Drug Permeation Research Articles

Effect of bicarbonate buffer on artificial membrane permeation of drugs

Background and purpose: The pH value of the small intestine is physiologically maintained by bicarbonate buffer (BCB). However, the effect of BCB on the membrane permeation of drugs has not been investigated. The purpose of this study was to investigate the effect of BCB on the passive membrane permeation of drugs. Experimental approach: The μFlux apparatus (pION Inc.) was used for permeability measurements. To avoid a pH change of BCB, a floating lid was newly developed for μFlux. The membrane filter was coated with a 10 % soybean lecithin-decane solution. The flux measurement was performed in an iso-pH condition (pH 6.5, BCB = 10 mM, buffer capacity ()= 4.4 mM pH-1). Phosphate buffer (PPB) with the same pH and β was used for comparison (PPB = 8 mM). Key results: The floating lid suppressed the pH increase to less than 0.1 for 120 min. The effective permeability (Pe) values of lipophilic weakly acidic and basic drugs were lower in BCB than in PPB (ketoprofen, naproxen, and propranolol). On the other hand, the Pe values in BCB and PPB were similar for unionizable drugs (caffeine and antipyrine) and hydrophilic weakly basic drugs (metoprolol and procainamide). Conclusion: Passive membrane permeation of lipophilic weakly acidic and basic drugs was slower in BCB than in PPB. This was suggested to be attributed to the slow neutralization rate of BCB, which affects the pH value adjacent to the membrane surface.

Enhancement of Transdermal Drug Delivery: Integrating Microneedles with Biodegradable Microparticles.

This investigation aimed to enhance transdermal methotrexate delivery through human skin by employing Dr. Pen microneedles and poly(d,l-lactide-co-glycolide) acid microparticles formulated from eight polymer grades (Expansorb DLG 95-4A, DLG 75-5A, DLG 50-2A, DLG 50-5A, DLG 50-8A, DLG 50-6P, DLG 50-7P, and DLL 10-15A). A comprehensive characterization of the microparticles was performed, encompassing various parameters such as size, charge, morphology, microencapsulation efficiency, yield, release kinetics, and chemical composition. The efficacy of microneedles in disrupting skin integrity was demonstrated by scanning electron microscopy, dye binding, histological examination, confocal laser microscopy, and pore size analysis. Microneedle-mediated skin microporation led to a substantial reduction in skin electrical resistance and a concomitant increase in transepidermal water loss. In vitro permeation experiments using human skin delivered microparticles into microporated skin and demonstrated a considerable difference in methotrexate delivery among the polymer groups. Microneedle treatment significantly amplified cumulative drug delivery, steady-state flux, diffusion coefficient, permeability coefficient, and drug concentration within skin layers while concurrently diminishing lag time (p < 0.05). Furthermore, a robust correlation was established between microparticle properties (cumulative release, release rate, encapsulation efficiency) and drug deposition in the skin. In conclusion, the synergistic combination of Dr. Pen microneedles and PLGA microparticles facilitated enhanced and regulated transdermal methotrexate delivery.

FORMULATION OF TOLNOFTATE LOADED CUBOSOMES FOR EFFECTIVE TRANSDERMAL DELIVERY: AN IN VITRO AND EX-VIVO STUDY

Objective: The novel topical application has several benefits over traditional dosing forms, such as preventing gastrointestinal discomfort, lowering liver drug metabolism, and increasing medication bioavailability. Tolnaftate is used as potential anti-fungal agent various fungal infections. Methods: The cubosomes were formulated by emulsification technique using probe sonicator. The formulation was optimized using different concentrations of glyceryl monooleate and poloxamer 407. Results: The formed cubosomes dispersion was subjected to entrapment efficiency, surface morphology, particle size, in vitro release, anti-fungal study and ex-vivo study. The improved formulation was then transformed to a cubosomal hydrogel by the addition of carbopol 934. The average particle size of the optimised cubosomes was 208.0 nm. Zeta potential has been found to be 49.8 mV, with an entrapment efficiency of almost 90.0%. The drug steady-state flux (Jss) values for Tolnaftate Cubosomal formulation, marketed formulation, and plain drug gel were nearly 11.98, 10.23, and 10.06 g/cm2. h. As compared to standard marketed preparation, the cubosome-loaded formulation demonstrated enhanced penetration, extended deposition, and prolonged drug release. Conclusion: The drug had low solubility and permeability; it was overcome and produced superior outcomes in the form of cubosomes, which considerably increased the drug's solubility and permeability.

