ability of composite bandages when compared to the control. The prepared bandages can be used on various types of infected wounds with large volume of exudates.
128 citations
TL;DR: This review describes the types of pharmaceutical grade excipients used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches, and details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations.
Abstract: The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.
TL;DR: This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition in cyclosporine-repaglinide DDI and the impact of dose staggering is illustrated.
Abstract: To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1. Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/− pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/− metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide. Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC50 ranging from 0.019–0.093 μM following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80–97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated. This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.
TL;DR: A review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value and suggest the induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress could explain all the effects observed.
Abstract: Oxidative stress, involved in many diseases, is defined as an impaired balance between reactive oxygen species (ROS) production and antioxidant defences. Antioxidant enzymes such as superoxide dismutase (SOD) play a key role in diminishing oxidative stress. Thus, the removal of ROS by exogenous SODs could be an effective preventive strategy against various diseases. The poor bioavailability of exogenous SODs has been criticized. However, improvements in SOD formulation may overcome this limitation and boost interest in its therapeutic properties. Here, we provide a review of animal and human studies about SODs supplementation in order to evaluate their therapeutic value. Protective effects have been observed against irradiation, carcinogenesis, apoptosis and neurodegeneration. SODs administration has also been reported to alleviate inflammatory, infectious, respiratory, metabolic and cardiovascular diseases and genitourinary and fertility disorders, raising the question of its mechanism of action in these diverse situations. Some authors have shown an increase in endogenous antioxidant enzymes after exogenous SODs administration. The induction of endogenous antioxidant defence and, consequently, a decrease in oxidative stress, could explain all the effects observed. Further investigations need to be carried out to test the hypothesis that SODs supplementation acts by inducing an endogenous antioxidant defence.
TL;DR: Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart, and provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
Abstract: To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD). Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations. The successful synthesis of DPA was demonstrated via 1H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups. This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
TL;DR: Results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationsic polar drugs.
Abstract: Purpose
Drug delivery to the brain is impeded by the blood-brain barrier (BBB) Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach
TL;DR: The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy.
Abstract: To investigate accelerated blood clearance (ABC) induction upon repeated injections of PLGA-PEG nanoparticles as a commonly used polymeric drug carrier. Etoposide-loaded PLGA-PEG NPs were developed and administered as the test dose to rats pre-injected with various NP treatments at certain time intervals. Pharmacokinetic parameters of etoposide and production of anti-PEG IgM antibody were evaluated. A notable ABC effect was induced by a wide range of polymer doses (0.1 to 20 mg) of empty NPs, accompanied by IgM secretion. However, a further increase in polymer dose resulted not only in the abrogation of the observed ABC induction but also in distinctly a higher value for AUC of the NPs relative to the control. The data from the PEG-negative group verified the fundamental role of PEG for ABC induction. The first injection of etoposide-containing PEGylated nanoparticles (a cell cycle phase-specific drug) produced a strong ABC phenomenon. Three sequential administrations of etoposide-loaded NPs abolished ABC, although a high level of IgM was still detected, which suggests saturation with insignificant poisoning of immune cells. The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy.
TL;DR: At low pH the aggregation propensity of the investigated antibodies does not correlate with antibody subclass, surface net charge and hydrophobicity of the non-native state.
Abstract: Purpose
To identify the aggregation mechanism and the stability characteristics of three different monoclonal antibodies under acidic conditions.
TL;DR: Insight is offered into the unique manner by which lipid-based formulations (LBFs) may enhance the absorption of poorly water-soluble drugs via co-stimulation of solubilization and supersaturation through incorporation of LBF into lipid digestion and absorption pathways.
