CA1107020A

CA1107020A - Cellulose acetate hollow fiber and method for making same

Info

Publication number: CA1107020A
Application number: CA306,020A
Authority: CA
Inventors: Michael J. Kell; Robert D. Mahoney
Original assignee: Cordis Dow Corp
Current assignee: Althin Medical Inc
Priority date: 1977-07-05
Filing date: 1978-06-22
Publication date: 1981-08-18
Also published as: FR2396780A1; JPS5442420A; ATA477578A; JPS62250215A; DE2827100C2; GB2000722B; AU519458B2; NL7807225A; MX153159A; IT1107799B; DK302078A; BE868708A; DE2827100A1; DK149600C; NO147979B; IT7850125A0; GB2000722A; AU3697178A; BR7804325A; AT364899B

Abstract

IMPROVED CELLULOSE ACETATE HOLLOW
FIBER AND METHOD FOR MAKING SAME

Abstract Of The Disclosure An improved cellulose acetate semi-permeable hollow fiber suitable for use in artificial kidneys and a process for making same with selectively controllable permeability characteristics which provide superior water and solute clearances, higher tensile strength and resistance to fiber breakage during fiber processing and assembly, and which possess the capacity to remove blood solutes such as urea creatine uric acid and water at rates which are higher than prior art cellulose capilliary fibers. The new fibers are made from a novel spin melt composition which can be melt spun into stronger hollow fibers with permeability characteristics enhanced by controlled post spin processing steps and the permeability varied and controlled by adjusting relative quantities of each of three constituents.

Description

7~20 Back~round of the In~ention:
Cellulose e~texs, including cellulose acetate have been formed into semi-permea~le ~ollow fibers and used as separatory membranes in a ~ariety of processes including desalinization of sea water, ultrafiltration of aqueous and non-aqueous solutions, ion exchange processes, concentration of salts, purifying waste streams and the like. Permeable separatory membranes prepared from film-forming cellulose esters are disclosed in many U.S. Patents, the most pertinent of which that are known to applicants are 3,532,527 and 3,494,780. U.S. Patents 3,532,527 and 3,494,780 describe a process of melt spinning cellulose esters, particularly cellulose triacetate and cellulose acetate, from a melt-spin composition consisting of a compati~le plasticizer of the tetramethylene sul~one type, such as those disclosed : in U.S. 2,219,006, U.S. 2,451,299 and U.S. 3,423,491 and a polyol having a molecular weight from about 62 to about 20,000;
the weight ratio of the sulfolane plasticizer to polyol in the mixture is disclosed to vary from about 0.66:1 to about 5:1 and preferably from about 0.8:1 to 1.3:1.
`The stated purpose of varying the relative proportions of these materials was to modify the ability of the fibers to separate salt from sea water. Such fibers made by the processes of U.S, Patents 3,532,527 and 3,494,780, while useful in the desalinization of sea water, are not satisfactoxy for use 11~37~20 in hemodialysis as hollow fibers in artificial kidneys.
Cellulose acetate membranes having diverse ~orms has been the subject of extensive research funded by the National Institutes of Health and the Office of Saline Water since about the middle 1960's. The ~ational Institute of Arthritis and ~letabolic Diseases has also funded research directed to the modification of kno~ cellulose acetate hollow fibers to evaluate their p~tential for use in artificial kidneys. A three year project of this type, having as its major objective the development of a cellulose acetate hollow fiber artificial kidney, was conducted by The Dow Chemical Company, Western Division Research Laboratories in 1971-1973, under NII~ Contract No. 70-2302. Under that contract cellulose acetate fibers were made by melt spinning a mixture of cellulose acetate and triethylene ~lycol, and some of the resultant fibers were in-corporated into artificial kidneys and clinically tested in hemodialysis. The best artificial kidneys which were made during tllat project, while successful in the sense that they were used safely in dialyzing a number of test patients in a clinic were nevertheless unsuccessful in that their concurrent transport properties for re-moval of water and low molecular weight solutes such as urea and creatinine were not as good as artificial kidneys then available which employed cellulose hollow fibers; tlle problem with these kidneys was that water removal rates were too high and the ratio o blood solute to water removed was too low, and the project was dropped.
Since the early 1970's, when hollow fiber artificial kidneys were first commercially made available by Cordis ~ow Corp.
in the ~nited States, the hollow fibers used in such commercial artificial kidncys have been substantially exclusively cell~llose fibers. These fibers have been either the product of the cuproammonium process or the process of Lipps ~- S- P~ent 3,546,~09. Although iL1~7$2~

