Search

Precision medicine is an emerging healthcare delivery approach that considers variability between patients, such as genetic makeups, in contrast to the current one-size-fits-all approach that is designed to treat the average patient. The White House launched the Precision Medicine Initiative in 2015, starting an endeavor to reshape healthcare delivery. To translate the concept of precision medicine from the bench to practice, advanced manufacturing will play an integral part, including the fabrication of personalized drugs and drug delivery devices and drug screening platforms. These products are highly customized and require robust yet flexible manufacturing systems. The advanced manufacturing field has rapidly evolved in the past five years. In this state-of-the-art review, products manufactured for precision medicine will be introduced, followed by a brief review of processing materials and their characteristics. A review on different manufacturing processes applicable to those aforementioned products is provided. The current status of the development of regulatory submission and quality control considerations are also discussed. Finally, this paper presents a future outlook on manufacturing processes used for precision medicine.

Bariatric surgery has been increasingly becoming popular due to the advancements in minimally invasive approaches and techniques. The aim of this study was to compare the long-term outcomes and clinical relevance of laparoscopic sleeve gastrectomy (LSG) and laparoscopic greater curvature plication (LGCP) in a matched controlled single-bariatric centre study. We collected data from 163 patients who underwent either LSG or LGCP over a period of at least 5 years. The outcome parameters included body mass index (BMI) changes, causes of revision surgery, endoscopic findings and effects on obesity-related comorbidities. A total of 79 patients underwent LGCP, while 84 underwent LSG for morbid obesity. At the fifth year of follow-up, a BMI of

Surgical therapy for post-bariatric surgery complications is associated with significant morbidity and mortality. Endoscopic options like primarily endoscopically placed fully covered self-expandable metallic stents (SEMS) offer significant benefits for the management of leaks and obstructions or stenosis, and even in case of mega stent failure, further endoscopic techniques could resolve the situation. We conducted a single-centre retrospective study on patients with leakage and stenosis/obstruction after bariatric surgery who were managed primarily by SEMS between January 2015 and January 2019. Clinical success rate was evaluated in terms of the cure of the reason for stenting, the need for other interventions, and the presentation of stent-related complications. There were 58 patients included, (50 with leak, 8 with stenosis/obstruction following bariatric surgery). Mean time to stent placement was 6.82 (±1.64) days for the leak group and 35 (±21.13) days for the stenosis group (p = 0.019). Successful outcomes with SEMS alone were achieved in 42 (72.41%) patients, while 16 patients had failed SEMS treatment, of whom 14 were successfully managed by endoscopic procedures while two cases needed surgical intervention. Of the SEMS-related complications encountered, 25.86% were ulcers; 24.13%, vomiting; 22.41%, gastroesophageal reflux disease (GerdQ≥8); 18.96%, stent migration; and 5.17%, stent intolerance. A mega stent is an effective and safe tool for the early management of post-bariatric surgery leakage and stenosis, and it is associated with acceptable rates of failure that can be managed by further endoscopic techniques in most of the patients.

To highlight the use of robotic surgical system in live liver donor hepatectomy. Our early experience with 175 robotic donor hepatectomies showed that the procedure is safe, feasible, and reproducible in the hands of an experienced surgeon. The robotic surgical system has added more benefits to the minimal invasive surgery rather than laparoscopy; it offers better visualization, better ergonomics, better range of movements, and reduced physiological tremors. Moreover, the amplified 3D view with steady instrumental movements ensured meticulous tissue handling; this encouraged many transplant centers to use the technique in live liver donor hepatectomy. Here, in this review, we highlight the pre-requisites of robotic liver donor program and our early outcome in 175 liver donor hepatectomies.

Robotic right lobe donor hepatectomy (RRLDH) is rarely performed, and data concerning its safety and efficacy are lacking. Here we compare our series of RRLDHs with a similar cohort undergoing open right lobe donor hepatectomy (ORLDH) with a propensity score-matched (PSM) analysis. Among 263 consecutive adult patients undergoing right lobe living donor hepatectomy from January 2015 until July 2019, 35 RRLDHs were matched to 70 ORLDHs. A 1:2 PSM analysis was performed to make the groups comparable for donor sex, age, and body mass index (BMI) and for recipient sex, age, BMI, Model for End-Stage Liver Disease score, and indication for transplant. Operative time was longer in RRLDHs compared with ORLDHs (504 ± 73.5 versus 331 ± 65.1 minutes; P

Background: Breast surgery is one of the most difficultfields of aesthetic surgery, because of the complexity ofsurgical procedures and the relative guidelines defining theaesthetically perfect breast.The goal in reduction mammaplasty is to achieve a pleasingbalance among size, shape, and projection of the breast withoptimal sensation and appropriate blood supply for the nippleareolaand breast. These goals are challenged by the amountof excess tissue and severely distorted breast landmarks inmassive breast hypertrophy and severe breast ptosis.The traditional treatment for massive breast hypertrophyor severe breast ptosis is breast amputation with free graftingof the nipple-areola or inverted T, inferior pedicle used tohave a relatively high number of complications and thedisadvantage. On the other hand, relying on inverted T,superior-medial pedicle can avoid the disadvantage of theprevise techniques and give reliable, stable and pleasant resultsin large reduction mammoplasties.Patients and Methods: This is a prospective randomizedstudy that included 20 healthy female patients suffering frombreast hypertrophy and they are candidate for reductionmammoplasty by the proposed technique. Design of skinmarking for superior-medial pedicle breast reduction techniquewas carried out with the standard Wise pattern. The amountof removed tissue was recorded, the aesthetic result and patientsatisfaction was estimated for the results.Results: This study includes 20 female patients of an ageranged between 24-45 years old and a breast size (suprasternalnotch to nipple distance) ranging from 33 to 42cm. The weightof removed tissues during surgery in our study was rangingfrom 1210 to 1970. We found that 75% of our results are ofexcellent aesthetic results, 15% good and 10% fair with 70%of patients were satisfied, 20% of patients were somewhatsatisfied/somewhat dissatisfied and 10% of patients weredissatisfied.Conclusion: From this study we concluded that the keyholepattern with superior medial pedicle was an efficient techniquefor excising more tissue in large breasts with pleasant aestheticresults.

