Hepatic First-pass Metabolism Research Articles

Mucin incorporated electrospun fibrous matrix of zein and PVP: Towards transmucosal propranolol hydrochloride delivery

Mucoadhesive drug delivery systems are being widely explored as a substitute for conventional drug delivery devices. Several polymers and their functional modifications are under investigations. In that scenario, the cohesive influence of mucin in the polymer system itself to the biologically available mucin in the mucosa is a novel approach. The added advantage of mucin in augmenting mucoadhesion was explored. A two-fold increase in the force of adhesion and an eight-fold increase in the work of adhesion were intriguing observations to be noted. Mucin incorporation in the matrix was done via EDC crosslinker. The results of the TNBS assay confirmed 39 % of mucin binding. A three-fold decrease of elongation at break (%) after mucin binding is a piece of quantitative information to corroborate the same. This work also investigates the efficiency of the mucoadhesive matrix towards the release of Propranolol Hydrochloride (PL). Low oral bioavailability of PL demands its administration via mucosal route to avoid hepatic first-pass metabolism. The release study of PL in PBS and permeation through RPMI 2650 cells revealed a burst release followed by a sustained release profile and best fitted with Korsmeyer Peppas model. PL permeation through the cell monolayer without a cell junction opening pursued a transcellular transport mechanism. Drug permeation through porcine buccal mucosa also assured adequate permeation in ex-vivo conditions. The sustained release of PL from MUZPVP and prolonged residence time of the matrix over mucosa due to increased mucoadhesion guarantees an optimistic drug delivery device to the biomedical discipline.

Bile salt integrated cerasomes: A potential nanocarrier for enhancement of the oral bioavailability of idarubicin hydrochloride

Cerasomes are a modified form of liposomes containing both inorganic and organic parts and due to their strong polyorganosiloxane surface have remarkably high morphological stability and provide easier functionalization compared with conventional liposomes. To investigate the potential of these nanocarriers for oral delivery, bile salt integrated cerasomes (named bilocerasomes) encapsulating idarubicin hydrochloride (IDA) were prepared and characterized. The optimum formulation showed excellent stability in the simulated gastrointestinal fluids as well as under storage conditions. The oral pharmacokinetics of the IDA solution, empty nanocarrier + drug solution, and IDA-loaded bilocerasome were evaluated. The nanoformulation significantly increased the area under the drug concentration–time curve and the mean residence time (∼14.3- and 9-fold, respectively). The results obtained from cell uptake and chylomicron flow blocking approach revealed that bilocerasomes are absorbed into the intestinal cells via a clathrin/caveolin-independent endocytosis pathway and transported to the systemic circulation extensively via the intestinal lymphatic vessels. Considering the high stability of the prepared bilocerasome, noticeable participation of lymphatic transport in its systemic absorption and marked enhancement in the oral absorption of IDA, bilocerasomes can be introduced as a capable carrier for improving the oral bioavailability of drugs, particularly those that hepatic first-pass metabolism seriously limits their oral absorption.

Preparation of nanoparticle and nanoemulsion formulations containing repaglinide and determination of pharmacokinetic parameters in rats

Repaglinide (RPG) belongs to the class of drugs known as meglitinides and is used for improving and maintaining glycemic control in the treatment of patients with Type 2 diabetes. RPG is a Class II drug (BCS) because of its high permeability and low water solubility. It also undergoes hepatic first-pass metabolism. The oral bioavailability of RPG is low (about 56 %) due to these drawbacks. Our aim in this study is to prepare two different nano-sized drug carrier systems containing RPG (nanoparticle: RPG-PLGA-Zein-NPs or nanoemulsion: RPG-NE) and to carry out a pharmacokinetic study for these formulations. We prepared NPs using PLGA and Zein. In addition, a single NE formulation was developed using Tween 80 and Pluronic F68 as surfactants and Labrasol as co-surfactant. The droplet size values of the blank-NE and RPG-NE formulations were found to be less than 120 nm. The mean particle sizes of blank-Zein-PLGA-NPs and RPG-Zein-PLGA-NPs were less than 260 nm. The Cmax and tmax values of RPG-Zein-PLGA-NPs and RPG-NE (523 ± 65 ng/mL and 770 ± 91 ng/mL; 1.41 ± 0.46 h and 1.61 ± 0.37 h, respectively) were meaningfully higher than those of free RPG (280 ± 33 ng/mL; 0.72 ± 0.28 h) (p < 0.05). The AUC0-∞ values calculated for RPG-Zein-PLGA-NPs and RPG-NE were approximately 4.04 and 5.05 times higher than that calculated for free RPG. These nanosized drug delivery systems were useful in increasing the oral bioavailability of RPG. Moreover, the NE formulation was more effective than the NP formulation in improving the oral bioavailability of RPG (p < 0.05).

