Assessing the Physicochemical Stability of a Compounded Neonatal Trace Element Solution.

PURPOSE: Alberta Health Services (AHS) recommends the adoption of a new neonatal multi-trace element formulation containing zinc sulfate, copper sulfate, selenious acid and sodium iodide to be compounded internally in appropriate AHS pharmacies. The objective of this study was to assess the physicochemical stability of this formulation under commonly used storage conditions. METHOD: Three batches of trace element solution were compounded by University of Alberta Hospital pharmacy staff using sterile compounding procedures. Appropriate amount of zinc sulfate (500 mg/mL), copper sulfate (40 mg/mL), selenious acid (4 mg/mL), sodium iodide (2 mg/mL) and sterile water for injection were mixed. Samples from each batch were divided in individual vials and syringes for each time point and kept protected from light either at room temperature (15-30°C) or fridge (2-8°C). Vial samples were also kept at room temperature for 12 h and then transferred to fridge. Vial samples were analyzed at time 0, 12 h, and 1, 3, 7, 9, 30, 60, 90 days for their physical appearance and pH, then centrifuged and assessed for the soluble zinc (atomic absorption), copper (atomic absorption), selenium (ICP-MS) and iodine (HPLC and ICP-MS) concentrations. Syringe samples were tested at time 0 and 12 h for element concentrations. RESULTS: Under all storage conditions, when stored in vials, samples' appearance, pH and soluble zinc, copper and selenium concentrations stayed within the USP acceptable limits up to 90 days. Iodine concentration was within the permitted limits only up to 7 days. The USP recommended HPLC method of iodine analysis seemed inadequate for this preparation and needed modifications, through frequent washing of the column with KI (2 %) solution. Samples kept in syringes at room temperature, showed lower than permitted concentration of Zn at 12h in this study. CONCLUSION: The AHS neonatal multi-trace element formulation seem to be physio-chemically stable up to 7 days in all three storage conditions when kept in vials.  A decline in iodine concentration is seen after 7 days irrespective of storage conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Pharmacokinetics of nebivolol in the rat: low oral absorption, loss in the gut and systemic stereoselectivity.

Nebivolol is a third-generation ß1-adrenoceptor blocker with ß3 agonistic properties (AR). It has a low oral bioavailability that is speculated to be due to its hepatic first-pass metabolism. Inflammation is known to suppress the clearance of drugs with efficient hepatic metabolism. However, inflammation does not influence nebivolol clearance. Therefore, we looked into the mechanism involved in the drug's low bioavailability and stereoselectivity. Single 1 mg/kg i.v. or intraperitoneal (i.p.) or 2 mg/kg oral doses were administered to male Sprague-Dawley rats and the plasma nebivolol concentration was measured using chiral and achiral assays. The passage of nebivolol enantiomers through the gut was also measured using everted rat sacs. The serum protein binding of the enantiomers was studied in vitro using the ultrafiltration method. Plasma nebivolol concentrations were significantly lower after p.o., but not after i.p., compared with i.v. doses suggesting the gut as the site of pre-systemic loss. Approximately 50% of the enantiomers were lost during 90 min incubation in the presence of gut. Only 0.1% of the added drug crossed the gut wall with no evidence of stereoselectivity. Thus stereoselectivity in the pharmacokinetics of nebivolol (+ > -) is likely at the level of plasma protein binding. The low nebivolol bioavailability is due to its loss in the gut as well as its limited permeability through the intestinal wall.

Development and pharmacokinetic evaluation of a self-nanoemulsifying drug delivery system for the oral delivery of cannabidiol.

The number of lipophilic drug candidates in pharmaceutical discovery pipelines has increased in recent years. These drugs often possess physicochemical properties that result in poor oral bioavailability, and their clinical potential may be limited without adequate formulation strategies. Cannabidiol (CBD) is an excellent example of a highly lipophilic compound with poor oral bioavailability, due to low water solubility and extensive first-pass metabolism. An approach that may overcome these limitations is formulation of the drug in self-nanoemulsifying drug delivery systems (SNEDDS). Herein, CBD-SNEDDS formulations were prepared and evaluated in vitro. Promising formulations (F2, F4) were administered to healthy female Sprague-Dawley rats via oral gavage (20 mg/kg CBD). Resulting pharmacokinetic parameters of CBD were compared to those obtained following administration of CBD in two oil-based formulations: a medium-chain triglyceride oil vehicle (MCT-CBD), and a sesame oil-based formulation similar in composition to an FDA-approved formulation of CBD, Epidiolex® (SO-CBD). Compared to MCT-CBD, administration of the SNEDDS formulations led to more rapid absorption of CBD (median Tmax values: 0.5 h (F2), 1 h (F4), 6 h (MCT-CBD)). Administration of F2 and F4 formulations also improved the systemic exposure to CBD by 2.2 and 2.8-fold compared to MCT-CBD; however, no improvement was found compared to SO-CBD.

Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma.

STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (p = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM.