CA1277597C - Treatment of plasma - Google Patents
Treatment of plasmaInfo
- Publication number
- CA1277597C CA1277597C CA000524935A CA524935A CA1277597C CA 1277597 C CA1277597 C CA 1277597C CA 000524935 A CA000524935 A CA 000524935A CA 524935 A CA524935 A CA 524935A CA 1277597 C CA1277597 C CA 1277597C
- Authority
- CA
- Canada
- Prior art keywords
- plasma
- starting material
- albumin
- solution used
- pore glass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
- A23J3/00—Working-up of proteins for foodstuffs
- A23J3/04—Animal proteins
- A23J3/12—Animal proteins from blood
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- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
ABSTRACT
A process for the treatment of plasma containing undesirable .alpha.-lipoprotein which comprises eluting a solution of said plasma through a column of controlled pore glass having a pore diameter of from about 240A to about 2000A, to provide an improved solution containing a lowered amount of .alpha.-lipoprotein. This process allows the preparation of an improved pasteurized albumin solution having relatively small amounts of .alpha.-lipoprotein.
A process for the treatment of plasma containing undesirable .alpha.-lipoprotein which comprises eluting a solution of said plasma through a column of controlled pore glass having a pore diameter of from about 240A to about 2000A, to provide an improved solution containing a lowered amount of .alpha.-lipoprotein. This process allows the preparation of an improved pasteurized albumin solution having relatively small amounts of .alpha.-lipoprotein.
Description
~:77597 TREATMENT OF PLASMA
This invention relates to the treatment of plasma and more particularly it relates to the treatment of plasma or a purified plasma protein fraction to remove or reduce the con-centration of undesirable products in said plasma or fraction.
It is known that it is difficult to remove all, or sub-stantially all, ~-lipoprotein from a solution of albumin. The presence of residual a-lipoprotein in an albumin solution is undesirable because such a solution becomes unstable during heat treatment. Since heat treatment is a requirement of most health regulatory authorities in order to pasteurize albumin, the presence of Q-lipoprotein leads to problems in providing a satisfactory, acceptable product.
We have now found, and herein lies our invention, that a treatment process by means of a chromatographic technique using a particular adsorbent leads to the removal of, or a substantial reduction of, the amount of a-lipoprotein in plasma or a purified plasma protein fraction, particularly in an albumin solution.
According to the invention, as claimed herein, we pro-vide a process for the treatment of plasma containing unde-sirable ~-lipoprotein which comprises eluting a solution of said plasma or said plasma protein fraction through a column of controlled pore glass (CPG) to provide an improved solu-tion containing a lowered amount of ~-lipoprotein.
The plasma solution used as starting material may be a purified plasma protein fraction, for example a purified albumin solution.
It is to be understood that various controlled pore glass types are effective in carrying out this process. A
controlled pore glass having a pore diameter of from about 240A to about 2000A may be suitable. A particularly useful controlled pore glass is one with a pore diameter of about 1400A and a particle size of from about 80 mesh to about 120 mesh (U.S. Standard Sieve Mesh Size), i.e., from about 177 microns to about 125 microns.
~Z~75~7 The process may be carried out using human p]asma or a purified protein fraction, such as albumin or immune serum globulin. The process is particularly useful for treatment of a purified albumin solution containing relatively small amounts of ~-lipoprotein. Under such conditions, the con-trolled pore glass effectively removes a substan-tial amount of the ~-lipoprotein with practically no loss of albumin so that the albumin solution recovered from the process has at least a 10-fold reduction of the level of ~-lipoprotein there in. The process is efficient and a small amount of controlled pore glass may be used relative to the volume of albumin sol-ution to be treated. Thus, for example, five volumes of al-bumin solution may be treated by using one volume of con-trolled pore glass.
The process may be carried out using a plasma solution of varying pH for elution through the controlled pore glass.
