Baxter elastomeric pumps: Weighing as an alternative to visual inspection.

Purpose Elastomeric pumps are used to administer 46-hour infusions of 5-fluorouracil (5FU). Baxter suggests patients visually monitor their pumps to ensure that infusions are proceeding correctly. This can be confusing and lead to concerns about under- or over-dosing. Baxter has not considered weighing pumps as a validated method for monitoring. This study aims to validate weighing as a more accurate method for patients and healthcare professionals, and describe real life Baxter Infusor™ variability. Methods Patients who had been started on a 46-hour 5FU infusion returned to the clinic approximately 24 h after starting treatment. The pump was weighed on a StarFrit kitchen scale, and date, time, and weights recorded. Patients were asked if they had a preference for weighing or visually inspecting their pump. Results Pumps ( n = 103) were weighed between 17.25 and 27.5 h after connection. The average weight of a pump was 189 g. Of 103 pumps weighed, 99 weighed less than expected, corresponding to average flow rates of 5.69 mL/h over the elapsed time. The expected flow rate is 5 mL/h with 10% variability. Average flow rates within the 17.25- to 27.5-hour window were 4.561 mL/h, which is 8.78% slower than expected, but within the 10% known variability. Forty-seven percent of patients didn't have a preference for either method, but for those who did have a preference, more than twice as many preferred weighing. Conclusion With proper education, weighing Baxter Infusors at home with kitchen scales can be an accepted and objective alternative to the current recommendation of visual inspection.

Baxter elastomeric pumps: Feasibility of weight estimates.

Purpose Elastomeric pumps are used to infuse a 46-h fluorouracil protocol and patients are asked to visually inspect the pump daily. The pump has a variability of ±10% and there are additional patient variables that can increase this. The feasibility of weighing the pump rather than a visual inspection along with the secondary objective to confirm the pump's variability in real world conditions was undertaken. Methods Empty pumps were weighed using both pharmacy and kitchen scales. Pumps upon completion of the 46-h infusion were also weighed using both pharmacy and kitchen scales. Results The kitchen scale was as accurate as the pharmacy grade scale. Disconnected pumps showed the expected variability from using these infusor pumps along with a few showing greater variability likely due to patient variables. Conclusion Weighing pumps appears to be feasible both at the pharmacy and home level. Next steps would be to weigh pumps during the infusion to validate an alternate method to simple visual inspection for patients to confirm proper infusing of the pump at their home.

Does the United States Pharmacopeia throat introduce de-agglomeration of carrier-free powder from inhalers?

PURPOSE: We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs). METHODS: Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery was obtained by HPLC and fine particle fraction computed. Air flow patterns were simulated using Computational Fluid Dynamics (CFD). RESULTS: The straight tube did not de-agglomerate emitted powder. However, the USP throat and AG further de-agglomerated powders from the Spinhaler, but not the Turbuhaler and Osmohaler. While budesonide powder deposited similarly in all induction ports, deposition was significantly higher in the AG for both DSCG and mannitol. CFD revealed agglomerates impacting on the USP throat with higher localized velocity compared with the straight tube. CFD further showed a more complex flow pattern with high-velocity air jets in the AG, which explains the higher FPF for DSCG and the lower FPF for mannitol using the AG. CONCLUSION: The USP throat further de-agglomerated the emitted powder from the DPI when it did not sufficiently disperse the powder. Other tools such as laser diffraction may be used for cross-examining to avoid artifacts in the results.

Formation of ciprofloxacin nanocrystals within liposomes by spray drying for controlled release via inhalation.

The present study was conducted to harness spray drying technology as a novel method of producing Ciprofloxacin nanocrystals inside liposomes (CNL) for inhalation delivery. Liposomal ciprofloxacin dispersions were spray dried with sucrose as a lyoprotectant in different mass ratios (0.5:1, 1:1 and 2:1 sucrose to lipids), along with 2% w/w magnesium stearate and 5% w/w isoleucine as aerosolization enhancers. Spray drying conditions were: inlet air temperature 50 °C, outlet air temperature 33-35 °C, atomizer rate 742 L/h and aspirator 35 m3/h. After spray drying, the formation of ciprofloxacin nanocrystals inside the liposomes was confirmed by cryo- transmission electron microscopy. The physiochemical characteristics of the spray dried powder (particle size, morphology, crystallinity, moisture content, drug encapsulation efficiency (EE), in vitro aerosolization performance and drug release) were determined. The EE of the liposomes was found to vary between 44 and 87% w/w as the sucrose content was increased from 25 to 57% w/w. The powders contained partially crystalline particles with a volume median diameter of ~1 µm. The powders had low water content (~2% wt.) and were stable at high relative humidity. Aerosol delivery using the Osmohaler® inhaler at a flow rate of 100 L/min produced an aerosol fine particle fraction (% wt. <5 µm) of 58-64%. The formulation with the highest sucrose content (2:1 w/w sucrose to lipid) demonstrated extended ciprofloxacin release from liposomes (80% released within 7 h) in comparison to the original liquid formulation (80% released within 2 h). In conclusion, a stable and inhalable CNL powder with controlled drug release was successfully prepared by spray drying.

Novel combination proliposomes containing tobramycin and clarithromycin effective against Pseudomonas aeruginosa biofilms.

Tobramycin (TOB) and clarithromycin (CLA) can potentially be used synergistically for the treatment of respiratory infections caused by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis (CF) patients. This study aimed to develop a novel combination proliposome formulation (TOB/CLA-CPROLips) containing both hydrophilic TOB and hydrophobic CLA via a core-carrier approach. The combination proliposomes were produced by spray drying a suspension comprising spray-driedmannitol (SD-MAN, 0.45%) and spray-dried tobramycin (SD-TOB, 0.05%) particles suspended in an ethanolic lipid solution of CLA (0.05%). The lipid layer coated on the surface of the dry proliposome particles conferred moisture protection and sustained drug release properties in comparison to the pure drugs. The optimized TOB/CLA-CPROLips formulation was stable after 3 months of storage at 60% relative humidity (RH) and 25 °C. The combination drug proliposomes showed a synergistic antimicrobial activity against planktonic cells and biofilm cultures of P. aeruginosa. In conclusion, the core-carrier method coupled with spray-drying provided a novel approach for the preparation of combination antibiotics proliposomes.

The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation.

BACKGROUND: Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment. METHODS: We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases. A Cox proportional hazards regression model was fitted to evaluate the associations between high prolactin receptor (PRLR) expression and time to bone metastasis, adjusting for estrogen receptor status, lymph node status, and chemotherapy status. We assessed osteoclast differentiation, osteoclast size, and measured pit formation in dentine slices. Statistical tests were two-sided. RESULTS: High PRLR expression in the primary breast tumor was associated with a shorter time to metastasis that includes bone (PRLRAQUA Max-per 100 unit hazard ratio = 1.04, 95% confidence interval = 1.00 to 1.07, P = .03). We observed the PRLR in rare samples of bone metastases and matched primary breast cancer. PRL treatment of breast cancer cells induced osteoclast differentiation and bone lysis via secreted factors and was abrogated by a PRLR antagonist (delta1-9-G129R-hPRL). We demonstrated that sonic hedgehog is a PRL-regulated cytokine in breast cancer cells and part of the mechanism that induces osteoclast differentiation. CONCLUSIONS: Our evidence indicates that PRL-PRLR can escalate the impact of breast cancer on bone metastasis and that the presence of the PRLR in the tumor microenvironment of breast cancer bone metastasis has the potential to modulate the microenvironment to induce lytic osteoclast formation.

Inhaled formulations and pulmonary drug delivery systems for respiratory infections.

Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'.