Establishing a General Atomistic Model for the Stratum Corneum Lipid Matrix Based on Experimental Data for Skin Permeation Studies

Understanding the permeation of drugs through the intercellular lipid matrix of the stratum corneum layer of skin is crucial for effective transdermal delivery. Molecular dynamics simulations can provide molecular insights into the permeation process. In this study, we developed a new atomistic model representing the multilamellar arrangement of lipids in the stratum corneum intercellular space for permeation studies. The model was built using ceramides in extended conformation as the backbone along with free fatty acids and cholesterol. The properties of the equilibrated model were in agreement with the neutron scattering data and hydration behavior previously reported in the literature. The permeability of molecules, such as water, benzene and estradiol, and the molecular mechanism of action of permeation enhancers, such as eucalyptol and limonene, were evaluated using the model. The new model can be reliably used for studying the permeation of small molecules and for gaining mechanistic insights into the action of permeation enhancers.

Drug-Loaded Hydrogel Microneedles for Sustainable Transdermal Delivery of Macromolecular Proteins.

Poly(methyl vinyl ether co-maleic acid) (PMVE/MA) hydrogel microneedles (HMN) are investigated for transdermal delivery of macromolecular drugs owing to their biocompatibility and super-swelling properties. However, the drug delivery efficacy reduces with increasing molecular weight due to the entrapment within the HMN matrices. Furthermore, integrating external drug reservoirs extends the drug diffusion path and reduces the efficiency of drug permeation. A direct drug loading approach in the HMN matrix was introduced in this work following a pH modification step. The effect of pH modification on the physicochemical properties of HMN was studied. Then, bovine serum albumin (BSA), a model protein, was loaded into the pH-modified HMN, and the morphological changes in HMN and protein stability were also assessed. Finally, the efficacy of BSA-loaded HMN in the transdermal delivery was evaluated ex vivo. A significant increase in swelling was recorded following the pH modification of HMN (p < 0.001). The structure of pH-modified hydrogel was highly porous, and ATR-FTIR spectra indicated a shift in the carboxylic peak. The secondary structure of BSA loaded in the pH-modified HMN was also preserved. The BSA-loaded HMN mediated a sustained ex-vivo drug release with a cumulative release of 64.70% (3.88 mg) in 24 h. Hence, the model drug-incorporated PMVE/MA HMN system shows potential for sustainable transdermal delivery of proteins.

Mechanistic Insights Underlying the Drug Release and Skin Permeation of Guanfacine Transdermal Patch with Various Acrylic Pressure-Sensitive Adhesives.

Acrylic pressure-sensitive adhesives (PSAs) are widely applied in transdermal drug delivery systems (TDDS). However, the molecular mechanisms underlying the effect of functional groups of PSAs on drug release and transdermal permeation properties remain insufficiently clear. In this study, we investigated the effect of acrylic PSAs' functional groups on the in vitro release and transdermal permeation properties of a model drug guanfacine (GFC). The rates of release and permeation were hydroxyl PSA (PSA-OH) > non-functional group PSA (PSA-None) > carboxyl PSA (PSA-COOH). Thermal analysis, molecular modeling, Raman spectroscopy, and FTIR were employed to characterize the drug-PSA interactions. The strength of the interaction force between GFC and PSA-None was determined to be negligible. The primary amino of GFC formed a medium-strength hydrogen bond with the hydroxyl of PSA-OH and a strong ionic interaction with the carboxyl of PSA-COOH. Compared to PSA-None, PSA-OH featured a weaker mechanical strength, a higher rheological phase shift angle (δ), and a lower glass transition temperature (Tg), resulting in improved molecular mobility. Furthermore, PSA-OH exhibited higher tack, viscosity, and polarity, providing superior skin adhesion. Overall, it has been demonstrated that drug release and permeation were determined by a combination of interaction strength, molecular mobility, and skin adhesion. The novel discovery expands our understanding of the molecular mechanism of drug-PSA-skin interactions, offering a crucial point of reference for the development‌ of GFC transdermal patches.