cellulose hollow fibers have enjoyed widespread market acceptance as the best form of semipermeable membrane for use in artificial kidneys to the present time, it is acknowledged by the skilled artisan that there are numerous, recurring production problems in melt spinning such fibers and incorporating them into leak-free arti~icial kidneys. ~or exa~nple, tensile strength of the fibers is relatively low and ~iber breakage makes handling during fiber processing and assembly int~ a dialysis chamber both complex and difficult. Because of such difficulties with cellulose capillary fibers there is a continuing need for semipenneable capillary fibers which are inexpensive, easy to melt spin and process into artificial kidneys on a commercial scale, and which possess the capacity to remove blood solutes such as urea, creatinine9 uric acid, and water at rates which are higher than those which characterize present day cellulose capillary fibers.
The primary objective of this invention is to provide a new cellulose acetate hollow fiber which is improved relative to heretofore known cellulose ester and cellulose hollow fibers in having selectively controllable permeability characteristics that make possible the fabrication of artificial kidneys containing such fibers which provide water and solute clearances that are superior to those which characterize present day commerical artificial kidneys containing cellulose hollow fibers. A related objective is to provide a process for making the i~proved cellulose acetate fibers of this invention.

Summar of the Invention Y
This invention provides novel cellulose acetate semipermeable hollow fibers having a combination of permeability and clearance characteristics for water and solutes in blood having molecular weights less than about 1400 that are variable relative to each other and controll-able so as to provide optimized operating characteristics when used in an ~ 7~2 /

artificial ~idney or hcmodialysis. Optimum operating characteristics for an artificial kidney refers to a high rate of clearance for waste blood solutes relative to the rate of water removal to thereby ena~le health protecting blood puriEication in minimum time.
The new fibers of this invention are made from a novel spin melt ~omposition. This composition enables ceilulose acetate to be dry spun, cooled in air and taken up on reels without prior leachingO The new spin melt composition comprises a mixtuTe of ~ellulose acetate and certain proportions of polyethylene glycol llaving a molecular weight bet~een about 150 and about 600 and certain propol~tions of glycerine; this composition can be melt spun into hollo~ fibers ~hich arè stronger and easier to process into artificial ~idneys than cellulose fibers and yet possess a favorable combination of water and blood solute permeability characteris~ics; these pèrmeability characteristics are further enhanced and optimized by subjecting the spun fibers to certain, controlled post-spin processinn steps. Permeability of these fibers can be varied and controlle~ by adjusting the relative quantities of each of the three constituents of the melt spinning composition and optimization of the ratio o-E
low molecular ~eight blood solute to water clearance results ~hen SIIC}I composition adjustments are made in conjunction with controllcd cooling and a controlled degree of cold dra~Ying, or stre~ching, of the spun iber immediately a~ter cooling and prior to leaclling from the spun fiber any of the glycerine or polyethylene glycol consti-tuents in the cooled fiber. By dry spinning into air at amb-ient temperature and appropriate control oI the degree of cold draw and careful selection of the amounts of each constituent in the melt spin composition it is possible to produce cellulose acetate fibers having preselected combination clearance properties and higher ratios of solute clearance to ~ater clearance than those of heIetororc ~no~n cellulose acctate hollow fibers.

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In one form, the inventi.on comprïses a cellulose acetate hollow fiber having an internal diameter in the range of about lO0 to about 350 microns and a wall thickness in the range of about 20 to about 6Q microns, said ~7all having a select.ve permeahility wh.en used in hemodialysis for water and solu~es to ~e removed from ~lood represented by an ultrafiltration coefficient in the range of a~out 2 to a~out 6 milliliters per hour per square meter per millimeter of mercury and a urea coefficient in the range of a~out 0.015 to about 0.045 centimeters per minute.
In another form, the invention comprises a process for making cellulose acetate hollow fi~ers, which process comprises the steps of: Cl~ providing an intimate mixture of about 41 to about SQ weight percent cellulose acetate, about 2 to about 20 weight percent glycerine, and a~out 30 to about 57 percent polyethylene glycol h.aving a molecular weight in the range of about lS0 to about 600, ~2~ fa~ricati.ng hollow flbers from a molten mass of said mixture, (3~ cooling said fibers, (4) cold drawing said fibers an amount in the range of about 2~ to about 20~ of said cooled fi~er length, (5) leaching said fi.bers to remove therefrom said polyethylene glycol and said glycerine, and (~6~ replasticiæing said fi~ers with glycerine and thereafter drying same.

Detailed Description of the Invention _ . .. . .
The ne~, improved cellulose acetate fibers of this invention descri~ed above will be further characterized and explained in connection wi.th th.e melt spin composition and process OI this invention which. are shown in Figures 1 and 2, respectively.

