Polyolefin Containers Research Articles

Physicochemical stability of lurbinectedin reconstituted at 500 μg/mL and diluted at 15, 30, and 70 μg/mL in 0.9% sodium chloride and 5% dextrose

Abstract Background: Lurbinectedin (ZEPZELCA) is a cytotoxic, with alkylating properties. The commercially available pharmaceutical form is a glass vial containing 4 mg of lyophilized powder of lurbinectedin. The recommended dose of lurbinectedin is 3.2 mg/m2. For a 1.7-m2 body surface area, the average dosage is 5.44 mg. The manufacturer indicates a 30-hour stability for the reconstituted solution which cannot give the possibility to re-use the vial for the following days resulting in an average loss of 3600 € per preparation. Objectives: The first objective was to study the stability of 500 μg/mL reconstituted lurbinectedin in water for injection after storage at 2 to 8°C. The second objective was to study the stability of 15 to 70 μg/mL diluted lurbinectedin in 0.9% NaCl or dextrose 5% in water stored at 2 to 8°C. Methods: Three solutions in glass tubes for each condition (reconstituted 15 and 70 μg/mL solutions) were prepared. Due to the high cost, only 1 infusion bag at 30 μg/mL in polyolefin container was prepared. At each time of the analysis, 3 samples for each vial were analyzed by high-performance liquid chromatography coupled to a photodiode array detector. Physical stability was evaluated by visual and subvisual inspection (spectrophotometry). Results: The analytical method was validated according to International Conference on Harmonisation guidelines Q2 (R1). The 500 μg/mL lurbinectedin reconstituted solution retained more than 95% of the initial concentration after 14 days as the 15 to 70 μg/mL diluted solutions. No interaction between the polyolefin infusion bag and lurbinectedin was observed. No physical changes were observed both visually and subvisually. Conclusion: The reconstituted solution and the diluted lurbinectedin solutions were physically and chemically stable for 14 days when stored at 2 to 8°C protected from light. This new data makes it possible to re-use the reconstituted vial and to store a preparation in case of cancellation of an administration.

Metal-Catalyzed Postpolymerization Strategies for Polar Group Incorporation into Polyolefins Containing C–C, C═C, and Aromatic Rings

Polymeric materials bearing polar groups constitute a class of macromolecules with interest in a number of uses. Because the direct synthesis employing polymerization strategies from polar monomers is very often precluded by catalyst poisoning or uncontrolled side reactions, the alternative postpolymerization route consisting in modifying a previously prepared polymer is continuously progressing. However, such a posteriori modification depends on the existence of potential reaction sites in the polymer. Because of this, polyolefins are the most challenging substrates to work with and, among them, the saturated ones. In this contribution, the current state of the art of the metal-catalyzed modification of polyolefins and subsequent polar group incorporation is provided.

In-use stability of diluted thiamazole (methimazole) infusion solutions in prefilled 0.9% sodium chloride infusion bags for continuous infusion

ObjectiveIn patients with severe hyperthyroidism unable to tolerate oral antithyroid therapy, diluted thiamazole infusion solutions (dose 120–240 mg) are administered by continuous infusion over 24 hours. Information about the type...

The Usefulness of Improved, Newly Developed Polyolefin Container of Platelet, PO-100, with Higher Oxygen Permeability and Content

