FACTORIAL STUDIES ON ENHANCEMENT OF DISSOLUTION RATE AND FORMULATION OF ACECLOFENAC TABLETS EMPLOYING Î’CDAND KOLLIPHOR HS15

Aceclofenac is an effective anti inflammatory and analgesic drug. It belongs to class II under Biopharmaceutical classification system and exhibit low and variable oral bioavailability due to its poor solubility. It is practically insoluble in water and aqueous fluids and its oral absorption is dissolution rate limited. It needs enhancement in solubility and dissolution rate for improvement of its oral bioavailability and therapeutic efficacy. The objective of the present study is to enhance the dissolution rate and formulation development of aceclofenac tablets with fast dissolution characteristics employing βCD and Kolliphor HS15, a non ionic surfactant. The individual and combined effects of βCD (factor A) and Kolliphor HS15 (factor B) on the dissolution rate of aceclofenac from solid inclusion complexes and their tablets were evaluated in a series of 22 factorial experiments. The feasibility of formulating aceclofenac - βCD-Kolliphor HS15 inclusion complexes into tablets with fast dissolution rate characteristics was also investigated. Kolliphor HS15 has not been investigated earlier for this purpose. The individual and combined effects of βCD and Kolliphor HS15 in enhancing the dissolution rate and dissolution efficiency of aceclofenac from solid inclusion complexes and their tablets were highly significant (P < 0.01). The dissolution of aceclofenac was rapid and higher in the case of aceclofenac- βCD and aceclofenac- βCD - Kolliphor HS15 complexes prepared when compared to aceclofenac pure drug. β CD alone gave a 8.66 fold increase and in combination with Kolliphor HS15 it gave 9.85 fold increase in the dissolution rate of (K1) of aceclofenac. Aceclofenac –βCD – Kolliphor HS15 inclusion complexes could be formulated into compressed tablets by wet granulation method and the resulting tablets also gave rapid and higher dissolution of aceclofenac. Aceclofenac tablets formulated with βCD and Kolliphor HS15 individually gave 4.75 and 6.1 fold increase in the dissolution rate and those containing drug - βCD -Kolliphor HS15 complex gave much higher enhancement (21.35 fold) in the dissolution rate when compared to tablets formulated with aceclofenac pure drug. Combination of βCD and Kolliphor HS15 gave much higher enhancement in the dissolution rate of aceclofenac tablets than is possible with them individually. A combination of βCD with Kolliphor HS15 is recommended to enhance the dissolution rate in the formulation development of aceclofenac tablets with fast dissolution rate characteristics

Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee

Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co‐administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors’ Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Co-evolution, opportunity seeking and institutional change: Entrepreneurship and the Indian telecommunications industry 1923-2009

"This is an Author's Original Manuscript of an article submitted for consideration in Business History [copyright Taylor & Francis]; Business History is available online at http://www.tandfonline.com/." 10.1080/00076791.2012.687538In this paper, we demonstrate the importance for entrepreneurship of historical contexts and processes, and the co-evolution of institutions, practices, discourses and cultural norms. Drawing on discourse and institutional theories, we develop a model of the entrepreneurial field, and apply this in analysing the rise to global prominence of the Indian telecommunications industry. We draw on entrepreneurial life histories to show how various discourses and discursive processes ultimately worked to generate change and the creation of new business opportunities. We propose that entrepreneurship involves more than individual acts of business creation, but also implies collective endeavours to shape the future direction of the entrepreneurial field

Dizaj i statistička optimizacija liposfera s glipizidom pomoću metodologije odgovora površine

A 32 factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X1) and proportion of stearic acid in the wax (X2) on geometric mean diameter (dg), percent encapsulation efficiency (% EE), release at the end of 12 h (rel12) and time taken for 50% of drug release (t50), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of dg, % EE, rel12 and t50 values for the optimized formulation were found to be 57.54 ± 1.38 µm, 86.28 ± 1.32 %, 77.23 ± 2.78 % and 5.60 ± 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats.32 faktorijalni dizajn primijenjen je za pripravu liposfera s glipizidom metodom separacije pomoću emulzija koristeći parafinski vosak i starinsku kiselinu kao tvari za usporavanje. Pomoću F-testa praćen je učinak kritičnih varijabli tijekom formuliranja, tj. količina parafinskog voska (X1) i udio stearinske kiseline (X2) na srednji promjer liposfera (dg), postotak inkapsulirane ljekovite tvari (% EE), oslobađanje ljekovite tvari nakon 12 h (rel12) te vrijeme potrebno za oslobađanje 50% ljekovite tvari (t50). Pomoću multiple linearne regresijske analize (MLRA) i analize varijabli (ANOVA) za svaki su parametar načinjeni matematički modeli koji sadrže samo značajne varijable. Proučavanje varijabli na oba načina ukazalo je na njihov značajan utjecaj (p < 0,05) na parametre liposfera. Postavljanjem ograničenja na zavisne i nezavisne varijable provedena je numerička optimizacija na principu poželjnosti. Eksperimentalne vrijednosti dg, % EE, rel12 i t50 optimiziranih formulacija bile su 57,54 ± 1,38 µm, 86,28 ± 1,32%, 77,23 ± 2,78% i 5,60 ± 0,32 h. Dobivene eksperimentalne vrijednosti iznosile su vrlo slične vrijednostima predviđenim matematičkim modelima. Oslobađanje glipizida iz liposfera slijedio je kinetiku prvog reda i okarakterizirano je Higuchijevim difuzijskim modelom. Optimizirane liposfere su nakon peroralne primjene na štakorima pokazale produljeni antidijabetički učinak

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April–30 July 2020 and 21 January–19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0–1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .)

Structural characteristics and antiviral activity of multiple peptides derived from MDV glycoproteins B and H

<p>Abstract</p> <p>Background</p> <p>Marek's disease virus (MDV), which is widely considered to be a natural model of virus-induced lymphoma, has the potential to cause tremendous losses in the poultry industry. To investigate the structural basis of MDV membrane fusion and to identify new viral targets for inhibition, we examined the domains of the MDV glycoproteins gH and gB.</p> <p>Results</p> <p>Four peptides derived from the MDV glycoprotein gH (gHH1, gHH2, gHH3, and gHH5) and one peptide derived from gB (gBH1) could efficiently inhibit plaque formation in primary chicken embryo fibroblast cells (CEFs) with 50% inhibitory concentrations (IC₅₀) of below 12 μM. These peptides were also significantly able to reduce lesion formation on chorioallantoic membranes (CAMs) of infected chicken embryos at a concentration of 0.5 mM in 60 μl of solution. The HR2 peptide from Newcastle disease virus (NDVHR2) exerted effects on MDV specifically at the stage of virus entry (i.e., in a cell pre-treatment assay and an embryo co-treatment assay), suggesting cross-inhibitory effects of NDV HR2 on MDV infection. None of the peptides exhibited cytotoxic effects at the concentrations tested. Structural characteristics of the five peptides were examined further.</p> <p>Conclusions</p> <p>The five MDV-derived peptides demonstrated potent antiviral activity, not only in plaque formation assays in vitro, but also in lesion formation assays in vivo. The present study examining the antiviral activity of these MDV peptides, which are useful as small-molecule antiviral inhibitors, provides information about the MDV entry mechanism.</p