Enhancing Antituberculosis Treatment Nanoparticles Encapsulated with Catalase and Levofloxacin Under Ultrasound Stimulation: A 3D Spheroid Study.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB). Tuberculous granuloma is the central and key pathological structure of tuberculosis and is characterized by tissue hypoxia and ineffective drug delivery. To address these issues, this study fabricated a composite nanoparticle loaded with catalase (CAT) and levofloxacin (LEV) (CAT@LEV-NPs) and then combined it with ultrasound (US) to investigate the bactericidal effect and underlying mechanisms using TB spheroids. The TB spheroids were constructed using attenuated Bacillus Calmette-Guérin (BCG) instead of MTB to facilitate operation under general experimental conditions. This study examined the physical properties and oxygen production efficiency of CAT@LEV-NPs. Subsequently, we treated TB spheroids with nanoparticles alone or in combination with US and found that ultrasound significantly increased drug permeability and activated CAT@LEV-NPs to produce a large number of reactive oxygen species (ROS). The combined treatment showed excellent antibacterial effects, resulting in more severe damage to the bacterial structure than other treatments. Additionally, the combined treatment induced a higher M1 polarization of macrophages, increased the apoptosis rate, and improved the anoxic microenvironment in TB spheroids. These factors may be closely related to the enhanced bactericidal effects of combined treatment. In conclusion, our study suggests that US combined with CAT@LEV-NPs could serve as a novel, noninvasive, safe, and effective treatment modality for intractable MTB infections.

Fully atomistic molecular dynamics modeling of photoswitchable azo-PC lipid bilayers: structure, mechanical properties, and drug permeation.

Phospholipid based vesicles called liposomes are commonly used as packaging in advanced drug delivery applications. Stimuli-responsive liposomes have been designed to release their contents under certain conditions, for example through heating or illumination. However, in the case of photosensitive liposomes based on azo-PC, namely phosphatidylcholine lipids with azobenzene incorporated into one of the two lipid tails, the release mechanism is not known. Here we show, using fully-atomistic molecular dynamics simulations of pure azo-PC bilayers, that drug permeation through the bilayer is driven by a light-induced gel-to-liquid lipid phase transition that softens the membrane bending rigidity by an order of magnitude, increases the area per lipid, and decreases the membrane thickness. Furthermore, using phenol as a model drug, we quantified its translocation free energy and its ability to cross the bilayer as a result of a chemical potential gradient induced through a double-bilayer simulation unit cell. The molecular level structural and dynamic information obtained in this study should be of help in designing new azo-PC based liposomes.

Polymeric Nanoparticles Revolutionizing Brain Cancer Therapy: A Comprehensive Review of Strategies and Advances.

Brain cancer continues to be one of the most formidable malignancies to manage, mainly attributable to the presence of the blood-brain barrier (BBB) limiting the permeability of drugs and the diverse characteristics of brain tumors complicating treatment. The management of brain tumors has been hampered by many different factors, including the impermeability of the BBB, which restricts the delivery of chemotherapeutic agents to the tumor site, as well as intertumoral heterogeneity and the influence of brain tumor stem cells. In addition, small molecular weight drugs cannot specifically accumulate in malignant cells and have a limited circulation half-life. Nanoparticles (NPs) can be engineered to traverse the BBB and transport therapeutic medications directly into the brain, enhancing their efficacy compared with the conventional delivery of unbound drugs. Surface modifications of NPs can boost their efficiency by increasing their selectivity towards tumor receptors. This review covers treatment methods for malignant gliomas, associated risk factors, and improvements in brain drug administration, emphasizing the future potential of polymeric NPs and their mechanism for crossing the BBB. To surmount these obstacles, the newly formulated drug-delivery approach utilizing NPs, particularly those coated with cell membranes, has demonstrated potential in treating brain cancer. These NPs provide targeted tumor specificity, biocompatibility, extended circulation, enhanced BBB penetration, and immune evasion. This review focuses on coating strategies for PLGA NPs, particularly dual-targeting methods, to enhance BBB permeability and tumor-targeted delivery of drugs in brain cancer.

