Hepatic First-pass Metabolism Research Articles

Formulation Development and Evaluation of Mucoadhesive Buccal Tablets of Acebutolol Hydrochloride

A mucoadhesive drug delivery system is an oral dosage form, where the tablet, gel, or patch is attached to the buccal region for direct absorption of the drug into blood circulation. This dosage form has been employed to improve the bioavailability of drugs that undergoes significant hepatic first-pass metabolism. Acebutolol is a beta sympatholytic agent used to treat high blood pressure and irregular heartbeat (arrhythmia). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. In present investigation, mucoadhesive buccal tablets of acebutolol HCl were prepared using carbopol 940 in varying concentrations with secondary polymer xanthan gum by direct compression method. Nine batches were prepared as per 32 factorial designs, to investigate the combined effects of independent variables namely carbopol 940 and xanthan gum on dependant variables namely swelling index, mucoadhesion strength and in-vitro drug release using design expert software version 8.0.7.1. Preformulation studies confirmed the identity and purity of the drug by means of UV spectroscopy, IR spectroscopy, DSC analysis, and melting point determination. The tablets were evaluated for hardness, thickness, weight variation, friability, and drug content concluded that all these parameters were in an acceptable range of pharmacopoeial specification. The buccal tablets were studied for surface pH, swelling index, in vitro drug release study, adhesion force, in vitro mucoadhesive strength, stability, and compatibility study to optimise the formula. Amongst all factorial batches (F1 to F9), batch F5 (30 mg carbopol 940 and 30 mg xanthan gum) showed maximum drug release of 99.96 % after 12 hr of study and also showed better contact with biological membrane. The drug release kinetics of batch F5 was found to be best fitted to zero order kinetic model and exhibited anomalous diffusion release mechanism. The formulation F5 exhibited good correlation (R2=0.992) for in-vitro drug release. All the evaluation parameters give positive results and comply with the standards. Stability studies were carried out on the developed formulations indicating that the formulations were stable during the period of 6 months. In conclusion, the formulation F5 is stable and effective for quick action and seems to be alternative to the conventional tablet.

Intestinal Absorption Study: Challenges and Absorption Enhancement Strategies in Improving Oral Drug Delivery.

The oral route is the most common and practical means of drug administration, particularly from a patient’s perspective. However, the pharmacokinetic profile of oral drugs depends on the rate of drug absorption through the intestinal wall before entering the systemic circulation. However, the enteric epithelium represents one of the major limiting steps for drug absorption, due to the presence of efflux transporters on the intestinal membrane, mucous layer, enzymatic degradation, and the existence of tight junctions along the intestinal linings. These challenges are more noticeable for hydrophilic drugs, high molecular weight drugs, and drugs that are substrates of the efflux transporters. Another challenge faced by oral drug delivery is the presence of first-pass hepatic metabolism that can result in reduced drug bioavailability. Over the years, a wide range of compounds have been investigated for their permeation-enhancing effect in order to circumvent these challenges. There is also a growing interest in developing nanocarrier-based formulation strategies to enhance the drug absorption. Therefore, this review aims to provide an overview of the challenges faced by oral drug delivery and selected strategies to enhance the oral drug absorption, including the application of absorption enhancers and nanocarrier-based formulations based on in vitro, in vivo, and in situ studies.

Lipid Nanocarriers for Neurotherapeutics: Introduction, Challenges, Blood-brain Barrier, and Promises of Delivery Approaches.