Abstract: Drugs with low aqueous solubility commonly show low and erratic absorption after oral administration. Myriad approaches have therefore been developed to promote drug solubilization in the gastrointestinal (GI) fluids. Here, we offer insight into the unique manner by which lipid-based formulations (LBFs) may enhance the absorption of poorly water-soluble drugs via co-stimulation of solubilization and supersaturation. Supersaturation provides an opportunity to generate drug concentrations in the GI tract that are in excess of the equilibrium crystalline solubility and therefore higher than that achievable with traditional formulations. Incorporation of LBF into lipid digestion and absorption pathways provides multiple drivers of supersaturation generation and the potential to enhance thermodynamic activity and absorption. These drivers include 1) formulation dispersion, 2) lipid digestion, 3) interaction with bile and 4) lipid absorption. However, high supersaturation ratios may also stimulate drug precipitation and reduce exposure where re-dissolution limits absorption. The most effective formulations are likely to be those that generate moderate supersaturation and do so close to the site of absorption. LBFs are particularly well suited to these criteria since solubilization protects against high supersaturation ratios, and supersaturation initiation typically occurs in the small intestine, at the absorptive membrane.
TL;DR: The maximum supersaturation ratio (SRM) provides an indication of the supersaturation ‘pressure’ exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro and may also prove effective in discriminating the in vivo performance of LBFs.
Abstract: Purpose
Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation – precipitation balance for a range of LBFs.
TL;DR: It is demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide, and the model quantitatively predicted several repaglinside DDIs, including the complex interactions with gemfibrozil.
Abstract: Purpose
Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.
TL;DR: The main disease targets for the local delivery of siRNA to specific tissues or organs, including the skin, the lung, the eye, the nervous system, the digestive system and the vagina, were explored.
Abstract: With the increasing number of studies proposing new and optimal delivery strategies for the efficacious silencing of gene-related diseases by the local administration of siRNAs, the present review aims to provide a broad overview of the most important and latest developments of non-viral siRNA delivery systems for local administration. Moreover, the main disease targets for the local delivery of siRNA to specific tissues or organs, including the skin, the lung, the eye, the nervous system, the digestive system and the vagina, were explored.
TL;DR: Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TGMCversus TGLC, and PS80 versus PEG400, and it is shown, for the first time, that solubilty in TGMC and TGLC can be predicted from rapidly calculated molecular descriptors.
Abstract: Purpose
To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties.
TL;DR: Nanoceria confirmed a strong anti-ROS action but, most interestingly, also showed beneficial effects on both cell differentiation and dopamine production, demonstrating a significant potential as pharmacological agent in the treatment of neurological disorders.
Abstract: Purpose
Oxidative stress has been found to play a key role in several diseases, that range from cancer to neurodegenerative disorders. Besides traditional anti-oxidant agents, in recent years much attention has been focused on nanotechnological solutions, including cerium oxide nanoparticles (nanoceria).
TL;DR: This review focuses on the nano-enabled system applications for the treatment and diagnosis of neurodegenerative diseases, in particular Alzheimer's, Parkinson’s and Prion diseases.
Abstract: Neurodegenerative disorders are becoming prevalent with the increasing age of the general population. A number of difficulties have emerged for the potential treatment of neurodegenerative diseases, as these disorders may be multi systemic in nature. Due to limitations regarding the blood brain barrier (BBB) structure, efflux pumps and metabolic enzyme expression, conventional drug delivery systems do not provide efficient therapy for neurodegenerative disorders. Nanotechnology can offer impressive improvement of the neurodegenerative disease treatment by using bio-engineered systems interacting with biological systems at a molecular level. This review focuses on the nano-enabled system applications for the treatment and diagnosis of neurodegenerative diseases, in particular Alzheimer’s, Parkinson’s and Prion diseases.
TL;DR: This study has demonstrated the impact HPMC-anionic surfactant interactions have during the dissolution of non-ionic hydrophilic polymer based solid dispersions and has highlighted the potential relevance of this to a fuller understanding of drug solubilisation/stabilisation in vivo.
Abstract: Purpose
To evaluate the role of polymer-surfactant interactions in drug solubilisation/stabilisation during the dissolution of spray-dried solid dispersions and their potential impact on in vivo drug solubilisation and absorption.
TL;DR: Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux.