We have found that the pH may be within the range of from ab-out 5.0 to about 8Ø A pH of 6.9 is a suitable pH for an albumin solution being eluted through the controlled pore glass.
Removal of ~-lipoprotein from an albumin solution may take place according to this process at various ionic stre-ngths. A preferred solution to be used for optimum removal of ~-lipoprotein is a solution having a sodium chloride con-centration of about 0.5M and a conductivity of about 50 mS/
cm. It is to be understood however, that a plasma solution used as starting material may have a sodium chloride concen-tration of from about 0.15M to about l.OM and a conductivity of from about 15 mS/cm to about 100 mS/cm.
The plasma solution used as starting material, such as an albumin solution, may have a concentration of from ab-out 2g% to about 8g%. In order to achieve best results, it is preferred that the albumin solution used as starting mat-erial should have a concentration of approximately 5g~.
Thus, as a preferred feature of the invention, we pro-vide a process for the treatment of a purified albumin solu~
tion containing relatively small amounts of ~-lipoprotein and 5~7 having a sodium chloride concentration of about 0.5M and a conductivity of about 50 mS/cm, said solution having a pH of about 6.9, which comprises eluting said solution through a column of controlled pore glass, said glass having a pore di-ameter of about 1400A and a particle size of from about 80 mesh to about 120 mesh (177 to 125 microns).
The purified albumin solution used as starting mater-ial is preferably a solution containing about 5g% of albumin.
In operating the process of this invention, the plasma solution, such as a purified albumin solution, is applied to the controlled pore glass column and the ~~lipoprotein conta-minants are adsorbed by the controlled pore glass. The re-maining unbound albumin-containing solution is collected as the eluate. There is a certain physical hold-up of residual unbound albumin-containing solution on the pore glass column and the column may therefore be washed with a 0.5M sodium chloride solution until all of the unbound albumin-containing solution has been collected. The ~-lipoprotein contaminants which have been removed from the albumin solution and which remain bound to the controlled pore glass column may readily be removed from the controlled pore glass in order to pro-vide pore glass suitable for reuse~ Thus, for example, the pore glass column may be washed with water, ethanol, acetic acid, sodium hydroxide or ammonium hydroxide. Alternatively, washing of the pore glass column may be carried out by use of an aqueous solution of a detergent, such as a 1~ aqueous sol-ution of sodium dodecyl sulphate. Other means of washing may be treatment of the pore glass column with a solution of high pH, such as a pH of about 10.0, followed by a solution of low pH, such as a pH of about 3Ø After the controlled pore glass in the column has been washed as indicated, the column can then be reused. The column can therefore be used re-peatedly, without removal and repacking of the pore glass in the column, since the pore glass may be cleaned free of ~-lipopro~ein contaminants in the column and may then be reused.
The invention is illustrated by, but not limited by, the following Examples describing the operation of the process of this invention.
~Z~7~;9~
A. ~Tuman plasma wa.s purified accordin~ to the procedure of A.D. Friesen in "Column Ion Exchange ChromatograPhic Production of Albumin, IV I~G and Factor lX from 75,000 - 100,000 J.itres of Plasma ~er Year" in "~la~ma Eractionation and Blood Transfusion" (Th. Smit Sibinga, P.C. ~as, S. Siedel, eds) pages 97-108, Martinus Ni~hoff Publishers (1986). The human plasma (450 ml) was first passed through a column containing 550 ml of DEAE-Sepharose CL-6B and the eluate thus obtained was then passed through a column containing 375 ml of CM-Sepharose CL-6B. The solution of albumin thus obtained as eluate from this second column was concentrated by ultrafiltration to a volume of 165 ml which then contained 5.5g% of albumin and had a pH of about 6.2. Sodium chloride was then added to the albumin solution to provide a concentration of 0.5M sodium chloride therein.
