Search results for: orphan drug production

Authors: Lynn Louis, Bor Shin Chee, Marion McAfee, Michael Nugent

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This article aims to develop a sustained release formulation of microspheres containing the mTOR inhibitor Everolimus (EVR) using Polyvinyl alcohol (PVA) to enhance the bioavailability of the drug and to overcome poor solubility characteristics of Everolimus. This paper builds on recent work in the manufacture of microspheres using the sessile droplet technique by freezing the polymer-drug solution by suspending the droplets into pre-cooled ethanol vials immersed in liquid nitrogen. The spheres were subjected to 6 freezing cycles and 3 freezing cycles with thawing to obtain proper geometry, prevent aggregation, and achieve physical cross-linking. The prepared microspheres were characterised for surface morphology by SEM, where a 3-D porous structure was observed. The in vitro release studies showed a 62.17% release over 12.5 days, indicating a sustained release due to good encapsulation. This result is comparatively much more than the 49.06% release achieved within 4 hours from the solvent cast Everolimus film as a control with no freeze-thaw cycles performed. The solvent cast films were made in this work for comparison. A prolonged release of Everolimus using a polymer-based drug delivery system is essential to reach optimal therapeutic concentrations in treating SEGA tumours without systemic exposure. These results suggest that the combination of PVA and Everolimus via a rheological synergism enhanced the bioavailability of the hydrophobic drug Everolimus. Physical-chemical characterisation using DSC and FTIR analysis showed compatibility of the drug with the polymer, and the stability of the drug was maintained owing to the high molecular weight of the PVA. The obtained results indicate that the developed PVA/EVR microsphere is highly suitable as a potential drug delivery system with improved bioavailability in treating Subependymal Giant cell astrocytoma (SEGA).

Keywords: drug delivery system, everolimus, freeze-thaw cycles, polyvinyl alcohol

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Authors: Debabrata Biswas

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The current trend in the development of antibiotic resistance by multiple bacterial pathogens has resulted in a troubling loss of effective antibiotic options for human. The emergence of multi-drug-resistant pathogens has necessitated higher dosages and combinations of multiple antibiotics, further exacerbating the problem of antibiotic resistance. Zoonotic bacterial pathogens, such as Salmonella, Campylobacter, Shiga toxin-producing Escherichia coli (such as enterohaemorrhagic E. coli or EHEC), and Listeria are the most common and predominant foodborne enteric infectious agents. It was observed that these pathogens gained/developed their ability to survive in the presence of antibiotics either in farm animal gut or farm environment and researchers believe that therapeutic and sub-therapeutic antibiotic use in farm animal production might play an important role in it. The mechanism of action of antimicrobial components used in farm animal production in genomic interplay in the gut and farm environment, has not been fully characterized. Even the risk of promoting the exchange of mobile genetic elements between microbes specifically pathogens needs to be evaluated in depth, to ensure sustainable farm animal production, safety of our food and to mitigate/limit the enteric infection with multiple antibiotic resistant bacterial pathogens. Due to the consumer’s demand and considering the current emerging situation, many countries are in process to withdraw antibiotic use in farm animal production. Before withdrawing use of the sub-therapeutic antibiotic or restricting the use of therapeutic antibiotics in farm animal production, it is essential to find alternative natural antimicrobials for promoting the growth of farm animal and/or treating animal diseases. Further, it is also necessary to consider whether that compound(s) has the potential to trigger the acquisition or loss of genetic materials in zoonotic and any other bacterial pathogens. Development of alternative therapeutic and sub-therapeutic antimicrobials for farm animal production and food processing and preservation and their effective implementation for sustainable strategies for farm animal production as well as the possible risk for horizontal gene transfer in major enteric pathogens will be focus in the study.

Keywords: food safety, natural antimicrobial, sustainable farming, antibiotic resistance

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Authors: F. Keller, G. Reinhart

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The efficient and economic allocation of resources is one main goal in the field of production planning and control. Nowadays, a new variable gains in importance throughout the planning process: Energy. Energy-efficiency has already been widely discussed in literature, but with a strong focus on reducing the overall amount of energy used in production. This paper provides a brief systematic approach, how energy-supply-orientation can be used for an energy-cost-efficient production planning and thus combining the idea of energy-efficiency and energy-flexibility.

Keywords: production planning, production control, energy-efficiency, energy-flexibility, energy-supply

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Authors: Wannee Sutthachaidee

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The study of the production process of coconut-shell product in Amphawa, Samutsongkram Province is objected to study the pattern of the process of coconut-shell product by focusing in the 3 main processes which are inbound logistics process, production process and outbound process. The result of the research: There were 4 main results from the study. Firstly, most of the manufacturer of coconut-shell product is usually owned by a single owner and the quantity of the finished product is quite low and the main labor group is local people. Secondly, the production process can be divided into 4 stages which are pre-production process, production process, packaging process and distribution process. Thirdly, each 3 of the logistics process of coconut shell will find process which may cause the problem to the business but the process which finds the most problem is the production process because the production process needs the skilled labor and the quantity of the labor does not match with the demand from the customers. Lastly, the factors which affect the production process of the coconut shell can be founded in almost every process of the process such as production design, packaging design, sourcing supply and distribution management.

