First-pass Metabolism Research Articles

The Comprehensive Review: Exploring Future Potential of Nasopulmonary Drug Delivery Systems for Nasal Route Drug Administration

This comprehensive review aims to explore the future potential of nasopulmonary drug delivery systems for the administration of drugs through the nasal route. Nasal drug delivery has gained significant attention due to its numerous advantages, including rapid absorption, avoidance of first-pass metabolism, and non-invasive administration. This review provides an overview of the nasal anatomy and physiology, highlighting the factors influencing drug absorption and bioavailability. Additionally, it discusses the various types of nasopulmonary drug delivery systems, such as nasal sprays, powders, and gels, along with their advantages and limitations. Furthermore, the review delves into the challenges associated with nasal drug delivery, including mucociliary clearance, nasal irritation, and formulation issues. The potential applications of nasopulmonary drug delivery systems in the treatment of various diseases, such as allergies, respiratory disorders, and systemic conditions, are also discussed. Finally, the review concludes with an outlook on the future prospects of nasopulmonary drug delivery systems, emphasising the need for further research and development to optimise their efficacy and safety.
 Keywords: nasal pulmonary; nasal spray; nasal mucosa; gels; drops; nasal approaches; nasal route; nasal delivery.

Impact of Procedure Time on First Pass Effect in Mechanical Thrombectomy for Anterior Circulation Acute Ischemic Stroke.

First pass effect (FPE) is a metric increasingly used to determine the success of mechanical thrombectomy (MT) procedures. However, few studies have investigated whether the duration of the procedure can modify the clinical benefit of FPE. We sought to determine whether FPE after MT for anterior circulation large vessel occlusion acute ischemic stroke is modified by procedural time (PT). A multicenter, international data set was retrospectively analyzed for anterior circulation large vessel occlusion acute ischemic stroke treated by MT who achieved excellent reperfusion (thrombolysis in cerebral infarction 2c/3). The primary outcome was good functional outcome defined by 90-day modified Rankin scale scores of 0-2. The primary study exposure was first pass success (FPS, 1 pass vs ≥2 passes) and the secondary exposure was PT. We fit-adjusted logistic regression models and used marginal effects to assess the interaction between PT (≤30 vs >30 minutes) and FPS, adjusting for potential confounders including time from stroke presentation. A total of 1310 patients had excellent reperfusion. These patients were divided into 2 cohorts based on PT: ≤30 minutes (777 patients, 59.3%) and >30 minutes (533 patients, 40.7%). Good functional outcome was observed in 658 patients (50.2%). The interaction term between FPS and PT was significant ( P = .018). Individuals with FPS in ≤30 minutes had 11.5% higher adjusted predicted probability of good outcome compared with those who required ≥2 passes (58.2% vs 46.7%, P = .001). However, there was no significant difference in the adjusted predicted probability of good outcome in individuals with PT >30 minutes. This relationship appeared identical in models with PT treated as a continuous variable. FPE is modified by PT, with the added clinical benefit lost in longer procedures greater than 30 minutes. A comprehensive metric for MT procedures, namely, FPE 30 , may better represent the ideal of fast, complete reperfusion with a single pass of a thrombectomy device.

Formulation and Optimization of Intra Nasal Niosomal Gel of Kynurenic Acid: In Vitro in Vivo Characterization

Kynurenic acid's (KNA) inability to cross the blood brain barrier (BBB) severely limits its usage as a neuroprotective drug, despite the fact that it may have significant therapeutic effects in neurological illnesses. Drug delivery devices are one of the new avenues we're exploring as a means for KNA to enter the brain. Due to its low absorption when taken orally, medication formulation faces a significant hurdle. Here, nasal drug delivery has emerged as a popular alternate method for increasing medication bioavailability. In light of this, the current investigation set out to increase KNA bioavailability by means of an intranasal formulation based on niosomal technology. Rapid onset and evasion of first-pass metabolism are both offered by the nasal route, whereas niosomes protect hydrophilic medicines inside their core. For the purpose of determining entrapment efficiency, particle size, and in vitro drug release, niosomes were synthesized by combining lipid, nonionic surfactant, and cholesterol in distinct ratios. With a vesicle size of 248.51±1.54nm, the optimized niosomal formulation demonstrated a superior drug content (DC) of 98216±0.11% and an entrapment efficiency (EE) of 89.23±0.35. The formulation also contained cholesterol in an equal proportion (1:1). A value of 24 minutes was shown in the in vitro drug diffusion testing, indicating that the formulation exhibited prolonged activity. Gelation occurred at 37 ⁰C, which is the body's physiological temperature, and the optimum in situ gel, which contained 1:2 carbopol 934 and benzalkonium chloride, had a t90 value of 24 hours, indicating prolonged activity. In comparison to KNA oral suspension, the results showed that the KNA-loaded niosomal gel had a much higher relative bioavailability and improved drug penetration through the nasal mucosa