Comparison of Pharmacokinetic Characteristics of Bilosomal Dispersion Versus Pure Solution of Oral Ropinirole Hydrochloride in Rats

Background: Ropinirole hydrochloride is a non-ergoline antiparkinson drug. It is a highly hydrophilic drug and classified as class III according to Biopharmaceutical Classification System with low absolute oral bioavailability of approximately 50% upon oral administration due to significant hepatic first-pass metabolism. Objective: to compare the pharmacokinetic parameters of Ropinirole, when administered orally in the form of a Ropinirole bilosomal dispersion in contrast to an oral Ropinirole solution. Methods: This study involved the use of twelve male Wistar rats, with an average weight of 220±11 g, and these rats were divided into two groups, comprising six rats each. A 1.1mg/kg doses of pure Ropinirole and Ropinirole bilosomes were administered orally through gavage after reconstituting in distilled water. Ropinirole was quantified in the rat's plasma using HPLC, subsequently establishing a spiked calibration curve with plasma samples and utilizing paracetamol as an internal standard. The statistics included mean values (± SD; n = 6) for pharmacokinetic parameters, with statistical significance assessed using a Student's t-test. Results: For the oral bilosomes, the values were 9.4±0.11 μg /ml for Cmax, 3±0.00 h for Tmax, and 55.56±2.12 μg h/ml for AUC0-24. In contrast, for the oral solution, the corresponding values were 7.2±0.14 μg/ml for Cmax, 1.5±0.00 h for Tmax, and 23.70±2.23 μg h/ml for AUC0-24. These parameters were significantly higher (P&lt;0.05) as compared with a pure drug solution. The comparative bioavailability of Ropinirole (AUC0-24 oral solution / AUC0-24 oral bilosomes ) is equal to 42.66%, which indicates the bioavailability of the oral RH solution was less than that of RH bilosomal dispersion. Conclusions: The use of nano vesicular carriers (bilosomes) shows significant potential as an effective delivery system for improving the oral bioavailability of ropinirole hydrochloride

Improving the bioavailability and therapeutic efficacy of felodipine for the control of diabetes-associated atherosclerosis: In vitro and in vivo characterization

Felodipine has proven to be effective as an atherosclerosis therapy because it increases blood flow to the vessel wall. However, the poor solubility, low bioavailability, and hepatic first-pass metabolism of oral felodipine compromise its therapeutic effectiveness. The study’s goal is to create a nasal pH-sensitive hydrogel of felodipine-loaded invasomes (IPHFI) that will improve felodipine’s release, permeation, bioavailability, and efficacy as a potential diabetes-associated atherosclerosis therapy. According to the pre-formulation study, the felodipine-loaded invasomes formulation composed of phospholipid (3%w/v), cholesterol (0.16%w/v), ethanol (3%v/v) and cineole (1%v/v) was chosen as the optimum formulation. The optimum formulation was characterized in vitro and then mixed with a mixture of chitosan and glyceryl monooleate to make the IPHFI formulation. The IPHFI formulation enhanced the release and permeation of felodipine by 2.99 and 3-fold, respectively. To assess the efficacy and bioavailability of the IPHFI formulation, it was studied in vivo using an experimental atherosclerosis rat model. Compared to oral free felodipine, the nasal administration of the IPHFI formulation increased the bioavailability by 3.37-fold and decreased the serum cholesterol, triglycerides, LDL, and calcification score by 1.56, 1.53, 1.80, and 1.18 ratios, respectively. Thus, nasal IPHFI formulation may represent a promising diabetes-associated atherosclerosis therapy.