Living donation in many countries is the main resource of organs. Healthy, volunteering individuals deserve the highest safety standards possible in addition to the least invasive technique to procure the organs. Since the introduction of living donor liver transplantation, many efforts have been made to minimize the surgical trauma inherent to living donor surgery. The journey started with a large Mercedes incision and evolved to a reverse L-shaped and small upper midline incisions before the introduction of minimally-invasive laparoscopic techniques originated. The technical difficulties of the laparoscopic approach due to suboptimal instrumentation, challenging ergonomics, and the long learning curve limited the application of the fully laparoscopic approach to a few centers. The recent introduction of the robotic platform with its superb optical system and advanced instruments allows for the first time, a genuine emulation of open donor surgery in a closed abdomen, thus allowing all liver donors to benefit from minimally-invasive surgery ([MIS], better cosmesis, less pain and morbidity, better quality of life) without compromising donor safety. This attribute in combination with the ubiquitous presence of the robot in major transplant centers, may well lead to the desired endpoint of this technology, namely, the widespread dissemination of minimally invasive donor surgery.

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6–11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety.

The concept of dual-graft liver transplantation was introduced to overcome the discrepancy between liver transplantation demand and liver donation. Dual-graft transplantation also mitigates cumulative family risk by decreasing individual donor risk through minimization of the resected liver volume from each donor. Here, we describe the first two cases performed in Saudi Arabia wherein a dual-graft living donor liver transplantation was facilitated by the use of one left lobe graft and one left lateral segment in both cases. These are the first two cases of dual-graft liver transplantation reported from Saudi Arabia and the Middle East. SIMILAR CASES PUBLISHED: Nine on the same subject in other parts of the world (Korea, Japan, Germany, China, and Brazil).

BACKGROUND There are still controversies in using the large left lateral segment in pediatrics LT, with the possibility of the problem of LFS grafts, and the use of monosegmental or reduced liver grafts in small infants. This study aimed to evaluate our experience with LFSG in pediatrics LT. METHODS A cohort retrospective analysis was conducted including pediatric recipients who underwent LT between January 2011 and October 2019. We compared recipients with GRWR ≥ 4% (LFS) vs GRWR

Physical breast phantoms can be used to evaluate x-ray imaging systems such as mammography, digital breast tomosynthesis and dedicated breast computed tomography (bCT). These phantoms typically attempt to mimic x-ray attenuation properties of adipose and fibroglandular tissues within the breast. In order to use these phantoms for task-based objective assessment of image quality, relevant diagnostic features should be modeled within the phantom, such as mass lesions and/or microcalcifications. Evaluating imaging system performance in detecting microcalcifications is of particular interest due to its' clinical significance. Many previously-developed phantoms have used materials that model microcalcifications using unrealistic chemical composition, which do not accurately portray their desired x-ray attenuation and scatter properties. We report here on a new method for developing real microcalcification simulants that can be embedded in breast phantoms. This was achieved in several steps, including cross-linking hydroxyapatite and calcium oxalate powders with a binder called polyvinylpyrrolidone (PVP), and mechanical compression. The fabricated microcalcifications were evaluated by measuring their x-ray attenuation and scatter properties using x-ray spectroscopy and x-ray diffraction systems, respectively, and were demonstrated with x-ray mammography and bCT images. Results suggest that using these microcalcification models will make breast phantoms more realistic for use in evaluating task-based detection performance of the abovementioned breast imaging techniques, and bode well for extending their use to spectral imaging and x-ray coherent scatter computed tomography.

This case report describes the first ex situ full-right/full-left splitting of a liver from a pediatric deceased donor in the Middle East with an excellent outcome for both recipients. The left lateral split-liver transplant requires division of the deceased donor liver into a left lateral lobe for a pediatric recipient and an extended right lobe for an adult recipient, thus producing only 1 graft for a pediatric recipient. Full-right/full-left liver transplant, which splits the liver along the line of Cantlie, is a much more complex and challenging surgery, even though the technique is fully developed, and is theoretically able to produce 2 sizeable grafts for 2 pediatric recipients. However, the full-right/full-left liver transplant remains limited because of the small vascular structures and therefore was not recommended and was not previously described in the literature.

Drug release from microparticle-based topical gels may affect their bioavailability, safety and efficacy. This work sought to elucidate spatial distribution of the drug within the microparticle matrix and how this impacts the product's critical performance attributes. The purpose of this research was to inform the development of in vitro characterization approaches to support a demonstration of bioequivalence. Drug-free microparticles were loaded with tretinoin or drug-loaded microparticles were separated from purchased Retin-A Micro® (tretinoin) topical gel drug products. The resultant microparticles were analyzed for tretinoin content, drug loading efficiency, morphology, surface topography, surface pore size distribution, particle size distribution and tretinoin release. The solid-state characteristics and chemical interaction of tretinoin with the microparticles were also investigated. Microparticles loaded with tretinoin made in-house and those separated from Retin-A Micro® (tretinoin) topical gel were spherical, polydisperse and free of aggregates. The surface porosity of the microparticles was ∼19.8% with an average pore size of ∼327 nm. Microparticles loaded with tretinoin in-house were smaller in size and exhibited faster drug release than those separated from Retin-A Micro® (tretinoin) topical gel. Tretinoin release was found to increase with an increase in the drug loading. Based on XRD and DSC data, tretinoin was present in an amorphous state. The FTIR spectra indicated a disappearance of carbonyl band of microparticles and shifting of the hydroxyl band of tretinoin due to hydrogen bonding. The extent of drug loading and the solid-state interaction of tretinoin with the microparticles may be critical for drug release. Additional characterization of the drug products is necessary to understand the effect of the factors examined in this work on the bioavailability and efficacy of tretinoin gels.

