Accelerated Stability Assessment of Extemporaneously Compounded Amiloride Nasal Spray.

Amiloride is a U.S. Food and Drug Administration-approved diuretic agent used to treat hypertension and congestive heart failure. Recent human and animal studies have suggested that amiloride may also have a role in treating anxiety through its acid-sensing ion channel antagonism. Intranasal administration of amiloride nasal spray via an extemporaneously compounded preparation has the potential for rapid delivery to the site of action to achieve therapeutic outcomes in individual patients with anxiety disorders. However, these patient-specific preparations do not have the pre-formulation characterization, including chemical stability, that conventional manufactured dosage forms have. The objective of this study was to assess the estimated chemical stability of compounded amiloride nasal spray over 6 months and 12 months utilizing accelerated degradation with high heat and the Arrhenius equation. A stability-indicating highperformance liquid chromatography analytical method was employed at appropriate intervals over a 12-month period to reveal that amiloride remained chemically stable over the period tested and by extrapolation. Physical stability and compatibility with the preservative benzyl alcohol were also confirmed via visual inspection, pH monitoring, and measurement of turbidity.

Current use of complementary and conventional medicine for treatment of pediatric patients with gastrointestinal disorders.

Infants, children, and adolescents are at risk of experiencing a multitude of gastrointestinal disorders (GID). These disorders can adversely affect the quality of life or be life-threatening. Various interventions that span the conventional and complementary therapeutic categories have been developed. Nowadays, parents increasingly seek complementary options for their children to use concurrently with conventional therapies. Due to the high prevalence and morbidity of diarrhea, constipation, and irritable bowel syndrome (IBS) in children, in this review, we decided to focus on the current state of the evidence for conventional and complementary therapies used for the treatment of these diseases in children. Diarrhea treatment focuses on the identification of the cause and fluid management. Oral rehydration with supplementation of deficient micronutrients, especially zinc, is well established and recommended. Some probiotic strains have shown promise in reducing the duration of diarrhea. For the management of constipation, available clinical trials are insufficient for conclusive recommendations of dietary modifications, including increased use of fruit juice, fiber, and fluid. However, the role of laxatives as conventional treatment is becoming more established. Polyethylene glycol is the most studied, with lactulose, milk of magnesia, mineral oil, bisacodyl, and senna presenting as viable alternatives. Conventional treatments of the abdominal pain associated with IBS are poorly studied in children. Available studies investigating the effectiveness of antidepressants on abdominal pain in children with IBS were inconclusive. At the same time, probiotics and peppermint oil have a fair record of benefits and safety. The overall body of evidence indicates that a careful balance of conventional and complementary treatment strategies may be required to manage gastrointestinal conditions in children.

Preparation and characterization of lutein loaded folate conjugated polymeric nanoparticles.

AIM: To prepare and characterise lutein-loaded polylactide-co-glycolide-polyethylene glycol-folate (PLGA-PEG-FOLATE) nanoparticles and evaluate enhanced uptake in SK-N-BE(2) cells. METHODS: Nanoparticles were prepared using O/W emulsion solvent evaporation and characterised using DLS, SEM, DSC, FTIR and in-vitro release. Lutein-uptake in SK-N-BE(2) cells was determined using flow-cytometry, confocal-microscopy and HPLC. Control was lutein PLGA nanoparticles. RESULTS: The size of lutein-loaded PLGA and PLGA-PEG-FOLATE nanoparticles were 189.6 ± 18.79 nm and 188.0 ± 4.06 nm, respectively. Lutein entrapment was ∼61%(w/w) and ∼73%(w/w) for PLGA and PLGA-PEG-FOLATE nanoparticles, respectively. DSC and FTIR confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies showed ∼1.6 and ∼2-fold enhanced uptake of lutein from PLGA-PEG-FOLATE nanoparticles compared to PLGA nanoparticles and lutein, respectively. Cumulative release of lutein was higher in PLGA nanoparticles (100% (w/w) within 24 h) compared to PLGA-PEG-FOLATE nanoparticles (∼80% (w/w) in 48 h). CONCLUSION: Lutein-loaded PLGA-PEG-FOLATE nanoparticles could be a potential treatment for hypoxic ischaemic encephalopathy.

Predictive modeling of aspirin-triggered resolvin D1 pharmacokinetics for the study of Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS-like features in NOD/ShiLtJ mice can be systemically halted using AT-RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti-inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT-RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration. MATERIALS AND METHODS: Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT-RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK-Sim® and MoBi® Version 7.4 software. RESULTS: The model provides high-value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design. CONCLUSIONS: Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short-term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.

Clotrimazole Loaded Ufosomes for Topical Delivery: Formulation Development and In-Vitro Studies.