Oral fast dissolving films for co-administration of breviscapine and matrine: Formulation optimization and in vitro characterization

Oral fast dissolving films (OFDFs) are popular dosage forms for enhanced oral absorption of active ingredients without experiencing gastrointestinal interference or first-pass metabolism. The primary challenge in OFDF design is balancing drug loading capacity with film properties, particularly for poorly soluble drugs. In the present work, an OFDF formulation containing co-amorphous mixture was successfully designed for co-administration of two natural products at a drug content of 14%. Breviscapine and matrine are commonly used for cardiovascular and cerebrovascular related diseases, but their clinical application was limited by low bioavailability, short biological half-life, and instability problems. Their co-administration as a compound remedy requires a novel product too enhance drug dissolution and patient compliance. A 33 Box-Behnken design was used to generate OFDF preparations by solvent casting method. The optimized blank film formulation, comprising 57.40% HPMC E50, 14.01% PEG 400 and 5.35% L-HPC, demonstrated a rapid disintegration in 18 s. XRD and FTIR analysis on drug-loaded films revealed good compatibility of drugs and polymers, and amorphous state of films with co-precipitates. The films were evaluated for morphology, folding endurance, disintegration time and in vitro BRE dissolution. Drugs incorporation extended the disintegration time of blank films, yet remained under 30 s. The co-amorphous mixture of BRE and MAT in films exhibited a faster BRE dissolution rate compared to the physical mixture. In conclusion, a compound OFDF formulation featuring a co-amorphous mixture of BRE and MAT offers an efficient strategy for hydrophobic drug delivery at high dose.

Quality by Design (QbD) Paradigm: An Integrated Multivariate Approach to Transdermal Patch System Development

: The International Council on Harmonization issued quality by design (QbD) guidelines, including Q8 (R2) pharmaceutical development, Q9 quality risk management, and Q10 pharmaceutical quality system, to ensure the quality of pharmaceutical products. For continual and consistent improvement of the quality of pharmaceutical drug products, QbD tools, such as risk assessment, design of experiment, and control strategy, are used, which can solve the narrow areas in product development. Transdermal patch systems (TPS) are gaining attention among scientists and are one of the strong-growing drug delivery systems in the market as a result of numerous benefits, including lowering the dosing frequency, adverse effects and invasiveness, avoiding pre-systemic metabolism, and better patient efficiency and compatibility. Transdermal patch systems are a likable dosage form when compared to other dosage forms. However, several challenges are faced in TPS product development which has hindered enormous products concerning the market status of TPS in comparison to the oral dosage forms. The implementation of the QbD concept was much focused on oral dosage forms. Additionally, the lack of understanding of the development of TPS leads to failure and withdrawal from markets. Therefore, to understand the QbD concepts of TPS, an attempt has been made to review the QbD approach for the development of TPS from the identification of the Quality Target Product Profile to the arrival of design space, which might help the formulator to navigate the sticky areas, in the TPS development.

Anesthetic management for large vessel occlusion acute ischemic stroke with tandem lesions

BackgroundEndovascular therapy (EVT) stands as an established and effective intervention for acute ischemic stroke in patients harboring tandem lesions (TLs). However, the optimal anesthetic strategy for EVT in TL patients...

