Quality-by-Design-Based Development of Rivaroxaban-Loaded Liquisolid Compact Tablets with Improved Biopharmaceutical Attributes.

Rivaroxaban (RXN) finds use in the management of pulmonary embolism and deep vein thrombosis. Its poor solubility (5-7 µg/mL) and P-gp-mediated efflux from intestinal lining limits the oral application of RXN. This work assessed the impact of liquisolid compact technique in augmenting the solubility and bioavailability of RXN. PEG 400, Avicel PH 200, and Aerosil 200 were used as non-volatile liquid, carrier, and coating material, respectively, to formulate RXN liquid-solid compacts (RXN LSCs). A 32-factor factorial design was used in the optimisation to assess the impacts of factors (load factor and carrier:coating ratio) on the responses (angle of repose and Q30 min). Pre-compression parameters of RXN LSCs suggested adequate flow and compressibility. Optimisation data suggested significant influence of factors on both the responses. Optimised RXN LSC-based tablets showed a significantly higher in vitro dissolution rate than RXN API and Xarelto® tablets due to improved solubility, reduced crystallinity, greater surface area, and enhanced wetting of RXN particles. XRD, DSC, and SEM data supported RXN's amorphization. The cytotoxicity (MTT assay) and permeation studies indicated the nontoxicity of prepared RXN LSC tablets and the role of PEG 400 in inhibiting P-gp. Pharmacokinetic study of RXN LSC-based tablets in Albino Wistar rats exhibited 2.51- and 1.66-times higher AUC in comparison to RXN API and Xarelto® tablets respectively, demonstrating that developed formulation had a greater oral bioavailability. The RXN LSC tablets showed longer bleeding times and higher rates of platelet aggregation than RXN API. Thus, RXN LSC tablets can be considered a facile, scalable technology.

Application of D-Optimal Mixture Design in the Development of Nanocarrier-Based Darifenacin Hydrobromide Gel.

BACKGROUND: Darifenacin hydrobromide, a BCS Class II drug, is poorly bioavailable due to extensive first-pass metabolism. The present study is an attempt to investigate an alternative route of drug delivery by developing a nanometric microemulsion-based transdermal gel for the management of an overactive bladder. METHODS: Oil, surfactant, and cosurfactant were selected based on the solubility of the drug, and surfactant: cosurfactant in surfactant mixture (Smix) was selected at a 1:1 ratio as inferred from the pseudo ternary phase diagram. The D-optimal mixture design was used to optimize the o/w microemulsion wherein the globule size and zeta potential were selected as dependable variables. The prepared microemulsions were also characterized for various physico-chemical properties like transmittance, conductivity, and TEM. The optimized microemulsion was gelled using Carbopol 934 P and assessed for drug release in vitro and ex vivo, viscosity, spreadability, pH, etc. RESULTS: Drug excipient compatibility studies showed that the drug was compatible with formulation components. The optimized microemulsion showed a globule size of less than 50 nm and a high zeta potential of -20.56 mV. The ME gel could sustain the drug release for 8 hours as reflected in in vitro and ex vivo skin permeation and retention studies. The accelerated stability study showed no significant change in applied storage conditions. CONCLUSION: An effective, stable, non-invasive microemulsion gel containing darifenacin hydrobromide was developed. The achieved merits could translate into increased bioavailability and dose reduction. Further confirmatory in vivo studies on this novel formulation, which is a cost-effective & industrially scalable option, can improve the pharmacoeconomics of overactive bladder management.

Intranasal delivery: An attractive route for the administration of nucleic acid based therapeutics for CNS disorders.

The etiologies of several cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases have implicated changes in the genetic set up or genetic mutations as the root cause. Nucleic acid based therapeutics (NBTs) is a new class of biologics that are known to regulate gene expression at the transcriptional and post-transcriptional level. The NBTs include oligonucleotides, nucleosides, antisense RNA, small interfering RNAs, micro RNA etc. In recent times, this new category of biologics has found enormous potential in the management of cardiovascular, inflammatory, neurological disorders, cancer, infectious diseases and organ transplantation. However, the delivery of NBTs is highly challenging in terms of target specificity (intracellular delivery), mononuclear phagocyte system uptake, stability and biodistribution. Additionally, management of the above mentioned disorders require regular and intrusive therapy making non-invasive routes preferable in comparison to invasive routes like parenteral. The nasal route is garnering focus in delivery of NBTs to the brain in the management of several CNS disorders due to the associated merits such as non-invasiveness, possibility of chronic delivery, improved patient compliance, avoidance of hepatic and gastrointestinal metabolism as well as ability to bypass the BBB. Hence in recent times, this route has been sought by the reserachers as an alternative to parenteral therapy for the delivery of several NBTs. This review shall focus on an array of NBTs delivered through nasal route, their challenges, applications and opportunities. The novel delivery systems for incorporating NBTs; their targeting strategies shall be critically reviewed. The challenges towards regulatory approvals and commercialization shall also be discussed at large. Comparison of learnings derived from the success and barriers in nasal delivery of NBTs will help in identification of futuristic opportunities for their translation from bench to bedside.