Fi.gure 1 i.s a three component diagram showing the proportions of the three components which are combined in the ~ melt spin compositions of this invention, as indicated by the area bounded by points A, ~, C and D.
Figure 2 schematically illustrates the steps used in processing the melt spin composïtions of Figure 1 to form the improved family of hollow capillary cellulose acetate fibers of this invention.

MEI.T SPIN COMPOSITION
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The melt spin composition of this invention comprises in weight percent about 41 to a~out 50~ cellulose acetate, about 2 to about 20~ glycerine, and the ~alance polyethylene glycol ha~ mg a molecular ~eigh.t in the range of a~out 150 to about 600. As shown in Figure 1, this family, or spectrum, of three component compositions lies within the area bounded by the extremes of each of the three components which generate the area A, B, C, D. Any of the specific compositions consisting of an amount of each of t~e three components within the area A, B, C, D of Fïgure 1 are suitable for melt spinning - 5a -` .
' into hollow ca~illary fibers; after coolin~ ater leaching out the glycol and glycerine and fabrication into an artificial kidney of current design such fibers function as ~ell, or better, than pre-sent da)r cellulose fibers made by the cuproammonium process OT the process of Lipps U.SO Patent 3,546,209. Preferred compositions ~hich are particularly ~ell suited to optimization -of opeTating characteristics for most intermittent dialysis patients are shown in Figure 1 bounded by the area E, F, G, H.
The three components celluose acetate, ethylene glycols and glycerine are separately old in membranes and cellulose acetate has been combined ~ith a polyol such as glycols in compositions which also contained a plas~ici~er, ol solvent, for the cellulose acetate of, for example, the sulfolane type as taught in U. S. Patent 3,53~,527. It ~as not knolYn prior to this invention~ ho~ever, that glycerine, a non-solvent for cellulose acetate at ambient temper- n atures, could be used in combination ~ith selected lo-~ molecular ~eight glycols to produce strong hollow fibers having modified permea-bility characteristics relative to those obtained in the presence of a sulfolane type solvent; similarly~ it ~as not Xno~n that certain proportions o glycerine in such compositions ~ould enable the modification and control of lo~. molecular weight solute transpol~t tllrough the fiber ~all relative to ~.~ater transport through that same ~all.
Cellulose acetate, as used in this specification and claims re~ers to cellulose diacetate. Cellulose diacetate, as commercially available in the United States, is satisfactory for use in this inven~ion and is preferred although amounts of mono-acetate ~nd tri-acetate may be present, for e~ample, up to about Z5%, smaller amoullts being normally present in comme]-cial cellulose diacetate.

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``: ' /IYhen cellulosc acetate is dissolved in a solvent such /as dimethyl sulfoxide, sulfolane, triethylene glycol ~r other lo~Y molecular weight glycol that is liquid at ambient temperatures and spun through a conventional spinnerette into a tow of fibers, the individual fibers tend to stick or weld together ~hen taken up on a core. Such fibers~ even though cooled beiow the gel point and hardened to solid fiber form, retain a quantity of solvent ~hich apparently keeps sur-face areas suficiently soft to cause stic~ing during take upO Heretofore, it has been necessary to leach solvent from the spun and cooled fiber before take up and a hot water leach bath has been used for this purpose. It was found, . ~ , .
ho~ever, that hollo~ capillary fibers fed immediately after cooling into a leach bath caused severe fiber pulsing and resultant non-uniform wall thic~ness and non-uniform internal diameter. It ~as found, in accordance ~ith this invention~ that fiber welding could be avoided without leaching prior to take up on cores by using a lo~
molecular ~eight glycol as solvent for the cellulose acetate, modified ~ith the above specified amounts of glycerine. Apparently, ~he ~_ glycerine reduces the surface softening effect of the glycol and the fibers can be ~ound, and even stretched and ~ound on cores under tension, without sticking or ~eldingD The resultant spun fibers possess improved uniformity in wall thickness and internal diameter and may be stored indefinitely at room tempeTature on COTeS for future processing into artificial kidneysO
Glycerine also apparently modifics the cellulose acetate gellation during cooling in such a manncr that the resultant porosity in the fiber ~all is changed. lYith glycerine present in the spin melt composîtion, as above defined, a gclled fiber results which is sufficiently strong to maintain îts integrity and substantially maintain its uniformity of l~all thic~ness and inside diameter dimension during stretching or cold dra~ing immediately aftcr gellation or solidificatiOn~ as ~ill bc explained hereinbelol~ in .

connection ~ith the step of cold drawing. Surprisingly, such cold drawing further modifies the fiber wall porosity such that low molecular wei~ht blood solutes pass more readily through that wall from blood flowing inside the fiber to a dialysate solution flowing outside the fiber. A substantial increase in such blood solute transport, that is solutes having a molecular ~eight up to about 1400 which includes urea, creatinine, uric acid and o~Xers up to and including Vitamin B 12, is obtained without increasing the ability of the fiber to transport ~ater through that same wall.
Although the mechanism of this change as the result o cold drawing is not fully understood, it has been found that the degree of cold dra~ing and the quanti~y of glycerine present in the spin melt composition are interrelated and interdependent. Generally stated, ~hen using a spin melt composition consisting of cellulose acetate dissolved in a polyethylene glycol having a molecular ~eight in the range of ~bout 150 to about fiO0 and at least about 2% of glycerine, some increase in the blood solute transport occurs as the cold drawing increases in an amolmt up to about 20% of the as spun fiber lengthO
Such increase cont;nues as the glycerine content increases but the relationship is not entirely linear; ~ith proportions of glycerine in the spin melt composition betweel- about 3~ and 10%, and cellulose acetate between about 42% and 47%, balance polyethylene glycol, improvement in the ratio of blood solute transport to ~ater transport occurs as the degree of cold dra~ing increases up to about 15% of the as spun fiber length an~ at 43~-45% cellulose acetate excellent results are obtained at abo~t lO~o . ~laximum improvement in the ratio of blood solute transport to water transport is obtained l~ith compositions selected from the preferred area EFGH as sho~n in Figure 1 and the optimum degree o~ co~d dra-~ can be easily established for the selected composition b~ a fe~ simple tests.

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Hollow Fiber Process Using Melt S~in Composition As may be seen in Figure 2/ t~e process comprises the steps of forming the above descrih~d melt spin composition, melt spinning hollow fi~ers and cooling same to a yelled self-supporting state and stretching or cold drawing the fibers. The stretched fibers may be stored, or a plurality of tows consolidated into bundles of fibers, for example, 3,000 to 30,000 fibers, for further processing in preparation for assembly into artificial kidneys.
The fibers in a consolidated bundle are passed through a leaching - 10 tank to remove the glycol and glycerine, thus forming a bundle of semipermeable hollow fibers. The leached bundle is then re-plasticized with a glycerine-water solution, excess glycerine removed and the fibers dried. The dried fibers are the improved product of this invention.
Formulating the melt spin composition may be accompllshed in any convenient manner ~ith conventional mixing equipment, the important feature being to insure sufficient mixing to obtain an intimate uniform mixture. For example, dry cellulose acetate powder is blended with a weighed amount of polyethylene glycol and ` glycerine in a high-shear HOBART mixer, the mixed material is further homogenized and blended by feeding the same into a heated counter-rotating twin screw extruder and the molten extrudate then forced through a spinnerrette, for example, a 16-32 hole spinner-rette of the ~ype including conventional gas supply means for injecting gas into the core of the extrudate. A preferred gas for this purpose is nitrogen but other gases may be satisfactorily employed, including car~on dioxide, air, or other innocuous gas.
The extrudate exiting from the spinnerrette is subjected to cooling, such as forced air cooling of varying force and/or temperature, to *Trademark :

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~7~20 cause gellation and solidification of the extrudate into solid, self-supporting fibers. The fibers are hollow with about 100 to about 350 microns internal diameter and a wall thickness in the range of about 20 to about 60 microns.
Typically, the fibers are capillary size, that is in the range of about 150 to about 300 microns internal diameter and having a wall - 9a-~1~
thickness in the range of about 20-50 microns. While the preferred Il, fibers of this invention are particularly adapted for use in hemo-dialysis in artif~cial kidneys, the advantages of dry spinning and forming of fibers which may be taken up on supporting cores without p~ior leaching are equally applicable to fibers adapted for other uses such as ultrafiltration, etc. Such other fiber may sati~factorily have outside ~iameters in the range of about 350 to ~100 microns and wall thicknesses in the range of about 10 to aboùt 80 microns.
In the process of this invention the short time period mn~ediately after the extrudate exits from the spinnerrette openings is extremèly important to the attainment of the desired permeability of the product fibers. During that period of time, the porosity, and thus permeability, of the resultant fiber is determined as a joint function of the cooling rate and the cold drawing or stretching to which the fibers are subjected. Porosity, for a given melt spin composition, is increased, at any given degree of tension on the fibers, by a drastic quenching of the molten fiber relative to the porosity ~hich results from a less drastic quench or a slo~er gellation of the extrudate into fibers. Increasing porosity which results from such quenching normally affects the ability of the fiber to transport water and may be employed, as needed, to preselect or modify the ultlafiltration rate of the resultant fiber when used in hemodialysis.
By increasing the rate of flow of ambient temperature air across the extrudate~ one ~ay effect minor adjustments in the resultant fiber porposity; similarly, a like effect may be obtained by lowering the temperature of the cooling medium or both may be adjusted to achieve optimum conditions. It is preferred to employ ambient temperature air for cooling, commercially satisfactory results having been obtained without resort to cooling to below ambient temperatures Cold drawing, or stretching, is satisfactorily effected by passing the extruded and solidified fibers over a series of rolls, or spaced apart series of rolls such as Godet roll,; the desired degree ~ 7~