Development of In-situ Gel of Bupropion Hydrochloride-loaded Chitosan Nanoparticles using an Inotropic Gelation Method for Smoking Cessation via Nose to Brain: In-vitro and Ex-vivo Characterization and Evaluation

Introduction: Tobacco use is the leading preventable cause of various diseases, disabili-ties, and death. It is estimated that 480000 deaths annually are attributed to cigarette smoking, in-cluding secondhand smoke exposure. The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to delivering drugs selectively and effec-tively to the brain. The blood-brain barrier (BBB) and first-pass metabolism constitute the major obstacle to the uptake of drugs into the brain following systemic administration. Intranasal delivery offers a non-invasive and convenient method to bypass the BBB and avoid first-pass metabolism, which leads to the delivery of therapeutics directly to the brain. Objective: The objective of this study was to develop an In-situ gel of Bupropion Hydrochloride-loaded chitosan nanoparticles using the inotropic gelation method for Smoking Cessation via the nose to the brain to improve the bioavailability of Bupropion Hydrochloride, avoiding first-pass me-tabolism and bypassing Blood Brain Barrier. Methods: Fourier transform infrared spectroscopy (FTIR) was used to determine the identity and purity of the drug. A UV Spectrophotometer was employed in the analytical procedure. Chitosan nanoparticles loaded with bupropion HCl were made using the ionic gelation method, and then the optimized batch was made using simulated in-situ gelation. Utilizing Central composite design, op-timization was done by Design Expert-13. Evaluation of polymeric nanoparticles was performed by measuring their particle size, PDI, and entrapment efficiency. Additionally, they were tested for drug release in vitro. The final nanoparticles were subsequently tested for gelation using nasal simulation fluid, and an ex vivo investigation was also conducted. An ion-sensitive polymer gellan gum was used as a gelling agent, which formed an immediate gel and remained for an extended period. The finished formulation was also subjected to several characteri-zations, including TEM and FTIR. Results: The developed formulation was stable and showed enhanced contact time in the nasal mu-cosa, minimizing the frequency of administration. In-vitro studies through Franz diffusion cell and Ex-vivo studies on sheep nasal mucosa showed good results. In the Histopathological study, the op-timized batch was found to be safe and stable in an accelerated stability study for one month. Conclusion: Bupropion HCl-loaded chitosan nanoparticles In-situ gel proved to be suitable for the administration of Bupropion HCl through the nasal route. The ease of administration coupled with less frequent administration enhanced patient compliance. The formulation was found to be liquid at the formulated condition and formed gel in the presence of ions present in the nasal mucosa. The gel formed in situ showed sustained drug release. The formulations were less viscous before instilla-tion and formed a strong gel after instilling in the nasal cavity.

Thrombectomy

Endovascular procedures have become the standard treatment for acute stroke caused by large vessel occlusion. Various strategies are available, including stent retrieval, aspiration catheter placement, and combined techniques. However, the first-pass effect can be maximized using the technique most familiar to each surgeon and institution. Therefore, it is necessary to understand the characteristics of each device and develop case-specific treatment strategies.

Electrical impedance measurements can identify red blood cell–rich content in acute ischemic stroke clots ex vivo associated with first-pass successful recanalization

BackgroundElectrochemical impedance spectroscopy can determine characteristics such as cell density, size, and shape. The development of an electrical impedance–based medical device to estimate acute ischemic stroke (AIS) clot characteristics could improve stroke patient outcomes by informing clinical decision making. ObjectivesTo assess how well electrical impedance combined with machine learning identified red blood cell (RBC)–rich composition of AIS clots ex vivo, which is associated with a successfully modified first-pass effect. MethodsA total of 253 clots from 231 patients who underwent thrombectomy in 5 hospitals in France, Japan, Serbia, and Spain between February 2021 and October 2023 were analyzed in the Clotbase International Registry. Electrical impedance measurements were taken following clot retrieval by thrombectomy, followed by Martius Scarlet Blue staining. The clot components were quantified via Orbit Image Analysis, and RBC percentages were correlated with the RBC estimations made by the electrical impedance machine learning model. ResultsQuantification by Martius Scarlet Blue staining identified RBCs as the major component in clots (RBCs, 37.6%; white blood cells, 5.7%; fibrin, 25.5%; platelets/other, 30.3%; and collagen, 1%). The impedance-based RBC estimation correlated well with the RBC content determined by histology, with a slope of 0.9 and Spearman’s correlation of r = 0.7. Clots removed in 1 pass were significantly richer in RBCs and clots with successful recanalization in 1 pass (modified first-pass effect) were richer in RBCs as assessed using histology and impedance signature. ConclusionElectrical impedance estimations of RBC content in AIS clots are consistent with histologic findings and may have potential for clinically relevant parameters.

Exploring Potential of Nano-formulations in the Treatment of Alzheimer's Disease through Nasal Route.

