Erratic Bioavailability Research Articles

A Complete Sojourn of Current Trends in Gastro-retentive Drug Delivery System: Recent Advances and Patent Survey.

The current work aims to provide a complete sojourn on gastro-retentive drug delivery system (GRDDS) along with formulation methods, polymer selection, and in vitro/ in vivo challenges with finished dosage forms. Ideally, a biopharmaceutical-hindered drug has a rapid clearance and erratic bioavailability due to its low aqueous solubility and permeability. Additionally, it also suffers from high first-pass metabolism and pre-systemic gut wall clearance. Gastro-retentive drug delivery systems have become an emerging technology where newer methodologies and scientific approaches have been used to provide the controlled release of drugs and provide a protective mechanism in the stomach. By the virtue of utilizing GRDDS as a dosage form, these formulations increase Gastroretention time (GRT) which prolongs the controlled release of the drug in the dosage form. GRDDS contribute to increased drug bioavailability and targeting at a site of action, which enhances therapeutic action and offers significant patient compliance. Furthermore, the present work also highlighted the critical role of polymers in favoring drug retention across GIT with the mechanism of gastro-retention and recommended concentration ranges. The emerging technology is also highlighted by the approved drug products and patented formulations in the recent decade which is depicted in a justified manner. GRDDS formulations have demonstrated clinical efficacy, which is supported by a compilation of patents for cutting-edge innovations in dosage forms that can be held in the stomach for an extended period of time.

Anthelmintic Effect of Cannabidiol against Echinococcus granulosus sensu stricto.

Cystic echinococcosis is a global parasitic zoonosis caused by infection with the larval stage of Echinococcus granulosus sensu lato. Cystic echinococcosis affects more than 1 million people worldwide, causing important economic costs in terms of management and livestock associated losses. Albendazole is the main drug used in treating human cystic echinococcosis. In spite of this, its low aqueous solubility, poor absorption, and consequently erratic bioavailability are the cause of its chemotherapeutic failures. Based on the described problem, new treatment alternatives urgently need to be developed. The aim of the present research was to study the in vitro and in vivo efficacy of cannabidiol (CBD), the second most abundant component of the Cannabis sativa plant, was demonstrated against E. granulosus sensu stricto. CBD (50 µg/mL) caused a decrease in protoscoleces viability of 80 % after 24 h of treatment which was consistent with the observed tegumental alterations. Detachment of the germinal layer was observed in 50 ± 10% of cysts treated with 50 µg/mL of CBD during 24 h. In the clinical efficacy study, all treatments reduced the weight of cysts recovered from mice compared with the control group. However, this reduction was only significant with ABZ suspension and the CBD + ABZ combination. As we could observe by the SEM study, the co-administration of CBD with ABZ suspension caused greater ultrastructural alteration of the germinal layer in comparison with that provoked with the monotherapy. Further in vivo research will be conducted by changing the dose and frequency of CBD and CBD + ABZ treatments and new available CBD delivery systems will also be assayed to improve bioavailability in vivo.

Preparation and characterization of novel mirabegron salts for sustaining dissolution and improving diffusion/permeability

Overactive bladder (OAB) is a disturbing and distressing condition associated with severe adverse consequences, such as depression, social isolation and participation restriction. Mirabegron (Mira.), used for the treatment of OAB is a BCS class-III drug that displays inconsistent bioavailability upon oral administration depending on dose, gender, and food intake. The present investigation aimed to synthesize sustained release/slow dissolving salts of Mira. to overcome its food intake dependent erratic bioavailability and to improve its permeability. The solvent evaporation method was used to prepare novel slow dissolving salts of Mira. by reacting it with various long-chain fatty acids (stearic acid, palmitic acid, myristic acid, and lauric acid). The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies suggested the genesis of a new crystalline phase due to a reaction between Mira. and fatty acids. Fourier-transform infrared spectroscopy (FTIR) and 1H Nuclear magnetic resonance (NMR) studies confirmed the transfer of proton between the primary amine group (-NH2) of Mira. and carboxylic acid group (-COOH) of fatty acids and thus the formation of salts. The prepared salts have significantly slower dissolution than Mira. in 6.8 pH phosphate buffer. The equilibrium solubility of prepared salts were lower than Mira in 6.8 pH phosphate buffer and water. The in-vitro diffusion study using the Franz diffusion cell proved better permeability of the prepared salts compared to Mira.