`of cold drawing may be obtained by control of the rate of rotation of the second roll, or second group o~ rolls in the line of flow of the fibers. Good correlation between the degree of fiber cold drawing and the pres~et, or measured, rate of rotation of ~he downstream set of rolls is usually obtained and for a particular desired percentage of cold draw, it is necessary only to accurately control the rate of rotation of the dot~nstream set of rolls relative to the upstream set of rolls.
Ta~e up or winding of the cold drawn, or stretched fibers on coTes or reels may be accomplished with commercially available windeTs such, for ~xample, as LEESONA winders, adequate care being taken to maintain ~light tension on the fibers during takeup.
In the preferred form of the process, a plurality of cold drawn cores or reels, are mounted to feed a plurality of to~s of fibers ~hrough a conventional gathering means to form a consolidated bundle and thereafter the consolidated fibers are leached to remove the glycerine and polyethylene glycol components. The leaching treatment can be carried out by any convenient means such as passing the bundle of fibers through a bath of selected solvent, OT by semi-batch immersion o~
the cores or rolls in such solvent. The leaching solvent may be any solvent which is a good solvent for the plasticizer and glycerine and a poor solvent foT cellulose acetate, l~ater being preferred. Aqueous solutions, alcohols and combinations thereof have been satisfactorily employed for example, methanol, ethanol, propanol, and mixtures thereo~, dilute aqueous solutions of sodium sulfate, magnesium sulfate and sodium chloride. Leaching may be carried out at ambient or elevated temperatureS and higher than ambient temper~tures are Tecommended up to, for example, 80-90 degrees C- Th~ preferred leaching procedure is to employ a primary and s~condar)~ leach bath~ the firs~ bath at a highcr temperature ~han am~ient and prefcrably in the range o about S0-90 de~rees C. f~r abou~ 5-30 ~econds ~nd the seco~dary leach ~or *Trademark .

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1-10, preferably 2-4 minutes at ambi~nt temperatures. As a guide to selecting the opt;~um primary leach temperature to produce fibers having the desired water transport rate, it has been found that as the percentage content of cellulose acetate increases between 41% and 50~
that the water transport rate, relative to cellulose fibers, decreases at a slower rate as the temperature of the leach increases from about 20 degrees C. up to about 80 degrees C. Increasing leach temperatures between about 50 degreees and 90 degrees C. tends to increase the transport permeability of the fibers for urea, creatinine, and other low molecular weight solutes up to and including Vitamin B 12.
~ fter the fibers have been leached~ and the desired per-meability thereby established, conversion of the fibers to a dry form requires replasticization with glycerine or its equivalent.
Replasticization is preferably accomplished with a water/glycerine solution which may satisfactorily contain from about 30% to about 60%
glycerine by weight with good results having been obtained with 50%
glycerine aqueous solution.
As a guide, as the glycerine concentration in the replasti-cization solution is decreased below about 50% the rate of water transport also decreases. As indicated in Figure 2~ after replasticization the fibers may be dried by passing through a conventional drying oven or by other means such as vacuum removal. Optionally, a portion of the glycerine may be removed by forced air blow off by passing the fiber bundle through or past, a set of opposed air knives at pressures and times to reduce the glycerine present in the fiber.
As the glycerine is reduced by drying, or vacuum or increasing air blow off pressures from about one to about six pounds per square inch a reduction occurs in both the water and blood solute transport capacities of the resultant fibers. Typically satisfactory drying conditions are about 40 degrees C- to 80 degrees C. for 1-6 minutes;
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~ -l2 --~7~2C~