The albumin solution was added to a 33 ml column of controlled pore glass (CPG-1400) which had been previously equilibrated with 0.5M sodium chloride solution. After pass-age of the albumin solution through the column, the column is eluted with 0.5M sodium chloride to remove residual amounts of the albumin solution. The volume of albumin solution (165 ml) added to the column and the total volume of albumin solution (310 ml) recovered from the column are shown in Table 1 below.
The proteins adsorbed by the controlled pore glass in the column are then eluted therefrom using 1% sodium dodecyl sulph-ate (SDS). The amount of albumin and ~-lipoprotein in the starting material and in the recovered eluate (shown as a percentage of recovery) are given in Table 1.
Recovery (%) Sample Volume Albumin~ -lipoprotein Initial 165 ml 100 100 Eluted 310 ml 99 2 * Trade Mark ' - ~ .
' . . :
-~27~5~7 It will be noted -that the purified albumin solution obtained as eluate contains only 1/50 of the amount of ~ -lipoprotein compared with the amount of ~ -]ipoprotein present in the starting material.
Human plasma from which cryoprecipitate and prothrombin complex have been removed, was adjusted by the addition of sodium chloride to provide a starting material having a concentration of 0.5M sodium chloride. One litre of this plasma was applied to a 1 litre column of controlled pore glass (CPG-1400) which had previouslv been equilibrated with 0.5M sodium chloride solution. The residual plasma on the column was eluted therefrom with 0.5M sodium chloride. The adsorbed ~ -lipoprotein on the column was eluted with 1%
sodium dodecyl sulphate (SDS). The volume of plasma applied to the column and the volume of eluate obtained from the column are shown in Table 2 and the amount of albumin and ~ lipoprotein present are shown as percentage recoveries.
TA~LE 2 Recovery (~) Sample ~olumeAlbumin ~-lipoprotein __ ____ .
Initial 1000 ml 100 100 Eluted 2800 ml 94 0 It will be seen that the plasma solution obtained as eluate contains no ~- lipoprotein.
This invention relates to the treatment of plasma and more particularly it relates to the treatment of plasma or a purified plasma protein fraction to remove or reduce the con-centration of undesirable products in said plasma or fraction.
It is known that it is difficult to remove all, or sub-stantially all, ~-lipoprotein from a solution of albumin. The presence of residual a-lipoprotein in an albumin solution is undesirable because such a solution becomes unstable during heat treatment. Since heat treatment is a requirement of most health regulatory authorities in order to pasteurize albumin, the presence of Q-lipoprotein leads to problems in providing a satisfactory, acceptable product.
We have now found, and herein lies our invention, that a treatment process by means of a chromatographic technique using a particular adsorbent leads to the removal of, or a substantial reduction of, the amount of a-lipoprotein in plasma or a purified plasma protein fraction, particularly in an albumin solution.
According to the invention, as claimed herein, we pro-vide a process for the treatment of plasma containing unde-sirable ~-lipoprotein which comprises eluting a solution of said plasma or said plasma protein fraction through a column of controlled pore glass (CPG) to provide an improved solu-tion containing a lowered amount of ~-lipoprotein.
The plasma solution used as starting material may be a purified plasma protein fraction, for example a purified albumin solution.
It is to be understood that various controlled pore glass types are effective in carrying out this process. A
controlled pore glass having a pore diameter of from about 240A to about 2000A may be suitable. A particularly useful controlled pore glass is one with a pore diameter of about 1400A and a particle size of from about 80 mesh to about 120 mesh (U.S. Standard Sieve Mesh Size), i.e., from about 177 microns to about 125 microns.
~Z~75~7 The process may be carried out using human p]asma or a purified protein fraction, such as albumin or immune serum globulin. The process is particularly useful for treatment of a purified albumin solution containing relatively small amounts of ~-lipoprotein. Under such conditions, the con-trolled pore glass effectively removes a substan-tial amount of the ~-lipoprotein with practically no loss of albumin so that the albumin solution recovered from the process has at least a 10-fold reduction of the level of ~-lipoprotein there in. The process is efficient and a small amount of controlled pore glass may be used relative to the volume of albumin sol-ution to be treated. Thus, for example, five volumes of al-bumin solution may be treated by using one volume of con-trolled pore glass.