Quality by Design and Characterization of Nimodipine Novel Carriers for the Treatment of Hypertension: Assessment of the Pharmacokinetic Profile

Background: Nimodipine is a highly lipophilic anti-hypertensive drug having 13% oral bioavailability (log P 3.41). Nimodipine is a prominent calcium channel blocker that must be given intravenously for an extended period of time (1-2 weeks) in order to treat cerebral vasospasm. It might be possible to substitute a sustained-release biodegradable formulation for the ongoing intravenous infusion used in this traditional therapy. Objectives: The primary goal of this study was to formulate and evaluate the potentiality of ethosomes to deliver nimodipine, a potent water-insoluble anti-hypertensive drug, through the deeper layers of the skin. The greatest challenge for drug formulation is its poor oral bioavailability and solubility. Methods: Nimodipine-loaded ethosomal gel was developed for transdermal drug delivery to increase solubility and skin penetration and to promote oral bioavailability. Central composite design employing a thin-film hydration method was used to prepare and optimize ethosomes. A better dispersion medium for nimodipine's preparation in ethosomes was selected based on the effect. The design consisted of independent variables as lipid (X1), ethanol (X2), and sonication time (X3). Concentrations were manipulated to examine the effects on three responses, namely the %entrapment efficiency (Y1), vesicle size (Y2), and %cumulative drug release (Y3). Surface morphology and other in vitro tests were used to identify ethosomes containing nimodipine. The preparation of ethosomal gel formulations began with incorporating a single ethosomal formulation (F4) into various concentrations of gelling agents. These studies performed physicochemical characterization, compatibility testing, and in vitro drug release tests on ethosomal gels. In vivo studies involving hypertensive rats were conducted after skin permeation, and ex vivo studies were performed. In order to assess the drug's permeability and deposition, we employed the abdomen skin of rats. Results: The optimal process parameters resulted in ethosomes with 89.9 ± 0.19 percent entrapment efficiency, a vesicle size of 102.37 ± 5.84 nm, and a cumulative drug release of 98.3 ± 0.13%. pH and drug content measurements were consistent with the homogeneous ethosomal gels. Viscosity was found to increase with the spreadability. The ethosomal gel formulation (G2) met the regulatory standards regarding appearance, spreadability, viscosity, and in vitro release studies. Compared to pure nimodipine, ethosomal suspension (F4) and ethosomal gel (G2) formulations had higher ex vivo permeation, steady-state flux, and drug retention. Rats' mean arterial pressure (146.11 ± 0.84 mmHg) was significantly lower (p &lt; 0.01) after after two hours of the experiment than it had been (p &lt; 0.001) (98.88 ± 0.63 mmHg) after six hours. Conclusion: To summarize, ethosomal gels have been found to be lipid carriers that enhance skin permeation and extend the anti-hypertensive effect of nimodipine. Compared to plain gel, ex vivo drug permeation through rat abdominal skin in ethosomal gel was enhanced. Gel-based ethosomal transdermal drug delivery formulations of nimodipine can be used to achieve a faster rate and extend the duration of drug delivery by more than 24 hours.

Overcoming drug delivery challenges with lipid-based nanofibers for enhanced wound repair.

Wound healing is a dynamic, multi-phase process that includes haemostasis, tissue regeneration, cellular proliferation, and matrix modification. Traditional wound care procedures frequently encounter complications such as delayed healing and infection, demanding new therapeutic approaches. In this context, nanomaterial-based devices provide considerable benefits due to their capacity to improve medication delivery and tissue healing. We suggest a lipid-based nanofiber formulation for wound treatment that overcomes the restricted skin penetration of hydrophilic niacin, a strong wound healing agent. Niacin-loaded nanofibers (NLNFs) were manufactured utilizing glyceryl monostearate (GMS) by a self-assembly process, which included high-pressure homogenization and probe sonication for optimum nanostructure creation. The NLNFs were physicochemically characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, scanning electron microscopy (SEM) and surface profilometry to determine their morphology and homogeneity, and a drop shape analyser was used to determine hydrophobicity. In vitro tests revealed prolonged drug release, great cytocompatibility, and strong antioxidant activity, indicating superior free radical scavenging capacity. Ex vivo tests, such as the Draize skin irritation test, skin permeation test, and drug retention assays, revealed low skin irritation, increased permeability, and efficient drug retention in skin layers. In vivo experiments showed rapid wound closure and positive histological results, which were backed by hemocompatibility tests such as hemolysis and whole blood clot analysis, validating the formulation's safety. ELISA results indicated that the NLNF-treated group had higher levels of critical wound-healing indicators than the controls. Overall, our findings suggest that NLNFs have tremendous potential as a unique and effective treatment alternative for controlling and improving wound healing processes.