Significant efforts have been made in research to discover newer neurotherapeutics, however, the rate of reported neurological disorders has been increasing at an alarming speed. Neurotherapeutics delivery in the brain is still posing a significant challenge, owing to the blood-brain barrier and blood-cerebrospinal fluid barrier. These physiological barriers restrict the passage of systemically available fractions of neurotherapeutics into the brain, owing to low permeability and drug localization factors. Neurotherapeutics encapsulating lipid carriers favor a significant increase in bioavailability of poorly water-soluble drugs by enhancing solubility in the gastrointestinal tract and favoring stability. Due to their small size and lipid-based composition, these carriers offer enhanced permeability across the semi-permeable blood-brain barrier to effectively transport encapsulated loads, such as synthetic drugs, nutraceuticals, phytoconstituents, herbal extracts, and peptides, thereby reducing incidences of off-target mediated adverse impacts and toxicity. The most significant advantage of such lipid-based delivery systems is non-invasive nature and targeting of neurotherapeutics to the central nervous system. Critical attributes of lipid-based carriers modulate release rates in rate-controlled manners, enable higher penetration through the blood-brain barrier, and bypass the hepatic first-pass metabolism leading to higher CNS bioavailability neurotherapeutics. The current review discusses a brief and introductory account of the limitations of neurotherapeutics, pharmacological barriers, challenges in brain-targeted delivery, and the potential of nanotechnology- processed lipid-based carriers in the clinical management of neuronal disorders.

Oromucosal products - Market landscape and innovative technologies: A review.

Strategies that rely on oral mucosal administration have increased in the last decade and oromucosal products are paving the way to overcome specific challenges, namely improving drug bioavailability when compared with the conventional oral route, due to a reduction of the hepatic first-pass metabolism and pre-systemic degradation. Overall, the advantages of these products make oromucosal route of administration attractive for the development of value-added medicines, which can address more properly the unmet medical needs of specific patients. Generally, such products have an easy and convenient administration since they do not require water for ingestion, which may be particularly relevant for geriatric and pediatric groups, or non-cooperative patients. Usually, the development of these products aims to provide a faster onset of action, critical for acute or emergency treatments. Although oriented to achieve better therapeutic outcomes, today's drug development is primarily focused on patient-centered care, meaning that patients' specific characteristics/needs are an important driving force behind product-development efforts. In accordance, pharmaceutical innovation can rely not only on new drug substances but also on re-formulation of already approved ones or alternative routes of administration, enhancing patient convenience, treatment efficacy and/or safety. Throughout this review, the oromucosal drug products, approved in the last decade, and a retrospective analysis of their critical quality attributes and specifications will be described. Furthermore, trends and opportunities of the latest technologies in this field, as well as the number of ongoing clinical studies, will be presented and discussed.

A simple and sensitive HPLC-FL method for bioanalysis of velpatasvir, a novel hepatitis C virus NS5A inhibitor, in rat plasma: Investigation of factors determining its oral bioavailability

Velpatasvir is a novel inhibitor of hepatitis C virus nonstructural protein 5A that received US Food and Drug Administration approval for the treatment of patients with chronic hepatitis C virus genotypes 1–6. In the present study, a sensitive bioanalytical method for velpatasvir was developed using high-performance liquid chromatography coupled with a fluorescence detector system, which was applied to elucidate the factors determining the oral bioavailability and disposition of velpatasvir. This method offered sufficient sensitivity, with a lower limit of quantification of 0.5 ng/mL, which is comparable to previously reported methods using liquid chromatography coupled with tandem mass spectrometry. Velpatasvir exhibited low oral bioavailability, moderate intestinal permeability, and significant biliary excretion in rats. It was also found to be significantly metabolized in the liver, with a low-to-moderate extraction ratio; however, its intestinal metabolism and enterohepatic circulation did not occur. Thus, our present results demonstrate that the oral bioavailability of velpatasvir is primarily dependent on gut absorption and hepatic first-pass metabolism. The fractions of velpatasvir dose unabsorbed from the gut and eliminated by the liver before reaching the systemic circulation following oral administration were estimated to be 32.8%–58.6% and 4.74%–30.54% of the oral dose, respectively. To our knowledge, this is the first systematic study to investigate the contributory roles of biopharmaceutical and pharmacokinetic factors on the oral bioavailability of velpatasvir, together with a new bioanalytical method for velpatasvir.

Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration.

Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood–brain barrier is the major drawback associated with brain drug delivery. To overcome it, intranasal administration has become more attractive, in some cases even surpassing the oral route. The unique anatomical features of the nasal cavity allow partial direct drug delivery to the brain, circumventing the blood–brain barrier. Systemic absorption through the nasal cavity also avoids the hepatic first-pass metabolism, increasing the systemic bioavailability of highly metabolized entities. Nevertheless, most neurotherapeutics present physicochemical characteristics that require them to be formulated in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixtures of oils, surfactants, and co-surfactants that, after aqueous dilution, generate micro or nanoemulsions loading high concentrations of lipophilic drugs. SEDDS should overcome drug precipitation in absorption sites, increase their permeation through absorptive membranes, and enhance the stability of labile drugs against enzymatic activity. Thus, combining the advantages of SEDDS and those of the intranasal route for brain delivery, an increase in drugs’ brain targeting and bioavailability could be expected. This review deeply characterizes SEDDS as a lipidic nanosystem, gathering important information regarding the mechanisms associated with the intranasal delivery of drugs loaded in SEDDS. In the end, in vivo results after SEDDS intranasal or oral administration are discussed, globally revealing their efficacy in comparison with common solutions or suspensions.

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The β2-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of −31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.

ANTI-NEOPLASTIC TRANSDERMAL PATCHES: A NOVEL APPROACH FOR TARGETED DRUG DELIVERY USING NANOCARRIERS IN CANCER THERAPY

Innovative Nano-carrier-based transdermal patches, a wonder of advanced technologies, have received overwhelming endorsement in medicinal applications primarily in the provision of anti-neoplastic drugs. The purpose of this study was to review the limitations of conventional therapeutic initiatives namely chemotherapy, having several adverse effects, including significant inflammation, toxicity, and discomfort. Antineoplastic transdermal patches can be used as a prophylactic treatment method to treat a variety of cancers through the skin. Novel transdermal methods and Nanocarrier formulations have evolved to resolve the skin constraints and delivering the active drug to the underlying tissue of the skin enabling access to the systemic absorption of drugs and eventually get within tumour cells by approaching different targeting mechanisms. The transdermal administration of antineoplastic drugs is a promising alternative for boosting site-specific application, minimizing adverse effects, hepatic first-pass metabolism and promoting therapeutic value. Furthermore, the utilization of nanocarriers serves as a permeation enhancer to broaden the spectrum of medicines accessible for transdermal administration that has emerged as a viable and intriguing option. This review examines the benefits of transdermal delivery for anti-neoplastic drugs to ensure a good insight into their effectiveness in terms of modern clinical demands, to present a highlighted overview of transdermal drug delivery, and seeks to better comprehend the nano-formulations employed in transdermal drug delivery system (TDDS). Conclusively, reflecting the framework for future research and promoting the chemotherapeutic use of transdermal delivery over conventional dosage forms.

A Oral Fast Dissolving Films Containing Lyophilized Labetalol HCL with Hydroxy Propyl β-Cyclodextrin/ Soluplus: Formulation Development, In Vitro Evaluation

Introduction: Labetalol HCL is an antihypertensive drug used to treat high blood pressure in the long term management of angina. Labetalol HCL is readily absorbed after oral administration. Labetalol HCl undergoes considerable hepatic first-pass metabolism due to its lipid-soluble nature. 
 Objective: The drug has an absolute bioavailability of approximately 25%. To overcome extensive hepatic first-pass metabolism the oral fast-dissolving film for labetalol HCL need to be developed. Lyophilized inclusion complexes of Labetalol HCL were developed with the hydrophilic carrier as Soluplus a Polyvinyl acetate polyethene glycol graft copolymer and Hydroxy Propyl β-cyclodextrin.
 Experimental: Lyophilized inclusion complexes of labetalol: Soluplus and labetalol HCL: HP-β-CD were prepared with 1:0.5 weight ratios. The prepared lyophilized inclusion complexes were evaluated for solubility estimation, drug content, and In-vitro dissolution study. 
 Results: The prepared inclusion complexes were characterized by Fourier transforms infrared spectroscopy and differential scanning calorimetry. Characterization of the lyophilized complex showed changed crystallinity of labetalol HCL. The fast dissolving oral film of labetalol HCL was prepared by solvent casting method by adding film-forming polymer as HPMC K 4M/ PVA in different proportions and Propylene Glycol was used as a plasticizer. The prepared batches of films were evaluated for weight variation, tensile strength, folding, endurance, disintegration time, surface pH, and drug content uniformity. All formulations prepared among F5 and F 7 showed a better result as compared to other formulations. 
 Conclusion: The study confirms the use of a lyophilized product containing Soluplus is best as that of HP-βCD for the preparation of fast dissolving film with HPMC/ PVA as film forming agent and propylene glycol as plasticizer respectively to improve dissolution rate and oral bioavailability of Labetalol HCl.

