Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump

Summary

We report a method for drug sorption evaluation using a pump and model drugs (diazepam and tacrolimus). After drug analysis using high-performance liquid chromatography, drug concentrations and sorption levels in the tubes of administration sets are calculated.

Abstract

Administration sets are delivery tools for the direct application of drugs into the body and are composed of a spike, a drip chamber, tubes, Luer adapters (connectors), a needle cover for protection, and other accessories. Drug sorption to tubes of administration sets is a critical issue in terms of safety and efficacy. Although drug sorption is an important factor in the quality of an administration set, there are no standard evaluation methods for the regulation of drug sorption to the tubes. Here, we describe an evaluation protocol for drug sorption to tubes of administration sets. Tubes made of polyvinyl chloride (PVC)- and non-PVC-based polymeric materials were cut to 1 m in length. Diazepam and tacrolimus were used as model drugs. In the kinetic sorption study, we selected the drug concentration and flow rate based on the clinical usage of these drugs. After the dilution of each drug in a glass bottle, the diluted drug solution was delivered through tubes of administration sets using a pump. Samples were collected in amber vials at appropriate time points and the drugs were analyzed using high-performance liquid chromatography. Drug concentrations and sorption levels to tubes of the administration sets were calculated. Acceptable criteria to ensure the quality of administration sets are recommended.

Introduction

Administration sets are composed of a spike, a drip chamber, tubes, Luer adapters (connectors), and a needle cover for protection. Other accessories, such as an airway check valve, a regulating clamp, an in-line filter, a Y-tube with cap (an injection port), and a needle, can also be attached to administration sets. Drug sorption to tubes is a critical issue in the delivery of injectable drugs¹. Sorption describes the adsorption of a drug to the polymer surface and the absorption of a drug into the polymeric matrix². Drug sorption to tubes in administration sets causes unpredictable drug loss and makes it difficult to control the delivered drug concentration. Drug sorption to polymeric tubes is therefore a major impediment to the precise transfer of injectable drugs into the body. However, there are no standard methods or regulatory guidelines for the evaluation of drug sorption to tubes in administration sets.

The levels of drug sorption to tubes in administration sets have been reported using various evaluation methods^1,2,3,4,5. Test methods and model drugs are key factors in sorption evaluation. The pump method^1,3 and drip method^4,5 have been widely used for sorption tests. In general, the pump method should be used in the case of drugs with low concentrations and low flow rates as the infusion conditions. Using various evaluation methods, many studies of drug sorption have been reported for polyvinyl chloride (PVC)- and non-PVC-based tubes in administration sets^1,2,3,5. Many sorptive drugs can be selected to investigate whether the tubes of the administration sets have drug sorption potential or not. Diazepam (Figure 1a)^{1, 2}, tacrolimus (Figure 1b)⁵, nitroglycerin², and cyclosporin A³ are representative drugs with high sorption in PVC- and non-PVC-based tubes.

For the evaluation of drug sorption to the tubes, test conditions such as flow rate and drug concentration are based on the clinical use of the selected drugs^{1, 6, 7}. In the case of diazepam, a high concentration of 100 µg/mL was used at a flow rate of 1 mL/min to mimic the initial dose for the treatment of status epilepticus¹. For tacrolimus, a concentration of 10 µg/mL was delivered at a flow rate of 10 mL/h. Dextrose solution (5%) was used for the dilution of drug injections, and tube length was fixed at 1 m. Glass bottles and vials should be used to prevent additional sorption during the experiment and storage.

In this study, we conducted a kinetic sorption study with the model drugs, diazepam and tacrolimus, using a pump method. Specific details of this protocol, from tube preparation to sorption evaluation, were described previously. Methods for the evaluation of drug sorption have already been used to confirm drug properties for injections and to recommend the clinical use of injections with administration sets on a case-by-case basis^{1,2,3,4,5,6,7}. This protocol may be used as a standard technique for the sorption evaluation of administration sets. International standards for the evaluation of drug sorption to tubes may be necessary to ensure the safety and efficacy of drug delivery.

Protocol

1. Preparation of Tubes in Administration Sets

NOTE: Precisely perform the cutting step to eliminate the effect of differences in tube length on drug sorption.