Background The coupling of increased life expectancy and improvements in both quality and access to chronic liver disease care, is culminating in an expanding population of septuagenarians (≥ 70 years) in need of liver transplantation (LT). The objective of this study is to partially alleviate this knowledge deficit and to add clarity to the current status and role of LDLT in this recipient population. Methods 295 adult patients underwent LDLT between January 1, 2011 and December 31, 2016. Twelve (4%) of these patients were septuagenarians and this group was compared to younger cohort (n=283) . Results Comorbidity profiles between the two groups were similar and no statistically significant differences were noted in warm/cold ischemia times, operative duration, or blood product utilization. ICU and total hospital stays were comparable. Septuagenarian 1-and 5-year graft and patient survivals were identical at 91.7%. Their younger counterparts had 1-and 5-year patient survivals of 91.1% and 84.0 % accompanied by 1-and 5-year graft survivals of 89.8% and 82.7%, respectively. Conclusion our study highlights a recognition that LDLT can afford highly-selected elderly patients to access to transplant with equivalent outcomes to those realized by younger recipients.

3D printing, and particularly fused deposition modeling (FDM), has rapidly brought the possibility of personalizing drug therapies to the forefront of pharmaceutical research and media attention. Applications for this technology, described in published articles, are expected to grow significantly in 2020. Where are we on this path, and what needs to be done to develop a FDM 2.0 process and make personalized medicines available to patients? Based on literature analysis, this manuscript aims to answer these questions and highlight the critical technical aspects of FDM as an emerging technology for manufacturing safe, high-quality personalized oral drug products. In this collaborative paper, experts from different fields contribute strategies for ensuring the quality of starting materials and discuss the design phase, printer hardware and software, the process, the environment and the resulting products, from the perspectives of both patients and operators.

Background. There is a growing interest in left lateral sectionectomy for donor hepatectomy. No data are available concerning the safety of the robotic (ROB) approach. Methods. A retrospective comparative study was conducted on 75 consecutive minimally invasive donor hepatectomies. The first 25 ROB procedures performed from November 2018 to July 2019 were compared with our first (LAP1) and last 25 (LAP2) laparoscopic cases performed between May 2013 and October 2018. Short-term donors and recipients' outcomes were analyzed. Results. No conversions were noticed in ROB whereas 2 conversions (8%) were recorded in LAP1 and none in LAP2. Blood loss was significantly less in ROB compared with LAP1 (P ≤ 0.001) but not in LAP2. Warm ischemia time was longer in ROB (P ≤ 0.001) with respect to the other groups. Operative time was similar in the 3 groups (P = 0.080); however, the hospital stay was shorter in ROB (P = 0.048). The trend in operative time in ROB was significantly shorter compared to LAP1 and LAP2: linear R20.478, P≤0.001; R20.012, P = 0.596; R30.004, P = 0.772, respectively. Donor morbidity was nihil in ROB, similar in LAP1 and LAP2 (n=3%-12%; P = 0.196). ROB procedures required less postoperative analgesia (P = 0.002). Recipient complications were similar for all groups (P = 0.274), and no early retransplantations were recorded. Conclusions. Robotic left lateral sectionectomy for donor hepatectomy is a safe procedure with results comparable to the laparoscopy in terms of donor morbidity and overall recipients' outcome when the procedure is performed by experts. Certainly, its use is currently very limited.

To understand effects of formulation variables on the critical quality attributes (CQA) of acyclovir topical cream, this study investigated effects of propylene glycol (PG), poloxamer, and sodium lauryl sulfate (SLS) concentrations, acyclovir particle size, and formulation pH of the acyclovir cream. Fifteen formulations were prepared and characterized for rheological properties, particle size distribution, drug release and in vitro skin permeation. Drug distribution between various phases of the cream was determined. The concentration of soluble acyclovir in the aqueous phase was determined as a surrogate of the equilibrium with other acyclovir species in the cream. The interaction among effects of the formulation variables on the amount of acyclovir retained by skin was also evaluated. The results showed that PG significantly (p 0.05) increased the yield stress, viscosity, drug concentration in the aqueous phase, and drug release. The PG and SLS significantly (p 0.05) increased acyclovir retention by skin samples. Particle size of acyclovir inversely affected the drug release. This study revealed that the employed concentrations of PG and SLS and particle size of the dispersed acyclovir are critical formulation variables that should be carefully controlled when developing acyclovir topical creams with desired performance characteristics.