Kinetics Aspects in Design and Release of Nasal Drug Delivery Systems

The traditional school of Indian medicine includes a sort of nasal therapy known as Nasya karma. There is a lot of recent interest in using the nasal route for administering difficult medications including tiny polar compounds, vaccines, hormones, peptides, and proteins. Nasal drug molecules are highly suited for systemic distribution and the absence of hepatic first-pass metabolism. Vaccination through the nose is thought to be a straightforward and economical method with improved patient compliance, and it may also provide immunity at numerous distant mucosal locations. Microparticle, nanoparticle, and liposomal nasal vaccination delivery technologies are now in development and show protection in animal models. Both pharmacokinetics &amp; pharmacodynamics of nasal administration devices have been studied in-vivo by a number of different research organizations. The purpose of this review was to summarise these studies and bring attention to the work done on nasal-based formulations to better treat conditions like epilepsy, schizophrenia, and neurodegenerative diseases.

D-α-tocopheryl polyethylene glycol succinate-decorated dual drug-loaded lipidic nanocarriers: A strategic approach for targeting lymphatic uptake and p-gp efflux modulation to enhance oral bioavailability in HIV-1 viral reservoirs

The toxicity potential and inadequate bioavailability of antiretroviral therapy restrict their effectiveness in completely eradicating HIV-1 from viral reservoirs, as the drugs encounter difficulties in accessing these reservoirs. This study presents a combinatorial d-α-tocopheryl polyethylene glycol succinate (TPGS)-decorated nano-structured lipid carrier of Etravirine (ETR) and Darunavir Ethanolate (DRVE) that was formulated, optimized, and characterized to achieve synergistic effects against HIV-1 infection. The effectiveness of the combinatorial approach was evaluated by in silico studies, and their docking score and free binding energy showed that both drugs demonstrate synergistic effects against their respective enzymes. The cellular research of ED (ETR and DRVE) in TMZ-b1 cell lines also showed that the best ratio of ETR and DRVE (1:6.5 μg/mL) produced a combined effect. The formulation, termed ED-TPGS-NLCs, underwent optimization using central composite rotational design (CCRD) through a modified emulsification process, followed by characterization based on globule size, polydispersity index (PDI), percentage entrapment efficiency, percentage drug loading, and transmission electron microscopy (TEM) analysis. In vitro release studies demonstrated a notable improvement of drug release from the optimized lipid nanosystem, conforming to the Korsmeyer-Peppas kinetics model. Besides, the in-vitro studies, the intestinal permeation enhancement study, the intestinal depth analysis, and the pharmacokinetic assessment of the optimized formulation in Wistar rats were performed to improve permeation and increase plasma drug concentration. ED-TPGS-NLCs also stopped HIV-1 infection in TMZ-b1 cell lines by 50 %, and the lowest concentration needed to do this was about 58 times lower than purified ED suspension. These studies ensure that ED-TPGS-NLCs were taken up due to the formation of chylomicrons and inhibit the p-gp efflux system by TPGS and solutol to inhibit the first-pass hepatic metabolism, which helps to improve the intestinal permeation and enhance plasma drug concentration, leading to enhanced oral bioavailability of ED. Hence, the improved bioavailability of ED in the nanoformulation also enhanced the anti-retroviral efficacy and improved the safety margins of ED-TPGS-NLCs. These findings can also reduce the side effects of high doses of antiretroviral drugs.

Enhancing Oral Bioavailability of Simvastatin Using Uncoated and Polymer-Coated Solid Lipid Nanoparticles.