1. Label the end of the tubes with the tube type (e.g., PVC, polyurethane (PU), and polyolefin (PO)) using a marker.
2. Remove all detachable accessories, such as connectors and needle covers.
3. Using a sharp razor to ensure clean edges, cut the tubes to 1 m in length from the connection of the drip chamber.

2. Dilution of Drug Injections

NOTE: Use a glass bottle (1 L) as the container for the injected drug solution. Perform the dilution step precisely. Verify the composition of the marketed drug product and use the same batch number for a whole experimental set.

1. Label bottles with the drug names (e.g., diazepam or tacrolimus).
2. Dilute the drug injections with 5% dextrose solution, from 5 mg/mL to 100 µg/mL for diazepam injections (2 mL of diazepam injection in 100 mL of 5% dextrose solution) and from 5 mg/mL to 10 µg/mL for tacrolimus injections (200 µL of tacrolimus injection in 100 mL of 5% dextrose solution).
   NOTE: Set up the tested concentrations of drugs and solvents based on the clinical usage.
3. Gently mix the diluted solutions in the bottle by swirling to obtain homogenous drug solutions.
4. Collect diluted solutions (1-10 mL) in amber vials using a glass graduated cylinder.
5. Verify the concentration, as described in step 4.
   NOTE: Use these concentrations of drugs as concentrations at the starting points.

3. Kinetic Sorption Study Using an Infusion Pump

NOTE: Confirm the tube-dependent flow rate using a pump prior to the sorption test due to the hardness of tubes. Collect samples at precise time points and use glass bottles and vials to prevent additional drug sorption during storage. Perform the test as shown in Figure 2. Protect the drug solution against light if the drug has photosensitivity. Perform the experiments in triplicate.

1. Without creating air bubbles, preload a diluted solution of the drug into the tube using a syringe.
   1. Connect one end of the tube to a syringe.
   2. Put the other end of the tube into the bottled drug solution.
   3. Pull back the syringe plunger until the tube is completely filled with the drug solution.
2. Install the tube into an infusion pump.
   1. Open the door of the infusion pump and push the release lever.
   2. Insert the preloaded tube into the infusion pump and keep it straight.
   3. Remove the syringe at the end of the tube after installation.
   4. Put the end of tube into a chemically resistant borosilicate glass graduated cylinder to collect the drug solution after it passes through the tube.
3. Set the flow rate based on the type of tube in the administration set (PVC, PU, or PO) and the drug (e.g., 1 mL/min for diazepam and 10 mL/h for tacrolimus).
4. Collect samples into amber vials at various time points, at room temperature.
   1. Collect 1-mL diazepam samples at 0.05, 0.30, 0.55, and 1.05 h.
   2. Collect 10-mL tacrolimus samples at 1.05, 2.05, 3.05, and 4.05 h.

4. Analysis of Drug Using High-performance Liquid Chromatography (HPLC)

NOTE: Recommended HPLC methods for drug analysis are described in references ^{1, 8,9}. Use tandem mass spectrometry (MS/MS) and immunoassay after sample preparation as alternative methods^{10, 11}. Perform the experiments in triplicate.

1. Weigh the drugs and dissolve them in organic solvents at a concentration of 1 mg/mL as stock solutions.
   1. Use methanol as a solvent for diazepam stock solution due to the low solubility of diazepam in 5% dextrose.
   2. Use acetonitrile as a solvent for tacrolimus stock solution due to the low solubility of tacrolimus in 5% dextrose.
2. Prepare standard solutions by diluting the stock solutions.
   1. Dilute diazepam stock solutions with methanol to 0.3125, 0.625, 1.25, 2.5, 5.0, 10.0, and 20.0 µg/mL.
   2. Dilute tacrolimus stock solutions with 5% dextrose to 2.5, 5.0, 10.0, 15.0, and 20.0 µg/mL.
3. Analyze standards using the HPLC method with UV detection^{1, 8, 9}.
   NOTE: Use an appropriate detection method (UV, fluorescence, etc.) for drug analysis.
   1. Inject 10 µL of standards into an HPLC system with UV detection equipped with a C₁₈ column (1.5 mm × 250 mm, 5 µm). See Table 1 for analysis conditions.
   2. Confirm the specificity and linearity^{1, 8, 9}.
      1. For specificity, monitor the drug peak (i.e., whether it was separated from other peaks in the chromatogram) to identify the drug.
      2. Confirm linearity at the calibration range (i.e., whether the peak area results are directly proportional to the concentrations).
   3. Obtain calibration curves.
      1. Create graphs based on concentration versus peak area value from chromatograms of the standards^{1, 8, 9}.
      2. Obtain linear regression equations with R² for the calibration curves (e.g., y = ax + b, x: concentration of drug, y: peak area)^{1, 8, 9}.
4. Dilute the samples from the sorption study with methanol for diazepam or 5% dextrose for tacrolimus as appropriate so that they fall within the calibration range and directly inject 10 µL of diluted sample into the HPLC system.