A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation.

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro.

Exploring Nanocarriers as Treatment Modalities for Skin Cancer.

Cancer is a progressive disease of multi-factorial origin that has risen worldwide, probably due to changes in lifestyle, food intake, and environmental changes as some of the reasons. Skin cancer can be classified into melanomas from melanocytes and nonmelanoma skin cancer (NMSC) from the epidermally-derived cell. Together it constitutes about 95% of skin cancer. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) are creditworthy of 99% of NMSC due to the limited accessibility of conventional formulations in skin cancer cells of having multiple obstacles in treatment reply to this therapeutic regime. Despite this, it often encounters erratic bioavailability and absorption to the target. Nanoparticles developed through nanotechnology platforms could be the better topical skin cancer therapy option. To improve the topical delivery, the nano-sized delivery system is appropriate as it fuses with the cutaneous layer and fluidized membrane; thus, the deeper penetration of therapeutics could be possible to reach the target spot. This review briefly outlooks the various nanoparticle preparations, i.e., liposomes, niosomes, ethosomes, transferosomes, transethosomes, nanoemulsions, and nanoparticles technologies tested into skin cancer and impede their progress tend to concentrate in the skin layers. Nanocarriers have proved that they can considerably boost medication bioavailability, lowering the frequency of dosage and reducing the toxicity associated with high doses of the medication.

Elucidating the complexation of nifurtimox with cyclodextrins

Chagas disease or American Trypanosomiasis, caused by the parasite Trypanosoma cruzi, is an endemic neglected infection found in 21 countries across Latin America. To date, nifurtimox is one of the only two drugs approved to treat Chagas disease but exhibits serious concerns related to its low aqueous solubility and erratic bioavailability. Thus, the aim of this work was to evaluate whether the formation of complexes with βcyclodextrin and sulfobutylether-β-cyclodextrin would improve drug solubility and dissolution rate. Drug-cyclodextrin interactions in solid-state were analyzed by differential scanning calorimetry, X-ray diffractometry, infrared spectroscopy, and nuclear magnetic resonance. The systems were characterized in solution by means of phase solubility, dissolution, and kinetic studies. Phase solubility study showed an AL-type diagram indicating the formation of inclusion complex in a 1:1 M ratio. The drug dissolution rate from sulfobutylether-β-cyclodextrin complexes was faster than that of the β-cyclodextrin complexes. The modification of the endothermic peak of nifurtimox revealed the presence of interactions between the drug and CDs. The crystalline character of the drug was greatly diminished after complexation with sulfobutylether-β-cyclodextrin. Microscopy evaluation revealed the formation of new structures of the solid particles, which suggest strong interactions between the drug and the carriers. The 1H and 13C nuclear magnetic resonance confirmed that the drug was included in the carriers. The selected nifurtimox complex stored at 25 °C and 40 °C during 6 months showed a remarkable stability in terms of drug dissolution and crystallinity.

An Overview of Nanoemulgels for Bioavailability Enhancement in Inflammatory Conditions via Topical Delivery.