The demand for platelet concentrate (PC) has been growing because of the increase of more intensive chemotherapy and hematopoietic stem cell transplantation, and highly invasive surgical operations of several specific areas (i.e. cardiovascular surgery, etc.), which has brought about considerable impact on its decent availability. Furthermore, the short storage period for room temperature stored PC, four days in Japan, five days in worldwide and seven days in the U.S. if they meet several requirements by FDA for the control of the risk of bacterial contamination, has put many PCs become outdated. In response to these requirements, measures have been taken to maximize platelet use, including development of polyolefin containers for platelets that elongate storage time and formulations of higher units.Here, we have developed a polyolefin container, PO-100, which has a 40%/m2 higher oxygen permeability than PO-80, a former, and standard platelet storage bags across the world. Furthermore, PO-100 has two types, one is PO-100/1000 with 1000mL capacity for 4-5 x 1011 platelets content and the other is PO-100/1500 with 1500mL capacity for over 6 x 1011 platelets content.In this study, we evaluated the influence of storage of higher content of platelet in PO-100 on the condition of platelet in the bag. The IRB of Nagasaki University approved this study. After informed consent was obtained from healthy volunteers, single-donor apheresis was performed. Then, platelets were pooled, separated equally into two types of bags, PO-100/1000 (n=6) or PO-100/1500 (n=6), and stored in plasma for up to day 7. We monitored various parameters, which related the quality of PC, in bags over the storage period.The result showed that the in vitro characteristics of platelets; platelet counts, mean platelet volume (MPV), and adenosine diphosphate (ADP)/collagen combined-induced platelet aggregation did not significantly change through 7 days storage period both in PO-100/1000 and PO-100/1500. Furthermore, MPV (fL) (8.63±0.35 vs 8.85±0.58, respectively, p=0.463) and platelet aggregation (%) (81.58±4.45 vs 84.67±1.21, respectively, p=0.118) were equivalent between these two conditions.Although pH gradually declined, it was maintained around 7.0 at day 7 without significant difference in both conditions (7.00±0.10 vs 6.92±0.08, respectively, p=0.063). On the other hand, lactate concentration elevated gradually, but there was no significant difference between two bags at day 7 (133.07±23.70 vs 104.52±15.56, respectively, p=0.097) and the pO2 declined by 30 to 40% from day 0 through day 1 in both conditions, suggesting aerobic metabolism was well maintained with efficient O2 consumption and less lactate accumulation in PO-110 bags regardless of its capacity.Intriguingly, our previous investigation demonstrated that pH and ADP-induced platelet aggregation in PO-80 bags decline steeply, notably after day 3, and values at day 7 were 6.67±0.24 and 56.67±11.34%, respectively, which suggested that higher oxygen permeability might contribute to keep platelets in better condition in PO-100 than PO-80.In conclusion, the present study demonstrated that PO-100 had significantly high utility as a noble container for PC. It was considered that better maintenance of the pH of the medium in PC within the appropriate range through improved higher oxygen permeability and efficient aerobic metabolism resulted in platelets in a better functional state even after 7 days storage. Furthermore, the results in this study might open the possibility of practical application of higher unit products, so that the supply chain of PCs could be conducted favorably. DisclosuresNagai:Kawasumi Laboratories Inc.: Research Funding; Kaneka Corporation: Research Funding; Ono Pharmaceutical Co.Ltd.: Consultancy. Yakushiji:Kawasumi Laboratories Inc.: Employment. Kino:Kawasumi Laboratories Inc.: Employment. Tokunaga:Kawasumi Laboratories Inc.: Employment. Yamaoka:Kawasumi Laboratories Inc.: Employment.

Viscoelastic, Mechanical, and Glasstomeric Properties of Precision Polyolefins Containing a Phenyl Branch at Every Five Carbons

Mechanical and viscoelastic properties of precision polyolefins, poly(4-phenylcyclopentene) (P4PCP) and its hydrogenated analog (H2-P4PCP) containing atactic phenyl branches at exactly every five carbons along the backbone are explored. Both materials are amorphous with a glass transition temperature of ∼17 ± 3 °C. Rheological investigations determined that P4PCP has an entanglement molar mass (Me = 10.0 kg mol–1) much higher and closer to polystyrene than H2-P4PCP (Me = 3.6 kg mol–1). Both materials have elastomeric and shape memory properties at ambient temperatures, which were further explored through strain hysteresis measurements. H2-P4PCP has an elastic recovery of ∼95% at max strain values up to 500% as determined by uniaxial tensile testing. Time–temperature superposition analysis, Williams–Landel–Ferry constants, and further mechanical analysis are discussed and compared to previously reported ethylene–styrene copolymers of similar phenyl-branch content within the microstructure.

