Unraveling the mysteries of silver nanoparticles: synthesis, characterization, antimicrobial effects and uptake translocation in plant-a review.

MAIN CONCLUSION: The study thoroughly investigates nanosilver production, properties, and interactions, shedding light on its multifaceted applications. It underscores the importance of characterizing nanosilver for predicting its behavior in complex environments. Particularly, it highlights the agricultural and environmental ramifications of nanosilver uptake by plants. Nowadays, silver nanoparticles (AgNPs) are a very adaptable nanomaterial with many uses, particularly in antibacterial treatments and agricultural operations. Clarification of key elements of nanosilver, such as its synthesis and characterization procedures, antibacterial activity, and intricate interactions with plants, particularly those pertaining to uptake and translocation mechanisms, is the aim of this in-depth investigation. Nanosilver synthesis is a multifaceted process that includes a range of methodologies, including chemical, biological, and sustainable approaches that are also environmentally benign. This section provides a critical evaluation of these methods, considering their impacts on repeatability, scalability, and environmental impact. The physicochemical properties of nanosilver were determined by means of characterization procedures. This review highlights the significance of analytical approaches such as spectroscopy, microscopy, and other state-of the-art methods for fully characterizing nanosilver particles. Although grasp of these properties is necessary in order to predict the behavior and potential impacts of nanosilver in complex biological and environmental systems. The second half of this article delves into the intricate interactions that plants have with nanosilver, emphasizing the mechanisms of absorption and translocation. There are significant ramifications for agricultural and environmental problems from the uptake of nanosilver by plants and its subsequent passage through their tissues. In summary, by summarizing the state-of-the-art information in this field, this study offers a comprehensive overview of the production, characterization, antibacterial capabilities, and interactions of nanosilver with plants. This paper contributes to the ongoing conversation in nanotechnology.

Cross-Linked Alginate Dialdehyde/Chitosan Hydrogel Encompassing Curcumin-Loaded Bilosomes for Enhanced Wound Healing Activity.

The current study aimed to fabricate curcumin-loaded bilosomal hydrogel for topical wound healing purposes, hence alleviating the poor aqueous solubility and low oral bioavailability of curcumin. Bilosomes were fabricated via the thin film hydration technique using cholesterol, Span® 60, and two different types of bile salts (sodium deoxycholate or sodium cholate). Bilosomes were verified for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and in vitro drug release besides their morphological features. The optimum formulation was composed of cholesterol/Span® 60 (molar ratio 1:10 w/w) and 5 mg of sodium deoxycholate. This optimum formulation was composed of a PS of 246.25 ± 11.85 nm, PDI of 0.339 ± 0.030, ZP of -36.75 ± 0.14 mv, EE% of 93.32% ± 0.40, and the highest percent of drug released over three days (96.23% ± 0.02). The optimum bilosomal formulation was loaded into alginate dialdehyde/chitosan hydrogel cross-linked with calcium chloride. The loaded hydrogel was tested for its water uptake capacity, in vitro drug release, and in vivo studies on male Albino rats. The results showed that the loaded hydrogel possessed a high-water uptake percent at the four-week time point (729.50% ± 43.13) before it started to disintegrate gradually; in addition, it showed sustained drug release for five days (≈100%). In vivo animal testing and histopathological studies supported the superiority of the curcumin-loaded bilosomal hydrogel in wound healing compared to the curcumin dispersion and plain hydrogel, where there was a complete wound closure attained after the three-week period with a proper healing mechanism. Finally, it was concluded that curcumin-loaded bilosomal hydrogel offered a robust, efficient, and user-friendly dosage form for wound healing.

Management of Complete Persistent Rectal Prolapse in Children: A Comparative Study Between Mesh Repair Versus Suturing Rectopexy.