Global incidence of superficial fungal infections caused by dermatophytes is high and affects around 40 million people. It is the fourth most common cause of infection. Clotrimazole, a broad spectrum imidazole antifungal agent is widely used to treat fungal infections. Conventional topical formulations of clotrimazole are intended to treat infections by effective penetration of drugs into the stratum corneum. However, drawbacks such as poor dermal bioavailability, poor penetration, and variable drug levels limit the efficiency. The present study aims to load clotrimazole into ufosomes and evaluate its topical bioavailability. Clotrimazole loaded ufosomes were prepared using cholesterol and sodium oleate by thin film hydration technique and evaluated for size, polydispersity index, and entrapment efficiency to obtain optimized formulation. Optimized formulation was characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). Skin diffusion studies and tape-stripping were performed using human skin to determine the amount of clotrimazole accumulated in different layers of the skin. Results showed that the optimized formulation had vesicle size <250 nm with ~84% entrapment efficiency. XRD and DSC confirmed the entrapment of clotrimazole into ufosomes. No permeation was observed through the skin up to 24 h following the permeation studies. Tape-stripping revealed that ufosomes led to accumulation of more clotrimazole in the skin compared to marketed formulation (Perrigo). Overall, results revealed the capability of ufosomes in improving the skin bioavailability of clotrimazole.

Development and Validation of a Stability-indicating High-performance Liquid Chromatographic Method for Quantification of Progesterone in Compounded Glycerinated Gelatin Troches.

The objective of this study was to develop a validated stability-indicating high-performance liquid chromatographic method that quantifies progesterone in compounded glycerinated gelatin troches. The mobile phase was composed of methanol and water (75:25 v/v), while the stationary phase was a Waters Nova-Pak C18 column (3.9 mm Å~ 15 cm Å~ 4.0 µm) with the column's temperature set to 40°C. The injection volume was 20 µL, while the gradient flow rate was maintained at 0.75 mL/min for a run time of 15 minutes. The detection wavelength for progesterone was set to 245 nm. In the forced degradation study, there was significant hydrolytic, oxidative, ultraviolet, and thermal degradation but insignificant photodegradation. However, no degradants co-eluted with progesterone. All method validation parameters met the respective acceptance criteria established by the International Conference on Harmonisation guidelines. This developed and validated method is suitable for both routine potency/strength testing as well as stability testing of progesterone in compounded glycerinated gelatin troche dosage forms. The method was utilized to successfully quantify progesterone in multiple compounded preparations from two different compounding pharmacies.

Chemical Stability of Progesterone in Compounded Oral Rapid-dissolving Tablets.

Progesterone is a naturally occurring female sex hormone, which plays an important role in the female reproductive cycle. Progesterone supplementation is used to treat a variety of conditions. When commercial dosage strengths are unavailable, rapid-dissolving tablets may be compounded. The objective of this study was to evaluate the chemical stability of progesterone when compounded in a rapid-dissolving tablet formulation and to establish an evidence-based beyond-use date. Triplicate test samples were prepared by diluting the pulverized progesterone rapid-dissolving tablets with a portion of methanol to a final concentration of 100 µg/mL. Samples were stored in a stability chamber under accelerated conditions at 60°C and 75% relative humidity and were evaluated at appropriate intervals (0, 6 months, and 12 months). Chemical stability was assessed initially and at appropriate intervals during the study periods with stability-indicating high-performance liquid chromatography analytical techniques based on the determination of drug concentrations. The results of high-performance liquid chromatography analysis indicated that the samples remained stable for 6 months at 60°C and 75% relative humidity. The remaining concentration of progesterone rapid-dissolving tablets at 6 months fell within the United States Pharmacopeia accepted limits (±10% of the initial concentration), which was consistent with the recommended beyond-use dating of 6 months for a non-aqueous formulation per United States Pharmacopeia guidelines.

The Use of Animated Videos to Illustrate Oral Solid Dosage Form Manufacturing in a Pharmaceutics Course.

Objective. To evaluate the impact of animated videos of oral solid dosage form manufacturing as visual instructional aids on pharmacy students' perception and learning. Design. Data were obtained using a validated, paper-based survey instrument designed to evaluate the effectiveness, appeal, and efficiency of the animated videos in a pharmaceutics course offered in spring 2014 and 2015. Basic demographic data were also collected and analyzed. Assessment data at the end of pharmaceutics course was collected for 2013 and compared with assessment data from 2014, and 2015. Assessment. Seventy-six percent of the respondents supported the idea of incorporating animated videos as instructional aids for teaching pharmaceutics. Students' performance on the formative assessment in 2014 and 2015 improved significantly compared to the performance of students in 2013 whose lectures did not include animated videos as instructional aids. Conclusions. Implementing animated videos of oral solid dosage form manufacturing as instructional aids resulted in improved student learning and favorable student perceptions about the instructional approach. Therefore, use of animated videos can be incorporated in pharmaceutics teaching to enhance visual learning.