The variation in the critical formulation variables during life-cycle of the drug product may result in undesirable changes in product performance. The current study aimed at evaluating the effects of formulation variables on the in vitro performance of carbopol-loaded testosterone gel. The formulation variables included concentrations of permeation enhancers, testosterone, ethanol, carbopol and sodium hydroxide. In vitro evaluation of the product performance included assessment of the rheological and morphological properties, kinetics of ethanol evaporation, and drug permeation through human cadaver skin. The results revealed that carbopol, sodium hydroxide and testosterone concentrations increased the viscosity of the gels significantly (p 0.05). However, carbopol concentration was the only critical variable to affect the yield stress of the gel. The concentration of ethanol was critical to metamorphosis of the gel due to solvent evaporation upon application to skin with minor contributions from other formulation variables. The increase in concentration of isopropyl myristate or isopropyl palmitate to 5%, ethanol to 70%, and testosterone to 2%, enhanced the testosterone permeation across the skin by ten-folds. Synergistic effects of ethanol and permeation enhancers on testosterone permeation was observed. In conclusion, strict control over the critical formulation variables should be exercised during manufacturing to ensure desired product performance.

The current study investigated the use of synthetic membranes in developing a bio-predictive in vitro permeation testing (IVPT) method for 1.62% testosterone gel. The IVPT studies were carried out using both Franz (FC), and Flow-through (FTC) diffusion cells. The experimental variables included the type of synthetic membranes (hydrophilic polyamide nylon, polysulfone tuffryn and STRAT-M (SM) membrane) and the type of receiver media (phosphate buffer containing various concentrations of sodium lauryl sulfate). In vivo drug release rates were obtained from published reports for 1.62% testosterone gel applied to either abdominal area (treatment group A), upper arms/shoulders (treatment group B), or alternating between abdomen and arms/shoulders (treatment group C). The in vitro-in vivo correlations were established using GastroPlus software. The best IVPT method was selected based on establishing point-to-point correlation with the in vivo data of treatment group A with minimal prediction errors (%PE) of AUC0-24 and Cmax. The results showed that the IVPT method which employed the FTC diffusion system, SM membrane and phosphate buffer without surfactant established the best IVIVR model with a correlation coefficient (R2) of 0.9966 and an exponential function of Y = (1.35)5 × X3.6. The in vivo data obtained from treatment group A and B was used for internal validation of the prediction model. The validation data was acceptable, with %PE of less than 10% for both AUC0-24 and Cmax. In conclusion, these results suggest that bio-predictive IVPT methods for testosterone gels may be developed using synthetic membranes and diffusion apparatus by varying the composition of the receiver medium.

Background The Model for End-Stage Liver Disease (MELD) score is a well-established tool for assessing hepatic failure. The present retrospective study investigated whether serum keratin 18 (M65) and caspase-cleaved cytokeratin (M30) were associated with liver dysfunction and post-transplant graft failure. Material/Methods A total of 147 patients with liver cirrhosis were categorized into 2 groups according to their baseline MELD score (group I: MELD score 1 year (p=0.004). In the regression analysis, serum M30 was associated with the MELD score (odds ratio [OR]=2.545, p=0.005), serum bilirubin (OR=2.605, p=0.005) and 1-year graft loss (OR=3.61, p=0.006). Conclusions Our data indicate that serum M30 levels reflect the degree of liver dysfunction and can predict 1-year graft loss.

The aim of the present study was to investigate association of serum amino (AA) acids and metabolites of AAs with post-transplant outcome in liver transplant recipients. Eighty-nine patients with end-stage liver diseases and available pre- and early post-transplant serum were characterised as patients with (GI) and without one-year mortality (GII) and patients with and without early graft dysfunction (EAD). A panel of pre- and early post-transplant serum levels of AAs and early and metabolites of tryptophan were measured using tandem mass spectrometry. Patient groups had significantly higher pre-transplant serum levels of phenylalanine, tryptophan, and tryptophan metabolites than healthy controls (for all p

The objective of the present study was to investigate the effect of isopropyl myristate (IPM) on the in vitro permeation of testosterone through human cadaver skin from carbopol gels. Six testosterone gel formulations were prepared using different IPM contents of 0%, 0.4%, 0.7%, 1%, 2%, and 3%. The gels were characterized for drug permeation, matrix morphology, pH, kinetics of ethanol evaporation, and viscosity. Mass balance studies were performed to estimate testosterone distribution among the compartments of diffusion cells. All formulations exhibited pH values of 5.1 and viscosities of 1.25-1.75 Pa.s depending on IPM contents. Under occlusive condition, testosterone flux was found to increase significantly (p < 0.05) by increasing IPM content. Gels containing 2% IPM exhibited 11-fold increase in flux compared with formulation devoid of IPM. Ethanol was found to have a synergistic effect with IPM in enhancing testosterone flux. Mass balance analysis showed that testosterone was in a saturated state in the skin. Conducting permeation experiments under nonocclusive condition was nondiscriminating because of the evaporation of alcohol and consequent precipitation of drugs. Based on demonstrated effect of IPM on product performance, the final IPM concentration should be controlled with minimal variation during manufacturing and shelf life of drug product.

Dermal drug delivery system which localizes methotrexate (MTX) in the skin is advantageous in topical treatment of psoriasis. The aim of the current study was to understand dilution effects and formulation variability for the potential formation of niosomes from proniosome gels of MTX. Box–Behnken’s design was employed to prepare a series of MTX proniosome gels of Span 40, cholesterol (Chol-X1) and Tween 20 (T20-X2). Short chain alcohols (X3), namely ethanol (Et), propylene glycol (Pg) and glycerol (G) were evaluated for their dilution effects on proniosomes. The responses investigated were niosomal vesicles size (Y1), MTX entrapment efficiency percent (EE%-Y2) and zeta potential (Y3). MTX loaded niosomes were formed immediately upon hydration of the proniosome gels with the employed solvents. Addition of Pg resulted in a decrease of vesicular size from 534 nm to 420 nm as Chol percentage increased from 10% to 30%, respectively. In addition, increasing the hydrophilicity of the employed solvents w...