BACKGROUND: Rectal prolapse is a relatively common, usually self-limiting illness in children. Peak incidence is between 1 and 3 years. The primary treatment of rectal prolapse is non-operative. Surgical intervention is needed in long-standing intractable cases of rectal prolapse, rectal pain/bleeding/ulceration and prolapse that needs frequent manual or difficult reduction. The aim of this study was to compare the efficacy and outcome of laparoscopic ventral mesh rectopexy versus laparoscopic suture rectopexy in the management of persistent rectal prolapse in children not responding to conservative management and/or recurrent after sclerotherapy or anal encirclement. MATERIALS AND METHODS: Twenty-four cases were randomised into two groups at the ratio of 1:1, Group 1 patients were managed by laparoscopic ventral mesh rectopexy, whereas Group 2 cases were managed by laparoscopic suture rectopexy. Patients with primary surgical conditions such as anorectal malformations, Hirschsprung's disease, rectal polyps or masses and Ectopia Vesicae were excluded from the study. Inclusion criteria were complete rectal prolapse cases with failed medical treatment for at least 6 months and/or recurrent after injection sclerotherapy or anal encirclement. RESULTS: In the mesh rectopexy group, one case had recurrence in the form of partial prolapse 3 weeks postoperatively which improved 2 months postoperatively with conservative management, one case had bleeding per rectum 2 months postoperatively, stool analysis was done revealing parasitic infestation which was treated medically. In the suture rectopexy group, one case had one attack of bleeding per rectum on the 2nd day postoperatively which resolved spontaneously and one case was readmitted on the 5th day postoperatively for non-bilious vomiting which improved by medical treatment. No recurrent cases of complete rectal prolapse were reported in both groups. CONCLUSION: Laparoscopic rectopexy can be an effective modality for the treatment of refractory complete rectal prolapse in children. It is effective, safe and easy. Although the current study has shown that laparoscopic suture rectopexy and mesh rectopexy have nearly the same results, a larger number of patients are needed to compare more deeply between the two groups.

Primary hyperaldosteronism is associated with increased mortality and morbidity in patients with hypertension and diabetes.

Aims: Primary hyperaldosteronism (PA) is a common cause of hypertension. It is more prevalent in patients with diabetes. We assessed the cardiovascular impact of PA in patients with established hypertension and diabetes. Methods: Data from the National Inpatient Sample (2008-2016) was used to identify adults with PA with hypertension and diabetes comorbidities and then compared to non-PA patients. The primary outcome was in-hospital death. Secondary outcomes included ischemic stroke, hemorrhagic stroke, acute renal failure, atrial fibrillation, and acute heart failure. Results: A total of 48,434,503 patients with hypertension and diabetes were included in the analysis, of whom 12,850 (0.03%) were diagnosed with primary hyperaldosteronism (PA). Compared to patients with hypertension and diabetes but no PA, those with PA were more likely to be younger [63(13) vs. 67 (14), male (57.1% vs. 48.3%), and African-Americans (32% vs. 18.5%) (p<0.001 for all). PA was associated with a higher risk of mortality (adjusted OR 1.076 [1.076-1.077]), ischemic stroke [adjusted OR 1.049 (1.049-1.05)], hemorrhagic stroke [adjusted OR 1.05 (1.05-1.051)], acute renal failure [adjusted OR 1.058 (1.058-1.058)], acute heart failure [OR 1.104 (1.104-1.104)], and atrial fibrillation [adjusted OR 1.034 (1.033-1.034)]. As expected, older age and underlying cardiovascular disease were the strongest predictors of mortality. However, the female gender conferred protection [OR 0.889 (0.886-0.892]. Conclusion: Primary hyperaldosteronism in patients with hypertension and diabetes is associated with increased mortality and morbidity.

Medium-Term Outcomes of Antegrade Continent Enema (ACE): Cairo University Specialized Pediatric Hospital (CUSPH) Experience.