Keywords: production process, coconut-shell product, Amphawa District, inbound logistics process

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Authors: Sean Hall

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Nanosystems for drug delivery are not new; as medicines evolve, so too does the desire to deliver a more targeted, patient-compliant medicine. Though, historically the widespread use of nanosystems for drug delivery has been fouled by non-replicability, scalability, toxicity issues, and economics. Examples include steps of manufacture and thus cost to manufacture, toxicity for nanoparticle scaffolding, autoimmune response, and considerable technical expertise for small non-commercial yields. This, unfortunately, demonstrates the not-so-obvious chasm between science and drug formulation for regulatory approval. Regardless there is a general and global desire to improve the delivery of medicines, reduce potential side effect profiles, promote increased patient compliance, and increase and/or speed public access to medicine availability. In this paper, the author will discuss NanoCelle®, a nano-delivery platform that specifically addresses degradation and solubility issues that expands from fundamental micellar preparations. NanoCelle® has been deployed in several Australian listed medicines and is in use of several drug candidates across small molecules, with research endeavors now extending into large molecules. The author will discuss several research initiatives as they relate to NanoCelle® to demonstrate similarities seen in various drug substances; these examples will include both in vitro and in vivo work.

Keywords: NanoCelle®, micellar, degradation, solubility, toxicity

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Authors: S. V. Patil, P. S. Dounde, S. S. Patil

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Emulgels have emerged as one of the most interesting topical delivery system as it has dual release control system that is gel and emulsion. The major objective behind this formulation is delivery of hydrophobic drugs to systemic circulation via skin. In fact presence of a gelling agent in water phase converts a classical emulsion in to emulgel. The emulgel for dermatological use has several favorable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, non-staining, water-soluble, longer shelf life, bio-friendly, transparent and pleasing appearance. Various penetration enhancers can potentiate the effect. So this can be used as better topical drug delivery systems over present conventional systems available in market. Piroxicam is a non-steroidal anti-inflammatory drug that has major problems when administered orally; it is an insoluble drug and has irritant effect on gastro intestinal tract lead to ulceration and bleeding. The aim of this study was to overcoming these problems through preparation of topical emulgel of this drug. Emulgel of Piroxicam was prepared using Carbopol 940 along with mentha oil and clove oil as permeation enhancer. The prepared emulgel were evaluated for their physical appearance, pH determination, viscosity, spreadability, in vitro drug release, ex vivo permeation studies. All the prepared formulations showed acceptable physical properties, homogeneity, consistency, spreadability, viscosity and pH value. The emulgel was found to be stable with respect to physical appearance, pH, rheological properties and drug content at all temperature and conditions for three month.

Keywords: emulgel, piroxicam, menthe oil, clove oil

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Authors: Vera Sovkova, Andrea Mickova, Matej Buzgo, Karolina Vocetkova, Eva Filova, Evzen Amler

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PCL (poly-ε-caprolactone) nanofibrous scaffolds with adhered liposomes were prepared and tested as a possible drug delivery system for various synthetic growth factors. TGFβ, bFGF, and IGF-I have been shown to increase hMSC (human mesenchymal stem cells) proliferation and to induce hMSC differentiation. Functionalized PCL nanofibers were prepared with synthetic growth factors encapsulated in liposomes adhered to them in three different concentrations. Other samples contained PCL nanofibers with adhered, free synthetic growth factors. The synthetic growth factors free medium served as a control. The interaction of liposomes with the PCL nanofibers was visualized by SEM, and the release kinetics were determined by ELISA testing. The potential of liposomes, immobilized on the biodegradable scaffolds, as a delivery system for synthetic growth factors, and as a suitable system for MSCs adhesion, proliferation and differentiation in vitro was evaluated by MTS assay, dsDNA amount determination, confocal microscopy, flow cytometry and real-time PCR. The results showed that the growth factors adhered to the PCL nanofibers stimulated cell proliferation mainly up to day 11 and that subsequently their effect was lower. By contrast, the release of the lowest concentration of growth factors from liposomes resulted in gradual proliferation of MSCs throughout the experiment. Moreover, liposomes, as well as free growth factors, stimulated type II collagen production, which was confirmed by immunohistochemical staining using monoclonal antibody against type II collagen. The results of this study indicate that growth factors enriched liposomes adhered to surface of PCL nanofibers could be useful as a drug delivery instrument for application in short timescales, be combined with nanofiber scaffolds to promote local and persistent delivery while mimicking the local microenvironment. This work was supported by project LO1508 from the Ministry of Education, Youth and Sports of the Czech Republic

Keywords: drug delivery, growth factors, hMSC, liposomes, nanofibres

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Authors: Konja Knüppel, Gerrit Meyer, Peter Nyhuis

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The increasing interconnectedness and complexity of production processes raise the susceptibility of production systems to failure. Therefore, the ability to respond quickly to failures is increasingly becoming a competitive factor. The research project "Sustainable failure management in manufacturing SMEs" is developing a methodology to identify failures in the production and select preventive and reactive measures in order to correct failures and to establish sustainable failure management systems.

Keywords: failure categorization, failure management, logistic performance, production optimization

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Authors: Yuhua Wang, Mu Li, Jinggen Liu

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Aim: To investigate the different effects of heroin and milk in activating the corticostriatal system that plays a critical role in reward reinforcement learning. Methods: Male SD rats were trained daily for 15 d to self-administer heroin or milk tablets in a classic runway drug self-administration model. Immunohistochemical assay was used to quantify Arc protein expression in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc), the dorsomedial striatum (DMS) and the ventrolateral striatum (VLS) in response to chronic self-administration of heroin or milk tablets. NMDA receptor antagonist MK801 (0.1 mg/kg) or dopamine D1 receptor antagonist SCH23390 (0.03 mg/kg) were intravenously injected at the same time as heroin was infused intravenously. Results: Runway training with heroin resulted in robust enhancement of Arc expression in the mPFC, the NAc and the DMS on d 1, 7, and 15, and in the VLS on d 1 and d 7. However, runway training with milk led to increased Arc expression in the mPFC, the NAc and the DMS only on d 7 and/or d 15 but not on d 1. Moreover, runway training with milk failed to induce increased Arc protein in the VLS. Both heroin-seeking behavior and Arc protein expression were blocked by MK801 or SCH23390 administration. Conclusion: The VLS is likely to be critically involved in drug-seeking behavior. The NMDA and D1 receptor-dependent Arc expression is important in drug-seeking behavior.

