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

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation

Shaimaa M Badr-Eldin,1,2 Osamaa AA Ahmed1,3 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia,&nbsp;Egypt Abstract: Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130&nbsp;nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (Cmax) and area under the curve and longer time to maxi&shy;mum plasma concentration (Tmax) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency. Keywords: sildenafil citrate, central composite design, transfersomes, edge activator, permeation, transdermal, pharmacokinetic

In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: formulation, characterization, and in vivo performance

Osama AA Ahmed,1,2 Shaimaa M Badr-Eldin1,3 1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt Background: Raloxifene hydrochloride (RLX) is approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis, in addition to reducing the risk of breast cancer in postmenopausal women. RLX has the disadvantages of low aqueous solubility, extensive presystemic intestinal glucuronidation, and first-pass metabolism, resulting in a limited bioavailability of only 2%. The aim of this work was to enhance the bioavailability of RLX via the formulation of an in situ nasal matrix (misemgel) comprising micelles made of vitamin E and D-&alpha;-tocopheryl polyethylene glycol 1000 succinate and nanosized self-emulsifying systems (NSEMS). Materials and methods: Optimization of the RLX-loaded NSEMS was performed using a mixture design. The formulations were characterized by particle size and then incorporated into an in situ nasal gel. Transmission electron microscopy, bovine nasal mucosa ex vivo permeation, and visualization using a fluorescence laser microscope were carried out on the RLX in situ misemgel comparing with raw RLX in situ gel. In addition, the in vivo performance was studied in rats. Results: The results revealed improved permeation parameters for RLX misemgel compared with control gel, with an enhancement factor of 2.4. In vivo studies revealed a 4.79- and 13.42-fold increased bioavailability for RLX in situ misemgel compared with control RLX in situ gel and commercially available tablets, respectively. The obtained results highlighted the efficacy of combining two different formulations to enhance drug delivery and the benefits of utilizing different possible paths for drug absorption. Conclusion: The developed in situ misemgel matrix could be considered as a promising multifunctional platform for nasal delivery which works based on a dual-absorption mechanism. Keywords: micelles, nanosized self-emulsifying systems, mixture design, fluorescence laser microscope, permeation, pharmacokinetic

Design and formulation of a topical hydrogel integrating lemongrass-loaded nanosponges with an enhanced antifungal effect: in vitro/in&nbsp;vivo&nbsp;evaluation

Hibah M Aldawsari,1 Shaimaa M Badr-Eldin,1,2 Gihan S Labib,1,3 Amal H El-Kamel3 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Abstract: Lemongrass oil (LGO) is a volatile oil extracted from the leaves of Cymbopogon citratus that has become one of the most important natural oils in the pharmaceutical industry because of its diverse pharmacologic and clinical effects. However, LGO suffers from low aqueous solubility, which could lead to a reduced effect. Moreover, the instability of its major active constituent, citral, could lead to volatilization, reaction with other formulation ingredients, and consequently, skin irritation. To surmount these problems, this research aims to formulate lemongrass-loaded ethyl cellulose nanosponges with a topical hydrogel with an enhanced antifungal effect and decreased irritation. The minimal inhibitory concentration and minimal fungicidal concentration of LGO against Candida albicans strain ATC 100231, determined using the broth macrodilution method, were found to be 2 and 8 &micro;L/mL, respectively. The emulsion solvent evaporation technique was used for the preparation of the nanosponges. The nanosponge dispersions were then integrated into carbopol hydrogels (0.4%). Nine formulations were prepared based on a 32 full factorial design employing the ethyl cellulose:polyvinyl alcohol ratio and stirring rate as independent variables. The prepared formulations were evaluated for particle size, citral content, and in vitro release. Results revealed that all the nanosponge dispersions were nanosized, with satisfactory citral content and sustained release profiles. Statistical analysis revealed that both ethyl cellulose:polyvinyl alcohol ratio and stirring rate have significant effects on particle size and percentage released after 6 hours; however, the effect of the stirring rate was more prominent on both responses. The selected hydrogel formulation, F9, was subjected to surface morphological investigations, using scanning and transmission electron microscopy, where results showed that the nanosponges possess a spherical uniform shape with a spongy structure, the integrity of which was not affected by integration into the hydrogel. Furthermore, the selected formulation, F9, was tested for skin irritation and antifungal activity against C. albicans, where results confirmed the nonirritancy and the effective antifungal activity of the prepared hydrogel. Keywords: Cymbopogon Citratus, Citral, Volatile oil, factorial design, ethyl cellulose, Candida albicans, ge