Objectives Liver retransplant is considered the only hope for patients with irreversible graft failure after primary transplant. In most Western centers, retransplantis done mainly from deceased donors; so far, only few published studies have reported on outcomes of liver retransplant with living donors. In this study, our aim was to analyze the outcomes of living-donor liver retransplant. Materials and methods Patients who underwent liver retransplant between February 2011 and February 2019 were included in the study. Preoperative, operative, and postoperative data were analyzed. Results from 2 patient groups were compared: liver retransplant with living donors and liver retransplant with deceased donors. Results Thirty-two patients underwent liver retransplant (21 adult and 11 pediatric patients). The most common indications for liver retransplant were hepatic artery thrombosis (28.5%) and primary graft nonfunction (23.8%) in adults and hepatic artery thrombosis (45.5%) and chronic rejection (36.4%) in pediatric patients. Seventeen retransplant patients (53.1%) required early retransplant (within 1 mo), mainly due to hepatic artery thrombosis (52.9%) and primary graft nonfunction (35.3%). Late retransplant was mainly due to chronic rejection (40%) and recurrence of primary disease (26.7%). Seventeen patients (53.1%) underwent living-donor retransplant, and 5 donors underwent robotic right hepatectomy. Graft and patient survival rates at 1, 3, and 5 years were 81.3% for living-donor and 51.4% for deceased-donor liver retransplant recipients (P = .08). On multivariate analyses, we observed significant differences between both groups in pretransplant Model for End-Stage Liver Disease and Pediatric End-Stage Liver Disease scores (P = .05), preoperative international normalized ratio (P = .012), and cold ischemia time (P = .046). Conclusions The use of living donors for liver retransplant, despite its technical demand, was shown to be a safe and feasible option, especially when there is scarcity of deceased donors.

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106–500 μm) and coarse (500–1000 μm) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3–5 kDa to 12–14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.

Pseudoephedrine (PSE) extracted from its dosage forms can be used as the starting material to prepare methamphetamine by drug abusers. Recently, some pseudoephedrine drug products marketed under the over the counter (OTC) monograph have been promoted as ‘meth-deterrent’. The goal of this investigation was to evaluate the extraction and dissolution of these product against controls of non-meth-deterrent products of pseudoephedrine. Immediate release (IR) PSE OTC Product-C, Product-D and Product-E with meth-deterrent claim on their packaging were selected for this study. Accordingly, OTC IR PSE tablet Product-A and OTC extended release (ER) PSE tablet Product-B, with no meth-deterrent claims, were used as controls. The extraction studies were performed on intact tablets or capsules and on manipulated products employing water, ethanol and 0.l N HCl as solvents. The extraction studies were also performed in water at elevated temperatures by heating the water in an oven and in a microwave. The dissolution studies were performed in water and 0.1 N HCl. The amount of PSE extracted from Product-C was found similar to the amount extracted from the non-meth-deterrent control Product-A. The amount of PSE extracted from Product-D and Product-E was found lower than the amount extracted from control Product-A under the conditions studied. Product-A, Product-B, and Product-C met their respective dissolution acceptance criteria. The IR Products D and E released less than 50% drug in 12 h and did not meet either IR or ER PSE tablet USP dissolution acceptance criteria. In summary, the extraction of Product-C was found to be high (approximately 85% in 30 min) and was similar in extraction to the control Product-A. The extraction of Product-D and Product-E was found less than the extraction of control Product-A. Also, Product-D and Product-E did not exhibit complete drug release. This study showed that PSE can be extracted from Product D and Product E.

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.

Spray dried dispersions (SDDs) have the potential to dramatically improve the oral bioavailability of drugs with poor water solubility. However, SDDs tend to have material attributes, such as small particle size, low bulk density, and poor flowability, which are undesirable for downstream processing such as tableting. The objective was to perform a comprehensive compaction characterization of both physical mixtures and SDDs consisting of itraconazole (ITZ) and hypromellose acetate succinate (HPMCAS) to elucidate process and material influences on compressibility and compactibility. We fabricated SDDs with 20% ITZ as a model BCS Class 2 drug and 80% HPMCAS as a polymer carrier. Results indicate that SDDs, as well physical mixtures of ITZ and HPMCAS, were easily deformable with similar compressibility profiles across all compression speeds. Analysis of Heckel plots revealed that yield pressures were fairly low for both physical mixtures and SDDs (43.97-59.75 MPa), indicative of ductile materials. SDDs had a much greater propensity to laminate, especially at higher compression speeds, compared to physical mixtures. This difference is likely due to the higher elastic recovery of SDDs. However, for intact tablets, the mechanical strength of compacts from SDDs tended to be higher than those produced from physical mixtures, likely due to the much smaller particle size of the SDDs. Importantly, examination of the compacts with differential scanning calorimetry did not detect any drug crystallization as a result of compaction. In conclusion, while spray drying did not significantly alter the compressibility of binary mixtures ITZ and HPMCAS, it dramatically impacted compactibility and tabletability, increasing elastic recovery, and making the mixtures more prone to lamination. However, at low compression speeds, SDDs produced tablets with higher tensile strength than physical mixtures.

