Claims for Patent: 4,696,748

Summary for Patent: 4,696,748

Title:	Plasma separator and a process for preparing the same
Abstract:	A plasma separator containing porous hollow fibers composed of a polyolefin having elliptic pores defined by microfibrils and knotted portions, in which the pores of the hollow fibers, together with the spaces between the inner surface of the vessel and the fibers and between and inside the fibers, are filled with a sterile water or sterile solution and which has been sterilized with a sterilizing gas before the filling operation of the sterile water or solution. Incorporation of the water or solution into the pores is attained by applying a pressure to the water or solution. The incorporation of the water or solution causes the limiting pore diameter of the pores of the precursor hollow fibers to expand, thereby changing the pore characteristics of the precursor hollow fibers. The plasma separator, exhibiting high plasma component permeabilities, can be used safely, without troubles of hemolysis and residual chemical or solvents, and readily, without troubles of priming and washing. Therefore, the plasma separator is useful for therapy and plasma collection.
Inventor(s):	Nitadori; Yoshiaki (Oita, JP), Nakano; Toru (Nobeoka, JP)
Assignee:	Asahi Medical Co., Ltd. (Tokyo, JP)
Application Number:	06/788,125
Patent Claims:	1. A plasma separator comprising: a vessel provided with a blood introduction means, a blood withdrawal means and a plasma withdrawal means; and a plurality of porous hollow fibers which are contained within the vessel, leaving spaces between the inner surface of said vessel and said plurality of porous hollow fibers and between and inside said plurality of porous hollow fibers; said blood introduction means and said blood withdrawal means communicating with each other through said plurality of porous hollow fibers fluid tightly connected therebetween; said hollow fibers being adapted to pass blood therethrough while causing the plasma component of the blood to be selectively passed through the walls of the hollow fibers and withdrawn through the plasma withdrawal means; each hollow fiber being made of a polyolefin oriented in the lengthwise direction of the hollow fiber and having elliptic pores defined by microfibrils that are oriented in the lengthwise direction of the hollow fiber and knotted portions that are cross-connected to said microfibrils and are each in the form of stacked lamellae, said pores including intermediate pores which are present within the wall of the porous hollow fiber in communicating relationship and end pores which open at the inner and outer wall surfaces of the hollow fiber and forming throughpaths running from the inner wall surface of the porous hollow fiber to the outer wall surface of the porous hollow fiber; each end pore which opens at the inner wall surface of the hollow fiber having: an average nominal major axis (dl) of from 0.3 to 3.0 .mu.m, and an average nominal minor axis (d.sub.s) of from 0.1 to 0.5 .mu.m; each hollow fiber having: a fraction of pores having a diameter of 0.25 .mu.m or more, relative to the whole pores, of 15% or more, as measured from a pore diameter distribution curve obtained in accordance with the wet membrane gas permeation method, a water permeability of from 5 to 20 l/hr.m.sup.2.mmHg, a permeability for colloidal silica, which has an average particle diameter of 0.08 .mu.m, of 70% or more, and a permeability for polymer latex, which has an average particle diameter of 0.2 .mu.m, of from 10% to 80%, and a limiting pore diameter (D.sub.L), as measured in accordance with the standard particle permeation method, satisfying an inequality: wherein d.sub.s is as defined above; said spaces and said pores being filled with a sterile water or sterile solution substantially not containing any non-physiological organic compound; and which separator has been sterilized with a sterilizing gas before said spaces and said pores are filled with the sterile water or sterile solution and is aseptically isolated from the environment after said spaces and said pores are filled with the sterile water or sterile solution. 2. A separator according to claim 1, wherein said polyolefin is a high density polyethylene. 3. A separator according to claim 1, wherein said sterilizing gas is ethylene oxide. 4. A separator according to claim 1, wherein the blood introduction means, the blood withdrawal means and the plasma withdrawal means are closed with stoppers to effect said aseptic isolation. 