Optimized vinpocetine-loaded vitamin E D-&alpha;-tocopherol polyethylene glycol 1000 succinate-alpha lipoic acid micelles as a potential transdermal drug delivery system: in vitro and ex vivo studies

Osama AA Ahmed,1,2 Khalid M El-Say,1,3 Bader M Aljaeid,1 Shaimaa M Badr-Eldin,1,4 Tarek A Ahmed1,3 1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; 4Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt Background: Vinpocetine (VNP), a semisynthetic natural product, is used as a vasodilator for cerebrovascular and age-related memory disorders. VNP suffers from low oral bioavailability owing to its low water solubility and extensive first-pass metabolism. This work aimed at utilizing D-&alpha;-tocopherol polyethylene glycol 1000 succinate (TPGS) and alpha lipoic acid (ALA) to develop efficient micellar system for transdermal delivery of VNP. Materials and methods: VNP-TPGS-ALA micelles were prepared, characterized for particle size using particle size analyzer, and investigated for structure using transmission electron microscope. Optimization of VNP-TPGS-ALA micelles-loaded transdermal films was performed using Box&ndash;Behnken experimental design. The investigated factors were percentage of ALA in TPGS (X1), citral concentration (X2), and propylene glycol concentration (X3). Elongation percent (Y1), initial permeation after 2&nbsp;hours (Y2), and cumulative permeation after 24 hours (Y3) were studied as responses. Results: Statistical analysis revealed optimum levels of 16.62%, 3%, and 2.18% for X1, X2, and X3, respectively. Fluorescent laser microscopic visualization of skin penetration of the optimized transdermal film revealed marked widespread fluorescence intensity in skin tissue after 0.5, 2, and 4 hours compared with raw VNP transdermal film formulation, which indicated enhancement of VNP skin penetration. Conclusion: The obtained results highlighted the potentiality of VNP nanostructure-based films for controlling the transdermal permeation of the drug and improving its effectiveness. Keywords: bioavailability, box behnken design, citral, fluorescent laser microscope, nanostructured-based films, permeatio

Optimized Nanostructured Lipid Carriers Integrated into in situ Nasal Gel for Enhancing Brain Delivery of Flibanserin [Retraction]

Fahmy UA, Ahmed OAA, Badr-Eldin SM, et al. Int J Nanomedicine. 2020;15:5253-5264. The Editor and Publisher of International Journal of Nanomedicine are retracting the above published article. An investigation by the Publisher, found overlap in images from Figure 6 of the published article above and the images from Figure 6 of the following published article: Ahmed OAA, Fahmy UA, Badr-Eldin SM, et al. Application of Nanopharmaceutics for Flibanserin Brain Delivery Augmentation Via the Nasal Route. Nanomaterials. 2020; 10(7):1270 (https://doi.org/10.3390/nano10071270). Specifically, this included: From the published article above, Figure 6B, plain in situ gel group, and 6D, optimized FLB-NLC in situ gel group, are the same images as Figure 6D, rats treated with optimized FLB-TRF hydrogel (gp4) and 6C, rats treated with raw FLB loaded in hydrogel (gp3), respectively, from Ahmed et al, 2020. Furthermore, the images in Figure 6 of the published article above are derived from the same image but used to describe different results. Specifically, this included: From the published article above, Figure 6A, Control untreated group; 6B, plain in situ gel group; 6C, raw FLB loaded in situ gel group and 6D, optimized FLB-NLC in situ gel group, are all derived from the same image but used to describe different results. The authors cooperated with the investigation and provided data and associated documents concerning the histopathological experiments from the reported study. However, the Editor and Publisher determined that the evidence provided did not establish sufficient justification for the duplication. Therefore, the Editor and Publisher are retracting the article. The authors have agreed to retract the article and have informed the Publisher that the first author, Usama A Fahmy, takes responsibility for the error which occurred. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as &#x201C;Retracted&#x201D;