Alzheimer's disease, a progressive neurodegenerative disorder, severely impacts cognitive function and daily living. The current treatment provides only symptomatic relief, and thus, disease-modifying therapies targeting underlying causes are needed. Although several potential therapies are in various stages of clinical trials, bringing a new Alzheimer's drug to market remains challenging. Hence, researchers are also exploring monoclonal antibodies, tau protein inhibitors, and anti-inflammatory drugs as treatment options. Conventionally designed dosage forms come with limitations like poor absorption, first-pass metabolism, and low bioavailability. They also cause systemic adverse effects because these designed systems do not provide target- specific drug delivery. Thus, in this review, the authors highlighted the current advancements in the development of intranasal nanoformulations for the treatment of Alzheimer's disease. This strategy of delivering anti-Alzheimer drugs through the nasal route may help to target the drug exactly to the brain, achieve rapid onset of action, avoid first-pass metabolism, and reduce the side effects and dose required for administration. Delivering drugs to the brain through the nasal route for treating Alzheimer's disease is crucial due to the limited efficacy of existing treatments and the profound impact of the disease on patients and their families. Thus, by exploring innovative approaches such as nose-to-brain drug delivery, it is possible to improve the quality of life for individuals living with Alzheimer's and alleviate its societal burden.

Interplay of Ritonavir-Boosted Oral Cabazitaxel with the Organic Anion-Transporting Polypeptide (OATP) Uptake Transporters and Carboxylesterase 1 in Mice.

Intravenously administered chemotherapeutic cabazitaxel is used for palliative treatment of prostate cancer. An oral formulation would be more patient-friendly and reduce the need for hospitalization. We therefore study determinants of the oral pharmacokinetics of cabazitaxel in a ritonavir-boosted setting, which reduces the CYP3A-mediated first-pass metabolism of cabazitaxel. We here assessed the role of organic anion-transporting polypeptides (OATPs) in the disposition of orally boosted cabazitaxel and its active metabolites, using the Oatp1a/b-knockout and the OATP1B1/1B3-transgenic mice. These transporters may substantially affect plasma clearance and hepatic and intestinal drug disposition. The pharmacokinetics of cabazitaxel and DM2 were not significantly affected by Oatp1a/b and OATP1B1/1B3 activity. In contrast, the plasma AUC0-120min of DM1 in Oatp1a/b-/- was 1.9-fold (p < 0.05) higher than that in wild-type mice, and that of docetaxel was 2.4-fold (p < 0.05) higher. We further observed impaired hepatic uptake and intestinal disposition for DM1 and docetaxel in the Oatp-ablated strains. None of these parameters showed rescue by the OATP1B1 or -1B3 transporters in the humanized mouse strains, suggesting a minimal role of OATP1B1/1B3. Ritonavir itself was also a potent substrate for mOatp1a/b, showing a 2.9-fold (p < 0.0001) increased plasma AUC0-120min and 3.5-fold (p < 0.0001) decreased liver-to-plasma ratio in Oatp1a/b-/- compared to those in wild-type mice. Furthermore, we observed the tight binding of cabazitaxel and its active metabolites, including docetaxel, to plasma carboxylesterase (Ces1c) in mice, which may complicate the interpretation of pharmacokinetic and pharmacodynamic mouse studies. Collectively, these results will help to further optimize (pre)clinical research into the safety and efficacy of orally applied cabazitaxel.

A REVIEW ON MOUTH DISSOLVING FILM- A NOVEL APPROACH

The oral route is one of the most important routes for local and systemic drug delivery due to its large surface area, high permeability and blood flow. Mouth dissolving films are the most advanced oral forms as they are simpler and easier to use than other dosage forms such as Oro-soluble tablets, sublingual tablets. Fast dissolving drug delivery system were rapidly developed in the 1970s as an alternative to capsules, syrups, and tablets for adults and adolescents who have difficulty swallowing conventional oral solid dosage form. The Oro- soluble film dissolves and disintegrates in less than a minute when placed in the mouth without drinking water or chewing. This form allows the drug to skip first-pass metabolism, which improve the bioavailability of the drug. This article provides a comprehensive review on mechanism of action, merits, formulation, evaluation and covering the aspects related to novel fast dissolving techniques.

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.

In vitro simulation of the liver first-pass effect with biotransformation-competent HepG2 cells to study effects of MG-132 on liver and cancer cells.