at longer drying times above 60 degrees C., blood solute transport rates decrease and thus lower temperatures should be used to optimize the ratio of blood solute to water removed durin~ inter-mittent hemodialysis.
The improved cellulose acetate hollow fibers of thls invention, which ma~ be inade from the above described ~elt spin compositions by using the`steps enumerated and selected conditions thereof as above explained, possess a combination of water transport and solute transport capabilities which distinguish them from heretofore known cellulose acetate hollow fibers. The defining properties of the fibers of this invention are most conveniently expressed as coefficients. The water transport permeability is expressed as the ultrafiltration coefficient, ~UFR' and is in the range of about 2 to about 6 millimeters per hour per square meter per millimeter of mercury pressure differential between the opposite sides of the membrane wall. The ~ FR coefficient provides a number representative of the ability of the semipermeable fiber to pass water per unit of pressure gradient across the effective membrane area.
The effective membrane area is the exposed portion of surface area of the semipermeable wall of the hollow Cibers which is in contact with ~he fluid and through which water transport may occur~ for example, per square meter, or other selected area.
The solute transport permeability is expressed as the over-all diffusive mass transfer, or dialysis, coefficient of the membrane, . The dialysis coefficient, Km, provides a number representative of the ability of the semipermeable cellulose acetate fiber to separate a dissolved component, or solute, in a fluid on one side of the semipermeable wall of the fiber and transport, or pass, that component to another fluid in contact with the opposite side of that same wall surface as a f~lDctioD of the effective area of the semi-permeable membrane and the concentration of the solute in the two .
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1uids on opposite sides of that semipermeable wall. I~}lile the rate at which solute is transported from the blood to the dialysate is critically important as the limiting variable ~hich determines the minimum required time to complete hemodialysis using an arti~icial kidney containing the cellulose acetate hollow fibers of this inven-tion, and that rate is determinable from the cle~rance for each solute ~hich is expressed in terms of milliliters o~ solute per minute~
~m provides a number ~hich indicates the ability of the fiber to pass solutes as a function of the molecular size, or weight, of the solute, and the units of Km are centimeters per minute. Clearance refers ~o the number designated as ~rU, for renal urea clearance, or ~rCr, for renal cr~a-tinine clearance, in milliliters per minute~
as defined in Chapter 41 by Frank A. Gotch in Vol~ II of the treatise entitled The Kidney. For the improved fibers of this invention the membrane coefficient for urea, KUreay is in the range of about Q.015 to about 0.045 centimeters per minute; the membrane coefficient for , KCreatinine~ is in the range of about 0 013 ~o ab t 0 02 centimeters per minute; and the membrane coefficient for ~itamin B 12, ~Bl2' is in the range of about 0.002 to about 0.005 centimeters per minute. The ratio of the dialysis coefficient of the membrane, ~m~
to the ultrafiltra*ion coefficient, KUFR~ is above about 3:1 based upon the abo~e stated ranges of coefficients and the units for each as statedO
For hemodialysis the preferred combination of ~ater and solute transport capability is a ~UFR in the range of about 3 to about 5 milliliters per hour per square meter per millimeteT of mercury, a KUrea above about 0.020 centimeters per minute and a ratio of rea/~UFR above 5:1. Such fibers ma~e possible the construction of artificial ~idneys of the gen~ral type manufactured by Cordis Dow Corporation ~hich substantially reduce the time recluired for a hemodialysis treatment and pro~ide flexibility and ease of control O ]4.

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during he~odialysis relative to commercial hollow fiber artificial kidneys which use semipermeable cellulose fibers made by the process of Lipps V. S. Patent 3,546,209. Relative to such artificial kidneys, which typically provide a ~ FR below about 1 millimeter per hour per square meter`per millimeter of mercury as operated at ambient room temperature the rate of water removal from blood being dialvzed ~ith artificial kidneys using the same effective area of the new cellulose acetate fibers of this invention under similar use conditions is two to six times as high. While a ~ R
above about 6 may require replacement of a part of the removed water before the treatment reaches its preselected water content at the end of the hemodialysis, a faster water removal rate presents certain advantages relating to ease and flexibility of control during the dialysis. Moreover, artificial kidneys using cellu~lse acetate fibers having the solute coefficients above defined, per square meter9 enable ~aster removal of the blood solutes such as urea, creatinine, uric acid, etc. For example, artificial kidneys providing 1 square meter of ef~ective surface of the cellulose acetate fibers of this invention having coefficients within the above given range typically provide a urea clearance in the range of about 100 to about 165 milliliters per minute, a creatinine clearance in the range of about 80 to about 135 milliliters per minute and a B12 clearance in t~e range of about 15 tc about 45 milliliters per minute.
This invention provides a range of spin compositions and variable processing parameters on the steps used to manufacture the herein described fibers whicll makes it relatively easy to preselect, and to manufacture cellulose acetate fibers having optimized ~ FR

and ~ characteristics and eO fabricate such fibers into artificial m kidneys preselected to satisfy particular patient requirements. By using particular melt spin compositions and selecting appropriate 1 5 .

processing conditions, it is relatively easy to produce cellulose acetate fibers of this invention concurrently ~ossessing an~
particular desired rate of ~ater and solute removal rates within the ranges above indicated Thus, it will ~e appreciated that the improved cellulose acetate fibers of this invention provide a con-venient means for facile, convenient fabrication of a fami~y of artificial kidneys offering control]ed and preselected rates for concurrent removal of water and solutes during hemodialysis.
The following examples specifically illustrate the best mode contemplated to make the new cellulose acetate fibers of this invention and will serve to further exemplify the effects on the ~UFR and ~m as a func~ion of melt spin composition, and the degree of cold dl~a~ing to which the fibers are subjected during processing;
they also illustrate typical fiber transport capabilities which charac-terize the improved cellulose fibers of this invention.