Establishment of endogenous canine MUC1 knock-out MDCKII cells using CRISPR-Cas9 and evaluation of drug permeation

Establishment of endogenous canine MUC1 knock-out MDCKII cells using CRISPR-Cas9 and evaluation of drug permeation

Membranes Containing Nanoparticles Incorporated with Metronidazole for Improved Permeability to Promote Periodontal Tissue Recovery

Background: Infection is the main reason for the failure of the clinical application of guided tissue regeneration (GTR). Objective: The aim of this study is to develop a membrane containing nanoparticles incorporated with the antimicrobial drug metronidazole (MTZ-NPs Membrane) to enhance drug permeation delivery into cells and promote periodontal tissue recovery and regeneration. Methods: We prepared membranes containing nanoparticles incorporated with metronidazole (MTZ-NPs Membrane) and characterized the properties, such as mechanical properties, physicochemical properties, and release. Coumarin-6 was used to prepare a membrane containing nanoparticles incorporated with Coumarin-6 (C6-NPs Membrane) to evaluate the efficiency of the nanoparticles-loaded membranes on transmembrane entry into cells. Moreover, in vivo experiments were conducted to assess the effectiveness of the membrane. Results: MTZ-NPs membrane had suitable mechanical strength; the drug was released by diffusion. Fourier Transform Infrared Spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) results showed the existence of metronidazole might be in the amorphous state in the membrane and had good compatibility with polymers. The in vitro cytotoxicity assays showed that the MTZ-NPs membrane was biocompatible. Cellular uptake of the C6-NPs membrane was significantly higher than that of the C6 membrane (p &lt; 0.0001), signifying that encapsulating the drug in nanoparticles increases drug permeability and improves drug transport efficiency across the cellular membrane. The histological analysis showed that the MTZ-NPs membrane could promote periodontal tissue recovery. Conclusion: MTZ-NPs membrane can improve drug penetration delivery into the cells and has a good prospect for the treatment of periodontal disease.

PEGylated solid lipid nanoparticles for the intranasal delivery of combination antiretroviral therapy composed of Atazanavir and Elvitegravir to treat NeuroAIDS.

Intranasal drug administration offers a promising strategy for delivering combination antiretroviral therapy (cART) directly to the central nervous system to treat NeuroAIDS, leveraging the nose-to-brain route to bypass the blood-brain barrier. However, challenges such as enzymatic degradation in the nasal mucosa, low permeability, and mucociliary clearance within the nasal cavity must first be addressed to make this route feasible. To overcome these barriers, this study developed solid lipid nanoparticles (SLNs) with varying PEGylation levels (0%, 5%, 10%, and 15% w/w of PEGylated lipid), co-encapsulated with Elvitegravir (EVG) and Atazanavir (ATZ) as an integrase and protease inhibitor, respectively. Pre-formulation studies confirmed the compatibility of the drugs with the excipients. Characterization showed that PEGylation reduces SLN size by approximately up to 12% while maintaining monodispersity and a high encapsulation efficiency of over 99% for both EVG and ATZ in their amorphous forms. Incubation of the formulations in artificial nasal mucus revealed that increased PEGylation consistently reduces nanoparticle aggregation and mean aggregate size, suggesting improved SLN stability in the mucus. Importantly, higher PEGylation levels significantly enhanced model drug permeability across the nasal mucus barrier by up to 10-fold. Lastly, cellular uptake studies using the RPMI 2650 nasal epithelial cell line indicated that PEGylation does not reduce nanoparticle uptake rates. These findings highlight the potential of PEGylated SLNs as an effective vehicle for enhancing the intranasal delivery of cART to treat NeuroAIDS. However, further in vivo studies are needed to confirm the brain targeting potential of this formulation.

Review topic: A detailed analysis of transdermal drug delivery system

Transdermal drug delivery systems (TDDS) are a novel approach for administering medications through the skin, offering several advantages over conventional methods like oral or intravenous delivery. TDDS allow for controlled and consistent drug release, effectively bypassing the gastrointestinal tract and avoiding first-pass metabolism, which can enhance bioavailability and reduce systemic side effects. However, the skin's barrier properties present significant challenges for drug permeation, particularly for larger or hydrophilic molecules. To address these challenges, various methods have been developed, including chemical permeation enhancers, microneedles, iontophoresis, and sonophoresis, to facilitate drug delivery. The typical components of TDDS include an active pharmaceutical ingredient, an adhesive matrix, a release liner, and a backing layer, each contributing to the controlled release and stability of the system. Despite these advancements, TDDS are primarily effective for small, lipophilic drugs, and issues such as skin irritation and limited permeation for larger molecules continue to be significant challenges. Recent innovations, such as the use of nanoparticles, 3D printing technology, and personalized delivery systems, show promise in overcoming these limitations. This review examines the principles, benefits, challenges, and recent developments in transdermal drug delivery systems, highlighting their potential applications in chronic disease management, hormone therapy, and vaccine delivery, as well as future directions for enhancing their efficacy and expanding their therapeutic range.