Liver biotransformation is the major route for drug metabolism in humans, often catalysed by cytochrome P450 (CYP) enzymes. This first-pass effect can lead to hepatotoxicity and influences the bioavailability of drugs. We aimed to establish in vitro culture systems simulating the liver first-pass to study effects of the proteasome inhibitor MG-132 simultaneously on hepatocytes and cancer cells. The first-pass effect was simulated by conditioned medium transfer (CMT) from pre-treated HepG2 CYP3A4-overexpressing cells to either pancreatic cancer cell line PANC-1 or primary colon cancer cells, and by indirect co-culture (CC) of liver and cancer cells in a shared medium compartment. Experimental proteasome inhibitor MG-132 was used as test substance as it is detoxified by CYP3A4. Cancer cells showed higher viabilities in the first-pass simulation by CMT and CC formats when compared to monocultures indicating effective detoxification of MG-132 by HepG2 CYP3A4-overexpressing cells. HepG2-CYP3A4 cells showed reduced viabilites after treatment with MG-132. We successfully established two different culture systems to simulate the liver first-pass effect in vitro. Such systems easily allow to study drug effects simultaneously on liver and on target cancer cells. They are of great value in pre-clinical cancer research, pharmaceutical research and drug development.

A Study on the Attitude, Abuse and Addiction to Tramadol among Sudanese University Students in Khartoum State, Sudan

Aim: This research was designed to study addiction to the drug Tramadol among university students in Khartoum State.&#x0D; Introduction: Tramadol is an atypical opioid that binds to μ-opioid receptors on neurons. It has a bioavailability of 70% and undergoes extensive first-pass metabolism in the liver. In most countries, it is a prescription-only medicine. Tramadol abuse has increased recently in the last few years between private universities in Khartoum state, Sudan. Common adverse effects of opioids are nausea, vomiting, relaxation, itching, mental confusion, delirium, urinary retention, sweating.&#x0D; Methodology: A study was conducted on 176 university students in Khartoum from August to September 2018. Ethical approval was obtained from sudan international university research commette and permission from each academic institution. A questionnaire sheet was developed to collect data related to drug abuse among students, including Sociodemographic data and knowledge about drug use without prescription. The collected data were statistically analyzed using ANOVA - IBM - Statistical Package for the Social Science version 16 programs-2008.&#x0D; Results: A study of 176 university students found that most were male (79.5%) and female (20.5%), with an age range of 21-25. Most were medical students, with a minority in engineering, literacy, and computing fields. Most were aware of tramadol analgesic "pain killer" effect, but only 53.7% knew its hallucinogenic effect. Most abusers used tramadol for less than a year, with most starting in university life. Most abusers consumed various doses, with most consuming daily. Adverse effects of tramadol included physical symptoms, psychological symptoms, and attempts at quitting. Reasons for failure to quit were mainly compliance.&#x0D; Conclusion: Tramadol abuse is prevalent among medical students in Sudan. Reasons for initiation include elation desire, avoidance of life conflicts, and curiosity.

A Concise Overview on Orodispersible Film along with their Formulation and Characterization Technique’s

Orally fast-dissolving medicine delivery techniques are increasingly common at present. Due to the desire for these delivery systems, oro-dispersible film (ODF) was recently introduced for the delivery of medicines via the oral route. Most of drugs are delivering through oral route in the form of tablets, capsules and liquids, because they are simple to make and have a greater level of patient compliance. But these conventional dosage forms have many problems including big size of dosage form, and fear of chocking. Oral rapid disintegrating/oro-dispersible drug delivery systems were created to tackle such issues. Fast dissolving films were invented for the patients who have swallowing issues with conventional/traditional oral solid dosage forms. They also have a quick onset of effect, taking only a few seconds, because the drug is absorbed directly from the injection site to the systemic circulation, avoiding first-pass metabolism. In the preparation of films, polymers, surfactants, flavoring agents, coloring agents, sweetening agents, saliva stimulating agents, drug, and plasticizer are used. The drug incorporated in ODF should have pleasing taste, low molecular weight, high stability, and high aqueous solubility. Solvent and semisolid casting, hot melt extrusion, and rolling techniques are routinely used to prepare ODFs. Thickness, loss on drying, tensile strength, and elongation percentage are commonly assessed for evaluating ODFs, as well as their resistance to tearing, weight variation, folding endurance, pH, swelling property, transparency, disintegration, dissolution rate, and stability. The purpose of this review article is to provide a quick overview of ODF delivery systems.