The process may be carried out using a plasma solution of varying pH for elution through the controlled pore glass.
We have found that the pH may be within the range of from ab-out 5.0 to about 8Ø A pH of 6.9 is a suitable pH for an albumin solution being eluted through the controlled pore glass.
Removal of ~-lipoprotein from an albumin solution may take place according to this process at various ionic stre-ngths. A preferred solution to be used for optimum removal of ~-lipoprotein is a solution having a sodium chloride con-centration of about 0.5M and a conductivity of about 50 mS/
cm. It is to be understood however, that a plasma solution used as starting material may have a sodium chloride concen-tration of from about 0.15M to about l.OM and a conductivity of from about 15 mS/cm to about 100 mS/cm.
The plasma solution used as starting material, such as an albumin solution, may have a concentration of from ab-out 2g% to about 8g%. In order to achieve best results, it is preferred that the albumin solution used as starting mat-erial should have a concentration of approximately 5g~.
Thus, as a preferred feature of the invention, we pro-vide a process for the treatment of a purified albumin solu~
tion containing relatively small amounts of ~-lipoprotein and 5~7 having a sodium chloride concentration of about 0.5M and a conductivity of about 50 mS/cm, said solution having a pH of about 6.9, which comprises eluting said solution through a column of controlled pore glass, said glass having a pore di-ameter of about 1400A and a particle size of from about 80 mesh to about 120 mesh (177 to 125 microns).
The purified albumin solution used as starting mater-ial is preferably a solution containing about 5g% of albumin.
In operating the process of this invention, the plasma solution, such as a purified albumin solution, is applied to the controlled pore glass column and the ~~lipoprotein conta-minants are adsorbed by the controlled pore glass. The re-maining unbound albumin-containing solution is collected as the eluate. There is a certain physical hold-up of residual unbound albumin-containing solution on the pore glass column and the column may therefore be washed with a 0.5M sodium chloride solution until all of the unbound albumin-containing solution has been collected. The ~-lipoprotein contaminants which have been removed from the albumin solution and which remain bound to the controlled pore glass column may readily be removed from the controlled pore glass in order to pro-vide pore glass suitable for reuse~ Thus, for example, the pore glass column may be washed with water, ethanol, acetic acid, sodium hydroxide or ammonium hydroxide. Alternatively, washing of the pore glass column may be carried out by use of an aqueous solution of a detergent, such as a 1~ aqueous sol-ution of sodium dodecyl sulphate. Other means of washing may be treatment of the pore glass column with a solution of high pH, such as a pH of about 10.0, followed by a solution of low pH, such as a pH of about 3Ø After the controlled pore glass in the column has been washed as indicated, the column can then be reused. The column can therefore be used re-peatedly, without removal and repacking of the pore glass in the column, since the pore glass may be cleaned free of ~-lipopro~ein contaminants in the column and may then be reused.
The invention is illustrated by, but not limited by, the following Examples describing the operation of the process of this invention.
~Z~7~;9~
A. ~Tuman plasma wa.s purified accordin~ to the procedure of A.D. Friesen in "Column Ion Exchange ChromatograPhic Production of Albumin, IV I~G and Factor lX from 75,000 - 100,000 J.itres of Plasma ~er Year" in "~la~ma Eractionation and Blood Transfusion" (Th. Smit Sibinga, P.C. ~as, S. Siedel, eds) pages 97-108, Martinus Ni~hoff Publishers (1986). The human plasma (450 ml) was first passed through a column containing 550 ml of DEAE-Sepharose CL-6B and the eluate thus obtained was then passed through a column containing 375 ml of CM-Sepharose CL-6B. The solution of albumin thus obtained as eluate from this second column was concentrated by ultrafiltration to a volume of 165 ml which then contained 5.5g% of albumin and had a pH of about 6.2. Sodium chloride was then added to the albumin solution to provide a concentration of 0.5M sodium chloride therein.
