Patent Application
20080087599
Hereinafter, the effects of the present invention will be described by Examples thereof, which, however, should not be construed as limiting the scope of the present invention in any way. The physical properties of the following Examples are evaluated as follows. In Examples, the abbreviation “ND” means “not detected”.
The area of membranes in a dialyzer was calculated by the following equation, based on the inner diameter of the hollow fiber membrane:
A(m2)=n×π×d×L
In the equation, n represents the number of hollow fiber membranes in the dialyzer; π represents the ratio of the circumference of a circle to its diameter; d represents the inner diameter (m) of the hollow fiber membrane; and L represents the effective length (m) of the hollow fiber membranes in the dialyzer.
Extraction and measurement were conducted according to the methods regulated in the approved standards for manufacturing dialyzer type artificial kidney devices. A sample of hollow fiber membranes (1 g) was admixed with pure water (100 mg), and the mixture was subjected to extraction at 70° C. for one hour to prepare a test solution. Then, the UV absorbance of this test solution at a wavelength of 220 to 350 nm was measured. According to the above standard, the maximum absorbance is regulated to lower than 0.1.
A case of polyvinyl pyrrolidone (PVP) as an example of hydrophilic polymers is described.
A module with its passage on the dialysing fluid side closed was connected to a silicone tube circuit, and pure water was allowed to pass through the passage on the blood side of the module to fill both the module and the circuit with pure water. After that, a 40 v/v % ethanol solution was allowed to pass through the passage on the blood side of the module at a flow rate of 150 ml/min., and 100 ml of the same solution was discharged from the outlet of the circuit. The inlet and the outlet of the passage on the blood side were closed with forceps, and the passage on the dialyzing fluid side was successively filled with the 40 v/v % ethanol solution, and was again closed. The 40 v/v ethanol solution, the circuit and the module were all controlled to 40° C., and the ethanol solution was circulated at a flow rate of 150 ml/min. Sixty minutes after, all the fluids in the circuit and the module were discharged and collected together with the circulating fluid to measure the volume of the mixture. The fluid on the dialysing fluid side was separately collected to measure its volume. The PVP contents of the respective fluids were measured according to the following procedure. A sample of each fluid (2.5 ml) was admixed with 0.2 mol/L citric acid (1.25 ml), and the mixture was stirred. Then, 0.006N iodine (500 μL) was added, and the resulting mixture was stirred and was left to stand at a room temperature for 10 minutes. After that, the absorbance of the resultant solution was measured. When the PVP content of the solution was high, the solution was diluted to be 10 or 100 times larger in volume, and then, the PVP content of the resulting solution was measured. The PVP content in the sample was calculated from an analytical curve prepared under the same conditions, to thereby calculate the amount of eluted PVP (mg/m2) per module (1.0 m2).
The measurement was conducted by gas chromatography, using a column filled with a molecular sieve (13X-S mesh 60/80 manufactured by GL Science), an argon gas as a carrier gas, and a detector of heat-conduction system. An analysis was made at a column temperature of 60° C. A gas within a packaging bag was collected by directly pricking the closed packaging bag with a syringe needle.
An oxygen permeability-measuring apparatus (OX-TORAN 100 manufactured by Modern Controls) was used to measure the oxygen permeability of the material of a packaging bag at 20° C. and 90% RH.
A water vapor permeability-measuring apparatus (PARMATRAN-W manufactured by Modern Controls) was used to measure the water vapor permeability of the material of the packaging bag at 40° C. and 90% RH.
To find a moisture content (mass %)of a hollow fiber membrane, the mass (a) of the hollow fiber membrane before dried and the mass (b) of the same hollow fiber membrane after dried at 120° C. in an oven for 2 hours (bone-dried) were measured. The moisture content was calculated by the following equation:
Moisture content (mass %)=(a−b)/a×100
wherein, if the mass (a) of the hollow fiber membrane is from 1 to 2 g, the hollow fiber membrane could be bone-dried in 2 hours (if bone-dried, the membrane shows no further change in mass).
A spinning dope was prepared from polyethersulfone (4800P, manufactured by Sumika Chem Tex Co., Ltd.) (18.6 mass %), polyvinyl pyrrolidone (Kollidon K90 manufactured by BASF) (3.4 mass %) as a hydrophilicity-imparting agent, water (2.0 mass %) as a non-solvent, triethylene glycol (TEG manufactured by MITSUI CHEMICALS, INC.) (30.4 mass %) and dimethylacetamide (DMAc) (manufactured by Mitsubishi Gas Chemical Corporation) (45.6 mass %). The spinning dope was extruded from the outer slit of a double spinneret maintained at 45° C., and water as an inner solution was extruded from the inner injection hole of the double spinneret. The resulting semi-solid hollow fiber was allowed to pass through an air gap with a length of 600 mm at a spinning rate of 60 m/minute, and was then dipped in a solidifying bath of 70° C. (DMAc:TEG:water=12:8:90). After that, the hollow fiber was washed with pure water of 45° C. for one minute followed by pure water of 80° C. for 90 seconds, and then was wound onto a hank. Thus, the hollow fiber membrane with an inner diameter of 199.5 μm and a thickness of 29.5 μm was obtained.