Chitosan/guar gum-based thermoreversible hydrogels loaded with pullulan nanoparticles for enhanced nose-to-brain drug delivery

The biopolymers-based two-fold system could provide a sustained release platform for drug delivery to the brain resisting the mucociliary clearance, enzymatic degradation, bypassing the first-pass hepatic metabolism, and BBB thus providing superior bioavailability through intranasal administration. In this study, poloxamers PF-127/PF-68 grafted chitosan HCl-co-guar gum-based thermoresponsive hydrogel loaded with eletriptan hydrobromide laden pullulan nanoparticles was synthesized and subjected to dynamic light scattering, Fourier transform infrared spectroscopy, thermal analysis, x-ray diffraction, scanning electron microscopy, stability studies, mucoadhesive strength and time, gel strength, cloud point assessment, rheological assessment, ex-vivo permeation, cell viability assay, histology studies, and in-vivo Pharmacokinetics studies, etc. It is quite evident that CSG-EH-NPs T-Hgel has an enhanced sustained release drug profile where approximately 86 % and 84 % of drug released in phosphate buffer saline and simulated nasal fluid respectively throughout 48 h compared to EH-NPs where 99.44 % and 97.53 % of the drug was released in PBS and SNF for 8 h. In-vivo PKa parameters i.e., mean residence time (MRT) of 11.9 ± 0.83 compared to EH-NPs MRT of 10.2 ± 0.92 and area under the curve (AUCtot) of 42,540.5 ± 5314.14 comparing to AUCtot of EH-NPs 38,026 ± 6343.1 also establish the superiority of CSG-EH-NPs T-Hgel.

Buccal drug delivery system

It is well known that certain medications suffer hepatic first-pass metabolism or deteriorate in the digestive system, the buccal drug delivery method may be an alternative to oral administration. Because it is painless and may be swiftly and readily removed if the treatment must be terminated or interrupted, the buccal mucosa has long been ideal for administering medications. This paper focuses on the buccal drug delivery system had the goal of gathering recent literature and presenting a concise explanation of buccal patches by discussing the characteristics of an ideal mucoadhesive system, benefits of buccal delivery and disadvantages thereof, factors affecting buccal absorption, and various types of patches as well as the preparation method and composition thereof. The compilation of the data is also enhanced by adding market products as well as the patented, so that reader will get the complete knowledge about the buccal drug delivery.