Simvastatin (SVA) is a well-prescribed drug for treating cardiovascular and hypercholesterolemia. Due to the extensive hepatic first-pass metabolism and poor solubility, its oral bioavailability is 5%. Solid lipid nanoparticles (SLNs) and hydrogel-coated SLNs were investigated to overcome the limited bioavailability of SVA. Four different lipids used alone or in combination with two stabilizers were employed to generate 13 SLNs. Two concentrations of chitosan (CS) and alginate (AL) were coating materials. SLNs were studied for particle size, zeta potential, in vitro release, rheology, and bioavailability. The viscosities of both the bare and coated SLNs exhibited shear-thinning behavior. The viscosity of F11 (Chitosan 1%) at 20 and 40 rpm were 424 and 168 cp, respectively. F11 had a particle size of 260.1 ± 3.72 nm with a higher release; the particle size of F11-CS at 1% was 524.3 ± 80.31 nm. In vivo studies illustrated that F11 had the highest plasma concentration when compared with the SVA suspension and coated chitosan (F11 (Chitosan 1%)). Greater bioavailability is measured as (AUC0→24), as compared to uncoated ones. The AUC for F11, F11-CS 1%, and the SVA suspension were 1880.4, 3562.18, and 272 ng·h/mL, respectively. Both bare and coated SLNs exhibited a significantly higher relative bioavailability when compared to that from the control SVA.

Optimizing bioavailability and antihypertensive activity of Carvedilol cubosomes using D-optimal design: Comparative analysis of Cremophor RH 40 and Polyvinyl alcohol as secondary stabilizers

Carvedilol (CARV) -a nonselective β-receptor antagonist indicated in treatment of hypertension-suffers from poor oral bioavailability due to its poor solubility and hepatic first-pass metabolism. This study aimed to optimize CARV-loaded cubosomes to enhance oral CARV bioavailability and prolong its action in the treatment of hypertension. D-optimal design was used to optimize CARV CUBs based on either Polyvinyl alcohol (PVA) or Cremophor RH 40 (RH 40) as secondary stabilizers. Furthermore, the effect of Poloxamer P407 percentage and secondary stabilizer concentration was studied. Comparing PVA-based to the RH 40-based CUBs, CARV-CUBs-RH40 showed lower particle size (PS), higher polydispersity index (PDI), lower zeta potential (ZP) and slightly lower CARV content. Optimized PVA-based and RH 40-based CUBs showed PS of 141 ± 1 nm and 105 ± 0 nm, PDI of 0.166 ± 0.00 and 0.247 ± 0.01, ZP of 4.9 ± 0.3 mV and 6.3 ± 0.3 and CARV content of 105.0 ± 1.4 % and 93.6 ± 0.9 %, respectively. TEM imaging confirmed the characteristic cubic morphology of the prepared CUBs. Moreover, the prepared CARV-CUBs exhibited an in vitro sustained release behavior and comparable in vivo antihypertensive performance.

2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin.

Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.

Internal exposure to heat-induced food contaminants in omnivores, vegans and strict raw food eaters: biomarkers of exposure to acrylamide (hemoglobin adducts, urinary mercapturic acids) and new insights on its endogenous formation.

The urinary mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) are short-term biomarkers of exposure from acrylamide and its metabolite glycidamide, respectively. The medium-term exposure to acrylamide and glycidamide is monitored by the adducts N-(2-carbamoylethyl)-Val (AA-Val) and N-(2-carbamoyl-2-hydroxyethyl)-Val (GA-Val) in hemoglobin (Hb), respectively. Three questions were addressed by application of these biomarkers in two diet studies including 36 omnivores, 36 vegans and 16 strict raw food eaters (abstaining from any warmed or heated food for at least four months): first, what is the internal acrylamide exposure following a vegan or a raw food diet in comparison to that in omnivores? Second, did the exposure change between 2017 and 2021? And third, what is the stability over time of AAMA/GAMA excretion compared to that of AA-Val/GA-Val levels in Hb between both time points? Median urinary AAMA excretion per day in non-smoking omnivores, vegans and raw food eaters were 62.4, 85.4 and 15.4µg/day, respectively; the corresponding median AA-Val levels were 27.7, 39.7 and 13.3pmol/g Hb, respectively. Median levels in strict raw food eaters were about 25% (AAMA excretion) and 48% (AA-Val) of those in omnivores. In comparison to 2017, AAMA and GAMA excretion levels were hardly altered in 2021, however, levels of AA-Val and GA-Val in 2021 slightly increased. There was a weak correlation between AAMA excretion levels determined four years apart (rS = 0.30), and a moderate correlation between levels of AA-Val (rS = 0.55) in this timeframe. Our data in strict raw food eaters confirm a significant endogenous formation to acrylamide in a size range, which is-based on the levels of AA-Val-distinctly higher than reported previously based on levels of urinary AAMA excretion. The relatively lower AAMA excretion in raw food eaters likely represents a lower extent of glutathione conjugation due to missing hepatic first-pass metabolism in case of endogenous formation of acrylamide, which leads to a higher systemic exposure.

