Versatility of hot-melt extrusion for dosage form design

Recently, Hot Melt Extrusion (HME) has attracted the attention of pharmaceutical companies and scientists as a technique for manufacturing a variety of dosage forms. In this research, HME was applied in different ways to achieve different goals, such as solubility enhancement, taste masking, solid state stability enhancement, and sustained release formulations for oral drug delivery, using one model drug, mefenamic acid. For solubility enhancement and taste masking formulations, Eudragit EPO was blended with MA in different ratios (20, 25, 30, and 40% of drug loads) and processed by a hot melt extruder to produce a solid dispersion system. FT-IR analysis suggested hydrogen bonding between the drug and the carrier up to 25% drug loading. SEM images indicated aggregation of MA at over 30% drug loading. Based on the FT-IR, SEM, and dissolution results for the extrudates, two optimized formulations (20% and 25% drug loads) were selected to formulate orally disintegrating tablets (ODTs). ODTs were successfully prepared with excellent friability and rapid disintegration time, in addition to the desired taste-masking effect. In chapter 3, HME was applied to enhance the solubility of class II drugs by making solid dispersion systems by mixing MA with hydrophilic polymers (polyvinylpyrrolidone, PVP) in different ways as follow: (1) to demonstrate the effect of polyvinylpyrrolidone (PVP) matrices on the release of the poorly water-soluble drug, MA was prepared using the hot-melt extrusion technique, (2) to investigate the effect of PEG as a plasticizer and swelling agent in dissolution studies, (3) to study the influence of MgO as an alkalizer on the modification of the microenvironmental pH of the matrices, and (4) to investigate the combined effect of PEG and MgO on the drug release behavior of the formulations. In addition, we have also studied the ability of HME techniques to produce sustained release formulations for oral drug delivery. Various drug loads of MA and Kollidon® SR as a polymeric carrier were blended and extruded using a twin-screw extruder (16-mm Prism EuroLab, ThermoFisher Scientific) to prepare a solid dispersion system. Thermal analyses were used to confirm thermal stability, miscibility and to select the optimum processing conditions for extrusion. Sustained release tablets were successfully prepared with excellent tablet characteristics of these formulations. The drug release from the 40% drug-loaded extrudate reached 20% within 2 hours and 80% within 12 hours, compared to more than 80% drug release of the corresponding physical mixture, and 100% of the pure drug and formulations with higher drug loads of 60% and 80% within 2 hours. Therefore, the drug release of MA was further retarded by increasing the concentration of this polymer, which indicates Kollidon® SR has a significant effect on MA sustained release formulations

Recent Progress in Lipid Nanoparticles for Cancer Theranostics: Opportunity and Challenges

Cancer is one of the major leading causes of mortality in the world. The implication of nanotherapeutics in cancer has garnered splendid attention owing to their capability to efficiently address various difficulties associated with conventional drug delivery systems such as non-specific biodistribution, poor efficacy, and the possibility of occurrence of multi-drug resistance. Amongst a plethora of nanocarriers for drugs, this review emphasized lipidic nanocarrier systems for delivering anticancer therapeutics because of their biocompatibility, safety, high drug loading and capability to simultaneously carrying imaging agent and ligands as well. Furthermore, to date, the lack of interaction between diagnosis and treatment has hampered the efforts of the nanotherapeutic approach alone to deal with cancer effectively. Therefore, a novel paradigm with concomitant imaging (with contrasting agents), targeting (with biomarkers), and anticancer agent being delivered in one lipidic nanocarrier system (as cancer theranostics) seems to be very promising in overcoming various hurdles in effective cancer treatment. The major obstacles that are supposed to be addressed by employing lipidic theranostic nanomedicine include nanomedicine reach to tumor cells, drug internalization in cancer cells for therapeutic intervention, off-site drug distribution, and uptake via the host immune system. A comprehensive account of recent research updates in the field of lipidic nanocarrier loaded with therapeutic and diagnostic agents is covered in the present article. Nevertheless, there are notable hurdles in the clinical translation of the lipidic theranostic nanomedicines, which are also highlighted in the present review along with plausible countermeasures.Peer reviewedFinal Published versio

Characteristics and anticancer properties of Sunitinib malate-loaded poly-lactic-co-glycolic acid nanoparticles against human colon cancer HT-29 cells lines