Study of mixing and segregation of granular materials was performed in a Bohle bin blender using both computational modeling and experiments. A multicomponent mixture of pharmaceutical excipients and coated theophylline granules, an active pharmaceutical ingredient (API) was considered as the blend formulation. A DEM (Discrete Element Method) Model was developed to simulate the flow and mixing of the multicomponent blend to compare with the experimental data. DEM is a numerical modeling technique which incorporates all the material properties (such as Particle size, density, elastic modulus, yield strength, Poisson’s ratio, work function etc.) to simulate granular flow (such as mixing, conveying) of particles. In simulation, the degree (Relative standard deviation) of mixing in a Bohle bin blender was assessed as a function of critical processing parameters (loading pattern, rotational rate, and fill percentage). Numerical simulation results reveal radial mixing in a Bohle bin blender is faster than axial mixing due to symmetric geometry limitation. This study investigates a numerical model-based approach to study the effect of the critical process parameters on the mixing dynamics in Bohle bin blender for a moderately cohesive pharmaceutical formulation. The DEM model can be used to provide crucial insights to developed optimized mixing protocols to ascertain the best mixing conditions for different formulation. As for example, as we try to develop a mixing protocol for another formulation with different operational parameters such as loading pattern, rotational speed, and fill percentage, one can device an optimized mixing protocol of the formulation with the help of this DEM model.

This study investigated the effects of drug recrystallization on the in vitro performance of testosterone drug-in-adhesive transdermal delivery system (TDS). Six formulations were prepared with a range of dry drug loading in the adhesive matrix from 1% to 10% w/w with the aim of generating TDS with various levels of drug crystals. We visually quantified the amount of crystals in TDS by polarized light microscopy. The effect of drug recrystallization on adhesion, tackiness, cohesive strength, viscoelasticity, drug release, and drug permeation through human cadaver skin were evaluated for these TDS samples. The Optical images showed no crystals in 1% and 2% testosterone TDSs; however, the amount of crystals increased by increasing testosterone loading from 4 to 10%. A proportional and significant decrease (p 0.05) in tack, peel, and shear strength of the adhesive matrix with increasing amount of crystals in TDS was observed. The drug crystals resulted in a proportional deterioration of the viscoelastic properties of the adhesive matrix. The 2% testosterone TDS showed faster drug release rate when compared to 1% testosterone TDS. The increase in drug loading from 2% to 4% w/w slightly increased the cumulative amount of testosterone released. Further increase in drug loading in TDS to 6, 8, and 10% was nonsignificant (p 0.05) to affect the drug release and permeation. In conclusion, this study demonstrated that the extent of drug recrystallization can be quantitatively correlated with the deterioration of performance characteristics of TDS products.

The rheological characteristics of pastes for 3D printing of tablets may not be described fully by the traditional rheological tests generally used for other pastes. In the present study, extrudability testing of carbopol based 3D printing pastes was performed to establish a constitutive rheological model for micro-extrusion. This model was developed for pastes that exhibit a non-linear plasto-viscoelastic behavior and follow the generalized Herschel–Bulkley flow rule. An analytical model was applied to extrudability data obtained by micro-extrusion through nozzles of 0.4 and 0.6 mm diameters. For this purpose, nineteen pastes were prepared per a fractional factorial design using various concentrations of the active ingredient and soluble and insoluble excipients. Critical material parameters (σ0, k and n) of the pastes were then calculated by analyzing extrudability data using a constitutive equation relating flow rate, nozzle and cartridge diameters, printing pressure and slip-flow angle. The accuracy of the constitutive model to predict paste yield stress, consistency and flow indices was evident by low RMSE values of 0.0691 bar, 0.034 and 6.3 bar/sn, respectively. Yield stress, flow and consistency parameters of the pastes were significantly affected by percentages of soluble and swellable excipients. The nozzle diameter had significant effect on flow index (n) but not on the consistency index (k). Hence, this study provides a mechanistic model to characterize the complex rheological behavior of pastes for 3D printing of tablets by a micro-extrusion process.

The future of pharmaceutical manufacturing may be significantly transformed by 3-dimensional (3D) printing. As an emerging technology, the indicators of quality for materials and processes used in 3D printing have not been fully established. The objective of this study was to identify the critical material attributes of semisolid paste formulations filled into cartridges for 3D printing of personalized medicine. Nineteen semisolid formulations were prepared per a fractional factorial design with three replicates of the center point. The variables investigated included percent loading of API and various soluble and insoluble excipients. Pastes were characterized for viscoelastic characteristics during the 3D printing process including creep recovery, cross-modulus and extrudability models. Packing efficiency of pastes into 3D printing cartridges was also evaluated by X-ray tomography. Changes in composition of 3D printing pastes resulted in significant variations in their viscoelastic parameters, namely their elastic deformation, flow and relaxation behaviors. The percent of soluble excipients incorporated was the most significant factor affecting the creep behavior of pastes. Cross-over stresses were assessed to indicate the minimum pressure needed for the pastes to initiate flow. Increasing solid and swellable contents of the pastes from 7% to 63% w/w increased significantly (p 0.05) the cross-over stress from 0.93 × 10

The potential of dual-energy mammography for microcalcification classification was investigated with simulation and phantom studies. Classification of type I/II calcifications was performed using the tissue attenuation ratio as a performance metric. The simulation and phantom studies were carried out using breast phantoms of 50% fibroglandular and 50% adipose tissue composition and thicknessess ranging from 3 to 6 cm. The phantoms included models of microcalcifications ranging in size between 200 and 900 μ m . The simulation study was carried out with fixed MGD of 1.5 mGy using various low- and high-kVp spectra, aluminum filtration thicknesses, and exposure distribution ratios to predict an optimized imaging protocol for the phantom study. Attenuation ratio values were calculated for microcalcification signals of different types at two different voltage settings. ROC analysis showed that classification performance as indicated by the area under the ROC curve was always greater than 0.95 for 1.5 mGy deposited mean glandular dose. This study provides encouraging first results in classifying malignant and benign microcalcifications based solely on dual-energy mammography images.