AIM OF THE STUDY: To assess the medium-term outcomes of ACE in children with fecal incontinence (FI). METHOD: Eligible children were recruited from the colorectal clinic between December 2016 and January 2020 and were followed prospectively for 2-6 years. A series of questionnaires were used to assess QOL, patients and parent satisfaction, and to assess the outcomes of the ACE. RESULT: 24 children aged 6-12 years (mean age 8.17 ± 1.95), including 18 males (75%) and 6 females (25% were studied. Cases included anorectal malformations (45.83%)., Hirschsprung disease (25%), neural tube defects (16.66%), sacrococcygeal teratoma (4.16%), and intractable pseudoincontinence (8.33%). QOL improved from (3) [3 -3] to (16) [16-16],p < 0.05. Fecal incontinence index showed significant improvement: 20 [20-20] versus 3 [0-4],p < 0.05. Bowel symptoms demonstrated improvement in the ability to decide when to pass stools and a decrease in soiling. Stooling survey showed lower scores representing better outcome. ACE questionnaire showed that the range of irrigation volumes used by parents is wide, and that all families recommend the ACE for children with similar condition. Postoperative complications were stenosis (16.66%), stomal prolapse (12.5%), leakage (4.16%), and false passage (4.16%). Satisfaction questionnaire showed a median score of 9 (range, 5-10). CONCLUSION: ACE is an effective method to keep the child with FI clean, more socially active, and with a better QOL and FII in the medium-term. The reported complications were stenosis, false passage, and leakage. ACE mucosa prolapse is a novel complication picked up on medium-term follow up.

Evaluation of Facial Esthetics Following NAM Versus CAD/NAM in Infants With Bilateral Cleft Lip and Palate: A Randomized Clinical Trial.

OBJECTIVE: The aim is to compare the facial esthetics following nasoalveolar molding (NAM) versus computer-aided design NAM (CAD/NAM) in patients with bilateral cleft lip/palate (CLP). DESIGN: The trial is a randomized comparative trial with a 1:1 allocation ratio. PARTICIPANTS: Thirty infants with bilateral complete cleft lip and palate were recruited. INTERVENTIONS: Patients were randomized between NAM and CAD/NAM groups. The treatment steps described by Grayson were followed for the NAM group. In the CAD/NAM group, digitized maxillary models were made to create a series of modified virtual models, which were used to fabricate the molding plates using 3-dimensional printing technology. The nasal stents were then added to the intraoral plates following the Grayson method. The study lasted for 4 months. MAIN OUTCOMES: The assessment of the changes observed in the interlabial gap and nasolabial esthetics was done using standardized 2-dimensional photographs. The correlation between dental arch changes and extraoral facial esthetics was studied. RESULTS: Both modalities showed improvement in nasolabial esthetics before the lip surgery. No statistically significant difference was found between NAM and CAD/NAM groups in any of the assessed variables. CONCLUSIONS: Both interventions were effective in the management of infants with bilateral CLP.

Investigating the bone regeneration activity of PVA nanofibers scaffolds loaded with simvastatin/chitosan nanoparticles in an induced bone defect rabbit model.

This study aims at preparing electrospun PVA NFs incorporating simvastatin/chitosan nanoparticles (SIM CS NPs) as a controlled drug eluting scaffold for bone regeneration. Optimization was performed by Design Expert® software through establishing two factor, three level factorial design, where the independent variables were the applied voltage, flow rate and PVA solution/SIM CS NPs ratio. Formulation variables values for the optimized formula were 18KV, 0.5 mL/h, and 3:1 respectively. NFs diameter and mesh pore size were chosen as the dependent variables. The optimized NFs were evaluated morphologically, chemically, and physically. Additionally, in-vitro SIM release from the scaffolds was investigated along 24 days. Optimum NFs possessed 136 nm diameter size and 6.5 nm porosity. Also, they showed sustained SIM release for 24 days to achieve the desired goal in bone regeneration. The optimized NFs were implanted within induced bone defects in rabbits. In-vivo assessments were performed through cone beam computed tomography 3D images, bone density measurements, histological analysis and bone morphogenetic protein 2 (BMP 2) level. The obtained results proved the high potential of the optimized NFs in promoting bone regeneration compared to untreated group, non-medicated NFs group, free SIM group and NFs loaded with SIM group after 6 weeks of implantation.