Purpose: To develop poly-lactic-co-glycolic acid (PLGA) -based nanoparticles (NPs) for the delivery of sunitinib malate (STM) to colon cancer cells.Methods: Three different formulations (F1 – F3) were developed by nano-precipitation technique using various concentrations of PLGA. The NPs were evaluated for particle size, polydispersity index, zeta potential, drug entrapment, and drug loading, using differential scanning calorimetry (DSC), Fouriertransform infrared spectroscopy (FTIR), x-ray diffraction (XRD), and scanning electron microscopy (SEM). Furthermore, in vitro drug release and anticancer studies were carried out on the formulations.Results: Among the three NPs, optimized NP (F3) of STM was chosen for in vitro anti-cancer study against H-29 human colon cancer cells lines based on its particle size (132.9 nm), PDI (0.115), zeta potential (-38.12 mV), entrapment efficiency (52.42 %), drug loading (5.24 %), and drug release (91.26 % in 48 h). A significant anti-cancer activity of the optimized NPs was observed, relative to free STM.Conclusion: These findings suggest that STM-loaded NPs possess significant anti-cancer activity against human colon cancer HT-29 cells lines.Keywords: Sunitinib malate, Poly-lactic-co-glycolic acid, Nanoparticles, Colon cance

Perceived Risk of falls among Acute Care Patients

Purpose: In an effort to lower the number of falls that occur among hospitalized patients, several facilities have begun introducing various fall prevention programs. However, the efficacy of fall prevention programs is diminished if patients do not consider themselves to be at risk for falls and do not follow recommended procedures. The goal of this study was to characterize how patients in four different acute care specialist services felt about their risk of falling while in the hospital. Methods: One hundred patients admitted to the study hospital with a Morse Fall Scale score of 45 or higher were given the Patient Perception Questionnaire, a tool designed to assess a patient's perception of their own fall risk, fear of falling, and motivation to take part in fall prevention efforts. Scores on the Morse Fall Scale were gathered through a historical assessment of medical records. Descriptive statistics, Pearson's correlation coefficients, and independent sample t tests were used to examine the data. Results: The average age was 65, and around half (52%) were men and half (48%) were women. Based on their ratings on the Morse Fall Scale, all 100 participants were classified as being at high risk for falls. However, only 55.5% of the individuals agreed with this assessment. The likelihood that a patient would seek assistance and the degree to which they feared falling both declined as their faith in their mobility improved. Patients hospitalized after a fall exhibited considerably lower confidence scores and greater fear scores than patients who had not been injured in a fall. Conclusions: Patients who have a high fall risk assessment score may not believe they are at risk for falls and may not take any steps to reduce their risk. The prevalence of falls in hospitals might be mitigated by the creation of a fall risk assessment technique that takes into account both objective and subjective factors

The need for national medical licensing examination in Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Medical education in Saudi Arabia is facing multiple challenges, including the rapid increase in the number of medical schools over a short period of time, the influx of foreign medical graduates to work in Saudi Arabia, the award of scholarships to hundreds of students to study medicine in various countries, and the absence of published national guidelines for minimal acceptable competencies of a medical graduate.</p> <p>Discussion</p> <p>We are arguing for the need for a Saudi national medical licensing examination that consists of two parts: Part I (Written) which tests the basic science and clinical knowledge and Part II (Objective Structured Clinical Examination) which tests the clinical skills and attitudes. We propose this examination to be mandated as a licensure requirement for practicing medicine in Saudi Arabia.</p> <p>Conclusion</p> <p>The driving and hindering forces as well as the strengths and weaknesses of implementing the licensing examination are discussed in details in this debate.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Experimental Design Based Optimization and Ex Vivo Permeation of Desmopressin Acetate Loaded Elastic Liposomes Using Rat Skin