Amalgamation of Solid Dispersion and Melt Adsorption Technique: Improved In Vitro and In Vivo Performance of Ticagrelor Tablets.

Ticagrelor (TG) suffers from low peroral bioabsorption (36%) due to P-gp efflux and poor solubility (10 µg/mL). TG solid dispersion adsorbates (TG-SDAs) were formulated using an amalgamation of solid dispersion and melt adsorption techniques which were simple, economic, scalable, and solvent-free. FTIR indicated no incompatibility between drug and excipients. DSC, XRD, and SEM suggested a reduction in TG crystallinity. Q30min from TG-SUSP and TG-conventional tablets was only 2.30% and 6.59% respectively whereas TG-SDA-based tablets exhibited a significantly higher drug release of 86.47%. Caco-2 permeability studies showed 3.83-fold higher permeability of TG from TG-SDAs. TG-SDA-based tablets exhibited relative bioavailability of 748.53% and 153.43% compared to TG-SUSP and TG-conventional tablets respectively in rats. TG-SDA-based tablets were devoid of any cytotoxicity as indicated by MTT assay and exhibited better antiplatelet activity in rats. Enhanced oral bioavailability of TG-SDAs can be attributed to inhibition of P-gp efflux by PEG 4000, increased wettability, and reduced crystallinity of drug leading to improved drug solubility and dissolution. Improved bioabsorption results in a reduction of dose, cost of therapy as well as dose-related side effects. Thus, SDAs can be considered a promising and scalable approach for the improvement of dissolution rate and solubility of TG. TG-SDAs can be translated to an effective and safe dosage form, whereby its rapid onset of action promotes the prevention of heart attack, stroke, and related ill events in individuals with the acute coronary syndrome. However, scale-up, validation, and clinical-studies are necessary for confirmation of the proof-of-concept.

Toxicological Aspects of Carbon Nanotubes, Fullerenes and Graphenes.

Nanomedicines exhibit unbelievable capability in overcoming the hurdles faced in biological applications. Carbon nanotubes (CNTs), graphene-family nanomaterials and fullerenes are a class of engineered nanoparticles that have emerged as a new option for possible use in drug/gene delivery for life-threatening diseases. Their adaptability to pharmaceutical applications has opened new vistas for biomedical applications. Successful applications of this family of engineered nanoparticles in various fields may not support their use in medicine due to inconsistent data on toxicity as well as the lack of a centralized toxicity database. Inconsistent toxicological studies and lack of mechanistic understanding have been the reasons for limited understanding of their toxicological aspects. These nanoparticles, when underivatized or pristine, are considered as safe, however less reactive. The derivatized forms or functionalization changes their chemistry significantly to modify their biological effects including toxicity. They can cause acute and long term injuries in tissues by penetration through the the blood-air barrier, blood-alveolus barrier, blood-brain barrier, and blood-placenta barrier. and by accumulating in the lung, liver, and spleen . The toxicological effects are manifested through inflammatory response, DNA damage, apoptosis, autophagy and necrosis. Other factors that largely influence the toxicity of carbon nanotubes, graphenes and fullerenes are the concentration, functionalization, dimensional and surface topographical factors. Thus, a better understanding of the toxicity profile of CNTs, graphene-family nanomaterials and fullerenes in humans, animals and the environment is of significant importance, to improve their biological safety, to facilitate their wide biological application and for the successful commercial application. The exploration of appropriate cell lines to investigate specific receptors and intracellular targets as well as chronic toxicity beyond the proof-of-concept is required.

Atopic Dermatitis: Drug Delivery Approaches in Disease Management.

In this review, we describe the very basic of atopic dermatitis (AD), the established management strategies, and the advances in drug delivery approaches for successful therapeutic outcomes. The multifactorial pathophysiology of AD has given rise to the clinician's paradigm of topical and systemic therapy and potential combinations. However, incomplete remission of skin disorders like AD is a major challenge to be overcome. Recurrence is thought to be due to genetic and immunological etiologies and shortcomings in drug delivery. This difficulty has sparked research in nanocarrier-based delivery approaches as well as molecular biology-inspired stratagems to deal with the immunological imbalance and to address insufficiencies of delivery propositions. In this review, we assess various novel drug delivery strategies in terms of their success and utility. We present a brief compilation and assessment of management modalities to sensitize the readers to therapeutic scenario in AD.

Protein functionalized tramadol-loaded PLGA nanoparticles: preparation, optimization, stability and pharmacodynamic studies.