Accuracy of the Traditional COVID-19 Phone Triaging System and Phone Triage-Driven Deep Learning Model.

OBJECTIVES: During the COVID-19 pandemic, a quick and reliable phone-triage system is critical for early care and efficient distribution of hospital resources. The study aimed to assess the accuracy of the traditional phone-triage system and phone triage-driven deep learning model in the prediction of positive COVID-19 patients. SETTING: This is a retrospective study conducted at the family medicine department, Cairo University. METHODS: The study included a dataset of 943 suspected COVID-19 patients from the phone triage during the first wave of the pandemic. The accuracy of the phone triaging system was assessed. PCR-dependent and phone triage-driven deep learning model for automated classifications of natural human responses was conducted. RESULTS: Based on the RT-PCR results, we found that myalgia, fever, and contact with a case with respiratory symptoms had the highest sensitivity among the symptoms/ risk factors that were asked during the phone calls (86.3%, 77.5%, and 75.1%, respectively). While immunodeficiency, smoking, and loss of smell or taste had the highest specificity (96.9%, 83.6%, and 74.0%, respectively). The positive predictive value (PPV) of phone triage was 48.4%. The classification accuracy achieved by the deep learning model was 66%, while the PPV was 70.5%. CONCLUSION: Phone triage and deep learning models are feasible and convenient tools for screening COVID-19 patients. Using the deep learning models for symptoms screening will help to provide the proper medical care as early as possible for those at a higher risk of developing severe illness paving the way for a more efficient allocation of the scanty health resources.

Diagnosis of coronavirus disease 2019 and the potential role of deep learning: insights from the experience of Cairo University Hospitals.

OBJECTIVES: Early detection of coronavirus disease 2019 (COVID-19) is crucial for patients and public health to ensure pandemic control. We aimed to correlate clinical and laboratory data of patients with COVID-19 and their polymerase chain reaction (PCR) results and to assess the accuracy of a deep learning model in diagnosing COVID-19. METHODS: This was a retrospective study using an anonymized dataset of patients with suspected COVID-19. Only patients with a complete dataset were included (n = 440). A deep analytics framework and dual-modal approach for PCR-based classification was used, integrating symptoms and laboratory-based modalities. RESULTS: Participants with loss of smell or taste were two times more likely to have positive PCR results (odds ratio [OR] 1.86). Participants with neutropenia, high serum ferritin, or monocytosis were three, four, and five times more likely to have positive PCR results (OR 2.69, 4.18, 5.42, respectively). The rate of accuracy achieved using the deep learning framework was 78%, with sensitivity of 83.9% and specificity of 71.4%. CONCLUSION: Loss of smell or taste, neutropenia, monocytosis, and high serum ferritin should be routinely assessed with suspected COVID-19 infection. The use of deep learning for diagnosis is a promising tool that can be implemented in the primary care setting.

Laparoscopic inguinal hernia repair in bladder exstrophy, a new modified solution to an old problem: A cohort study.

PURPOSE: Open inguinal hernia repair in children with bladder exstrophy is challenging and associated with a high recurrence rate (15%-22%). We report our initial experience with laparoscopic repair of inguinal hernias in five children with repaired bladder exstrophy. This study is the third describing inguinal hernia repair in bladder exstrophy patients using the laparoscopic approach. In this study, we report a different laparoscopic technique. METHODS: This retrospective study was performed on data regarding laparoscopic inguinal hernia repair collected over one year (July 2019-2020). We carried out the laparoscopic inguinal hernia repair, closing the internal inguinal ring using a non-resorbable sliding knot suture and incorporating the transversalis fascia for reinforcement, followed by purse-string closure of the peritoneum. Peri- and postoperative outcome parameters, including recurrence rate, were evaluated over a follow-up period of 14 months. RESULTS: A total of seven male patients from July 2019 to 2020 were admitted to our center with a history of repaired bladder exstrophy and reducible inguinal hernias. Two patients had open inguinal hernia repair due to parental preference and five patients had laparoscopic repair. In the laparoscopic group three patients had bilateral inguinal hernias in one of them a metachronous hernia was discovered intraoperstively, and the remaining two patients had unilateral hernias, one on the right side and the other on the left side. All patients in the laparoscopic group had an uneventful recovery and were discharged within 24 h and there were no complications or recurrences during follow-up. CONCLUSION: Laparoscopic inguinal hernia repair is a better alternative to managing inguinal hernias in children with bladder exstrophy.

