Stability study of docetaxel solution (0.9%, saline) using Non-PVC and PVC tubes for intravenous administration
© Park and Chung; licensee BioMed Central. 2015
Received: 15 July 2014
Accepted: 28 November 2014
Published: 28 January 2015
Di-2-ethylhexyl phthalate (DEHP) are added to poly(vinyl chloride)(PVC) infusion tubes as a plasticizer to ensure tube flexibility. In addition to previously reported disadvantages of DEHP, released DEHP molecules from PVC tubes can easily interact with surfactants in anticancer drug solutions (i.e., polysorbate 80 for Taxotere®-Inj) and reduce the solubility of docetaxel in aqueous solution during anticancer drug administration.
In this study, we investigated the in vitro stability of docetaxel in a 0.9% saline solution under an intravenous administration condition using a PVC tube (high DEHP content) and non-PVC infused tube.
The docetaxel solution circulating through the non-PVC tube had better solution stability than through the PVC tube(high DEHP content).
Poly(vinyl chloride) (PVC) is a widely used material for intravenous infusion tubes for administration of drugs in clinical practice and blood bags for blood storage after blood-gathering. Most intravenous infusion PVC tubes contain di-2-ethylhexyl phthalate (DEHP) as a plasticizer to provide flexibility of the infusion tube.
Many reports exist regarding DEHP’s toxic effects released from the PVC tube during intravenous infusion of aqueous drug solutions [1,2]. Leached DEHP affects human metabolism [3,4] and can decrease the medicinal efficacy owing to drug adsorption on the inner surface of the PVC infusion tube . In addition to the drug adsorption effect due to DEHP release, surfactants(such as polysorbate 80 [Tween®80] and polyethoxylated castor oil [Cremophor®EL]) which are meant enhance anticancer drug solubility in the solvent, can interact with leached DEHP from the infusion tube . The plasticizer can affect the surfactants efficacy and reduce the solubility of the lyophilic anticancer drug in the aqueous solution, thus the precipitated anticancer drug (which finally occur concentration difference in anticancer drug solution) may not retain enough of its original pharmaceutical efficacy.
In this study, to confirm the plasticizer effect in chemotherapy using clinical infusion tubes, we investigated the stability of docetaxel solution (0.9 wt% in saline) circulating through commercial PVC (high DEHP content), manufactured PVC (low DEHP content) and non-PVC (polyolefin) infusion tubes.
The docetaxel solution (anticancer agent, Taxotere®-Inj) was purchased from Sanofi-Aventis Korea Co. Ltd. (Seoul, Korea). Commercial PVC infusion tubes (DEHP content: 25 wt%) were purchased from Becton Dickinson Co. Ltd. (Franklin Lakes, NJ, USA). Another PVC (DEHP content: 10 wt%) tube and non-PVC infusion tubes as control group were manufactured by Polyscientech Co. Ltd. (Hwaseong, Korea) using commercial PVC resin (Hanwha Chemical, Co. Ltd., Seoul, Korea) and polyolefin composite as the polyethylene (PE) elastomer/polypropylene(PP) elastomer/polybutadiene(PB) blend(25/50/25 weight ratio), respectively. The PE elastomer (Infuse®, melt index, g/min, 190°C, 2.16 Kg; 5.0) and PP elastomers (Vistamaxx®, melt index, g/min, 190°C, 2.16 Kg; 3.0) were obtained from Dow Chemical Co. Ltd. (Midland, MI, USA) and Exxon-Mobil Chemical Co. Ltd. (Houston, TX, USA), respectively. The PB elastomer (syndiotactic 1,2- polybutadien, melt index, g/min, 150°C, 21.2 N; 3.0) was obtained from JSR Corporation (Japan Synthetic Rubber Corporation, Tokyo, Japan).
The three tubes were adapted for comparison of the time-dependent solution stability of docetaxel during the infusion period (approximately 1 hr).
Composition of the Taxotere®-Inj anticancer drug
Dehydrated ethyl alcohol
0.395 g (0.5 mL)
The circulating rate of the drug solution through the three types of tubes was maintained between 1.2 - 3.0 mL/min to maintain a constant circulating volume considering the different inner diameters of the infusion tubes. The stability of drug solution was evaluated by measuring the visible light (600 nm) transmittance changes of the circulating drug solution at predetermined time intervals (every 10 min).
And then concentration differences of docetaxel solution after circulation was evaluated by measuring the high-performance liquid chromatography (HPLC). The HPLC system was equipped with Waters 1525 binary HPLC pump, Waters 2487 dual λ absorbance detector. HPLC separation was achieved on a Gemini 5 μ C18 column (150 × 4.60 mm, 5micron) (Phenomenex®). Column effluent was monitored at 227 nm. The mobile phase was a mixture of distilled/deionized water and acetonitrile (50:50 v/v) with 1 ml/min flow rate . Standard solution of docetaxel is prepared by dissolving 20 mg of docetaxel in 100 ml of 0.9 wt% saline solution. And standard solutions were prepared in the range of 40-200 μg/ml. The retention time of docetaxel was about 8.0 min.
Results and discussion
This phenomenon can be explained by the released DEPH from the commercial PVC infusion tube during the circulation process contacting the surfactant molecules (polysorbate 80 in Taxotere®-Inj solution) and readily forming complexes through physical interactions . Therefore, the surfactant content in the Taxotere®-Inj solution was decreased and the docetaxel solubility in the Taxotere®-Inj solution was also reduced. The docetaxel molecules were extracted from the Taxotere®-Inj solution after 1 hr of circulation, indicating that when a PVC infusion tube is used for anticancer therapy in the clinical field, anticancer drug (i.e., docetaxel) molecules are extracted from the Taxotere®-Inj solution during intravenous administration. Therefore, the effective drug concentration can be altered during intravenous administration and the original efficacy of the anticancer drug may not be maintained during chemotherapy.
But, the change in docetaxel solubility passing through the non-PVC tube and manufactured PVC tube for the 1 hr circulation was not observed because that the above mentioned interaction between DEHP and polysorbate 80 was minimized and solution stability was remained (Figures 3b and 3c).
From our previous report , the non-PVC tube showed almost identical mechanical properties as the commercial PVC tube in spite of lacking DEHP. And in the case of manufactured PVC tube, the interaction between small amount of released DEHP and surfactants was negligible and docetaxel precipitation was avoided during circulation. In the non-PVC tube and manufactured PVC tube, a decrease in solubility (as shown by lower transmittance) was not observed and drug efficacy during clinical drug injection was preserved.
From pre-mentioned results, manufactured PVC tube may be suitable for infusion tube under the only consideration of negligible interaction with surfactants. But, minimum amount of DEHP was adapted for tube processing, the manufactured PVC tube is not able to recover to original shape after bending (or folding) and is too hard not to use as infusion tube in clinical field.
Therefore, the non-PVC(Olefin) tube is a good candidate for the substitution of PVC infusion tube in chemotherapy.
The efficacy of an injected anticancer drug was not preserved when commercial PVC infusion tube (containing DEHP as a plasticizer at high content) was used for clinical drug administration. Conversely, a non-PVC infusion tube (polyolefin), which did not contain DEHP, maintained drug efficacy in chemotherapy. Therefore, alternative administration using non-PVC tubes and storage bags should be used widely in medical fields to avoid the risks of DEHP leaching and reduction of drug efficacy.
Availability of supporting data
This work was supported by a grant from the Next Generation Eco-Innovation Program funded by the Ministry of Environment, Korea (Project No.; 405-112032).
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