Keywords: arc, mesocorticolimbic system, drug rewarding behavior, NMDA receptor

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Authors: Debalke Dale, Bezabh Geneta, Yohannes Amene, Yordanos Bergene, Mohammed Yimam

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Background: A drug therapy problem (DTP) is an event or circumstance that involves drug therapies that actually or potentially interfere with the desired outcome and requires professional judgment to resolve. Heart failure is an emerging worldwide threat whose prevalence and health loss burden constantly increase, especially in the young and in low-to-middle-income countries. There is a lack of population-based incidence and prevalence of heart failure (HF) studies in sub-Saharan African countries, including Ethiopia. Objective: The aim of this study was designed to assess drug therapy problems and associated factors among patients with HF in the medical ward of Arba Minch General Hospital(AGH), Ethiopia, from June 5 to August 20, 2022. Methods: A retrospective cross-sectional study was conducted among 180 patients with HF who were admitted to the medical ward of AGH. Data were collected from patients' cards by using questionnaires. The data were categorized and analyzed by using SPSS version 25.0 software, and data were presented in tables and words based on the nature of the data. Result: Out of the total, 85 (57.6%) were females, and 113 (75.3%) patients were aged over fifty years. Of the 150 study participants, 86 (57.3%) patients had at least one DTP identified, and a total of 116 DTPs were identified, which is 0.77 DTPs per patient. The most common types of DTP were unnecessary drug therapy (32%), followed by the need for additional drug therapy (36%), and dose too low (15%). Patients who used polypharmacy were 5.86 (AOR) times more likely to develop DTPs than those who did not (95% CI = 1.625–16.536, P = 0.005), and patients with more co-morbid conditions developed 3.68 (AOR) times more DTPs than those who had fewer co-morbidities (95% CI = 1.28–10.5, P = 0.015). Conclusion: The results of this study indicated that drug therapy problems were common among medical ward patients with heart failure. These problems are adversely affecting the treatment outcomes of patients, so it requires the special attention of healthcare professionals to optimize them.

Keywords: heart failure, drug therapy problems, Arba Minch general hospital, Ethiopia

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Authors: Fakhreldin O. Suliman, Alia H. Al-Battashi

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This work explored the interaction of three different imidazoline drugs, naphazoline nitrate (NPH), oxymetazoline hydrochloride (OXY) and xylometazoline hydrochloride (XYL) with two different synthesized cucurbit[n]urils CB[n], cucurbit[7]uril (CB[7]) and cucuribit[8]uril (CB[8]). Three binary inclusion complexes have been investigated in solution and in the solid state. The solid complexes were obtained by lyophilization, whereas the physical mixtures of guests and hosts at a stoichiometric ratio of 1:1 were obtained for each drug. 1HNMR, electrospray ionization mass spectrometry (ESI-MS), and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry was used to study the complexes prepared in aqueous media. The lyophilized solid complexes were characterized by Fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). MS, FT-IR and PXRD experimental results established in this work reveal that NPH, OXY and XYL molecules form stable inclusion complexes with the two hosts. The TGA and DSC confirmed the enhancement of the thermal stability of each drug and the production of a thermally stable solid complex. The 1HNMR has shown that the protons of the guests faced shifting in ppm and broadening of their peaks upon the formation of inclusion complexes with the selected CB[n]. The aromatic protons of the guest exhibited the highest changes in the chemical shifts and shape of the NMR peaks, suggesting their inclusion into the cavity of the CB[n]. The diffusion coefficients (D), developed from the diffusion-controlled NMR Spectroscopy (DOSY) measurements, for the complexation of the selected imidazoline drugs with CB[7] and CB[8], were decreased in the presence of hosts compared to the free guests indicating the formation of the guest-host adduct. Furthermore, we conducted molecular dynamic simulations and quantum mechanics calculations on these complexes. The results of the theoretical study corroborate the experimental findings and have also shed light on the mechanism of inclusion of the guests into the two hosts. This study generates initial data for potential drug delivery or drug formulation systems for these three selected imidazoline drug compounds based on their inclusion into the CB[n] cavities.

Keywords: cucurbit[n]urils, imidazoline, inclusion complexes, molecular dynamics, DFT calculations, mass spectrometry

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Authors: Humraaz Kaja, Kofi Mensah, Frasia Oosthuizen