The anti-inflammatory drugs that are generally available possess the disadvantage of hydrophobicity, which leads to poor permeability and erratic bioavailability. Nanoemulgels (NEGs) are novel drug delivery systems that aim to improve the solubility and permeability of drugs across the biological membrane. The nano-sized droplets in the nanoemulsion enhance the permeation of the formulation, along with surfactants and co-surfactants that act as permeation enhancers and can further improve permeability. The hydrogel component of NEG helps to increase the viscosity and spreadability of the formulation, making it ideal for topical application. Moreover, oils that have anti-inflammatory properties, such as eucalyptus oil, emu oil and clove oil, are used as oil phases in the preparation of the nanoemulsion, which shows a synergistic effect with active moiety and enhances its overall therapeutic profile. This leads to the creation of hydrophobic drugs that possess enhanced pharmacokinetic and pharmacodynamic properties, and simultaneously avoid systemic side effects in individuals with external inflammatory disorders. The nanoemulsion's effective spreadability, ease of application, non-invasive administration, and subsequent ability to achieve patient compliance make it more suitable for topical application in the combat of many inflammatory disorders, such as dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis and so on. Although the large-scale practical application of NEG is limited due to problems regarding its scalability and thermodynamic instability, which arise from the use of high-energy approaches during the production of the nanoemulsion, these can be resolved by the advancement of an alternative nanoemulsification technique. Considering the potential advantages and long-term benefits of NEGs, the authors of this paper have compiled a review that elaborates the potential significance of utilizing nanoemulgels in a topical delivery system for anti-inflammatory drugs.

Role of intravenous aspirin versus oral aspirin in the treatment of acute coronary syndrome: Answering a clinical query by systematic review and meta-analysis of randomized controlled trials.

Aspirin is indicated in the emergency management of acute coronary syndrome. However, oral aspirin has erratic bioavailability compared to i.v. formulation. The objective of this study was to evaluate the comparative efficacy and safety of intravenous (IV) and oral aspirin in acute coronary syndrome. This was a systematic review and meta-analysis. Two randomized controlled trials were included. Compared to oral aspirin, lower platelet aggregability was seen with IV aspirin at 5 min and 20 min. Lower thromboxane B2 and lower platelet CD-62p levels were noted in the IV group; however, no significant difference was observed in terms of "composite cardiovascular death, stroke, and myocardial infarction (MI) at 4-6 weeks," "any cause mortality," "cardiovascular mortality," "occurrence of stroke," and "occurrence of MI/reinfarction." However, no difference was noted in terms of the occurrence of serious adverse events. IV aspirin showed some advantages in terms of platelet aggregability biomarkers at 20 min and 1 week with comparable safety to oral aspirin. No difference was seen in terms of clinical outcomes (at 24 h, 7, and 30 days) and the occurrence of serious adverse events.

A New Challenge for the Old Excipient Calcium Carbonate: To Improve the Dissolution Rate of Poorly Soluble Drugs.

Calcium carbonate is an excipient traditionally used in solid dosage forms with several functions such as a diluent, a quick dissolution agent, a buffer and an opacifier. Recently, many other challenges have arisen for calcium carbonate and, among them, the possibility of using it as an excipient for improving the dissolution rate of poorly soluble drugs. As a consequence of their poor solubility in biological fluids, many active ingredients suffer from low and erratic bioavailability when administered by the oral route and thus, many formulation strategies and excipients have been proposed to overcome this problem. Among them, calcium carbonate has been proposed as an excipient for improving dissolution rates. Calcium carbonate has many interesting characteristics, in fact it dissolves quickly in gastric fluid, is inexpensive and is safe. It exists in different polymorphic forms and in porous morphology and recently a porous functionalized calcium carbonate has been proposed as a new excipient. This review is the first overview on the use of calcium carbonate as an excipient for improving drug dissolution rates. The drug loading procedure, the physical characterization of the drug/CaCO3 samples and their dissolution profiles will be described. Moreover, the possible mechanisms of dissolution improvement, such as the presence of the drug in amorphous or polymorphic forms, in small crystals, and the effects of CaCO3 dissolution in acidic medium will be discussed. Different polymorphic forms of calcium carbonate and the presence of porosity and functionalization will be analyzed as well and their effects on dissolution rates will be discussed.