Poly (d,l-lactide-co-glycolide acid) (PLGA) Nanoparticles (NPs) with sustained drug release and enhanced circulation time presents widely explored non-invasive approach for drug delivery to brain. However, blood-brain barrier (BBB) limits the drug delivery to brain. This can be overcome by anchoring endogenous ligand like Transferrin (Tf) and Lactoferrin (Lf) on the surface of NPs, allowing efficient brain delivery via receptor-mediated endocytosis. The aim of the present investigation was preparation, optimization, characterization and comparative evaluation of targeting efficiency of Tf- vs. Lf-conjugated NPs. Tramadol-loaded PLGA NPs were prepared by nanoprecipitation techniques and optimized using 3(3) factorial design. The effect of polymer concentration, stabilizer concentration and organic:aqueous phase ratio were evaluated on particle size (PS) and entrapment efficiency (EE). The formulation was optimized based on desirability for lower PS (<150 nm) and higher EE (>70%). Optimized PLGA NPs were conjugated with Tf and Lf, characterized and evaluated for stability study. Pharmacodynamic study was performed in rat after intravenous administration. The optimized formulation had 100 mg of PLGA, 1% polyvinyl alcohol (PVA) and 1:2 acetone:water ratio. The Lf and Tf conjugation to PLGA NPs was estimated to 186 Tf and 185 Lf molecules per NPs. Lyophilization was optimized at 1:2 ratio of NPs:trehalose. The NPs were found stable for 6 months at refrigerated condition. Pharmacodynamic study demonstrated enhanced efficacy of ligand-conjugated NPs against unconjugated NPs. Conjugated NPs demonstrated significantly higher pharmacological effect over a period of 24 h. Furthermore Lf functionalized NPs exhibited better antinociceptive effect as compared to Tf functionalized NPs.

Comparative receptor based brain delivery of tramadol-loaded poly(lactic-co-glycolic acid) nanoparticles.

Receptor mediated endocytosis or transcytosis has been reported for drug delivery across Blood-brain barrier (BBB) and hence, the aim of the present investigations was to prepare and compare brain targeting efficiency of tramadol-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface modified with transferrin (Tf) and lactoferrin (Lf). Nanoparticles of tramadol were prepared using nanoprecipitation technique and surface conjugated with Tf and Lf using epoxy linker. Prepared nanoparticles were characterized for their size, surface charge, drug entrapment, transmission electron microscopy and in vitro drug release. The surface density of Tf and Lf was estimated by protein estimation. The drug distribution in blood, brain and other tissues was studied in mice after intravenous administration. Tf and Lf anchored nanoparticles exhibit enhanced uptake with 2.38 and 3.85 folds higher targeting respectively in the brain when compared with unconjugated nanoparticles. The brain targeting observed for Lf anchored PLGA nanoparticles (Lf-TMD-PLGA-NP) was 1.62 folds that of Tf anchored PLGA nanoparticles (Tf-TMD-PLGA-NP). Hence, the study revealed Tf and specially Lf as promising ligand for enhanced brain deposition of tramadol.

Patents review in siRNA delivery for pulmonary disorders.

siRNA inhibits protein expression by degrading complementary mRNA sequence and hence, it is widely applicable for the treatment of various diseases where single or multiple gene knock down is necessary. Due to the severity and lethality of pulmonary diseases, siRNA has been focused for improved health in these diseases. Pulmonary accumulation of siRNA can be achieved by different means like intranasal or inhalation administration or intratracheal route which is mainly utilized for in vivo animal studies. However, various pulmonary obstacles and intracellular barriers for siRNA transport challenge this novel therapeutic moiety. Researchers have utilized different viral and non-viral delivery vectors for intracellular delivery of siRNA to knock down target mRNA. The promise of RNA interference, mediated by siRNAs, has revolutionized the prospects for modulating gene expression as a way to achieve therapeutic aims in disease treatment. This review focuses on patents describing the siRNA delivery either in naked form or along with a single/multiple delivery vectors. Many inventors have shown promising results for pulmonary utilization of siRNA and more concentration on delivery system may make this genomic approach available to the clinics soon.

Suppression of cytokine gene expression and improved therapeutic efficacy of microemulsion-based tacrolimus cream for atopic dermatitis.

Tacrolimus ointment being occlusive is known to give higher dermal penetration but offers limited patient acceptance in treatment of atopic dermatitis, especially in tropical countries. Hence, the aim of this study was to develop, characterize, and evaluate a microemulsion-based cream formulation of tacrolimus against ointment in hapten-induced murine model of dermatitis. Tacrolimus-loaded microemulsion having mean globule size below 25 nm was mixed with cetomacrogol cream base. The microemulsion-based cream exhibited a significantly faster drug release through semipermeable cellulose acetate membrane in comparison to commercially available ointment. The drug retention in rodent and human cadaver skin with cream was almost twofold greater in comparison to the commercially available ointment. Further, in vivo evaluation using a fluorescent marker revealed a greater and deeper accumulation of marker in skin with cream. In vivo studies in mice revealed a prompt and significant reduction in ear swelling. The reduction in inflammatory cytokine gene expression as evaluated by semiquantitative reverse transcriptase polymerase chain reaction was also significantly higher with cream. The better efficacy of cream was reflected in histopathology as well as in morphological observations at the site of application. Thus, microemulsion-based cream presents a possibility of development of an efficacious cream vehicle and a scope for dose reduction which needs to be confirmed in clinical studies.