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Background and Aim: Vilazodone was approved in 2011 as an antidepressant to treat the major depressive disorder. As a relatively new drug, it is not clear if all adverse effects have been identified. The aim of this study was to review the adverse effects reported to the WHO Programme for International Drug Monitoring (PIDM) in order to add to the knowledge about the safety profile and adverse effects caused by vilazodone. Method: Data on adverse effects reported for vilazodone was obtained from the database VigiAccess managed by PIDM. Data was extracted from VigiAccess using Excel® and analyzed using descriptive statistics. The data collected was compared to the patient information leaflet (PIL) of Viibryd® and the FDA documents to determine adverse drug reactions reported post-marketing. Results: A total of 9708 adverse events had been recorded on VigiAccess, of which 6054 were not recorded on the PIL and the FDA approval document. Most of the reports were received from the Americas and were for adult women aged 45-64 years (24%, n=1059). The highest number of adverse events reported were for psychiatric events (19%; n=1889), followed by gastro-intestinal effects (18%; n=1839). Specific psychiatric disorders recorded included anxiety (316), depression (208), hallucination (168) and agitation (142). The systematic review confirmed several psychiatric adverse effects associated with the use of vilazodone. The findings of this study suggested that these common psychiatric adverse effects associated with the use of vilazodone were not known during the time of FDA approval of the drug and is not currently recorded in the patient information leaflet (PIL). Conclusions: In summary, this study found several adverse drug reactions not recorded in documents emanating from clinical trials pre-marketing. This highlights the importance of continued post-marketing surveillance of a drug, as well as the need for further studies on the psychiatric adverse events associated with vilazodone in order to improve the safety profile.

Keywords: adverse drug reactions, pharmacovigilance, post-marketing surveillance, vilazodone

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Authors: Mia I. Allen, Bernard N. Johnson, Gagan Deep, Yixin Su, Sangeeta Singth, Ashish Kumar, , Michael A. Nader

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With no FDA-approved treatments for cocaine use disorders (CUD), research has focused on the behavioral and neuropharmacological effects of cocaine in animal models, with the goal of identifying novel interventions. While the majority of people with CUD also use tobacco/nicotine, the majority of preclinical cocaine research does not include the co-use of nicotine. The present study examined nicotine and cocaine co-use under several conditions of intravenous drug self-administration in monkeys. In Experiment 1, male rhesus monkeys (N=3) self-administered cocaine (0.001-0.1 mg/kg/injection) alone and cocaine+nicotine (0.01-0.03 mg/kg/injection) under a progressive-ratio schedule of reinforcement. When nicotine was added to cocaine, there was a significant leftward shift and significant increase in peak break point. In Experiment 2, socially housed female and male cynomolgus monkeys (N=14) self-administered cocaine under a concurrent drug-vs-food choice schedule. Combining nicotine significantly decreased cocaine choice ED50 values (i.e., shifted the cocaine dose-response curve to the left) in females but not in males. There was no evidence of social rank differences. In delay discounting studies, the co-use of nicotine and cocaine required significantly larger delays to the preferred drug reinforcer to reallocate choice compared with cocaine alone. Overall, these results suggest drug interactions of nicotine and cocaine co-use is not simply a function of potency but rather a fundamentally distinctive condition that should be utilized to better understand the neuropharmacology of CUD and the evaluation of potential treatments.

Keywords: polydrug use, animal models, nonhuman primates, behavioral pharmacology, drug self-administration

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Authors: Chuan Yin

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Cancer stem cells (CSCs) represent a subpopulation of cancer cells that possess the characteristics associated with normal stem cells. CD133 is a phenotype of melanoma CSCs responsible for melanoma metastasis and drug resistance. Although adriamycin (ADR) is commonly used drug in melanoma therapy, but it is ineffective in the treatment of melanoma CSCs. In this study, we constructed CD133 antibody conjugated ADR immunoliposomes (ADR-Lip-CD133) to target CD133+ melanoma CSCs. The results showed that the immunoliposomes possessed a small particle size (~150 nm), high drug encapsulation efficiency (~90%). After 72 hr treatment on the WM266-4 melanoma tumorspheres, the IC50 values of the drug formulated in ADR-Lip-CD133, ADR-Lip (ADR liposomes) and ADR are found to be 24.42, 57.13 and 59.98 ng/ml respectively, suggesting that ADR-Lip-CD133 was more effective than ADR-Lip and ADR. Significantly, ADR-Lip-CD133 could almost completely abolish the tumorigenic ability of WM266-4 tumorspheres in vivo, and showed the best therapeutic effect in WM266-4 melanoma xenograft mice. It is noteworthy that ADR-Lip-CD133 could selectively kill CD133+ melanoma CSCs of WM266-4 cells both in vitro and in vivo. ADR-Lip-CD133 represent a potential approach in targeting and killing CD133+ melanoma CSCs.

Keywords: cancer stem cells, melanoma, immunoliposomes, CD133

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Authors: Raj Kumar, Prem Felix Siril

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The poor aqueous solubility of many pharmaceutical drugs and potential drug candidates is a big challenge in drug development. Nanoformulation of such candidates is one of the major solutions for the delivery of such drugs. We initially developed the evaporation assisted solvent-antisolvent interaction (EASAI) method. EASAI method is use full to prepared nanoparticles of poor water soluble drugs with spherical morphology and particles size below 100 nm. However, to further improve the effect formulation to reduce number of dose and side effect it is important to control the delivery of drugs. However, many drug delivery systems are available. Among the many nano-drug carrier systems, solid lipid nanoparticles (SLNs) have many advantages over the others such as high biocompatibility, stability, non-toxicity and ability to achieve controlled release of drugs and drug targeting. SLNs can be administered through all existing routes due to high biocompatibility of lipids. SLNs are usually composed of lipid, surfactant and drug were encapsulated in lipid matrix. A number of non-steroidal anti-inflammatory drugs (NSAIDs) have poor bioavailability resulting from their poor aqueous solubility. In the present work, SLNs loaded with NSAIDs such as Nabumetone (NBT), Ketoprofen (KP) and Ibuprofen (IBP) were successfully prepared using different lipids and surfactants. We studied and optimized experimental parameters using a number of lipids, surfactants and NSAIDs. The effect of different experimental parameters such as lipid to surfactant ratio, volume of water, temperature, drug concentration and sonication time on the particles size of SLNs during the preparation using hot-melt sonication was studied. It was found that particles size was directly proportional to drug concentration and inversely proportional to surfactant concentration, volume of water added and temperature of water. SLNs prepared at optimized condition were characterized thoroughly by using different techniques such as dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and differential scanning calorimetry and Fourier transform infrared spectroscopy (FTIR). We successfully prepared the SLN of below 220 nm using different lipids and surfactants combination. The drugs KP, NBT and IBP showed 74%, 69% and 53% percentage of entrapment efficiency with drug loading of 2%, 7% and 6% respectively in SLNs of Campul GMS 50K and Gelucire 50/13. In-vitro drug release profile of drug loaded SLNs is shown that nearly 100% of drug was release in 6 h.