A critical appraisal on ferulic acid: Biological profile, biopharmaceutical challenges and nano formulations

Ferulic acid (4-hydroxy-3-methoxy cinnamic acid) is a common phenolic acid in the plant kingdom and an important component of Chinese medicine herbs like Angelica Sinensis, Cimicifuga heracleifolia, and Lignsticum chuanxiong. Ferulic acid rarely occurs in a free state in plants and is typically conjugated with mono- and oligosaccharides, polyamines, lipids, and polysaccharides. Ferulic acid is essential for the synthesis of significant chemical molecules such as coniferyl alcohol, vanillin, synaptic, di ferulic acid, and curcumin as well as for giving the cell wall stiffness. It serves as a precursor to vanillin, amongst the most significant aromatic flavourings found in foods, drinks, medicines, and fragrances. Ferulic acid is now a prime choice of phytochemicals which is used in combination with different anti-depressants and hepatoprotective drugs for enhancing activity. This novel molecule suffers from poor biopharmaceutical properties such as poor solubility and erratic bioavailability which hinders its therapeutic efficacy. The current review highlights the most recent research on ferulic acid, as well as its metabolism profile and issues related to its biopharmaceutical delivery. This review also focused on different nano-formulations reported along with the patent survey.

In vitro efficacy of albendazole-loaded β-cyclodextrin against protoscoleces of Echinococcus granulosus sensu stricto

BackgroundCystic echinococcosis (CE), a widespread helminthic disease caused by the larval stage of the dog tapeworm Echinococcus granulosus represents a public health concern in humans. Albendazole (ABZ) is the first-line treatment for CE; however therapeutic failure of ABZ against CE occurs because of size and location of formed cysts as well its low aqueous solubility and consequently its erratic bioavailability in plasma. Serious adverse effects have also been observed following the long-term use of ABZ in vivo. MethodsWe evaluated the apoptotic effects of ABZ-loaded β-cyclodextrin (ABZ-β-CD) against protoscoleces (PSCs) versus ABZ alone. After 15 h of exposure, Caspase-3 enzymatic activity was determined by fluorometric assay in PSCs treated with ABZ and ABZ-β-CD groups. To assess the treatment efficacy of ABZ-β-CD against PSCs, mRNA expression of Arginase (EgArg) and Thioredoxin peroxidase (EgTPx) were quantified by Real-time PCR. ResultsA significant scolicidal activity of ABZ was observed only at a concentration of 800 μg/mL (100% PSCs mortality rate after 4 days of exposure), while the 200 and 400 μg/mL ABZ reached 100% PSCs mortality rate after 9 sequential days. The 400 μg/mL ABZ-β-CD had 100% scolicidal rate after 5 days of exposure. Morphological alterations using scanning electron microscopy in treated PSCs revealed that 400 μg/mL ABZ-β-CD induced higher Caspase-3 activity than their controls, indicating a more potent apoptotic outcome on the PSCs. Also, we showed that the 400 μg/mL ABZ-β-CD can down-regulate the mRNA expression of EgArg and EgTPx, indicating more potent interference with growth and antioxidant properties of PSCs. ConclusionsIn the present study, a significant scolicidal rate, apoptosis intensity and treatment efficacy was observed in PSCs treated with 400 μg/mL ABZ-β-CD compared to ABZ alone. This provides new insights into the use of nanostructured β-CD carriers with ABZ as a promising candidate to improve the treatment of CE in in vivo models.

Novel Mucoadhesive Chitosomes as a Platform for Enhanced Oral Bioavailability of Cinnarizine.