Abstract 3936: Orally bioavailable 'lymphatropic' kinase inhibitors

Abstract Cancer signaling pathways can readily adapt to evade therapy through intrinsic resistance or compensatory mechanisms driving a resistant state. The prominence of oncogenic kinase signaling in a multitude of cancer types has inspired development of molecularly targeted drugs, facilitating combination treatment strategies designed to overcome adaptations such as signaling crosstalk and activation of downstream effectors. Treatments using inhibitor combinations, however, remain a challenge as clinical trials have been fraught with dose-limiting toxicities. Avoidance of hepatic first-pass metabolism by transport and sequestration into mesenteric gastrointestinal lymphatic vessels may improve drug exposure and reduce dose-limiting toxicities often observed in combination therapy studies. Despite potential advantages, lymphatically directed kinase inhibitors have remained unexplored due in part to limited understanding of the physicochemical properties required for lymphatic uptake of small molecules. We demonstrate a first-in-class series of orally bioavailable small molecule kinase inhibitors which are intrinsically ‘lymphatropic’, undergoing lymphatic absorption to achieve sustained circulatory drug levels and therapeutic benefit, with no observable toxicity. Single agent multifunctional inhibitors of high-value targets (MEK/PI3K, MEK/PI3K/mTOR, & MEK/mTOR) were designed and synthesized. Compounds had unique physiochemical properties, demonstrating high lymphatic uptake in a mesenteric lymphatic vessel cannulation model and in isolated lymph nodes extracts. Pharmacokinetic studies in mice following oral administration revealed that sustained plasma blood levels were achieved within the therapeutic window for up to 24 hours. Oral bioavailability in mice was found to be 80-85% of drug administered and was constant over a single-dose range study (100 to 1,000 mg/kg). On-target in vitro and in vivo inhibition of activated MEK and PI3K was also demonstrated, revealing high potency of both the parent molecule and therapeutically active metabolites. Together, these studies revealed that lymphatic sequestration of orally dosed compounds serves to provide a reservoir that circumvents pharmacotoxicity through controlled physiological drug release into the systemic circulation and avoidance of first-pass hepatic metabolism. This platform provides a template for further development of additional lymphatropic small molecule inhibitors presenting opportunities in which multi-targeted cancer treatment options can now be evaluated. Exciting new therapeutic prospects offered by lymphatropic agent development is anticipated to transform treatment options for a wide variety of cancer types such as metastasis and lymphoma along with a myriad of other diseases including autoimmune disorders. Citation Format: Brian D. Ross, Youngsoon Jang, Amanda Welton, Christopher A. Bonham, Kevin Heist, Lucas McDonald, Gary D. Luker, Thomas L. Chenevert, Marcian Van Dort. Orally bioavailable 'lymphatropic' kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3936.

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework

Tizanidine, a centrally acting skeletal muscle relaxant, is predominantly metabolized by CYP1A2 and undergoes extensive hepatic first-pass metabolism after oral administration. As a highly extracted drug, the systemic exposure to tizanidine exhibits considerable interindividual variability and is altered substantially when coadministered with CYP1A2 inhibitors or inducers. The aim of the current study was to compare the performance of a permeability-limited multicompartment liver (PerMCL) model, which operates as an approximation of the dispersion model, and the well stirred model (WSM) for predicting tizanidine drug-drug interactions (DDIs). Physiologically based pharmacokinetic models were developed for tizanidine, incorporating the PerMCL model and the WSM, respectively, to simulate the interaction of tizanidine with a range of CYP1A2 inhibitors and inducers. Whereas the WSM showed a tendency to underpredict the fold change of tizanidine area under the plasma concentration-time curve (AUC ratio) in the presence of perpetrators, the use of PerMCL model increased precision (absolute average-fold error: 1.32-1.42 versus 1.58) and decreased bias (average-fold error: 0.97-1.25 versus 0.63) for the predictions of mean AUC ratios as compared with the WSM. The PerMCL model captured the observed range of individual AUC ratios of tizanidine as well as the correlation between individual AUC ratios and CYP1A2 activities without interactions, whereas the WSM was not able to capture these. The results demonstrate the advantage of using the PerMCL model over the WSM in predicting the magnitude and interindividual variability of DDIs for a highly extracted sensitive substrate tizanidine. SIGNIFICANCE STATEMENT: This study demonstrates the advantages of the PerMCL model, which operates as an approximation of the dispersion model, in mitigating the tendency of the WSM to underpredict the magnitude and variability of DDIs of a highly extracted CYP1A2 substrate tizanidine when it is administered with CYP1A2 inhibitors or inducers. The physiologically based pharmacokinetic modeling approach described herein is valuable to the understanding of drug interactions of highly extracted substrates and the source of its interindividual variability.