Stability of Bendamustine Solutions: Influence of Sodium Chloride Concentration, Temperature and Container

Abstract Background Bendamustine is used for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukaemia and myeloma. The stability of bendamustine is highly dependent on temperature and chloride-ion concentration. Limited stability data are available. The objective of this work was to study the stability of the bendamustine reconstituted solution at 2.5 mg/mL and the diluted solution in normal saline and 1.5 % sodium chloride to evaluate a potential increase in stability. Methods A stability indicating High Performance Liquid Chromatography method with Diode Array Detection was used. A first study was carried out in glass vials and then in polyolefin containers at 0.25 and 0.60 mg/mL. Solutions were stored at room temperature and at 2–8 °C for 7 days. Results Stability was defined as a concentration above 95 % of the initial concentration [10]. The reconstituted solution at 2.5 mg/mL was stable for only 2 hours at room temperature and 8 hours at 2–8 °C. The stability of diluted solutions was in accordance with the manufacturer’s recommendations of 3.5 hours at room temperature and 48 hours at 2–8 °C. The addition of sodium chloride doesn’t increase the stability for preparation in infusion in daily practice. Conclusions The information brought by this study is an 8-hour stability of the reconstituted solution at 2–8 °C.

Stability of tacrolimus solutions in polyolefin containers.

Results of a study to determine the stability of tacrolimus solutions stored in polyolefin containers under various temperature conditions are reported. Triplicate solutions of tacrolimus (0.001, 0.01, and 0.1 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection were prepared in polyolefin containers. Some samples were stored at room temperature (20-25 °C); others were refrigerated (2-8 °C) for 20 hours and then stored at room temperature for up to 28 hours. The solutions were analyzed by stability-indicating high-performance liquid chromatography (HPLC) assay at specified time points over 48 hours. Solution pH was measured and containers were visually inspected at each time point. Stability was defined as retention of at least 90% of the initial tacrolimus concentration. All tested solutions retained over 90% of the initial tacrolimus concentration at all time points, with the exception of the 0.001-mg/mL solution prepared in 0.9% sodium chloride injection, which was deemed unstable beyond 24 hours. At all evaluated concentrations, mean solution pH values did not change significantly over 48 hours; no particle formation was detected. During storage in polyolefin bags at room temperature, a 0.001-mg/mL solution of tacrolimus was stable for 24 hours when prepared in 0.9% sodium chloride injection and for at least 48 hours when prepared in 5% dextrose injection. Solutions of 0.01 and 0.1 mg/mL prepared in either diluent were stable for at least 48 hours, and the 0.01-mg/mL tacrolimus solution was also found to be stable throughout a sequential temperature protocol.

Intravenous meropenem stability in physiological saline at room temperature

ObjectivesTo evaluate the stability of solutions of 6 mg/mL, 8 mg/mL and 12 mg/mL meropenem in 0.9% NaCl in a polyolefin container (Viaflo), at room temperature, with a view to...

Functional Polyolefins Containing Disulfide and Phosphoester Groups: Synthesis and Orthogonal Degradation

Disulfide-containing polyolefins were prepared by ring-opening metathesis polymerization (ROMP) of disulfide containing cyclic olefin 1, (Z)-3,4,7,8-tetrahydro-1,2-dithiocine, with other cyclic olefins. This allowed the generation of new degradable polyolefins with nearly 30 mol % disulfide monomer in the backbone, along with functional cyclooctene comonomers bearing pendent hydroxyl, amino, and pentafluorophenyl ester groups. Integration of disulfide groups into the polymer provides redox responsiveness as well as mechanisms for polymer degradation through added reducing agents, thiols for degradative equilibrium exchange, or UV irradiation. This ROMP copolymerization strategy was extended to terpolymers containing both disulfides and phosphoesters that exhibit orthogonal degradation properties.