Cinnarizine (CIN) is a class II BSC drug, suffering from erratic bioavailability due to its pH-dependent solubility. It has preferential absorption in the stomach. In this study, new chitosan (CS) coated niosomes of CIN (CIN-loaded chitosomes) have been developed to extend the gastric retention and ameliorate CIN oral bioavailability. Various CIN-loaded niosomes were fabricated by thin-film hydration technique and fully characterized. Based on the predetermined criteria of low particle size (PS) and high entrapment efficiency percent (EE%), niosomal formulation F1 was selected and further coated with different CS concentrations. The optimized chitosomal formulation (C2) was evaluated through solid state characterization and mucoadhesive efficiency testing. It was also subjected to cytotoxicity study on Caco-2 cells; besides, in vitro drug release, stability and pharmacokinetic studies were assessed. The optimized chitosomal formulation (C2) exhibited an EE% of 58.30±2.75%, PS of 440 ±13.03 nm, PDI of 0.335±0.21 and ZP of +28.1±0.10 mv. Solid state characterization results revealed the compatibility between the vesicle components and the entrapment of CIN within niosomal vesicles. C2 formulation demonstrated favorable mucoadhesive efficiency. The cytotoxicity study on Caco-2 cells manifested the safety of the optimized chitosomal formulation (C2) over the free drug. Additionally, it displayed a remarkable sustaining of CIN in vitro release up to 8 h and exhibited a good stability at the refrigerated temperature up to 3 months. In vivo pharmacokinetic assessment revealed that the CIN bioavailability from the optimized chitosomal formulation C2 was enhanced by 2.79 and 1.92 folds compared to the free drug and uncoated niosomal formulation F1, respectively. The priority of the chitosomal formulation (C2) over the niosomal one (F1) was also conferred. Novel formulation of chitosan coated niosomes (chitosomes) could be presented as a promising platform to improve the oral bioavailability of drugs with narrow absorption window.

Optimal delivery of poorly soluble drugs using electrospun nanofiber technology: Challenges, state of the art, and future directions.

Poor aqueous solubility of both, existing drug molecules and those which are currently in the developmental stage, have posed a great challenge to pharmaceutical scientists because they often exhibit poor dissolution behavior and subsequent poor and erratic bioavailability. This has triggered extensive research to explore nanotechnology-based technology platforms for possible rescue. Recently, nanofibers have been exploited widely for diverse biomedical applications including for drug delivery. Electrospun nanofibers are capable of preserving the homogeneously loaded therapeutic agents in amorphous state potentialy impairing devitrification. The present review aims at providing an overview of the various key factors that affect the electrospinning process and characteristics of the nanofibers while fabrication of drug loaded nanofibers for poorly soluble drug candidates. The review explores various methodological advancements in the electrospinning process and set-ups for production scale-up. The various types of electrospun nanofibers (like simple matrix, core-sheath, Janus, and inclusion complex nanofibers) that have been exploited for the delivery of poorly soluble drugs are also critically assessed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

A REVIEW ON ADVANCES IN PHARMACEUTICAL CO-CRYSTAL PREPARATION ROUTES, INTELLECTUAL PROPERTY PERSPECTIVE AND REGULATORY ASPECTS

As in recent years, due to the pervasiveness of poorly soluble APIs that demonstrates poor and erratic bioavailability, pharmaceutical cocrystal’s applicability to tailor the physicochemical properties has gained attention. Pharmaceutical cocrystal has been an exciting field of interest to researchers as this encouraged several regulatory bodies to create regulatory standards, which led to the approval of these crystals for marketing in various nations. With the upsurge in the growth of pharmaceutical cocrystals, the major concern is over the intellectual property perspective and regulatory status of cocrystals. With the new guidelines from the United States Food and Drug Administration (USFDA) and European Medicines Agency (EMA), the manufacturing and characterization of cocrystal have become less complicated. In this article, various preparation routes are mentioned along with this intellectual property perspective and regulatory perspective, including regulatory guidelines, which give an idea of whether cocrystals meet the criteria for patent eligibility and how they would change the current state of the pharmaceutical industry. Here, we also reviewed some recently approved patients on pharmaceutical crystals, which provided benefits over poor physicochemical property of drug substances and also enhanced the therapeutic effectiveness of that drugs.