Effect of Intravaginal Application of Palasha Udumbaradi Ointment on Pelvic Organ Prolapse

Prolapse is a downward descent of the female pelvic organs as a result of weakness of the structures that normally retain them in position. The main symptoms of pelvic organ prolapse include micturition disturbances like stress incontinence, imperfect control of micturition, a feeling of lump coming down, postural low back ache, constipation and leucorrhoea. The management of pelvic organ prolapse includes preventive conservative and surgical measures. Surgery is indicated when conservative management fails. The three different conditions like Phalini, Prasramsini and Mahayoni vyapath mentioned by different Acharyas explain the prolapsed condition according to the stage and part prolapsed out. Palasha udumbaradi yoga mentioned in Bhaishajya Ratnavali containing ingredients such as Palasha beeja, Udumbara phala, Thilathaila and Madhu was taken for this study. The Lepa was applied in the modified form of an ointment. The study is an attempt to assess the effect of Palasha udumbaradi ointment on uterine prolapse. The ointment was applied intra vaginally. The presence of dense blood vasculature makes the vagina a potential site for local and systemic drug administration. The key advantages of vaginal drug delivery over oral administration is that this is able to circumvent the harsh gastric environment and also bypass hepatic first-pass metabolism. A 38 year woman with complaints of increased frequency of micturition, stress incontinence, burning micturition, low back ache and dyspareunia consulted the OPD of Govt. Ayurveda Medical College, Tripunithura. Palasha udumbaradi ointment was self-applied intra-vaginally. Administration of ointment was advised for 60 consecutive days excluding the days of menstruation with follow up on 90th day. Assessment was done on 0th, 30th and 60th day and follow up was done on 90th day using POP-Q Scale, urinary incontinence scale, and visual analogue scale.

Fabrication and in vitro–in vivo evaluation of ligand appended isoniazid loaded nanoparticulate systems for the treatment of tuberculosis

Isoniazid (INH) is amongst the first-line antibiotics that have been employed for the treatment of Tuberculosis (TB). Despite its potent anti-tubercular action, susceptibility to rapid hepatic first-pass metabolism and elimination largely limits its oral bioavailability, and has been associated with the induction of drug resistance and adverse effects. This presents study aims at the development and evaluation of unique mannosylated INH loaded solid lipid nanoparticles (Mn-INH-SLNs) for the treatment of TB. The Mn-INH-SLNs demonstrated a particle size of 466 ± 11 nm, which was acceptable for macrophage targeting and had % entrapment efficiency of 80.41 ± 1.37% (n = 6). The dissolution studies depicted a dual-phase drug release profile, i.e., burst release followed by a sustained release, revealing the best fit with the Korsmeyer-Peppas model. The MTT assay (cytotoxicity study) performed utilizing J774A.1 cells with optimized Mn-INH-SLNs deemed them to be safe and nontoxic. Mannosylated SLNs tagged with coumarin-6 (C6 – an established fluorescent marker) showed a substantially high intracellular internalization (1.11-folds) when analyzed through flow cytometric analysis (FACS). The in vivo pharmacokinetic evaluation following per-oral administration in rats demonstrated a significant rise in relative bioavailability (∼5.5-folds) with Mn-INH-SLNs compared to pure drug solution. The bio-distribution (drug disposition) studies exhibited greater lung accumulation of Mn-INH-SLNs (2.13-folds) in comparison to the unconjugated INH-SLNs (Un-INH-SLNs). The promising results of the study depict that the targeted-optimized Mn-INH-SLNs may be a propitious and potent tool to fight TB.