The albumin solution was added to a 33 ml column of controlled pore glass (CPG-1400) which had been previously equilibrated with 0.5M sodium chloride solution. After pass-age of the albumin solution through the column, the column is eluted with 0.5M sodium chloride to remove residual amounts of the albumin solution. The volume of albumin solution (165 ml) added to the column and the total volume of albumin solution (310 ml) recovered from the column are shown in Table 1 below.
The proteins adsorbed by the controlled pore glass in the column are then eluted therefrom using 1% sodium dodecyl sulph-ate (SDS). The amount of albumin and ~-lipoprotein in the starting material and in the recovered eluate (shown as a percentage of recovery) are given in Table 1.
Recovery (%) Sample Volume Albumin~ -lipoprotein Initial 165 ml 100 100 Eluted 310 ml 99 2 * Trade Mark ' - ~ .
' . . :
-~27~5~7 It will be noted -that the purified albumin solution obtained as eluate contains only 1/50 of the amount of ~ -lipoprotein compared with the amount of ~ -]ipoprotein present in the starting material.
Human plasma from which cryoprecipitate and prothrombin complex have been removed, was adjusted by the addition of sodium chloride to provide a starting material having a concentration of 0.5M sodium chloride. One litre of this plasma was applied to a 1 litre column of controlled pore glass (CPG-1400) which had previouslv been equilibrated with 0.5M sodium chloride solution. The residual plasma on the column was eluted therefrom with 0.5M sodium chloride. The adsorbed ~ -lipoprotein on the column was eluted with 1%
sodium dodecyl sulphate (SDS). The volume of plasma applied to the column and the volume of eluate obtained from the column are shown in Table 2 and the amount of albumin and ~ lipoprotein present are shown as percentage recoveries.
TA~LE 2 Recovery (~) Sample ~olumeAlbumin ~-lipoprotein __ ____ .
Initial 1000 ml 100 100 Eluted 2800 ml 94 0 It will be seen that the plasma solution obtained as eluate contains no ~- lipoprotein.
Claims (29)
1. A process for the treatment of plasma containing undesirable .alpha.-lipoprotein which comprises eluting a solution of said plasma through a column of controlled pore glass to provide an improved solution containing a lowered amount of .alpha.-lipoprotein.
2. The process of claim 1 wherein the plasma is a purified plasma protein fraction.
3.- The process of claim 1 wherein the plasma is an albumin solution.
4. The process of claim 1, 2 or 3 wherein the con-trolled pore glass has a pore diameter of from about 240A
to about 2000A.
to about 2000A.
5. The process of claim 1, 2 or 3 wherein the con-trolled pore glass has a pore diameter of about 1400A.
6. The process of claim 1, 2 or 3 wherein the con-trolled pore glass has a particle size of from about 80 mesh to about 120 mesh (U.S. Standard Sieve Mesh Size).
7. The process of claim 1, 2 or 3 wherein the ratio of the volume of plasma solution used as starting material to the volume of controlled pore glass is within the range of from about 1:1 to about 5:1.
8. The process of claim 1, 2 or 3 wherein the ratio of the volume of plasma solution used as starting material to the volume of controlled pore glass is about 5:1.
9. The process of claim 1, 2 or 3 wherein the pH of the plasma solution used as starting material is from about 5.0 to about 8Ø
10. The process of claim 1, 2 or 3 wherein the pH of the plasma solution used as starting material is about 6.9.
11. The process of claim 1, 2 or 3 wherein the plasma solution used as starting material has a sodium chloride con-centration of from about 0.15M to about 1.0M and a conductiv-ity of from about 15 mS/cm to about 100 mS/cm.