INFLUENCE OF INTERACTION OF MILK FAT ON RELEASE, CHARACTERISTICS AND ABSORPTION OF THEOPHYLLINE

Considerable evidence that drug bioavailability is influenced by food, in conjunction with the poor and erratic bioavailability of sparingly soluble drugs, serve as a stimulus in the research field for examining new formulations that may provide more consistent absorption. The in vitro and in vivo availability of freeze dried and spray dried drug-milk products were studied under “high-fat meal” conditions. In vitro drug release profile showed that though the freeze-dried product released the maximum drug, release was sporadic. Spray dried product increased the drug release but lesser than freeze dried products. The spray dried product also showed consistent release of drug. The interaction of theophylline with milk fat influenced all pharmacokinetic parameters such as, the action of theophylline being observed to be sustained for a longer period. Spray dried product also increased the rate and extent of absorption. The main feature of this system is that the drug-milk product is regenerated by adding water to the freezedried and spray dried drug-milk formulation just prior to administration. Thus, a drug-milk product with most of the drug in solution is effectively ingested. One important factor which has shown effect on drug bioavailability is the potential influence of regenerated fluid volume on drug absorption.

Enteric and hydrophilic polymers enhance dissolution and absorption of poorly soluble acidic drugs based on micro-environmental pH-modifying solid dispersion

The oral bioavailability of poorly water-soluble active pharmaceutical ingredient (API) is often inadequate for the desired therapeutic effect. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is an effective method for enhancing the dissolution of pH-dependent soluble APIs. However, erratic bioavailability of these drugs was often found when the micro pHm SD of the drugs was orally administrated and passed through the gastrointestinal tract. Because the added alkalizer in micro pHm SD could be neutralized by the acid in the stomach, as a result not enough alkalizer is left to form alkaline micro-environment around the drug in the intestine, leading to poor dissolution and bioavailability of API. Enteric polymers are applicable materials for site-specific drug delivery that are insoluble in gastric tract but soluble in the intestine targeted for drug release. In this study, a poorly water-soluble model drug, toltrazuril (TOL), was prepared as enteric micro pHm SD with enteric, hydrophilic polymers and alkalizer. The surface of enteric micro pHm SD tablets staining and alkalizer protection test in the acid dissolution medium qualitatively and quantitatively confirmed the protective effects of the enteric polymer on the alkalizer. Dissolution studies revealed that the drug release from the enteric micro pHm SDs was improved significantly compared with micro pHm SD with no enteric polymer. The pH-dependent solubility of enteric polymer had effects on the dissolution of APIs from the SDs in neutral medium. Enteric micro pHm SDs with higher proportion of enteric polymer showed higher Cmax and dissolution rate of TOL. The physicochemical characterization and the molecular interaction between drug and matrix were analyzed by electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR), finding that the formation of hydrogen bonds between TOL and matrix was helpful to promote dissolution of TOL. Ca(OH)2-TOL-PVPk30-HPMCAS 8: 8: 18: 6 was determined as the most optimal enteric micro pHm SD, which significantly improved the bioavailability of TOL and its active metabolism (TOLSO, TOLSO2) in pharmacokinetic study and could effectively reduce the irritation of the gastrointestinal mucosa caused by the alkalizer Ca(OH)2 when the SD was orally administrated to rabbits. The present study demonstrates that formulating APIs with poor water solubility as enteric micro pHm SD is an effective method for protecting the alkalizer in SD and improving the dissolution of APIs and the bioavailability following oral administration.