QbD approach for developing Fast-dissolving Tablets containing Loperamide hydrochloride using Super Disintegrant Blends and Subliming Materials

Mouth dissolving pills, which dissolve or disintegrate quickly on the tongue or buccal cavity, have been developed in response to the growing demand for more patient-compliant dosage forms. It is utilized to improve bioavailability by reducing dose frequency in order to reduce adverse effects and make tablets with high first-pass metabolism more cost-effective. The most commonly used drug for diarrhoea is loperamide hydrochloride. It is an opioid receptor agonist that targets the mu opioid receptors in the large intestines of the myenteric plexus. It specifically works by lowering myenteric plexus activity, which lowers the motility of the circular and longitudinal smooth muscles of the intestinal wall. It is a synthetic anti-diarrheal that is used to treat the symptoms of inflammatory bowel disease-related chronic diarrhoea as well as acute, non-specific diarrhoea. Due to substantial hepatic first-pass metabolism, loperamide hydrochloride has a very limited systemic bioavailability. Therefore, the primary goal of the study was to develop Loperamide hydrochloride orally disintegrating tablets to obtain a better breakdown rate, enhance the drug's bioavailability, and provide very rapid relief from diarrhoea. The pre-compression parameters, such as bulk density, compressibility, angle of repose, etc., for orally disintegrating tablets manufactured by direct compression and using three super disintegrants, croscarmellose sodium (CCS), Microcrystalline cellulose (MCC), and sodium starch glycolate (SSG), were prepared and assessed. The manufactured batches of tablets passed tests for satisfactory results. The highest amount of medicine was released at all-time intervals in the optimised formulation, which also displayed a favourable release profile.

A Novel Approch for Nasal Drug Delivery System

The oral route is the most favored technique for administering the drug orally in the body. As a result of certain limitations such as drug absorption, poor bioavailability, first-pass hepatic metabolism and medicine target to particular organs, may cause problems for administration via oral route. Therefore parenteral route, transmucosal route and transdermal route are preferred over oral route. Intranasal route is deemed to be a desirable route because of the time profile of concentration a drug is close to that of the intravenous route. The nasal route has also been successfully used for bypassing the blood-brain barrier and afterword delivering drug molecules to the central nervous system .The in-situ gelling system is a process in which is in a solution form before the administration in the body but it converts in to a gel form after administration . The formation of gel depends on factors like temperature modulation, pH change, presence of ions from which drug get released in sustained and controlled manner. Therefore this review focuses on nasal drug delivery, a variety of aspects of nasal anatomy and physiology, nasal absorption mechanism, and In-Situ gels evaluations.

Enhancing the bioavailability of clozapine through microwave-assisted formulation of a stable β-cyclodextrin inclusion complex

The low oral bioavailability of clozapine due to its poor aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism poses a challenge to the effective treatment of psychiatric disorders. The objective of the current research was to address the above issues by developing a clozapine inclusion complex (CLZ-IC) using the microwave irradiation method. To optimize the formulation and processing variables, namely the molar ratio of CLZ to β-CD (X1) and the irritation reaction time (X2), a 32 factorial design was performed. The phase solubility study revealed the formation of a stable inclusion complex with a stoichiometry of 1:1, suggesting that β-cyclodextrin could effectively solubilize clozapine. The characterization data confirmed the formation of the inclusion complex of clozapine in β-cyclodextrin. The optimized inclusion complex showed a solubility of 342 ± 26 µg/ml and a percentage dissolution of 91.1 ± 3.4% after four hours. The inclusion-complex tablets exhibited excellent physical properties and showed an improved in vitro dissolution profile, with 80% of the drug being released within 100 minutes, compared to marketed tablets (80% release in 300 min). In vivo pharmacokinetic studies conducted in a rat model demonstrated an increase in Cmax, area under the curve (AUC), and relative bioavailability by a factor of 2.26 with the optimized formulation, indicating a significant improvement in drug absorption compared to the marketed tablet. The techno-economic analysis suggests a cost-benefit ratio of 25.08 after 7 years, indicating the suitability for large-scale production. Overall, using Design of Experiment, in silico, and in vivo studies proved effective in optimizing the inclusion-complex formation and enhancing the bioavailability of clozapine. In conclusion, the optimized clozapine-β-cyclodextrin inclusion complex prepared using a time-saving (90 sec) and cost-effective microwave irradiation method exhibited excellent physical properties and demonstrated significant improvements in the drug's solubility, dissolution rate, and pharmacokinetic performance.

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.

Lipid Horizons: Recent Advances and Future Prospects in LBDDS for Oral Administration of Antihypertensive Agents.