. . _ Three batches of cellulose acetate fibers were prepared using different mele spin compositions. The first composition contained in percent by weight7 43~ cellulose acetate and 57%
polyethyle~e glycol having a ~olecula~ weight of approximately 400; the second composition contained 43% cellulose acetate, 50Z
polyethylene glycol having a molecular weight of approximately 400 and 7X glycerine and the third mel~ spin composition contained 43~ cellulose acetate, 39X polyethylene glycol having a molecular weight of about 400 and 18~D glycerine. The same cellulose acetate material was used in each of the three melt spin compositions.and was obtained from Eastman Chemical Products, Inc., Kin~sport, Tennessee, under the designation CA -400-25, which cellulose acetate contains an approximate acetyl content of 3g.9% as defined by AS~M Method D-8~1-72 and a falling ball viscosity of 17-35 seconds as measured by ASTM Method V-1343. The polyethylene glycol in each of the three melt spin compositions was USP Grade PEG E-400 from The Dow Chemical Company and the glycerine was USP Grade from The Dow Che~ical Company, Midland, Michigan.

Each batch was prepared by thoroughly mixing the powdered cellulose acetate with the polyeth~71ene glycol, and with the glycerine, in a standard laboratory HOBARTmixer by slo~ly addin~
the liquid ingredients with the mixer paddle turning. After unifor~
ad~ixture, the mixture was introduced into the feed zone of a hea~ed extruder maintained at about 390 degrees ~. and the e~truded mass ~ was then forced through a multi-opening spinner~ette outitted so as to introduce air through the center of each spinnerrette to thus form hollow fibers.

*Trademark 7~211~

Three spools of fibers were prepared from each batch by varying the take-up conditions between the spinnerrettes and spooling. A first spool of fibers having no cold forming, or stretching, was formed by passing the fibers through air to a first and second set o~ rolls rotating at the same speed. A
second spool of fibers was formed by controllin~ the speed of the second set of rolls to a rotation rate 10~ faster than the first set of rolls, and a third spool resulted from the second set of rolls operating at a 20% faster speed than the first set.
The nine spools of fibers thus produced were used to establish water and urea ~ansport coefficients in a laboratory test apparatus for the fibers as will now be described. The test apparatus consisted of a fluid reservoir equipped with a magnetic stirrer, and a dialyzer test beaker fitted wlth a magnetic stirrer, a top closure plate having pressure fittings and connectors for receiving the ends of the potting sleeves attached to each end of a bundle of fibers containing between 160 and 192 fibers per bundle.
The fiber bundle was bent into a U-shape and inserted into the beaker and connected to the closure plate; one sleeve was connected by a fluid line to a pump connected with a line to the reservoir and the other sleeve was connected by a return line to the reservoir to thereby enable fluid from the reservoir to be pumped under controllable pressure through the lumens of the fibers located in the dîalysis beaker. The beaker was also provided with dialysate inlet and outlet connections and during testing the fibers were immersed in a surrounding stirred pool of either water for the ~U~R test or a water-urea solution for the KUrea The water transport coefficient, ~ FR~ was determined by pumping water under pressure ti-rough the fibers and measuring the increase in water volume external to the fibers in the dialyzer beaker, the tests bein~ run at 21 degrees C. ~ FR was then calculated

2~

for each test using the fibers identified in Ta~le J in milliliters per s~uare meter per hour per millimeter of mercury pressure differ-ential as shown in Table llo The urea coefficient, ~urea~ w~s determined by providing a ~ater pool in the supply reservoir and pumping same through the fiber lumens, the pool surrounding the fibers in the dialysis beaker beîng initially a l~ater-urea solution. Measurements ~ere made to determine the urea concentration in the rec;rculating fluid at time intervalsO
The tests were conducted at 21 C. and there ~as no pres-sure diferential across the fiber ~all surface during the tests.
The urea c~efficient, KUrea, was determined by taking into account the difference in the concentrations of urea in the supply reservoir and in the dialysis beaker on the outside of the fibers as a function of time and the fiber area in accordance with~
the equation:
N = KUREA~ A ~Cl - C2) wherein N represents ~he -flux across the membrane in moles per minute, Cl is the initial urea concentration, C2 is the inal, OT n-easured, concentration and A
is the area of the fiber wall or membrane bet-~een the two solutions~
In a t~o-chamber system ~ithout a pressure differential or resultant ultrafiltration the transfer of urea across the membrallc ~all may be integrated over a time interval, t, to yield the furt]ler equation:

Cl - C2)t=o-l r(Vl ~ V2~ l ~ ~(C - C ~k ~ ~Vl V2j J XUREA' t wherein Vl is the volume of supply reservoir solution, and V2 is the volume of the solution in the dialysis bea~er.