The efficacy and effectiveness of the COVID-19 vaccines in reducing infection, severity, hospitalization, and mortality: a systematic review.

With the relatively rapid development of the COVID-19 pandemic, vaccine development has become crucial for limiting disease transmission. The accelerated growth in the approved COVID-19 vaccines has sparked concerns about their efficacies which have been assessed by many studies. This systematic review compares the efficacy and effectiveness of seven COVID-19 vaccines. A comprehensive systematic literature search was performed using several databases to identify studies reporting the effectiveness or the efficacy of the vaccines. Only 42 studies met our inclusion criteria, which revealed that the COVID-19 vaccines have successfully reduced the rates of infections, severity, hospitalization, and mortality among the different populations. The full-dose regimen of the Pfizer/BioNTech vaccine is the most effective against infections with the B.1.1.7 and B.1.351 variants. Despite of the high effectiveness of some of the COVID-19 vaccines, more efforts are required to test their effectiveness against the other newly emerging variants.

Laparoscopic Resurrection of an Old Technique: A New Approach for Total Urogenital Separation and Rectal Pull-Through in Patients with Long Common Channel Cloacal Malformation.

Background and Aims: Before the significance of urethral length was highlighted in patients with cloacal malformation, total urogenital mobilization using a posterior sagittal approach was recommended for common channel (CC) length <3 cm, those >3 cm it was followed by urogenital separation. However, many urologists are advocating that the urethral length rather than length of the CC should influence the choice of operation. It is also recommended that total urogenital mobilization should be avoided in patients with short urethral length as intraoperative decision to shift to urogenital separation will risk devascularization of the urethra, advocating total urogenital separation (TUS) from the start; the later technique was deemed difficult using open approach. We describe our experience with laparoscopic TUS and rectal pull-through in patients with cloacal malformation. Methods: Six patients were operated for a period of 3 years from December 2017 to July 2021; they underwent laparoscopic TUS and rectal pull-through. Preoperative investigations included cystoscopy, genitogram, and MRI pelvis and abdominal ultrasound. IRB approval has been obtained from research ethical committee at Cairo University. Results: Six female patients born with single perineal opening had colostomy at birth. Age during the second operation ranged from 1 to 4 years. Length of the CC ranged between 2 and 5 cm. Proximal urethral length ranged between 0.5 and 1.5 cm and vaginal depth >3 cm. Average operative time was 4.25 hours. Postoperative period was 1-5 days and uneventful. On the long-term follow-up. No patient developed urethrovaginal fistula and one patient developed vaginal stenosis. All patients had no urinary problems, dry over 4-hour interval, voiding spontaneously, and had normal kidney functions. Conclusions: Laparoscopic urogenital separation, as well as vaginal and rectal pull-through for cloacal malformation, is feasible in cloacal malformation providing anatomical repair.