Stability of alemtuzumab solutions at room temperature

The 24-hour stability of alemtuzumab solutions prepared at concentrations not included in the product label and stored in glass or polyolefin containers at room temperature was evaluated. Triplicate solutions of alemtuzumab (6.67, 40, and 120 μg/mL) in 0.9% sodium chloride were prepared in either glass bottles or polyolefin containers and stored at room temperature under normal fluorescent lighting conditions. The solutions were analyzed by a validated stability-indicating high-performance liquid chromatography (HPLC) assay at time zero and 8, 14, and 24 hours after preparation; solution pH values were measured and the containers visually inspected at all time points. Stability was defined as the retention of ≥90% of the initial alemtuzumab concentration. HPLC analysis indicated that the percentage of the initial alemtuzumab concentration retained was >90% for all solutions evaluated, with no significant changes over the study period. The most dilute alemtuzumab solution (6.67 μg/mL) showed some degradation (91% of the initial concentration retained at hour 24), whereas the retained concentration was >99% for all other preparations throughout the study period. Solution pH values varied by drug concentration but did not change significantly over 24 hours. No evidence of particle formation was detected in any solution by visual inspection at any time during the study. Solutions of alemtuzumab 6.67 μg/mL stored in glass bottles and solutions of 40 and 120 μg/mL stored in polyolefin containers were stable for at least 24 hours at room temperature.

Properties of pediatric aliquots of apheresis platelets stored in a polyolefin container

Properties of pediatric aliquots of apheresis platelets stored in a polyolefin container

Stability of the ready-to-use solutions of eribulin for intravenous infusion

A simple HPLC-UV method was developed to determine the stability of ready-to-use eribulin solutions under different storage conditions. The developed method was validated with respect to linearity, accuracy, precision and ruggedness. The following admixtures were prepared: 3-mL polypropylene syringes at concentration of 440 μg/mL and multilayer laminate polyolefin containers containing 0.9% sodium chloride (50 mL) at concentrations of 15.4 and 43.3 μg/mL. The open-vial stability of eribulin was also evaluated. The following storage conditions were tested: 4 °C in the refrigerator; 20 °C under room light exposure; and 20 °C with light-protection. The drug was also subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The retention time of eribulin was 4.9 min. Admixtures of eribulin solutions in vials, syringes or polyolefin bags at clinically relevant concentrations were physically compatible and chemically stable for at least 14 days at 4 °C in the refrigerator and at 20 °C with or without any protection against light. Degradation was only found to occur under oxidation conditions.

Stability of levothyroxine injection in glass, polyvinyl chloride, and polyolefin containers

The 24-hour stability of a levothyroxine solution admixed and stored in three common infusion containers and infused through polyvinyl chloride (PVC) tubing was evaluated. Levothyroxine sodium 1-μg/mL injection prepared in glass bottles and PVC and polyolefin bags were assayed using high-performance liquid chromatography at 0, 1, 3, 6, 12, and 24 hours; samples drawn directly from the containers, as well as from the distal end of attached PVC tubing, were assayed. The area under the time-versus-concentration curve (AUC) for predicted and delivered doses was calculated; analysis of variance was used for comparison of the percentages of predicted and actual AUC values. The levothyroxine concentration was stable in glass bottles and polyolefin bags through 24 hours (mean ± S.D. percentage of initial concentration remaining, 103.5% ± 2.5% and 100.0% ± 2.9%, respectively). In the PVC infusion bags, the amount of drug decreased to 90% of the initial concentration within 1 hour and then rose and remained within acceptability limits. The levothyroxine concentration of the samples infused through PVC line from glass and polyolefin containers decreased after 1 hour by about 13%; the loss of the drug from the samples infused from PVC bags was higher (18%), presumably due to additive adsorptive effects. In all samples tested, the drug concentration rebounded and remained above 90% to the end of the study. Levothyroxine sodium 1-μg/mL solution was stable for 24 hours in glass bottles and polyolefin bags but when stored in PVC bags, the concentration decreased by 10% after 1 hour.