A Review on Lipid Based Oral Drug Delivery Systems

The main problem in oral drug formulations is low and erratic bioavailability, which is mainly due to poor aqueous solubility. This can lead to high inter- and intra-individual variability, lack of dose proportionality, and failure. Improving the bioavailability of drugs with such properties presents one of the greatest challenges in formulations. Oral lipid-based formulations are interesting considerable attention due to their ability to improve solubility, facilitate gastrointestinal absorption, and reduce or eliminate the effect of food on poor water absorption. soluble lipophilic drug and therefore increases bioavailability. This review describes recent findings on Potential Advantages of these Systems, Types of Lipid-Based Drug Delivery Systems, Guidelines for Design of Lipid-Based Formulations, problems solved by LBDDS, Characterization of Lipid-Based Drug Delivery Systems, Applications of lipid-based formulations, including traditional medicine (TM), new trends in LBDDS, Regulatory Aspects has also been examined in the current revision.

Self-nanoemulsifying Drug Delivery System: A Versatile Carrier for Lipophilic Drugs.

Lipid-based systems such as self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions and offer many useful drug delivery opportunities. In the modern drug discovery era, there is a constant increase in the number of poorly soluble new chemical entities that suffer from poor and erratic bioavailability problems. The oral route possesses some major disadvantages, such as lack of constant drug levels in plasma, firstpass metabolism, which results in poor bioavailability. To address these problems, various lipidbased therapeutic systems are available from which self-enanoemulsifying systems have the potential to increase the bioavailability of poorly soluble drugs. SNEDDS is the isotropic mixture of oils, surfactant, and co-surfactant having droplet size in the range of 100-200 nm, which spontaneously emulsifies when it contacts with aqueous media in gastrointestinal (G.I) fluid. Various preparative methods are available for SNEDDS, such as high-pressure homogenizer, microfluidization, sonication, phase inversion, and shear state methods. These methods show favorable benefits in drug delivery. Self-nanoemulsifying drug delivery system possesses some disadvantages like precipitation of drug in G.I fluid or possible drug leaving in the capsule dosage form due to incompatibility issues, which can be overcome by more advanced techniques like supersaturated SNEDDS containing a precipitation inhibitor or Solid SNEDDS. These areformulated either through spray drying or using a solid carrier. The lipid-based nanocarrier (SNEDDS) plays a significant role in drug delivery to overcome the poor solubility and oral bioavailability. This review highlights the elaborative aspects of the diverse advantages of SNEDDS based formulations.

A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects.

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% w/w lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients.

A comparative study of the effects of chloroquine and praziquantel on splenomegaly in experimental Schistosomiasis mansoni

Background Splenomegaly is a major morbid sequela of schistosomiasis. Praziquantel (PZQ) is the only recommended schistosomicidal drug despite its erratic bioavailability and growing resistance. Moreover, neglecting early treatment of splenomegaly eventually necessitates splenectomy. With drug repurposing, the antimalarial drug chloroquine (CLQ) has gained much interest because of its anti-inflammatory effect. Additionally, CLQ inhibits hemozoin formation essential for in vivo survival of blood-feeding parasites. Aim To investigate the schistosomicidal effect of CLQ and its role in splenomegaly modification, with or without PZQ in an experimental model. Patients and methods The study was conducted on 180 mice equally divided into three groups: control; infected and early treated with CLQ, PZQ, or both drugs; and infected and late treated. In group II, each drug was given in its optimum time of action to study the effect on worm eradication/reproductivity and pathology development. In group III, repeated drug regimens were applied to study the effect on the already established splenomegaly. Mice were euthanized 7 weeks P.I. to calculate the parasitic load and 15 weeks post infection (P.I.) to assess tissue pathology by hematoxylin and eosin staining. Results Combined CLQ and PZQ administration produced a significant reduction of parasitic load compared with CLQ alone. A highly significant decrease (P<0.001) in hepatic granulomas mean number and splenic index was also recorded in early combined subgroup, with improved structure. With late treatment, the combined rather than single therapy showed an overall less pathology; however, early therapy showed better outcome. Conclusions CLQ combined with PZQ has a synergistic schistosomicidal, has a valuable anti-inflammatory effect, and restrains the effect on splenomegaly, especially with early administration.