12. The process of claim 1, 2 or 3 wherein the plasma solution used as starting material has a sodium chloride con-centration of about 0.5M and a conductivity of about 50 mS/cm.
13. The process of claim 1, 2 or 3 wherein the plasma solution used as starting material has a concentration of from about 2g% to about 8g%.
14. The process of claim 1, 2 or 3 wherein the plasma solution used as starting material has a concentration or about 5g%.
15. A process for the treatment of a purified albumin solution containing undesirable .alpha.-lipoprotein which comprises passing said solution through a column of controlled pore glass and thereby recovering an albumin solution containing a reduced amount of .alpha.-lipoprotein.
16. The process of claim 15 wherein the albumin solu-tion has a sodium chloride concentration of from about 0.15M
to about 1.0M and a conductivity of from about 15 mS/cm to about 100 mS/cm.
to about 1.0M and a conductivity of from about 15 mS/cm to about 100 mS/cm.
17. The process of claim 15 wherein the albumin solu-tion has a sodium chloride concentration of about 0.5M and a conductivity of about 50 mS/cm.
18. The process of claim 15, 16 or 17 wherein the con-trolled pore glass has a pore diameter of from about 240A to about 2000A.
19. The process of claim 15, 16 or 17 wherein the con-trolled pore glass has a pore diameter of about 1400A.
20. The process of claim 15, 16 or 17 wherein the con-trolled pore glass has a particle size of from about 80 mesh to about 120 mesh (U.S. Standard Sieve Mesh Size).
21. The process of claim 15, 16 or 17 wherein the ra-tio of the volume of albumin solution used as starting mat-erial to the volume of controlled pore glass is within the range of from about 1:1 to about 5:1.
22. The process of claim 15, 16 or 17 wherein the ra-tio of the volume of albumin solution used as starting mat-erial to the volume of controlled pore glass is about 5:1.
23. The process of claim 15, 16 or 17 wherein the pH
of the albumin solution used as starting material is from about 5.0 to about 8Ø
of the albumin solution used as starting material is from about 5.0 to about 8Ø
24. The process of claim 15, 16 or 17 wherein the pH
of the albumin solution used as starting material is about 6.9.
of the albumin solution used as starting material is about 6.9.
25. The process of claim 15, 16 or 17 wherein the al-bumin solution used as starting material has a sodium chlor-ide concentration of from about 0.15M to about 1.0M and a conductivity of from about 15 mS/cm to about 100 mS/cm.
26. The process of claim 15, 16 or 17 wherein the al-bumin solution used as starting material has a sodium chlor-ide concentration of about 0.5M and a conductivity of about 50 mS/cm.
27. The process of claim 15, 16 or 17 wherein the al-bumin solution used as starting material has a concentration of from about 2g% to about 8g%.
28. The process of claim 15, 16 or 17 wherein the al-bumin solution used as starting material has a concentration of about 5g%.
29. A process for the treatment of a purified albumin solution containing undesirable .alpha.-lipoprotein which comprises passing said albumin solution of pH about 6.9 and containing about 5g% of albumin and having a sodium chloride concentra-tion of about 0.5M and a conductivity of about 50 mS/cm through a column of controlled pore glass, said glass having a pore diameter of about 1400A and a particle size of from about 80 mesh (177 microns) to about 120 mesh (125 microns), and thereby obtaining a purified albumin solution containing a lowered amount of .alpha.-lipoprotein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000524935A CA1277597C (en) | 1986-12-10 | 1986-12-10 | Treatment of plasma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000524935A CA1277597C (en) | 1986-12-10 | 1986-12-10 | Treatment of plasma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1277597C true CA1277597C (en) | 1990-12-11 |
Family
ID=4134526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524935A Expired - Lifetime CA1277597C (en) | 1986-12-10 | 1986-12-10 | Treatment of plasma |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1277597C (en) |
-
1986
- 1986-12-10 CA CA000524935A patent/CA1277597C/en not_active Expired - Lifetime
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19930613 |