About 10,100 hollow fiber membranes thus obtained were inserted into a polyethylene pipe, which was then cut with a predetermined length. After that, the hollow fiber membranes in the pipe were dried in a hot air drier at 40° C. until the moisture content in the hollow fiber membranes became 0.6 mass %. Thus, a bundle of the hollow fiber membranes was obtained.
The bundle was inserted into a casing, and the end portions of the bundle were bonded with an urethane resin. After that, the end portions of the bundle were cut out. Thus, a blood purifier of which the selectively permeable separation membranes were opened at their both ends was made up. This blood purifier was sealed in a packaging bag together with two moisture-release type oxygen scavengers (Ageless Z-200PT manufactured by Mitsubishi Gas Chemical Company, Inc.). In this regard, the packaging bag was made of an aluminum lamination sheet which had an outer layer of a polyester film, an intermediate layer of an aluminum foil and an inner layer of a polyethylene film and which had an oxygen permeability of at most 0.5 cm3/(m2.24hr.atm) and a water vapor permeability of at most 0.5 g/(m2.24hr.atm). After the sealing, the packed blood purifier was stored at a room temperature. The humidity and the oxygen concentration in the inner atmosphere of the packaging bag, the moisture content of the selectively permeable separation membranes, and the UV absorbance of an eluate and the amount of an extract from ethanol in an elution test were measured and determined after 1 day, 1 month and 3 months have passed after the sealing, respectively. The results are shown in Tables 1 and 2.
A blood purifier was made up of the same selectively permeable separation membranes as those used in Example 1, in the same manner as in Example 1. A blood purifier package was obtained in the same manner as in Example 1, except that the blood purifier was packed in a packaging bag, together with two general-purpose type oxygen scavengers (TAMOTSU® manufactured by OJITAC). The resultant blood purifier package was stored in the same manner as in Example 1. The results of the evaluation of the selectively permeable separation membranes which changed in properties with time are shown in Tables 1 and 2. It was supposed that the amount of an eluate increased since the entanglement of the hydrophilic polymer and the hydrophobic polymer became weak because of too small a moisture content in the packaging bag.
A bundle of selectively permeable separation membranes was obtained in the same manner as in Example 1, except that the moisture content of the selectively permeable separation membranes, found immediately after the drying, was changed to 8.8 mass % by lowering the drying degree of the same membranes.
While a blood purifier was made up in the same manner as in Example 1, a failure in the adhesion of the membranes occurred because of the foaming of the urethane resin. This foaming was supposed to occur because of the reaction between the urethane resin and the moisture in the selectively permeable separation membranes.
A blood purifier package was obtained in the same manner as in Example 1, except that no oxygen scavenger was used, and the resultant blood purifier package was stored in the same manner as in Example 1. The results of the evaluation of the blood purifier which changed in properties with time are shown in Tables 1 and 2. It was supposed that the amount of an eluate from the blood purifier increased with time since the oxidation and decomposition of the hydrophilic polymer proceeded because of the influence of the oxygen in the system.
A blood purifier package was obtained in the same manners as in Example 1, except that the blood purifier was sealed in a packaging bag, together with the same general-purpose oxygen scavenger as that used in Comparative Example 1, and a humectant which was prepared by sealing zeolite powder having adsorbed water (zeolite (10 g)+water content (10 g)) in a perforation type moisture permeable packing material (having a water vapor permeability of 500 g/(m2.24hr.atm) (40° C., 90% RH). The resultant blood purifier package was stored in the same manner as in Example 1. The results of the evaluation of the blood purifier which changed in properties with time are shown in Tables 1 and 2.
A blood purifier package of Example 2 was obtained in the same manners as in Example 1, except that an electron ray exposure apparatus with an acceleration voltage of 5,000 KV was used instead of the γ-ray. The results of the evaluation of the blood purifier which changed in properties with time are shown in Tables 1 and 2.
The blood purifier, sterilized by exposure to a radioactive ray and/or an electron ray according to the sterilization method of the present invention, is markedly improved on its reliability in safety when used for hemocatharsis, because there can be inhibited the formation of various extracts from the blood purifier, attributed to the deterioration of the components of the blood purifier, particularly to the deterioration of the selectively permeable separation membranes with time during and after the above exposure. Therefore, the present invention will significantly contribute to this industry.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2004-301779 | Oct 2004 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP05/18862 | 10/13/2005 | WO | 00 | 12/12/2007 |