5. A process for preparing a plasma separator, which comprises the steps of: (1) spinning a polyolefin to obtain a preliminary hollow fiber and subjecting the preliminary hollow fiber to cold stretching and, then, hot stretching to obtain a precursor porous hollow fiber oriented in the lengthwise direction of the porous hollow fiber and having elliptic pores defined by microfibrils that are oriented in the lengthwise direction of the hollow fiber and knotted portions that are cross-connected to said microfibrils and are each in the form of stacked lamellae, said pores including intermediate pores which are present within the wall of the hollow fiber in communicating relationship and end pores which open at the inner and outer wall surfaces of the hollow fiber and forming throughpaths running from the inner wall surface of the hollow fiber to the outer wall surface of the hollow fiber; (2) preparing a preliminary separator using a bundle of the precursor hollow fibers of predetermined lengths, said preliminary separator comprising: a vessel provided with a blood introduction means, a blood withdrawal means and a plasma withdrawal means; and a plurality of porous hollow fibers which are contained within the vessel, leaving spaces between the inner surface of said vessel and said plurality of porous hollow fibers and between and inside said plurality of porous hollow fibers; said blood introduction means and said blood withdrawal means communicating with each other through said plurality of porous hollow fibers fluidtightly connected therebetween; (3) exposing the preliminary separator to a sterilizing gas thereby to effect sterilization thereof; (4) evacuating the preliminary separator; (5) filling said spaces with a sterile water or sterile solution substantially not containing any non-physiological organic compound, and applying a pressure to the sterile water or sterile solution thereby to introduce the sterile water or sterile solution into said pores; and (6) aseptically isolating from the environment the resulting sterilized separator in which said spaces and said pores are filled with the sterile water or sterile solution. 6. A process according to claim 5, wherein: in step (1) said cold stretching and hot stretching are effected under such conditions that said precursor hollow fiber has the following characteristics: (a) each end pore which opens at the inner wall surface of the hollow fiber having: an average nominal major axis (d.sub.lA) of from 0.3 to 3.0 .mu.m, and an average nominal minor axis (d.sub.sA) of from 0.1 to 0.5 .mu.m; and (b) said precursor hollow fiber having: a fraction of pores having a diameter of 0.25 .mu.m or more, relative to the whole pores, of 10% or less, as measured from a pore diameter distribution curve obtained in accordance with the wet membrane gas permeation method, a water permeability (F.sub.A) of from 2 to 8 l/hr.m.sup.2.mmHg, a permeability for colloidal silica, which has an average particle diameter of 0.08 .mu.m, of 50% or less, and a permeability for polymer latex, which has an average particle diameter of 0.2 .mu.m, of 5% or less, and a limiting pore diameter (D.sub.LA), as measured in accordance with the standard particle permeation method, satisfying an inequality: wherein d.sub.sA is as defined above; and in step (5) the pressure is applied to a level sufficient to expand said limiting pore diameter while keeping said end pores substantially unaltered so that the resulting porous hollow fiber has the following characteristics: (a') each end pore which opens at the inner wall surface of the hollow fiber having: an average nominal major axis (d.sub.lB) of from 0.3 to 3.0 .mu.m, and an average nominal minor axis (d.sub.sB) of from 0.1 to 0.5 .mu.m, the values of d.sub.lB and d.sub.sB being substantially the same as the values of d.sub.lA and d.sub.sA, respectively; and (b') the resulting hollow fiber having; a fraction of pores having a diameter of 0.25 .mu.m or more, relative to the whole pores, of 15% or more, as measured from a pore diameter distribution curve obtained in accordance with the wet membrane gas permeation method, a water permeability (F.sub.B) of from 5 to 20 l/hr.m.sup.2.mmHg, F.sub.B and F.sub.A satisfying an inequality: a permeability for colloidal silica, which has an average particle diameter of 0.08 .mu.m, of 70% or more, and a permeability for polymer latex, which has an average particle diameter of 0.2 .mu.m, of 10% to 80%, and a limiting pore diameter (D.sub.LB), as measured in accordance with the standard particle permeation method, satisfying an inequality: wherein d.sub.sB is as defined above. 7. A process according to claim 5, wherein said polyolefin is a high density polyethylene. 8. A process according to claim 5, wherein said sterilizing gas is ethylene oxide. 9. A process according to claim 5, wherein: in step (4) before said evacuation, needle-stabbable stoppers are applied to the blood introduction means, blood withdrawal means and plasma withdrawal means and needles are stabbed through the plasma withdrawal means and the blood introduction means or blood withdrawal means; and in steps (4) to (5), said evacuation, said filling with the sterile water or sterile solution and said application of a pressure are performed through the needles.

Details for Patent 4,696,748

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2004-10-16