Keywords: nanoparticles, delivery, solid lipid nanoparticles, hot-melt sonication, poor water soluble drugs, solubility, bioavailability

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Authors: Camilla Trevor, Matthew K. Higgins, Andrea Gonzalez-Munoz, Mark Carrington

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Trypanosomiasis is a devastating disease affecting both humans and livestock in sub-Saharan Africa. The diseases are caused by infection with African trypanosomes, protozoa transmitted by tsetse flies. Treatment currently relies on the use of chemotherapeutics with ghastly side effects. Here, we describe the development of effective antibody-drug conjugates that target the T. brucei transferrin receptor. The receptor is essential for trypanosome growth in a mammalian host but there are approximately 12 variants of the transferrin receptor in the genome. Two of the most divergent variants were used to generate recombinant monoclonal immunoglobulin G using phage display and we identified cross-reactive antibodies that bind both variants using phage ELISA, fluorescence resonance energy transfer assays and surface plasmon resonance. Fluorescent antibodies were used to demonstrate uptake into trypanosomes in culture. Toxin-conjugated antibodies were effective at killing trypanosomes at sub-nanomolar concentrations. The approach of using antibody-drug conjugates has proven highly effective.

Keywords: antibody-drug conjugates, phage display, transferrin receptor, trypanosomes

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Authors: S. S. Patil, B. U. Janugade, S. V. Patil

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Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at the right time and in the right amount, thus providing spatial and temporal delivery thus increasing patient compliance. These systems are designed according to the circadian rhythm of the body. Chronotherapeutics is the discipline concerned with the delivery of drugs according to inherent activities of a disease over a certain period of time. It is becoming increasingly more evident that the specific time that patients take their medication may be even more significant than was recognized in the past. The tradition of prescribing medication at evenly spaced time intervals throughout the day, in an attempt to maintain constant drug levels throughout a 24-hour period, may be changing as researcher’s report that some medications may work better if their administration is coordinated with day-night patterns and biological rhythms. The potential benefits of chronotherapeutics have been demonstrated in the management of a number of diseases. In particular, there is a great deal of interest in how chronotherapy can particularly benefit patients suffering from allergic rhinitis, rheumatoid arthritis and related disorders, asthma, cancer, cardiovascular diseases, and peptic ulcer disease.

Keywords: pulsatile drug delivery, chronotherapeutics, circadian rhythm, asthma, chronobiology

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Authors: Ria Ghosh, Soumendra Singh, Dipanjan Mukherjee, Susmita Mondal, Monojit Das, Uttam Pal, Aniruddha Adhikari, Aman Bhushan, Surajit Bose, Siddharth Sankar Bhattacharyya, Debasish Pal, Tanusri Saha-Dasgupta, Maitree Bhattacharyya, Debasis Bhattacharyya, Asim Kumar Mallick, Ranjan Das, Samir Kumar Pal

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Drug delivery to a target without adverse effects is one of the major criteria for clinical use. Herein, we have made an attempt to explore the delivery efficacy of SDS surfactant in a monomer and micellar stage during the delivery of the model drug, Toluidine Blue (TB) from the micellar cavity to DNA. Molecular recognition of pre-micellar SDS encapsulated TB with DNA occurs at a rate constant of k1 ~652 s 1. However, no significant release of encapsulated TB at micellar concentration was observed within the experimental time frame. This originated from the higher binding affinity of TB towards the nano-cavity of SDS at micellar concentration which does not allow the delivery of TB from the nano-cavity of SDS micelles to DNA. Thus, molecular recognition controls the extent of DNA recognition by TB which in turn modulates the rate of delivery of TB from SDS in a concentration-dependent manner.

Keywords: DNA, drug delivery, micelle, pre-micelle, SDS, toluidine blue

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Authors: Sharmin Akhter, M. Salahuddin, Sukalyan Kumar Kundu, Mohammad Fahim Kadir

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Relatively insoluble candidate drug like carbamazepine (CBZ) often exhibit incomplete or erratic absorption; and hence wide consideration is given to improve aqueous solubility of such compound. Solid dispersions were formulated with an aim of improving aqueous solubility, oral bioavailability and the rate of dissolution of Carbamazepine using different hydrophyllic polymer like Polyethylene Glycol (PEG) 6000, Polyethylene Glycol (PEG) 4000, kollidon 30, HPMC 6 cps, poloxamer 407 and povidone k 30. Solid dispersions were prepared with different drug to polymer weight ratio by the solvent evaporation method where methanol was used as solvent. Drug-polymer physical mixtures were also prepared to compare the rate of dissolution. Effects of different polymer were studied for solid dispersion formulation as well as physical mixtures. These formulations were characterized in the solid state by Fourier Transform Infrared (FTIR) spectroscopy and Scanning Electron Microscopy (SEM). Solid state characterization indicated CBZ was present as fine particles and entrapped in carrier matrix of PEG 6000 and PVP K30 solid dispersions. Fourier Transform Infrared (FTIR) spectroscopic studies showed the stability of CBZ and absence of well-defined drug-polymer interactions. In contrast to the very slow dissolution rate of pure CBZ, dispersions of drug in polymers considerably improved the dissolution rate. This can be attributed to increased wettability and dispersibility, as well as decreased crystallinity and increase in amorphous fraction of drug. Solid dispersion formulations containing PEG 6000 and Povidone K 30 showed maximum drug release within one hour at the ratio of 1:1:1. Even physical mixtures of CBZ prepared with both carriers also showed better dissolution profiles than those of pure CBZ. In conclusions, solid dispersions could be a promising delivery of CBZ with improved oral bioavailability and immediate release profiles.