A Detailed Review on Fast Dissolving Niosomal Films for Sublingual Drug Delivery

Fast dissolving or Quick-dissolving dosage forms have great importance in the pharmaceutical field due to their special properties and advantages. Fast-dissolving dosage forms breakdown immediately in the salivary fluids of the oral cavity within a minute, where they release the active pharmaceutical ingredient. Sublingual drug delivery system is a novel route of drug administration in which the drug substance is placed under the tongue and is directly absorbed via the blood vessels and produces the immediate onset of action. Noisome are closed bilayer vesicles formed by self-assembly of nonionic surfactant in an aqueous medium. Noisome is similar to liposome but has the ability to increase the stability of the drug. Formulated niosomes are added into the film-forming polymers to obtain sublingual niosomal films. Fast dissolving niosomal film is suitable for the drugs which show high first-pass metabolism or hepatic metabolism, low bioavailability drugs, and have a short half-life drugs. Fast Dissolving Niosomal Films used to improve the oral bioavailability and reduce the dose and dosing frequency, which reduce systemic side effects and as well as cost-effective. Niosomes allow the prolonged release of the drug and film was used to increase the bioavailability of drugs via the sublingual route of drug administration. Fast dissolving niosomal films have great importance during emergency conditions like allergy, short-term spasm, and asthma whenever an immediate onset of action is required. Fast dissolving films are also suitable for pediatric, geriatric, and dysphasic patients or patients with fear of choking.

Mucoadhesive Nanocarriers as a Promising Strategy to Enhance Intracellular Delivery against Oral Cavity Carcinoma.

Oral cancer, particularly squamous cell carcinoma (SCC), has posed a grave challenge to global health due to its high incidence, metastasis, and mortality rates. Despite numerous studies and favorable improvements in the therapeutic strategies over the past few decades, the prognosis of this disease remains dismal. Moreover, several drawbacks are associated with the conventional treatment; including permanent disfigurement and physical impairment that are attributed to surgical intervention, and systemic toxicity that results from aggressive radio- or chemotherapies, which impacts patients’ prognosis and post-treatment quality of life. The highly vascularized, non-keratinized oral mucosa appears as a potential route for cytotoxic drug administration in treating oral cancer. It acts as a non-invasive portal for drug entry targeting the local oral lesions of the early stages of cancer and the systemic metastasis sites of advanced cancer. The absorption of the poorly aqueous-soluble anti-cancer drugs can be enhanced due to the increased permeability of the ulcerous mucosa lining in the disease state and by bypassing the hepatic first-pass metabolism. However, some challenges in oral transmucosal drug delivery include the drugs’ taste, the limited surface area of the membrane lining the oral cavity, and flushing and enzymatic degradation by saliva. Therefore, mucoadhesive nanocarriers have emerged as promising platforms for controlled, targeted drug delivery in the oral cavity. The surface functionalization of nanocarriers with various moieties allows for drug targeting, bioavailability enhancement, and biodistribution at the site of action, while the mucoadhesive feature prolongs the drug’s residence time for preferential accumulation to optimize the therapeutic effect and reduce systemic toxicity. This review has been focused to highlight the potential of various nanocarriers (e.g., nanoparticles, nanoemulsions, nanocapsules, and liposomes) in conferring targeting, solubility and bioavailability enhancement of actives and mucoadhesive properties as novel tumor-targeted drug delivery approaches in oral cancer treatment.

Design and Characterization of Thermosensitive Mucoadhesive Nasal Gel for Meclizine Hydrochloride

Background: The current study was to develop a thermoreversible nasal in-situ gel for meclizine hydrochloride. As meclizine hydrochloride is water-insoluble and is having a hepatic first-pass metabolism it becomes necessary to prepare a formulation that will enhance the absorption of the drug and gives sustained action in the body. 
 Method: The FT-IR and DSC study revealed that there was no incompatibility between the drug and the excipient. The inclusion complex of meclizine hydrochloride was prepared by employing Sulfobutyl-ether- β- Cyclodextrin (SBEβCD) and then using this complex the thermoreversible gel was prepared by using the cold method. The thermoreversible gel was prepared by incorporating various types of polymers like Carrageenan, HPMC, carbopol-934, and Sodium Alginate in different concentrations and was evaluated for the various evaluation parameters to identify the optimized formulation from the batches B1-B8. 
 Result: From the prepared formulation B6 was found to be optimized as it was having a higher drug concentration of 98.33±2.1547%, the mucoadhesive strength of 28.98±1.5692 dyne/cm2 in B6 showed that more drug can be retained in the body as compared with other formulations, more sustained release of drug was seen i.e. 87.42±1.4113% of drug release in 8 hours than compared with the other prepared formulation. The kinetics study reveals peppas model was best fitted to the optimized formulation with the regression coefficient of 0.9832. From the stability study, it was concluded that the prepared formulation was stable during the full time study and does not change its property with time. 
 Conclusion: The concentration of polymers was a significant factor in the % drug release in the formulation and also in the mucoadhesive strength of the formulation. Hence, it was concluded that the prepared thermoreversible nasal in situ gel was a successful approach in increasing the drug absorption in the body.