First pass effect in patients undergoing endovascular treatment for posterior circulation acute ischemic stroke

ObjectiveThis study aims to investigate the impact of first pass effect (FPE) on outcomes in the posterior circulation acute ischemic stroke (PC-AIS) and the independent predictors of FPE. MethodsThis was a multicenter, retrospective study. PC-AIS patients who underwent endovascular treatment were reviewed. The cohort achieving complete or nearly complete reperfusion (defined as expanded treatment in cerebralischemia [eTICI] ≥ 2c) was categorized into the FPE and multiple pass effect (MPE) groups. FPE was defined as achieving eTICI ≥ 2c with a single pass and without the use of rescue therapy. Modified FPE (mFPE) was defined as meeting the criteria for FPE but with eTICI ≥ 2b. The association of FPE with 90-day clinical outcomes and predictors for FPE were both investigated. ResultsThe study included a total of 328 patients, with 69 patients (21 %) in the FPE group. For primary outcome, FPE had a significant higher favorable outcome (mRS ≤ 3) rate than MPE (65.2 % vs. 44.8 %, p = 0.003). Similar outcomes were observed in the mFPE. Furthermore, FPE was significantly associated with favorable outcome (adjusted OR 2.23, 95 % CI 1.06-4.73, p = 0.036). Positive predictors for FPE included occlusion in the distal basilar artery, the first-line aspiration or combination, and cardioembolic etiology. Negative predictors for FPE included hypertension and general anesthesia. ConclusionFor PC-AIS patients due to large or medium vessel occlusion, FPE is associated with favorable clinical outcomes. The first-line techniques of aspiration or combination, as well as avoiding general anesthesia, contribute to a better realization of FPE.

Optimized mucoadhesive niosomal carriers for intranasal delivery of carvedilol: A quality by design approach

Carvedilol (CV), a β-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy.

Addressing the ADME Challenges of Compound Loss in a PDMS-Based Gut-on-Chip Microphysiological System.

Microphysiological systems (MPSs) are promising in vitro technologies for physiologically relevant predictions of the human absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates. However, polydimethylsiloxane (PDMS), a common material used in MPSs, can both adsorb and absorb small molecules, thereby compromising experimental results. This study aimed to evaluate the feasibility of using the PDMS-based Emulate gut-on-chip to determine the first-pass intestinal drug clearance. In cell-free PDMS organ-chips, we assessed the loss of 17 drugs, among which testosterone was selected as a model compound for further study based on its substantial ad- and absorptions to organ chips and its extensive first-pass intestinal metabolism with well-characterized metabolites. A gut-on-chip model consisting of epithelial Caco-2 cells and primary human umbilical vein endothelial cells (HUVECs) was established. The barrier integrity of the model was tested with reference compounds and inhibition of drug efflux. Concentration-time profiles of testosterone were measured in cell-free organ chips and in gut-on-chip models. A method to deduce the metabolic clearance was provided. Our results demonstrate that metabolic clearance can be determined with PDMS-based MPSs despite substantial compound loss to the chip. Overall, this study offers a practical protocol to experimentally assess ADME properties in PDMS-based MPSs.

Advancements of Polymer-Based Transdermal Drug Delivery Systems in Drug Bioavailability and Patient Compliance in United States

Transdermal drug delivery system (TDDS) helps in overcoming drug molecule barriers such as particle size, lipophilicity, permeability, and transports the medication directly to the blood circulation by employing physical and chemical penetration enhancers using polymers. The use of skin as a drug delivery route is challenging due to the stratum corneum's barrier properties that restrict the therapeutic bioavailability of the medications. Both, natural and synthetic polymers are used in TDDS to transport the medication into circulation via diffusion, and swelling control. TDDS is generally achieved by using transdermal patches containing one or more pharmaceutical active entities that are placed on unbroken skin for delivering active entities directly to the bloodstream by crossing the skin barrier. TDDS is the trendiest -delivery system as it is painless, non-invasive, self-administrative, avoids hepatic first-pass metabolism, and delivers poorly soluble drugs and increases the bioavailability. An overview of TDDS is provided in this review article, including its advantages over traditional dosage forms, limitations, different components of transdermal patches, modern techniques as well as transdermal products available in US market.