Keywords: carbamazepine, FTIR, kollidon 30, HPMC 6 CPS, PEG 6000, PEG 4000, poloxamer 407, water solubility, povidone k 30, SEM, solid dispersion

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Authors: Surya R. Niraula, Devendra B Chhetry, Girish K. Singh, S. Nagesh, Frederick A. Connell

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Background: Although random sampling is generally considered to be the gold standard for population-based research, the majority of drug abuse research is based on non-random sampling despite the well-known limitations of this kind of sampling. Method: We compared the statistical properties of two surveys of drug abuse in the same community: one using snowball sampling of drug users who then identified “friend controls” and the other using a random sample of non-drug users (controls) who then identified “friend cases.” Models to predict drug abuse based on risk factors were developed for each data set using conditional logistic regression. We compared the precision of each model using bootstrapping method and the predictive properties of each model using receiver operating characteristics (ROC) curves. Results: Analysis of 100 random bootstrap samples drawn from the snowball-sample data set showed a wide variation in the standard errors of the beta coefficients of the predictive model, none of which achieved statistical significance. One the other hand, bootstrap analysis of the random-sample data set showed less variation, and did not change the significance of the predictors at the 5% level when compared to the non-bootstrap analysis. Comparison of the area under the ROC curves using the model derived from the random-sample data set was similar when fitted to either data set (0.93, for random-sample data vs. 0.91 for snowball-sample data, p=0.35); however, when the model derived from the snowball-sample data set was fitted to each of the data sets, the areas under the curve were significantly different (0.98 vs. 0.83, p < .001). Conclusion: The proposed method of random sampling of controls appears to be superior from a statistical perspective to snowball sampling and may represent a viable alternative to snowball sampling.

Keywords: drug abuse, matched case-control study, non-probability sampling, probability sampling

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Authors: Mostafa M. Abo Elsoud, Heba I. Elkhouly, Nagwa M. Sidkey

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Production of rhamnolipids by Pseudomonas aeruginosa has attracted a growing interest during the last few decades due to its high productivity compared with other microorganisms. In the current work, rhamnolipids production by P. aeruginosa PAO1 was statistically modeled using Taguchi orthogonal array, numerically optimized and validated. Prickly Pear Peel (Opuntia ficus-indica) has been used as a carbon source for production of rhamnolipid. Finally, the optimum conditions for rhamnolipid production were applied in 5L working volume bioreactors at different aerations, agitation and controlled pH for maximum rhamnolipid production. In addition, kinetic studies of rhamnolipids production have been reported. At the end of the batch bioreactor optimization process, rhamnolipids production by P. aeruginosa PAO1 has reached the worldwide levels and can be applied for its industrial production.

Keywords: rhamnolipids, pseudomonas aeruginosa, statistical optimization, tagushi, opuntia ficus-indica

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Authors: S. Bouameur, S. Chirani

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The aim of this study was to evaluate the potential use of EthylCellulose in the preparation of microspheres as a Drug Delivery System for sustained release of phenobarbital. The microspheres were prepared by solvent evaporation technique using ethylcellulose as polymer matrix with a ratio 1:2, dichloromethane as solvent and Polyvinyl alcohol 1% as processing medium to solidify the microspheres. Size, shape, drug loading capacity and entrapement efficiency were studied.

Keywords: phenobarbital, microspheres, ethylcellulose, polyvinylacohol

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Authors: Fatma M. Benrabha

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The aim of the study was to determine the type and pattern of antibiotic susceptibility of the pathogenic microorganisms causing chronic suppurative otitis media (CSOM), which could lead to better therapeutic decisions and consequently avoidance of appearance of resistance to specific antibiotics. Most frequently isolated agents were Pseudomonas aeruginosa 28.5%; followed by Staphylococcus aureus 18.2%; proteus mirabilis 13.9%; Providencia stuartti 6.7%; Bacteroides melaninogenicus, Aspergillus sp., candida sp., 4.2% each; and other microorganisms were represented in 3-0.2%. Drug sensitivities pattern of Pseudomonas aeruginosa showed that ciprofloxacin was active against the majority of isolates (93.9%) followed by ceftazidime 86.2%, amikacin 76.2% and gentamicin 40.8%. However, Staphylococcus aureus isolates were resistant to penicillin 72.7%, erythromycin 28.6%, cephalothin 18.2%, cloxacillin 8.3% and ciprofloxacin was active against 96.2% of isolates. The resistance pattern of proteus mirabilis were 55.6% to ampicillin, 47.1% to carbencillin, 29.4% to cephalothin, 14.3% to gentamicin and 4.8% to amikacin while 100% were sensitive to ciprofloxacin. We conclude that ciprofloxacin is the best drug of choice in treatment of CSOM caused by the common microorganisms.