Chitosan ‘s role in enhancing nasal drug absorption

The nasal drug delivery system (NDDS) offers a promising route for the administration of therapeutically active compounds, particularly for those requiring rapid onset of action or bypassing the first-pass metabolism. The system provides a direct pathway to the bloodstream, enhancing bioavailability and enabling effective treatment of both local and systemic conditions. Among various enhancement strategies, chitosan, a biopolymer derived from the exoskeletons of crustaceans, has garnered attention as a potent nasal absorption enhancer. Its mucoadhesive properties and ability to temporarily open tight junctions in the nasal epithelium allow for improved drug permeation, particularly for hydrophilic drugs, peptides, and macromolecules. This research focuses on the extraction, characterization, and application of chitosan derived from crab and prawn shells to formulate an effective nasal drug delivery system, particularly for the treatment of migraines. The study aims to develop a nasal spray formulation containing sumatriptan Succinate commonly used migraine medication, to enhance its absorption through the nasal mucosa. The role of chitosan in improving the bioavailability and targeting of drugs to the brain is examined, alongside its biocompatibility and safety profile. Through various in-vitro and ex-vivo studies, the pharmacokinetics, pharmacodynamics, and toxicity of the chitosan-based nasal formulation are evaluated. The findings suggest that chitosan enhances the therapeutic potential of nasal drug delivery systems, providing faster relief with improved drug absorption. This study underscores the potential of natural polysaccharides in revolutionizing drug delivery technologies and improving patient outcomes.

A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs.

Current in vitro cell-based methods, relying on single cell types, have structural and functional limitations in determining lung drug permeability, which is a contributing factor affecting both local and systemic drug levels. To address this issue, we investigated a 3D human lung airway model generated using a cell culture insert, wherein primary human lung epithelial and endothelial cells were cocultured at an air-liquid interface (ALI). To ensure that the cell culture mimics the physiological and functional characteristics of airway tissue, the model was characterized by evaluating several parameters such as cellular confluency, ciliation, tight junctions, mucus-layer formation, transepithelial electrical resistance, and barrier function through assaying fluorescein isothiocyanate-dextran permeability. To understand how the characterized ALI quality attributes influenced the absorption of inhaled drugs through the epithelial-endothelial barrier, we measured the permeability and epithelial intracellular concentrations of albuterol sulfate (AL), formoterol fumarate (FO), and fluticasone furoate (FL). The presented characterization results overall demonstrate that this culture platform mimicked the airway-specific structure and barrier function. An apparent permeability (P app) of 5.7 × 10-6 cm/s and an intracellular concentration below 1% were quantified for AL over 3 h. The P app of FO was 8.5 × 10-6 cm/s, with an intracellular concentration of 3.8%. Due to its high lipophilicity, FL showed a higher intracellular concentration (17.4%) compared to AL and FO, but also a 73.1% loss of the compound over 3 h due to nonspecific binding, with a P app as low as 1.3 × 10-7 cm/s. While the model exhibited physiologically relevant properties, its utility in estimating the permeability of inhaled drugs may be drug-specific, warranting further optimization and study.

Formulation and evaluation of novel vesicular nanoethosomal patches for transdermal delivery of zidovudine: In vitro, ex vivo, and in vivo pharmacokinetic investigations