The objective of the current study was to optimize for the first time the formulation variables of self-emulsified drug delivery system (SEDDS) based on drug solubilization during lipolysis under a biorelevant condition of digestion such as lipase activity, temperature, pH, fed-fasting state, etc. Nimodipine (ND), a BCS class II, was used as a model drug to prepare the SEDDS. Various oils, surfactants, and cosurfactants were screened for their solubilization potential of ND. Area of self-emulsification was identified using various ternary phase diagrams. Box-Behnken design was employed to investigate effects of formulation variables on various dispersion, emulsification, and lipolysis characteristics of SEDDS. Among 26 candidate formulations, highest ND solubility of 12.72%, 11.09% and 11.2% w/w were obtained in peppermint oil as the oily phase, Cremphor EL as the surfactant and PEG400 as the cosurfactant, respectively. Cremphor EL was the most significant factor to decrease SEDDS droplet size to 30.16 nm. On the other hand, increasing the oil concentration was found to significantly increase the polydispersity index up to 0.31. A faster emulsification rate of 3.37%/min was obtained at higher Cremphor El/PEG 400 ratio. Increasing the percentage of lipid components of SEDDS resulted in lower rate of lipolysis with less recovery of ND in aqueous phase. Under fed state, percentage of lipolysis of optimized formulation was less than that observed under fasted state. However, lowest rate and percentage of lipolysis were observed in lipolysis media without phospholipids and bile salts. Hence, this study demonstrated that in vitro lipolysis could be used as a surrogate approach to distinguish effects of formulation variables on fate of SEDDS upon digestion. Further studies are in progress to identify the lipolytic products of the employed excipients by LC-MS/MS.

We report a novel method for developing gelatin-based phantom materials for transmission x-ray imaging with high stability at room temperature and tunable x-ray attenuation properties. This is achieved by efficiently cross-linking gelatin in a glycerin solution with only 10% water by volume and systematically decreasing their x-ray attenuation coefficients by doping with microbubbles that are originally designed to be used as lightweight additives for paints and crack fillers. For demonstration, we mimic breast glandular and adipose tissues by using such gelatin materials and also study the feasibility of 3D printing them based on the extrusion-based technique. Results from x-ray spectroscopy (15-45 keV) show the materials to have stable x-ray attenuation properties of glandular and adipose tissues over a period of two months. Micro-CT analysis of independently prepared samples shows the materials to be uniform and easy to reproduce with minimum variability in attenuation values. These materials can be used to 3D print realistic phantoms that mimic x-ray properties of various biological tissues.

Through the integration of orthogonal central composite design and desirability function, this work aimed to explore the potential of quality by design in understanding the formulation of phospholipid-stabilized tacrolimus nanodispersions by microfluidization. The influence of homogenization pressure, microfluidization time and phospholipid concentration (X1-X3) on nanodispersion performance was studied. Nanodispersions were characterized by differential scanning calorimetric (DSC), X-ray diffractometer (XRD) and Fourier transform infrared (FTIR) analysis. Moreover, masking the unpalatable taste of tacrolimus and reducing the gastric complications were also evaluated. FTIR analysis indicated its interaction with phospholipid. DSC and XRD analysis revealed the amorphous transformation of tacrolimus within nanodispersions. The dissolution was enhanced by 35 folds and 15 folds after 0.5 and 2 h, respectively. Maximum tacrolimus content, yield, polydispersity index, percentages dissolved after 0.5 and 2 h of 99.3%, 100%, 0.864, 39.7% and 95.3%, respectively, with particle size of 160 nm were obtained at X1, X2 and X3 values of 20 000 psi, 6 min and 30%, respectively. The Euclidean distance values demonstrated masking the unpalatable taste and taste perversion to stimuli of tacrolimus in its optimized nanodispersion. Moreover, the ulcerative indices following raw tacrolimus and its optimized nanodispersion oral administration were 6.73 and 2.45, respectively, to indicate that nanodispersion was significantly less irritating to the gastric mucosa.

This study was aimed at developing risperidone oral disintegrating mini-tablets (OD-mini-tablets) as age-appropriate formulations and to assess their suitability for infants and pediatric use. An experimental Box-Behnken design was applied to assure high quality of the OD-mini-tablets and reduce product variability. The design was employed to understand the influence of the critical excipient combinations on the production of OD-mini-tablets and thus guarantee the feasibility of obtaining products with dosage form uniformity. The variables selected were mannitol percent in Avicel (X1), swelling pressure of the superdisintegrant (X2), and the surface area of Aerosil as a glidant (X3). Risperidone-excipient compatibilities were investigated using FTIR and the spectra did not display any interaction. Fifteen formulations were prepared and evaluated for preand post-compression characteristics. The prepared ODmini- tablet batches were also assessed for disintegration in simulated salivary fluid (SSF, pH 6.2) and in reconstituted skimmed milk. The optimized formula fulfilled the requirements for crushing strength of 5 kN with minimal friability, disintegration times of 8.4 and 53.7 s in SSF and skimmed milk, respectively. This study therefore proposes the risperidone OD-mini-tablet formula having robust mechanical properties, uniform and precise dosing of medication with short disintegration time suitable for pediatric use.