Keywords: otitis media, chronic suppurative otitis media (CSOM), microorganism, drug sensitivity

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Authors: Reena K., Mamatha H. G., Somshekarayya, P. Kumar

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Objectives: The annual proficiency testing of intermediate reference laboratories is conducted by the National Reference Laboratory (NRL) to assess the efficiency of the laboratories to correctly identify Mycobacterium tuberculosis and to determine its drug susceptibility pattern. The proficiency testing results from 2013 to 2017 were analyzed to determine laboratories that were consistent in reporting quality results and those that had difficulty in doing so. Methods: A panel of twenty cultures were sent out to each of these laboratories. The laboratories were expected to grow the cultures in their own laboratories, set up drug susceptibly testing by all the methods they were certified for and report the results within the stipulated time period. The turnaround time for reporting results, specificity, sensitivity positive and negative predictive values and efficiency of the laboratory in identifying the cultures were analyzed. Results: Most of the laboratories had reported their results within the stipulated time period. However, there was enormous delay in reporting results from few of the laboratories. This was mainly due to improper functioning of the biosafety level III laboratory. Only 40% of the laboratories had 100% efficiency in solid culture using Lowenstein Jensen medium. This was expected as a solid culture, and drug susceptibility testing is not used for diagnosing drug resistance. Rapid molecular methods such as Line probe assay and Genexpert are used to determine drug resistance. Automated liquid culture system such as the Mycobacterial growth indicator tube is used to determine prognosis of the patient while on treatment. It was observed that 90% of the laboratories had achieved 100% in the liquid culture method. Almost all laboratories had achieved 100% efficiency in the line probe assay method which is the method of choice for determining drug-resistant tuberculosis. Conclusion: Since the liquid culture and line probe assay technologies are routinely used for the detection of drug-resistant tuberculosis the laboratories exhibited higher level of efficiency as compared to solid culture and drug susceptibility testing which are rarely used. The infrastructure of the laboratory should be maintained properly so that samples can be processed safely and results could be declared on time.

Keywords: annual proficiency testing, drug susceptibility testing, intermediate reference laboratory, national reference laboratory

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Authors: A. Shashank Tiwari, S. P. Mahapatra

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Scale-up is defined as the process of increasing batch size. Scale-up of a process viewed as a procedure for applying the same process to different output volumes. There is a subtle difference between these two definitions: batch size enlargement does not always translate into a size increase of the processing volume. In mixing applications, scale-up is indeed concerned with increasing the linear dimensions from the laboratory to the plant size. On the other hand, processes exist (e.g., tableting) where the term ‘scale-up’ simply means enlarging the output by increasing the speed. To complete the picture, one should point out special procedures where an increase of the scale is counterproductive and ‘scale-down’ is required to improve the quality of the product. In moving from Research and Development (R&D) to production scale, it is sometimes essential to have an intermediate batch scale. This is achieved at the so-called pilot scale, which is defined as the manufacturing of drug product by a procedure fully representative of and simulating that used for full manufacturing scale. This scale also makes it possible to produce enough products for clinical testing and to manufacture samples for marketing. However, inserting an intermediate step between R&D and production scales does not, in itself, guarantee a smooth transition. A well-defined process may generate a perfect product both in the laboratory and the pilot plant and then fail quality assurance tests in production.

Keywords: scale up, research, size, batch

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Authors: Alaa Hamed Salama, Rehab Nabil Shamma

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Introduction: Polymeric micelles that can deliver drug to intended sites of the eye have attracted much scientific attention recently. The aim of this study was to review the aqueous-based formulation of drug-loaded polymeric micelles that hold significant promise for ophthalmic drug delivery. This study investigated the synergistic performance of mixed polymeric micelles made of linear and branched poly (ethylene oxide)-poly (propylene oxide) for the more effective encapsulation of Lornoxicam (LX) as a hydrophobic model drug. Methods: The co-micellization process of 10% binary systems combining different weight ratios of the highly hydrophilic poloxamers; Synperonic® PE/P84, and Synperonic® PE/F127 and the hydrophobic poloxamine counterpart (Tetronic® T701) was investigated by means of photon correlation spectroscopy and cloud point. The drug-loaded micelles were tested for their solubilizing capacity towards LX. Results: Results showed a sharp solubility increase from 0.46 mg/ml up to more than 4.34 mg/ml, representing about 136-fold increase. Optimized formulation was selected to achieve maximum drug solubilizing power and clarity with lowest possible particle size. The optimized formulation was characterized by 1HNMR analysis which revealed complete encapsulation of the drug within the micelles. Further investigations by histopathological and confocal laser studies revealed the non-irritant nature and good corneal penetrating power of the proposed nano-formulation. Conclusion: LX-loaded polymeric nanomicellar formulation was fabricated allowing easy application of the drug in the form of clear eye drops that do not cause blurred vision or discomfort, thus achieving high patient compliance.

Keywords: confocal laser scanning microscopy, Histopathological studies, Lornoxicam, micellar solubilization

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Authors: Ayodeji O. Falade, Leonard V. Mabinya, Uchechukwu U. Nwodo, Anthony I. Okoh

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Given the high utility of peroxidase in several industrial processes, the search for novel microorganisms with enhanced peroxidase production capacity is of keen interest. This study investigated the process conditions for optimum peroxidase production by Ensifer sp, new ligninolytic proteobacteria with peroxidase production potential. Also, some agricultural residues were valorized for peroxidase production under solid state fermentation. Peroxidase production was optimum at an initial medium pH 7, incubation temperature of 30 °C and agitation speed of 100 rpm using alkali lignin fermentation medium supplemented with guaiacol as the most effective inducer and ammonium sulphate as the best inorganic nitrogen. Optimum peroxidase production by Ensifer sp. was attained at 48 h with specific productivity of 12.76 ± 1.09 U mg⁻¹. Interestingly, probable laccase production was observed with optimum specific productivity of 12.76 ± 0.45 U mg⁻¹ at 72 h. The highest peroxidase yield was observed with sawdust as solid substrate under solid state fermentation. In conclusion, Ensifer sp. possesses the capacity for enhanced peroxidase production that can be exploited for various biotechnological applications.