The lipid-based drug delivery system (LBDDS) is a well-established technique that is anticipated to bring about comprehensive transformations in the pharmaceutical field, impacting the management and administration of drugs, as well as treatment and diagnosis. Various LBDDSs verified to be an efficacious mechanism for monitoring hypertension systems are SEDDS (self-nano emulsifying drug delivery), nanoemulsion, microemulsions, vesicular systems (transferosomes and liposomes), and solid lipid nanoparticles. LBDDSs overcome the shortcomings that are associated with antihypertensive agents because around fifty percent of the antihypertensive agents experience a few drawbacks including short half-life because of hepatic first-pass metabolism, poor aqueous solubility, low permeation rate, and undesirable side effects. This review emphasizes antihypertensive agents that were encapsulated into the lipid carrier to improve their poor oral bioavailability. Incorporating cutting-edge technologies such as nanotechnology and targeted drug delivery, LBDDS holds promise in addressing the multifactorial nature of hypertension. By fine-tuning drug release profiles and enhancing drug uptake at specific sites, LBDDS can potentially target renin-angiotensin-aldosterone system components, sympathetic nervous system pathways, and endothelial dysfunction, all of which play crucial roles in hypertension pathophysiology. The future of hypertension management using LBDDS is promising, with ongoing reviews focusing on precision medicine approaches, improved biocompatibility, and reduced toxicity. As we delve deeper into understanding the intricate mechanisms underlying hypertension, LBDDS offers a pathway to develop next-generation antihypertensive therapies that are safer, more effective, and tailored to individual patient needs.

Formulation and Evaluation of Phenylephrine Nasal Gels

The primary objective of this study is to develop and evaluate phenylephrine nasal gels, aiming for stable blood levels with lower drug doses through consistent administration, avoiding first-pass hepatic metabolism. Compatibility among the drug, polymers, and lipids was confirmed using FTIR and DSC spectra. Phenylephrine nasal gels were formulated, and their clarity assessed. The gels (ONGF1-ONGF8) had pH values of 6.1-7.2, spreadability of 18.33-21.62 g/cm/sec, and viscosity of 934.2-966.2 centipoises. Drug concentration in these formulations varied from 85.52% to 98.88%, indicating acceptable medication content. Gel strength ranged from 64% to 95%. In-vitro drug release of phenylephrine showed 77% to 95% diffusion for ONGF1. The release kinetics followed first order, zero order, Higuchi model, and Korsemeyer-Peppas equations. Kinetic values for all formulations were tabulated. ONGF1 exhibited the most efficient release, with 95% of the drug released within 7 hours, demonstrating a diffusion mechanism followed by non-Fickian transport, adhering to both zero order and Korsemeyer-Peppas models.Top of Form

Revolutionizing transdermal drug delivery: unveiling the potential of cubosomes and ethosomes.

The area of drug delivery systems has witnessed significant advancements in recent years, with a particular focus on improving efficacy, stability, and patient compliance. Transdermal drug delivery offers numerous benefits compared to conventional methods of drug administration through the skin. It helps in avoiding gastric irritation, hepatic first-pass metabolism, and gastric degradation of the drug. It bypasses the gastrointestinal tract, eliminating the risk of first-pass metabolism and allowing drugs to be administered without being affected by pH, enzymes, or intestinal bacteria. Additionally, it allows for sustained release of the drug, is noninvasive, and enhances patient adherence to the treatment regimen. The transdermal drug delivery system (TDDS) can serve as an alternative route for drug administration in individuals who cannot tolerate oral medications, experience nausea, or are unconscious. When compared to intravenous, hypodermic, and other parenteral routes, TDDS stands out due to its ability to eliminate pain, reduce the risk of infection, and prevent disease transmission associated with needle reuse. Consequently, the overall patient compliance is significantly improved with the utilization of TDDS. Among the noteworthy developments are cubosomes and ethosomes, two distinct yet promising carriers that have garnered attention for their unique properties. In conclusion, this review synthesizes the current knowledge on cubosomes and ethosomes, shedding light on their individual strengths and potential synergies. The exploration of their application in various therapeutic areas underscores their versatility and establishes them as key players in the evolving landscape of drug delivery systems.