This study is aimed at developing glimepiride (GMD) liposomal films using quality by design (QbD) and process analytical technology (PAT) principles. Risk analysis and Plackett-Burman design were utilized to evaluate formulation variables in two paths. Internal path included liposomal parameters (phosphatidylserine, cholesterol and drug concentrations, and pH of hydration medium). External path constituted films parameters, namely, polymer, plasticizer, and permeation enhancer percentages. As a PAT tool, near infrared (NIR)-based chemometric analysis was used in quantifying GMD contents. Liposomal formulations showed maximum GMD entrapment capacity of 41.9% with vesicular size of 0.51 μm at phospholipid to cholesterol to drug weight ratio of 2:1:0.8. Its transdermal films showed elongation ratio of 75%, folding endurance of 700-fold, 16.6% and 26.8% drug release after 1 and 12 h, respectively. Moreover, 3D response spaces for GMD entrapment and release characteristics were established. Regarding NIR analysis, partial-least-square regression model was accurate in quantifying drug content as indicated by the low root-mean-squared error of calibrations and prediction of 0.031 and 0.032, and bias values of 0.0015 and 0.0021, respectively. In conclusion, this study highlights the level of understanding that can be accomplished through a well-designed research based on QbD and PAT paradigms.

Currently, many pharmacologically active compounds are formulated as sterile dosage forms. These include parenteral, nasal, pulmonary, and ocular preparations. Different nanosystems have been successfully formulated and loaded into these dosage forms. Delivery of these nanosystems via invasive and noninvasive routes offers many advantages. Despite being invasive, parenteral administration of nanosystems remains the route of choice, owing to the overcoming absorption barriers and rapidity of action, while noninvasive routes such as pulmonary, ocular and nasal are widely investigated due to the advantages of localizing drug action and minimizing adverse events. In this chapter, the composition, characteristic and different types of these sterile dosage forms were outlined. In-process and release specifications of these preparations were also generally mentioned. Delivery of nanoformulation and their applications via invasive and noninvasive routes were discussed.

Leachables derived from multi-component drug-device syringe systems can result in changes to the quality of drug products. Diphenylguanidine (DPG), a leachable released from styrene butadiene rubber syringe plungers, interacts with Oxytocin to form protein-adducts. This study investigated the mechanism and kinetics of this interaction in both solid and solution states through in-vitro tests and spectroscopic methods For solid state interaction, the protein-adducts with DPG were characterized using SEM, XRD, DSC, FTIR, 13C ss NMR, and dissolution analysis. For solution state interaction, LC-HRMS was used to assess stability of Oxytocin solutions in presence of various concentrations of DPG at 25°C and 40°C for 4 weeks. Moreover, molecular docking analysis was used to identify possible molecular configurations of the interaction.Results were consistent with the formation of a new solid state with distorted surface morphology for oxytocin-DPG adducts, in which the oxytocin carbonyl group(s) and the secondary amine groups of DPG interact. This interaction was also confirmed by molecular docking analysis through hydrogen bonding (2.31A) and Van der Waal attraction (3.14A). Moreover, LC-HRMS analysis revealed an increase in Oxytocin stability and suppression of Oxytocin dimerization by DPG. A potential reduction in the rate of Oxytocin dissolution from the formed adducts was indicative of its strong association with DPG. Hence, the leaching potential of DPG from rubber closures and plungers should be monitored and controlled to maintain the quality and stability of the pharmaceutical product.

Crystal B Spinks,1 Ahmed S Zidan,2,3 Mansoor A Khan,4 Muhammad J Habib,1 Patrick J Faustino2 1Department of Pharmaceutical Sciences, School of Pharmacy, Howard University, Washington, DC, 2Division of Product Quality Research, Office of Pharmaceutical Quality, Food and Drug Administration, Silver Spring, MD, USA; 3Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; 4Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, College Station, TX, USA Abstract: Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10mM Na2PO4/acetonitrile pH 7.4 (95:5v/v). The flow rate was 1mL/min with a 12min elution time. Injection volume was 10µL with ultraviolet detection at 270nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that calibration curves were linear with r2 > 0.9995 over the analytical range of 1–10µg/mL. Inter- and intraday accuracy and precision values ranged from 95% to 101% and 0.3% to 2.6%, respectively. The method was determined to be specific and robust. Regarding the potential of the prepared vectors to potentiate tenofovir permeability through the Caco-2 model, a 10-fold increase in tenofovir apparent permeability was observed compared to its oral solution. In conclusion, this novel and validated method was successfully applied to characterize both in vitro encapsulation efficiency and Caco-2 permeability transport for the pharmaceutical assessment of novel tenofovir formulations. Keywords: liposomes, tenofovir, targeting, chromatography, entrapment, permeation

Efficacy of central nervous system-acting medications is limited by its localization and ability to cross the blood-brain barrier (BBB); therefore, the crux is in designing delivery systems targeted to cross the BBB. Toward this objective, this study proposed pegylated and glycosylated citalopram hydrobromide (Cit-HBr) liposomes as a delivery approach for brain targeting. The multicomponent liposomes were evaluated for drug encapsulation, vesicular size, size distribution, conductivity and drug release characteristics. Moreover, the interaction among the employed components was evaluated by Fourier transform infrared, differential scanning calorimetric and X-ray diffraction analysis. Through a systematic screening design of formulation and process variables in the optimization phase, an improvement of Cit-HBr loading, fine vesicular size with narrow size distribution, greater stability and sustained release features were achieved. The compatibility studies unveiled a significant interaction between Cit-HBr and dicetyl phosphate to control drug encapsulation and release properties. The optimization process showed a minimal range of design space to achieve the preset desirability; more precisely dicetyl phosphate, polyethylene glycol, N-acetyl glucosamine and freeze-thaw cycles of 3%, 5%, 4% and 2 cycles, respectively, were used. Using brain endothelial cell models, the optimized formulations showed an acceptable cell viability with preserved monolayer integrity and an enhanced flux and permeability. Thus, this study has proposed an optimized pegylated and glycosylated vector that is a promising step for brain targeting.