Keywords: catalase-peroxidase, enzyme production, peroxidase, polymerase chain reaction, proteobacteria

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Authors: Choupani Andisheh, Temucin Elif Sevval, Bediz Bekir

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Due to their various advantages compared to many other drug delivery systems such as hypodermic injections and oral medications, microneedle arrays (MNAs) are a promising drug delivery system. To achieve enhanced performance of the MN, it is crucial to develop numerical models, optimization methods, and simulations. Accordingly, in this work, the optimized design of dissolvable MNAs, as well as their manufacturing, is investigated. For this purpose, a mechanical model of a single MN, having the geometry of an obelisk, is developed using commercial finite element software. The model considers the condition in which the MN is under pressure at the tip caused by the reaction force when penetrating the skin. Then, a multi-objective optimization based on non-dominated sorting genetic algorithm II (NSGA-II) is performed to obtain geometrical properties such as needle width, tip (apex) angle, and base fillet radius. The objective of the optimization study is to reach a painless and effortless penetration into the skin along with minimizing its mechanical failures caused by the maximum stress occurring throughout the structure. Based on the obtained optimal design parameters, master (male) molds are then fabricated from PMMA using a mechanical micromachining process. This fabrication method is selected mainly due to the geometry capability, production speed, production cost, and the variety of materials that can be used. Then to remove any chip residues, the master molds are cleaned using ultrasonic cleaning. These fabricated master molds can then be used repeatedly to fabricate Polydimethylsiloxane (PDMS) production (female) molds through a micro-molding approach. Finally, Polyvinylpyrrolidone (PVP) as a dissolvable polymer is cast into the production molds under vacuum to produce the dissolvable MNAs. This fabrication methodology can also be used to fabricate MNAs that include bioactive cargo. To characterize and demonstrate the performance of the fabricated needles, (i) scanning electron microscope images are taken to show the accuracy of the fabricated geometries, and (ii) in-vitro piercing tests are performed on artificial skin. It is shown that optimized MN geometries can be precisely fabricated using the presented fabrication methodology and the fabricated MNAs effectively pierce the skin without failure.

Keywords: microneedle, microneedle array fabrication, micro-manufacturing structural optimization, finite element analysis

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Authors: Shreya Asthana

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Testers know that the feature they tested on stage is working perfectly in production only after release went live. Sometimes something breaks in production and testers get to know through the end user’s bug raised. The panic mode starts when your staging test results do not reflect current production behavior. And you started doubting your testing skills when finally the user reported a bug to you. Testers can deploy their confidence on release day by testing on production. Once you start doing testing in production, you will see test result accuracy because it will be running on real time data and execution will be a little faster as compared to staging one due to elimination of bad data. Feature flagging, canary releases, and data cleanup can help to achieve this technique of testing. By this paper it will be easier to understand the steps to achieve production testing before making your feature live, and to modify IT company’s testing procedure, so testers can provide the bug free experience to the end users. This study is beneficial because too many people think that testing should be done in staging but not in production and now this is high time to pull out people from their old mindset of testing into a new testing world. At the end of the day, it all just matters if the features are working in production or not.

Keywords: bug free production, new testing mindset, testing strategy, testing approach

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Authors: Aminu Bashir Mohammad, Agwu Ezera, Abdulrazaq G. Habib, Garba Iliyasu

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Background: Drug resistance tuberculosis (DR-TB) continues to be a challenge in developing countries with poor resources. Routine screening for primary DR-TB before commencing treatment is not done in public hospitals in Nigeria, even with the large body of evidence that shows a high prevalence of primary DR-TB. Data on drug resistance and its genetic determinant among follow up TB patients is lacking in Nigeria. Hence the aim of this study was to determine the prevalence and genetic determinant of drug resistance among follow up TB patients in a tertiary hospital in Nigeria. Methods: This was a cross-sectional laboratory-based study conducted on 384 sputum samples collected from consented follow-up tuberculosis patients. Standard microbiology methods (Zeil-Nielsen staining and microscopy) and PCR (Line Probe Assay)] were used to analyze the samples collected. Person’s Chi-square was used to analyze the data generated. Results: Out of three hundred and eighty-four (384) sputum samples analyzed for mycobacterium tuberculosis (MTB) and DR-TB twenty-five 25 (6.5%) were found to be AFB positive. These samples were subjected to PCR (Line Probe Assay) out of which 18(72%) tested positive for DR-TB. Mutations conferring resistance to rifampicin (rpo B) and isoniazid (katG, and or inhA) were detected in 12/18(66.7%) and 6/18(33.3%), respectively. Transmission dynamic of DR-TB was not significantly (p>0.05) dependent on demographic characteristics. Conclusion: There is a need to strengthened the laboratory capacity for diagnosis of TB and drug resistance testing and make these services available, affordable, and accessible to the patients who need them.

Keywords: drug resistance tuberculosis, genetic determinant, intensive phase, Nigeria

Procedia PDF Downloads 256