Abstract: Superior bioavailability of BCS Class 2 compounds incorporated into SNEDDS was previously reported. This study aims to elucidate the underlying mechanisms accountable for this phenomenon. SNEDDS of amiodarone (AM) and talinolol were developed. Pharmacokinetic parameters were assessed in vivo. Effect on intestinal permeability, P-gp efflux and toxicity was evaluated in vitro (Caco-2) and ex vivo (Ussing). Solubilization was assessed in vitro (Dynamic Lipolysis Model). Effect on intraenterocyte metabolism was evaluated using CYP3A4 microsomes. Oral administration of AM-SNEDDS and talinolol-SNEDDS resulted in higher and less variable AUC and Cmax. In vitro, higher talinolol-SNEDDS Papp indicated Pgp inhibition. Lipolysis of AM-SNEDDS resulted in higher AM concentration in the fraction available for absorption. Incubation of AM-SNEDDS with CYP3A4 indicated CYP inhibition. SNEDDS didn’t alter mannitol Papp and TEER. SNEDDS effect was transient. Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux. SNEDDS effect is reversible and doesn’t cause intestinal tissue or cell damage. These comprehensive findings can be used for intelligent selection of drugs for which oral bioavailability will improve upon incorporation into SNEDDS, based on recognition of the drug’s absorption barriers and the ability of SNEDDS to overcome them.
TL;DR: The pulmonary delivery of vaccines, methods of preparing NPs for antigen delivery and targeting, the importance of targeting DCs and different techniques involved in formulating dry powders suitable for inhalation are discussed.
Abstract: Pulmonary vaccine delivery has gained significant attention as an alternate route for vaccination without the use of needles. Immunization through the pulmonary route induces both mucosal and systemic immunity, and the delivery of antigens in a dry powder state can overcome some challenges such as cold-chain and availability of medical personnel compared to traditional liquid-based vaccines. Antigens formulated as nanoparticles (NPs) reach the respiratory airways of the lungs providing greater chance of uptake by relevant immune cells. In addition, effective targeting of antigens to the most ‘professional’ antigen presenting cells (APCs), the dendritic cells (DCs) yields an enhanced immune response and the use of an adjuvant further augments the generated immune response thus requiring less antigen/dosage to achieve vaccination. This review discusses the pulmonary delivery of vaccines, methods of preparing NPs for antigen delivery and targeting, the importance of targeting DCs and different techniques involved in formulating dry powders suitable for inhalation.
TL;DR: It is confirmed that the microneedles of new-MH, as well as those on the authors' old-MH that contained collagen, could easily pierce stratum corneum without severe skin irritation, and that TCI using new- MH efficiently increased antibody titer with comparable to TCi using old- MH.
Abstract: Purpose
We previously reported the safety and efficacy in animal experiments of transcutaneous immunization (TCI) using a self-dissolving microneedle patch (MicroHyala; MH) made of hyaluronic acid and collagen. However, this MH was an unsuitable TCI device for the human skin, as collagen is suspected to induce inflammation. In this study, we developed an improved collagen-free MH (new-MH) and conducted clinical study to evaluate the fundamental properties and safety in human.
TL;DR: It is demonstrated that genipin-crosslinking combined with spray-drying technique could be used as a promising tool to develop solid redispersible casein nanoparticles with sustained drug release properties.
Abstract: Purpose
To propose a simple method for the development of genipin-crosslinked casein micelles as a new delivery platform for prolonged release of alfuzosin hydrochloride.
TL;DR: This study demonstrated SSTr2-targeting specificity along with direct chelator-free 89Zr-labeling of LPs and dual PET/MR imaging properties.
Abstract: Purpose
Dual-modality PET/MR platforms add a new dimension to patient diagnosis with high resolution, functional, and anatomical imaging. The full potential of this emerging hybrid modality could be realized by using a corresponding dual-modality probe. Here, we report pegylated liposome (LP) formulations, housing a MR T1 contrast agent (Gd) and the positron-emitting 89Zr (half-life: 3.27 days), for simultaneous PET and MR tumor imaging capabilities.