Solid lipid nanoparticles containing 7-ethyl-10-hydroxycamptothecin (SN38): Preparation, characterization, in vitro, and in vivo evaluations.

7-Ethyl-10-hydroxycamptothecin (SN38) is a biologically active metabolite of irinotecan. Due to the variability of irinotecan metabolism rate to SN38, and poor solubility of this compound in pharmaceutically acceptable solvents, SN38 has not been successfully used in the clinic. In the present study, we prepared solid lipid nanoparticle (SLN) formulations containing SN38 and evaluated the in vitro and in vivo efficacy of these nanoparticles. SLNs and PEGylated SLNs containing SN38 (SLN-SN38 and PEG-SLN-SN38) were prepared using ultrasonication technique. Nanoparticles were characterized for size, zeta potential, and drug encapsulation efficiency. In vitro cytotoxicity of these compounds was evaluated in two colorectal carcinoma cell lines, namely C-26 and HT-116. In vivo antitumor efficacy of the formulations was evaluated in C-26 xenograft tumor mice models. Mice survival was also explored through 60days post IV injection. Mean size of SLN-SN38 and PEG-SLN-SN38 was around 103 and 131nm, respectively. Polydispersity index (PDI) for all the formulations was around 0.2 and zeta potential was negative (-5 to -15mV). Nearly 90% of the drug was encapsulated in SLNs. SLN-SN38 and PEG-SLN-SN38 compared to irinotecan were significantly more toxic to C-26 and HT-116 cell lines after 48h of exposure. Calculation of IC50 suggests higher sensitivity of HT-116 cells than C-26 cells to SLN-SN38 and PEG-SLN-SN38. Tumor inhibitory efficacy presented the highest efficacy in SLN-SN38. However, both SLN-SN38 and PEG-SLN-SN38 carriers showed higher efficiency to inhibit tumors compared to irinotecan (25mg/kg).

Recent Advances in Topical Ocular Drug Delivery.

Topical ocular drug delivery has been considered to be an ideal route of administration for treatment of ocular diseases related to the anterior segment of the eye. However, topical ocular delivery is a challenging task because of barriers such as nasolacrimal drainage, corneal epithelium, blood-ocular barriers, and metabolism in the eye. Approaches to improve ocular bioavailability include physical approaches such as formulations of drugs as solutions (Zymaxid(™)), suspensions (Zigran(®)), gels (Akten(®)) and chemical approaches such as prodrugs (Xalatan(™)), chemical delivery systems, and soft drugs. The purpose of this review article is to summarize recent advances in topical drug delivery to the anterior segment of the eye. Functional transporters in the corneal epithelium were also discussed as they provide prospects in topical ocular delivery. In addition to conventional delivery systems, novel delivery systems involving nanocarriers were also investigated for topical ocular delivery. Furthermore, due to increased interest, gene therapy applications of topical ocular delivery of genes to the anterior segment of the eye were also discussed. Research in topical ocular delivery is active for more than 50 years and proven to be advantageous for the treatment of many ocular diseases. However, there is scope for innovation in topical drug delivery to develop delivery systems with a high patient safety profile and compliance for effective clinical usefulness.

Recent trends in cancer drug resistance reversal strategies using nanoparticles.

INTRODUCTION: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc. AREAS COVERED: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors. EXPERT OPINION: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.

Novel approach for delivery of insulin loaded poly(lactide-co-glycolide) nanoparticles using a combination of stabilizers.

Insulin stability during microencapsulation and subsequent release is essential for retaining its biological activity. The successful delivery of insulin relies on the proper selection of stabilizers in addition to other parameters. Attempts were made to address the problem with a few combination of stabilizers for maintaining the integrity of insulin during formulation and delivery. Insulin loaded nanoparticles with different stabilizers such as pluronic F68, trehalose, and sodium bicarbonate were prepared by the double emulsion evaporation method using two different copolymer ratios of poly(DL-lactide-co-glycolide) (50:50 and 85:15). The presence of stabilizers in the nanoparticles resulted in an increase in the particle size but a reduction of encapsulation efficiency. Insulin release rate was comparatively higher for the batches containing stabilizers when compared with controls for both the copolymer ratios. Also the presence of stabilizers resulted in sustained release of insulin resulting in prolonged reduction of blood glucose levels in streptozotocin induced diabetic rats. From the in vitro and in vivo studies, we concluded that a combination of stabilizers results in beneficial effects without compromising the advantages of delivery systems.