19 o In the tests, the volumes, Vl and V2 and the area A are constants so that a plot of the values on each side of the integrated equation produces a straight line, the slope of which allows K re in units of centimeter per minute to be calculated.
The values thus developed for the nine fiber lots are -sho~n in Table II
in the column headed, KUREA min ~ 10

3 ~ O o u~
g ~-S-E~ ~r ~
. __ a~ ~ ~ ~r ~ I~
~I N 1~. ~I ~ `1 I~ ~
. I

~
~ H ~--_ .. ~ _ _ = _ ~ ~_ 3: h t) 8 o o ~
~ ~S ~ ~r . .
,~ ~ ,, ~ ~ ' ' O ~D ~
Q N t~l ~ ~ ~1 ~1 ~ a-H l .. _ _ . __.____ _ ~:1 . g CO
1 ~ ~1 1 ~N
H ~a--. __ ~: Q ~ ~ Il~ U~
e .,,.,, s~ e - 1- ...

o N ~'e U~ o ~--_ _ _ S~ ~ In ~ ~ . . o ~ o~ r~
ra N ~ 1~ ,1 ~--1 H ~1 'E4'u~ H~e' -r o ~ a)¦^ I ~ a~I^ a)I^ h¦ h¦
H u) N1 ¦ u~ N1 N¦O ~ N O N

IC D~ Z ~ o O ~

H ~ oP oP ¦ IJ d~ o~O oP ~) oP oP o~
d ~ O
u~ ~ ~ ~ I m ~r ~ '` :q ~ ~ ~ I

~ 7~
` ,- , I D E 3 ¦ ~ co a~ ~ ~ ~ 1 ~L~L , ~ ~r_ j~ D ¦ , ~ U~ Ll~
l x o ~ E ~i ~

H ¦ a o 1-~ E ~, D D ~ ~
",, ~ ~

~ ~ . ~ ~ ~
3 ~ ~ ___ - I _ ~ ~, CO , c ~ ~ .
1:~ h _ ._ - _ _ O InN ~0 h ~ ~/ N ¦o N

Z ~4 S ---- 'U -- -- -- C
H YoP oP ~ o\O o\O o\O .jJ oP ~\ oP
~`\i ~ Lq ~ ~ 22 -

Claims

WHAT IS CLAIMED IS:

1. A cellulose acetate hollow fiber having an internal diameter in the range of about 100 to about 350 microns and a wall thickness in the range of about 20 to about 60 microns, said wall having a selective permeability when used in hemodialysis for water and solutes to be removed from blood represented by an ultrafiltration coefficient in the range of about 2 to about 6 milliliters per hour per square meter per millimeter of mercury and a urea coefficient in the range of about 0.015 to about 0.045 centimeters per minute.

2. A fiber in accordance with claim 1 wherein said selective permeability is also represented by a creatinine coefficient in the range of about 0.013 to about 0.027 centimeters per minute.

3. A fiber in accordance with claim 2 wherein said selective permeability is also represented by a Vitamin B 12 coefficient in the range of about 0.002 to about 0.005 centimeters per minute.

4. A fiber in accordance with claim 1, wherein said ultrafiltration coefficient is in the range of about 5 to about 6 and said urea coefficient is in the range of about 0.030 to about 0.045.

5. A fiber in accordance with claim 2, wherein said creatinine coefficient is in the range of about 0.020 to about 0.027.

6. A process for making cellulose acetate hollow fibers which comprises the steps of (1) providing an intimate mixture of about 41 to about 50 weight percent cellulose acetate, about 2 to about 20 weight percent glycerine, and about 30 to about 57 percent polyethylene glycol having a molecular weight in the range of about 150 to about 600, (2) fabricating hollow fibers from a molten mass of said mixture, (3) cooling said fibers, (4) cold drawing said fibers an amount in the range of about 2% to about 20% of said cooled fiber length, (5) leaching said fibers to remove therefrom said polyethylene glycol and said glycerine, and (6) replasticizing said fibers with glycerine and thereafter drying same.

7. A process in accordance with claim 6 wherein said cellulose acetate in said mixture is in the range of about 42 to about 47 weight percent.

8. A process in accordance with claim 6 wherein said cold drawing is an amount in the range of about 10 to about 15%
of the length of said cooled fibers.