The study aimed to develop elastic-liposome-based transdermal delivery of desmopressin acetate for enhanced permeation to control enuresis, central diabetes insipidus, and traumatic injury. Elastic liposomes (ELs)-loaded desmopressin acetate was prepared, optimized, and evaluated for improved transdermal permeation profiles using rat skin. Full factorial design with independent factors (X1 for lipid and X2 for surfactant) at three levels was used against four responses (Y1, Y2, Y3, and Y4) (dependent variables). Formulations were characterized for vesicle size, polydispersity index (PDI), zeta potential, % entrapment efficiency (% EE), in vitro drug release, in vitro hemolysis potential, ex vivo drug permeation and drug deposition (DD), and ex vivo vesicle–skin interaction using scanning electron microscopy studies. The optimized formulation ODEL1 based on desirability function was found to have vesicle size, % EE, % DR, and permeation flux values of 118.7 nm, 78.9%, 75.1%, and 5.3 µg/h·cm2, respectively, which were close to predicted values. In vitro release profiles indicated slow and sustained delivery. Permeation flux values of ODEL1 and ODEL2 were 5.3 and 3.1 µg/h·cm2, respectively, which are 7.5- and 4.4-fold higher as compared to DS (0.71 µg/h·cm2). The obtained flux was relatively higher than the clinical target value of the drug for therapeutic efficacy. Moreover, the DD value of ODEL1 was significantly higher than ODEL2 and DS. Hemocompatibility study confirmed safety concerns. Finally, vesicle–skin interaction corroborated mechanistic views of permeation through rat skin. Conclusively, the transdermal delivery may be a suitable alternative to oral and nasal delivery to treat nocturnal enuresis, central diabetes insipidus, hemophilia A and von Willebrand’s disease, and any traumatic injuries

Formulation of Piperine Ternary Inclusion Complex Using β CD and HPMC: Physicochemical Characterization, Molecular Docking, and Antimicrobial Testing

The present study was designed to evaluate the effect of hydroxyl propyl methyl cellulose (HPMC) on the complexation efficiency and dissolution of piperine (PPR) and &beta; cyclodextrin (&beta; CD) complex. The binary and ternary inclusion complexes were prepared using solvent evaporation and microwave irradiation methods. The samples were further evaluated for physicochemical evaluation, morphology, antimicrobial, and antioxidant activities. The binary and ternary samples showed high stability constant (Ks) value and complexation efficiency (CE). The dissolution study results revealed marked enhancement in the release of the binary inclusion complex and ternary inclusion complex compared to pure PPR. Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and molecular docking results confirm the complex formation. X-ray powder diffractometry (XRD) and scanning electron microscopy (SEM) data revealed modification in the structure of PPR. 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and antimicrobial results showed enhanced activity in the PPR complex in comparison to pure PPR. In conclusion, a remarkable enhancement in dissolution, antioxidant and antimicrobial activities were attained due to marked improvement in solubility through complexation of PPR with HPMC/&beta; CD

Luteolin-Loaded Elastic Liposomes for Transdermal Delivery to Control Breast Cancer: In Vitro and Ex Vivo Evaluations

The study aimed to prepare and optimize luteolin (LUT)-loaded transdermal elastic liposomes (LEL1-LEL12), followed by in vitro and ex vivo evaluations of their ability to control breast cancer. Various surfactants (Span 60, Span 80, and Brij 35), and phosphatidyl choline (PC) as a lipid, were used to tailor various formulation as dictated by “Design Expert® software (DOE). These were characterized for size, polydispersity index (PDI), and zeta potential. The optimized formulation (OLEL1) was selected for comparative investigations (in vitro and ex vivo) against lipo (conventional liposomes) and drug suspension (DS). Moreover, the in vitro anticancer activity of OLEL1 was compared against a control using MCF-7 cell lines. Preliminary selection of the suitable PC: surfactant ratio for formulations F1–F9 showed relative advantages of Span 80. DOE suggested two block factorial designs with four center points to identify the design space and significant factors. OLEL1 was the most robust with high functional desirability (0.95), minimum size (202 nm), relatively high drug release, increased drug entrapment (92%), and improved permeation rate (~3270 µg/cm2) as compared with liposomes (~1536 µg/cm2) over 24 h. OLEL1 exhibited a 6.2- to 2.9-fold increase in permeation rate as compared with DS (drug solution). The permeation flux values of OLEL1, and lipo were found to be 136.3, 64 and 24.3 µg/h/cm2, respectively. The drug disposition values were 670 µg, 473 µg and 148 µg, for OLEL1, lipo and DS, respectively. Thus, ex vivo parameters were significantly better for OLEL1 compared with lipo and DS which is attributed to the flexibility and deformability of the optimized formulation. Furthermore, OLEL1 was evaluated for anticancer activity and showed maximized inhibition as compared with DS. Thus, elastic liposomes may be a promising approach for improved transdermal delivery of luteolin, as well as enhancing its therapeutic efficacy in controlling breast cancer