5. Calculation of Drug Concentration and Sorption Level

1. Calculate the drug concentrations of the samples using calibration curves (unknown x and known y).
2. Calculate the sorption levels of the drugs using the following equation:
   
   where S: Sorption level (%)
   Co: Drug concentration after the dilution of the injections (µg/mL)
   Cp: Drug concentration passed through the tubes (µg/mL)

Results

The sorption to tubes in the administration set was kinetically monitored using the model drugs, diazepam (Figure 1a) and tacrolimus (Figure 1b), and the pump method (Figure 2). Diluted drug (Figure 2a) was passed through PVC- and non-PVC-based tubes (Figure 2b) at a fixed flow rate using an infusion pump (Figure 2c). The glass bottle was opened slightly to allow the insertion of the admi...

Discussion

Drug sorption to administration sets is a cause of unexpected drug loss in intravenous drug delivery. During sorption, drugs are generally partitioned to polymeric materials of tubes at the early phase of infusion; after sorption equilibrium is reached, the delivered amount of drug is stabilized¹. The sorption levels of drugs should be evaluated and minimized. Several evaluation methods for drug sorption have been studied, such as a pump method and a drip method. Compared to the drip method, the p...

Materials

Name	Company	Catalog Number	Comments
PVC IV sets	Becton Dickinson (BD) Co. Ltd. (Franklin Lakes, NJ, USA)		Internal diameter: 2.54 mm
PU IV sets	Tianjin Hanaco Medical (THM) Co.Ltd. (Tianjin, China)		Non-PVC Internal diameter: 2.54 mm
Non-PVC Polyolefin IV sets	Polyscientech, Co. Ltd (Anseong, Korea)		Non-PVC [PE elastomer/PP elastomer/PB elastomer (25/50/25, weight ratio) blend] Internal diameter: 2.54 mm
Syringe	Korea Vaccine Co. Ltd. (Seoul, Korea)	KOVAX-SYRINGE 1 mL 26G 1/2"
Daewon diazepam injection	Daewon Pharma. Co. Ltd. (Hwaseong, Gyunggi, Korea)		5 mg/mL, total 2 mL Batch No.: P003 Composition: diazepam, propylene glycol, ethanol, benzyl alcohol, sodium benzoate, bezoic acid, water for injection
Tacrobel injection	Chong Keun Dang, Co. Ltd. (Seoul, Korea)		5 mg/mL, total 1 mL Batch No.: AG002 Composition: tacrolimus hydrate, polyoxyl 60 hydrogenated castor oil (HCO-60), dehydrated alcohol
5% Dextrose	JW Pharmaceutical (Seoul, Korea)	500 mL
5% Dextrose	Daehan Pharmaceutical (Seoul, Korea)	200 mL	Bottle (glass)
Amber vials		20 mL	Glass
Terumo infusion pump	Terumo (Medical Corp., USA)	TE-135
HPLC system with UV detector	Agilent (Santa Clara, CA, USA)	Agilent 1260
CAPCELL PAK C18 column	Shiseido (Japan)	90404	1.5 mm x 250 mm, 5 μm
Diazepam			From Daewon Pharma. Co., Ltd.
Tacrolimus	Teva Czech industries  (Czech Republic)		From Chong Keun Dang, Co. Ltd.
Acetonitrile	Burdick and Jackson Co., Ltd. (MI, USA)	3/1/9017
Methanol	Burdick and Jackson Co. Ltd. (MI, USA)	AH230-4
Water	Burdick and Jackson Co. Ltd. (MI, USA)	3/1/4218
Sodium dihydrogen phosphate	Sigma (St. Louis, MO, USA)
Phosphoric acid	Sigma (St. Louis, MO, USA)