ChemInform Abstract: New Approaches in Precise Synthesis of Polyolefins Containing Polar Functionalities by Olefin Copolymerizations Using Transition Metal Catalysts

AbstractReview: about 50 refs.

New Approaches in Precise Synthesis of Polyolefins Containing Polar Functionalities by Olefin Copolymerizations Using Transition Metal Catalysts

Recent successful examples for synthesis of new polyolefins containing polar functionalities by adopting the approaches by (a) direct copolymerization of olefin with polar monomer using living radical or coordination insertion methods, (b) direct alkane C-H activation/functionalization (post functionalization of polyolefins), and by (c) controlled incorporation of reactive functionalities (and the subsequent introduction of polar funtionalities under mild conditions) by coordination polymerization in the presence of transition metal complex catalysts have been described. In particular, our recent efforts for precise synthesis of polyolefins containing polar functionalities by (i) efficient incorporation of reactive functionality by copolymerization of ethylene with nonconjugated diene using nonbridged half-titanocene catalysts and (ii) subsequent chemical modifications under mild conditions have been introduced.

Stability of docetaxel diluted to 0.3 or 0.9 mg/mL with 0.9% sodium chloride injection and stored in polyolefin or glass containers

The stability of docetaxel diluted to 0.3 or 0.9 mg/mL with 0.9% sodium chloride injection and stored in polyolefin or glass containers was studied. Vials of docetaxel injection concentrate were reconstituted with the entire contents of the solvent vial and carefully homogenized to avoid the formation of foam. Solutions were aseptically prepared with nominal docetaxel concentrations of 0.3 and 0.9 mg/mL by adding the appropriate quantities to polyolefin containers or glass bottles, to which had been added the appropriate volume of 0.9% sodium chloride injection, yielding a final volume of 50 mL. Three identical polyolefin containers and one control glass bottle for each concentration were prepared. All test solutions were stored at 19-21 degrees C and protected from light. Chemical stability was measured by using a stability-indicating high-performance liquid chromatographic (HPLC) assay with ultraviolet-light detection. Physical stability was determined by visual inspection. No evidence of precipitation was observed during the first 24 hours of the study. However, after a day of storage, the HPLC assay revealed large relative standard deviation values for diluted docetaxel solutions in some containers. These values were predictive for the formation of precipitates and compatible with the existence of microprecipitates at 24 hours. These results suggest that the diluted docetaxel infusions were not stable when stored at 19-21 degrees C. Docetaxel 0.3 and 0.9 mg/mL in 0.9% sodium chloride injection was not physically stable for more than one day when stored at 19-21 degrees C. Docetaxel stability in diluted solutions appears sensitive to slight changes in temperature and degree of agitation.

Recent Progress in Precise Synthesis of Polyolefins Containing Polar Functionalities by Transition Metal Catalysis

Recent successful examples for synthesis of new polyolefins containing polar functionalities by transition metal complex catalysis have been reviewed. The contents are consisted of the following sections: 1) background, 2) radical copolymerization, 3) direct alkane activation/functionalization (post functionalization of polyolefins), 4) controlled incorporation of reactive functionalities (and the subsequent introduction of polar funtionalities under mild conditions) by coordination polymerization. In particular, we wish to introduce our recent approach for synthesis of polyolefins containing polar functionalities via copolymerization of ethylene with nonconjugated diene using nonbridged half-titanocenes. Keywords: Polyolefin, olefin polymerization, ATRP, C-H activation, homogeneous catalysis

Survival and recovery of apheresis platelets stored in a polyolefin container with high oxygen permeability