Physicochemical Characterizations and Pharmacokinetic Evaluation of Pentazocine Solid Lipid Nanoparticles against Inflammatory Pain Model.

Pentazocine (PTZ), a narcotic-antagonist analgesic, has been extensively used in the treatment of initial carcinogenic or postoperative pain. Hepatic first-pass metabolism results in low oral bioavailability and high dose wastage. Herein, 10 mg (-)-Pentazocine (HPLC-grade) was incorporated to solid lipid nanoparticles (SLNs) using a double water-oil-water (w/o/w) emulsion by solvent emulsification–evaporation technique, followed by high shear homogenization to augment its oral bioavailability, considering the lymphatic uptake. The resulting SLNs were characterized for zeta potential (ZP), particle size (PS), and polydispersity index (PDI) using a zetasizer. The entrapment efficiency (EE) and loading capacity (LC) were calculated. Chemical interactions, through the identification of active functional groups, were assessed by Fourier-transformed infrared (FTIR) spectroscopy. The nature (crystallinity) of the SLNs was determined by X-ray diffractometry (XRD). The surface morphology was depicted by transmission electron microscopy (TEM). In vitro (in Caco-2 cells) and in vivo (in male Wistar rats) investigations were carried out to evaluate the PTZ release behavior and stability, as well as the cellular permeation, cytotoxicity, systemic pharmacokinetics, antinociceptive, anti-inflammatory, and antioxidative activities of PTZ-loaded SLNs, mainly compared to free PTZ (marketed conventional dosage form). The optimized PTZ-loaded SLN2 showed significantly higher in vitro cellular permeation and negligible cytotoxicity. The in vivo bioavailability and pharmacokinetics parameters (t1/2, Cmax) of the PTZ-loaded SLNs were also significantly improved, and the nociception and inflammation, following carrageenan-induced inflammatory pain, were markedly reduced. Concordantly, PTZ-loaded SLNs showed drastic reduction in the oxidative stress (e.g., malonaldehyde (MDA)) and proinflammatory cytokines (e.g., Interleukin (IL)-1β, -6, and TNF-α). The histological features of the paw tissue following, carrageenan-induced inflammation, were significantly improved. Taken together, the results demonstrated that PTZ-loaded SLNs can improve the bioavailability of PTZ by bypassing the hepatic metabolism via the lymphatic uptake, for controlled and sustained drug delivery.

Nose-to-brain lipid nanocarriers: An active transportation across BBB in migraine management

The present study focused on the development and evaluation of nanotechnology-based carrier systems of solid lipid nanoparticles (SLNs) to enhance the permeation and bioavailability of zolmitriptan across blood-brain-barrier (BBB). SLNs are the emerging field of nanotechnology with numerous applications like cosmetics and pharmaceutical research. Zolmitriptan-loaded SLNs were prepared by high-pressure homogenization method for targeted drug delivery to the brain. The SLNs were found to be round in shape with particle size ranging from 110 to 200 nm and zeta potential upto − 24.83 ± 3.03 mV which indicates good colloidal stability. The maximum entrapment efficiency of zolmitriptan in SLNs was found to be 84.17 ± 12.24%. The in-vitro drug release and ex-vivo release studies exhibited 95.85 ± 2.44% and 82.06 ± 2.94% drug release, respectively for 24 h. In-vivo studies was performed on male Wistar rats wherein the concentration of zolmitriptan was estimated in cerebrospinal fluid by LC-MS method. The selected formulation incorporated with SLNs showed significant enhancement in pharmacokinetic parameters like AUC (37.05 ± 2.45 ng/mL), Cmax (42.08 ± 1.32 ng/mL), Tmax (30 min), and t1/2 (1.28 h). Zolmitriptan-loaded SLNs via intranasal administration offers a novel approach to effectively circumvent first-pass hepatic metabolism than conventional oral route with 4-fold alleviation in permeation and 2-fold improvement in bioavailability.