Ethosomes are novel soft malleable nanovesicles composed mainly of phospholipids, ethanol (relatively high concentration), glycol, and water. They are used for enhanced drug delivery through the skin. These zidovudine (ZV) vesicles were formulated by cold technique using phospholipids, cholesterol, propylene glycol, and ethanol. The nanoethosomal dispersion was transformed to transethosomal patches using HPMC E15 and chitosan as polymers, a mixture of dichloromethane (DCM) and methanol (1:1 ratio) as solvent, triethyl citrate as plasticizer, and span 80 as permeation enhancer. The physical features of the prepared patches were found to be within acceptable limits. The in vitro study showed drug diffusion of 71.25 − 88.19% through the semipermeable egg membrane in 24 hours. The ex vivo study showed drug permeation of 78.35 − 91.45% through the goat ear membrane in 24 hours. The combination of HPMC and EP4 transdermal patch was determined to be the most effective formulation for transdermal drug administration with sustained drug release, outperforming all other formulations based on acceptable physicochemical parameters, in vitro and ex vivo evaluation studies. Compared with the other formulations, the EP4 formulation had superior penetration kinetics, as proven by its highest permeation co-efficient (2.56 mg/cm2/h), flux (0.494 mg/cm2/h), and enhancement ratio (2.43). Moreover, dermal irritation tests demonstrated that topical therapy did not cause any irritation, indicating its safety. The in vivo bioavailability studies revealed that the AUC showed good bioavailability, which was approximately 188.99 times greater than that of the marketed product. According to the in vitro–in vivo correlation, the ex vivo (in vitro) data can represent physiological conditions that are exact replicas of those found in vivo. Therefore, the ZV transdermal patches exhibit enhanced drug permeation and good bioavailability for better therapeutic outcomes.

Multiphysics modelling of the impact of skin deformation and strain on microneedle-based transdermal therapeutic delivery.

Microneedle patches (MNs) hold enormous potential to facilitate the minimally-invasive delivery of drugs and vaccines transdermally. However, the micro-mechanics of skin deformation significantly influence the permeation of therapeutics through the skin. Previous studies often fail to appreciate the complexities in microneedle-skin mechanical interactions. This may impede the accuracy of MNs pre-clinical assessments. Here, we develop a multiphysics finite element model which simulates the biomechanics of microneedle skin penetration and the subsequent permeation of therapeutics. Employing the aqueous pore path hypothesis, we consider how strain (induced through the insertion of a MN), affects pore geometry in the skin and therefore the diffusion of therapeutics. Our models show that considering the insertion-induced skin deformation alone reduces the transdermal permeation of insulin by 25%, while considering the effect of strain can reduce the overall permeation by a further 45% over 24 hours. Our model also indicates that once the mechanical strain is removed i.e. through removal or dissolution of the array, the permeation through the skin will recover. Furthermore, our results indicate that the delivery of high molecular weight compounds may be most susceptible to strain-induced changes in drug permeation. These findings could have significant implications for the preferred type of microneedle administration when targeting, for example, intradermal or transdermal delivery. STATEMENT OF SIGNIFICANCE: This manuscript presents an advanced computational model of microneedle insertion into human skin. Here, we adopt a multiphysics modelling strategy, where we predict the influence of microneedle insertion on skin deformation and strain and how that influences subsequent therapeutic permeation through the skin. Our model predicts that whether or not the microneedle remains in situ, the resultant change in tissue deformation and strain has a major impact on how quickly the therapeutic diffuses through the skin. This has important implications for transdermal device design, administration strategies and protocols and associated clinical studies, where either intradermal or transdermal therapeutic delivery is being targetted.

High-performance liquid chromatography method for measuring Captopril: an empirical study on hydrogel film permeability test.

High-performance liquid chromatography (HPLC) has emerged as a highly sensitive and versatile analytical technique for quantifying antihypertensive drugs, such as Captopril (CAP). This study focused on the optimization and validation of an HPLC method for quantifying CAP in an in vitro hydrogel permeability test. The main objective of this study was to develop and validate an HPLC method for quantifying CAP in an in vitro hydrogel permeability test. The HPLC method employed a C18 column (Waters, Sunfire, 5μm; 250 × 4.6mm) and a mobile phase consisting of methanol-water (85% v/v orthophosphoric acid) in a 55:45 (v/v) ratio at a flow rate of 0.5 mL/min. The UV-Vis detector was configured to detect CAP at a wavelength of 220nm. The hydrogel film used in the permeability test was prepared using poly (vinyl alcohol)/poly (vinyl caprolactam) (PVA/PNVCL) with citric acid as a crosslinking agent. All results met the validation parameters according to ICH Guideline. The HPLC method showed consistent retention time (4.7-4.9min), linearity (1-50µg/mL; r = 0.9995), accuracy (98.11-101.78%), precision (RSD ≤ 2%), and LoD/LoQ (0.19/0.62µg/mL). The developed HPLC method was successfully applied to an in vitro permeability test using horizontal diffusion cells. The results demonstrated that CAP permeated through the swollen hydrogel film, with a cumulative drug permeation exceeding 30%. This highlighted the method's utility in assessing drug transport properties through hydrogels. The validated HPLC method demonstrates robustness and reliability for quantifying CAP in the hydrogel permeability test.