Oxygen permeability is important in platelet storage media. We compared a new polyolefin container with enhanced oxygen permeability (PO-80; Kawasumi, Tokyo, Japan) to a widely used alternative (PL2410; Baxter Healthcare, Deerfield, IL, USA). In vitro characteristics of paired platelet concentrates (PCs; mean 4.2 x 10(11)/250 ml plasma/bag) stored in PO-80 or PL2410 were assessed through 9 days of storage. In vivo recovery and survival of 7-day-old autologous PCs were assessed according to the Murphy method. Laboratory assessment of platelet quality favoured PO-80 during 9 days of storage with statistically significant differences in glucose consumption (2.75 vs. 4.93 mmol/10(12)/24 h in the interval 120-168 h), lactate generation (4.37 vs. 8.11 mmol/10(12)/24 h in the interval 120-168 h), pressure of oxygen (pO(2)) (59.3 vs. 38.1 mmHg at day 1), and HCO(3)(-) (14.7 vs. 13.4 mmol/l at day 1). Statistically significant differences were not seen in aggregation, hypotonic shock response or pH. In vivo assessment of autologous platelets stored 7 days in the PO-80 container revealed that recovery was 82.1% and survival was 81.0% of fresh control. Seven-day stored PCs in PO-80 were shown in vivo to be non-inferior to fresh platelets, with upper confidence limits (UCL(95)) in recovery and survival of stored PCs below the maximum acceptable difference (MAD); 15.3% UCL(95) < 20.4% MAD and 2.1 days UCL(95) < 2.1 days MAD. The in vitro characteristics of PCs stored in a highly oxygen-permeable container were stable at least 7 days. The in vivo study supports the suitability of PO-80 for 7-day platelet storage.

Drug compatibility with new polyolefin infusion solution containers

The compatibility of new polyolefin (VISIV) containers with seven drugs that have exhibited sorption to polyvinyl chloride (PVC) containers and sets and an additional four drugs that have exhibited leaching of plasticizer or other polymer matrix components from PVC containers and sets was studied. For the sorption portion of the study, amiodarone hydrochloride, carmustine, regular human insulin, lorazepam, nitroglycerin, sufentanil citrate, and thiopental sodium and their respective reference standards were used. For the leaching portion of the study, docetaxel, paclitaxel, tacrolimus, teniposide, and diethylhexyl phthalate (DEHP) reference standard, were used. A 350-mL quantity of each test admixture was prepared, and 100-mL aliquots were transferred into three of the VISIV containers. The containers were stored at ambient temperature and exposed to fluorescent light. Samples for analysis were taken initially and after 24 hours for all drugs except carmustine, which was evaluated for only 6 hours because of its limited stability. High-performance liquid chromatography was used to evaluate each test solution. Of the seven drugs subject to sorption to PVC, only insulin showed a substantial loss in the VISIV containers. Carmustine exhibited a loss consistent with the drug's known chemical stability. None of the drugs that are known to leach plastic components, such as DEHP plasticizer, from PVC equipment exhibited any leached components in the VISIV containers. Of the drugs tested, only insulin exhibited sorption to the new VISIV polyolefin containers. No leaching of plastic components, such as plasticizer, from the containers was found with any of the surfactant-containing drugs.

Synthesis of Polyolefins Containing Silacycloalkane Units in the Main Chain, 1

AbstractSummary: Copolymerizations of ethylene and disubstituted diallylsilanes (CH2CHCH2)2R2Si (R = CH3, C6H5) have been investigated with various zirconocene catalysts using methylaluminoxane as a cocatalyst. The bridged stereospecific catalysts showed a higher reactivity for disubstituted diallylsilanes than the non‐bridged aspecific catalysts. Disubstituted diallylsilanes were incorporated into the polymer chain via cyclization insertion preferentially, and formed 3,5‐disubstituted silacyclohexane units in the polyethylene main chain. A zirconocene catalyst, dimethylsilylenebis(indenyl)zirconium dichloride, produced a copolymer containing pendant allyl groups derived from the 1,2‐insertion of diallyldiphenylsilane without cyclization. magnified image