Transdermal Drug Delivery System: A Novel Alternative for Drug Delivery

Orally administered pharmaceuticals now account for 74% of all prescriptions, however studies have shown that oral medications are often less effective due to first pass metabolism and not stable drug blood level etc. Transdermal drug delivery system (TDDS) was developed to enhance such qualities. Every 2.2 years, the FDA grants approval for a new transdermal medication delivery system, fueling a multibillion dollar industry. An extensive evaluation of the technology, business, and products has been warranted since the FDA initially authorized the first transdermal medicine patch around 40 years ago. Transdermal medication delivery systems on demand are made possible by patches, a special kind of patch. The transdermal medication delivery system's adhesive plays a key role in the product's safety, effectiveness, and quality. Compared to more traditional delivery modalities, such as oral or invasive injection, topical therapy provides several benefits. Limiting hepatic first-pass metabolism, improving therapeutic efficacy, and maintaining a constant plasma level are all benefits of transdermal drug administration. Types of transdermal patches, production techniques, mechanism of action, kinetics, clinical concerns, and their physicochemical methods of assessment are all covered in this article.

Pharmacokinetic Study of Mucoadhesive Itopride Hydrochloride In Situ Nasal Gel Formulations in a Comparative In Vivo Study and Histopathological Safety Evaluation

Hepatic first-pass metabolism has been a major cause of reduced bioavailability for many drugs. Using the nasal route as an alternative route to deliver drugs to the systemic circulation provided the solution to this problem. One of the drugs which are highly affected by first-pass metabolism is itopride hydrochloride (ITO HCl). It is a prokinetic agent used for the treatment of various gastrointestinal motility disorders, mainly gastroesophageal reflux. The objective of this study was to determine the pharmacokinetic parameters of selected mucoadhesive in situ nasal gel formulations (F1 and F17) of itopride hydrochloride (ITO HCl) and to evaluate their safety after topical application on the nasal mucosa. The tested formulations contained 18% w/v poloxamer 407 with 0.5% w/v of HPMC K4M (F1), or with 0.5% w/v MC (F17). A randomized cross-over study was done on six rabbits after administration of F1, F17, and commercial oral tablets (Ganaton®). Plasma levels were assessed using high-performance liquid chromatography (HPLC) to compare the nasal gel formulations with the conventional oral tablets. Histopathological study of the nasal mucosa was performed in rats after nasal application of both in situ gel formulas. The in vivo pharmacokinetic profiles of in situ nasal gel formulas F1 and F17 provided showed improvement in Cmax, Ke, t1/2, AUC0–24, AUC24–inf, AUC0–inf, AUMC24–inf, AUMC0–inf, MRT, Vd, and Cmax/AUC0–24 values over commercial tablets (p < 0.05). No statistically significant difference was found between both nasal gel formulas (F1 and F17). The percentage relative bioavailability of ITO HCl nasal in situ gel F1 and F17 was found to be 171.22% and 178.91%, respectively, in comparison with the commercial tablet. Histopathological study of the nasal mucosa revealed the safety of nasal in situ gel formulations to the nasal mucosa after 14 days of application. The study showed that the formulation of itopride hydrochloride as a mucoadhesive in situ nasal gel has enhanced the drug bioavailability due to avoidance of first-pass metabolism. The study points to the potential of mucoadhesive nasal in situ gel in terms of safety and efficiency.