Neurological Immune-Related Adverse Events After COVID-19 Vaccination: A Systematic Review.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of individuals worldwide. The global scientific effort to design an effective vaccine against this virus has led to the development of several vaccine candidates. The expedited rollout of these vaccines has created some public distrust regarding the safety of these new vaccines. This review compiles clinical data from reports of diagnosed immune-related neurological events that have occurred after COVID-19 vaccine administration with the exception of those secondary to hematological abnormalities. A systematic literature search was performed, using several databases, to identify reports of postvaccination adverse neurological events. The search resulted in 18 studies that met our criteria. These studies included 61 patients who had received COVID-19 vaccines and experienced at least 1 neurological adverse effect. The most common neurological event was facial nerve palsy (50% of all events). Other less frequently reported events included the reactivation of herpes zoster, Guillain-Barre syndrome, other demyelinating diseases, and neuropathy. The underlying mechanism was hypothesized to be related to vaccine-induced type 1 interferon production leading to decreased tolerance of the myelin sheath antigens. Other hypotheses include vaccine-induced transient lymphopenia and immune dysregulation. Most of the reported events were time limited and resolved spontaneously. Given the rarity of reported neurological events compared to the total number of vaccines administered, and the similarity in the incidence of events between COVID-19 vaccines and other more common vaccines, there is little evidence to support a causal relationship between COVID-19 vaccines and adverse neurological events.

Different Curcumin-Loaded Delivery Systems for Wound Healing Applications: A Comprehensive Review.

Curcumin or turmeric is the active constituent of Curcuma longa L. It has marvelous medicinal applications in many diseases. When the skin integrity is compromised due to either acute or chronic wounds, the body initiates several steps leading to tissue healing and skin barrier function restoration. Curcumin has very strong antibacterial and antifungal activities with powerful wound healing ability owing to its antioxidant activity. Nevertheless, its poor oral bioavailability, low water solubility and rapid metabolism limit its medical use. Tailoring suitable drug delivery systems for carrying curcumin improves its pharmaceutical and pharmacological effects. This review summarizes the most recent reported curcumin-loaded delivery systems for wound healing purposes, chiefly hydrogels, films, wafers, and sponges. In addition, curcumin nanoformulations such as nanohydrogels, nanoparticles and nanofibers are also presented, which offer better solubility, bioavailability, and sustained release to augment curcumin wound healing effects through stimulating the different healing phases by the aid of the small carrier.

The phenotypic spectrum of dihydrolipoamide dehydrogenase deficiency in Saudi Arabia.

BACKGROUND: Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. MATERIALS AND METHODS: We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. RESULTS: Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. CONCLUSIONS: We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.

Repurposing of nifedipine loaded in situ ophthalmic gel as a novel approach for glaucoma treatment.

Glaucoma is a chronic eye disease characterized by elevated intraocular pressure (IOP) which causes severe complications to the eyes and may lead to vision loss. The effective treatment of such diseases motivated the search for novel and unique drugs and delivery systems. It has been reported that, nifedipine (NF) is effective in reducing the elevated IOP due to vasodilatation of eye vascular smooth muscles. NF loaded thermo-sensitive in situ gels were prepared by the cold method using poloxamer 407 (P407) and hydroxypropyl methyl cellulose (HPMC) polymers adopting Box-Behnken experimental design. All the prepared formulae were tested for homogeneity, clarity, pH, isotonicity, gelling capacity, rheological behavior, in vitro drug release and were tested in vivo on rabbits. The prepared in situ gels were homogenous, transparent, having a pH ranged from 5 to 5.5 and undergo sol-gel transition within few seconds physiological temperature. The in situ gels showed sustained in vitro release of NF where about 76% of the loaded drug was released over 12 h. NF loaded in situ gels showed a 45.83 ± 2.91% reduction in the IOP, with no sign of toxicity or irritation to the eye in rabbits. The current investigations clarified the efficiency of this novel and unique NF loaded in situ gel for the control of the IOP compared to the conventional ophthalmic dosage forms.

Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products.

BACKGROUND: FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing. RESEARCH DESIGN AND METHODS: We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed. RESULTS: NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular PolyoxTM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients. CONCLUSIONS: Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.

In Situ-Forming Microparticles for Controlled Release of Rivastigmine: In Vitro Optimization and In Vivo Evaluation.

In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.