New PMMA Membrane for Better Quality of Life

Hollow Fiber Dialyzer

Filtryzer BG-U Series

New Membrane Structure by “Sophisticated Pore Control Technology”

iso-PMMA

syn-PMMA

CH3

O

C

200 2 5 10 50

200

500

Pure water permeability λ Lp (cm3 • sec/g)

Pore

size

r(Å)

Pore

dens

ity∝

∆H•T

p2(°

C•c

al•g

–1)

100

50

20

200

100

50

20

B2 B1 B1-U BG BK-F

“FILTRYZER” is Polymethylmethacrylate membrane (PMMA) and TORAY is the only manufacturer which succeeded in developing it as dialysis membrane. FILTRYZER was intro-duced in 1977 and it has enjoyed a good reputation all over the world due to high biocompatibility, high removal performance, wide range of UFR, and unique adsorption characteristics for various proteins.

PMMA is synthetic membrane by mixing 2 kinds of poly-mer, isotactic PMMA (Iso-PMMA) and syndiotactic PMMA (Syn-PMMA). These polymers form the stereocomplex structure as shown in the picture. The pore structure in the membrane can be widely adjusted by controlling the process condi-tions including the chemical structure, the composition of the PMMAs (i.e., ratio of Iso-PMMA to Syn-PMMA), the concen-tration, cooling speed of dope solution, and the heat setting.

With this wide range of pore structure, FILTRYZER has met the new targets of physicians and has been used in many clinical studies for more than 20 years.

PMMA has established excellent reliability in its long his-tory based on many kinds of clinical data and accumulated technology. For further improvement of the patients’ quality of life, TORAY has been investigating the potential of PMMA through reserch and trials.

Our “Sophisticated Pore Control Technology”, which combines the process conditions and copolymerization, made it possible to create brand new PMMA membrane “FILTRYZER BG-U series”. This new PMMA membrane has obtained both the controlled pore size around 70Å and uniform distribution of pore size.

At the same time, this membrane has higher porosity and unprecedented adsorption capability.

This structure can improve both UFR and permeability or adsorption performance of not only small molecules but also low molecular weight proteins like β2-microglobulin.

Relationship of pore size, pore density and water permeability of PMMA membranes

As shown in the figure, BG membrane is designed by homogenizing the pore size and increasing the number of pores, resulting in the improvement of the re-moval through small molecules to low molecular weight proteins such as β2-MG.

1,000

800

600

400

200

0

Creatinine

Uric acid

Phosphate

Vitamin B12

BG-1.6UBK-1.6PBK-1.6U

(ml/min)

BUN

Diff

usive

perm

eabi

lity

(KoA

)

755

809

839

484

504

515

387

401

408

361

361

423

178

183

189

Internal data

Structure of new PMMA membrane BGPore structure SEM observation

Inside Center Outside

PMMA(BK)

NewPMMA

BG

Improved diffusive permeability (KoA)

As for several KoAs (the product of overall mass transfer coefficient and area) for small molecules, Filtryzer BG has an improving per-formance compared with the other types of high-flux PMMA membranes, BK-U and BK-P.

Proven Biocompatibility

Comparison of removal for several cytokines (in vitro)

Rem

oval

(pg/

3hr)

1,2001,000

800

600

400

200

0

BS-U

PS-UW

BK-F

PAN-SFBG-U

TNF-α(MW: 17,000 + α2-MG)

Polysulfone

PMMA

Rem

oval

(pg/

3hr)

3,000

2,500

2,000

1,500

1,000

500

0

BS-U

PS-UW

PAN-SF

BK-F

BG-U

IL-6(MW: 21,000)

Polysulfone

PMMA

The time course of complement fragment C3a, white blood cell count and platelet count.

Removal amount; pg/3hr

Filtration amount

adsorption amount

QP: 1.15mL/minQF: 0.15mL/minmembrane area; 25cm2

perfusion; 3 hours

primary concentrationTNF-α: 65 pg/mLIL-6: 320 pg/mL

Kawanishi H. Intensive & Critical Care Medicine 12, S7–S8, proceedings 2000

Higher adsorptive removal for cytokinesRemoval of cytokines with BG-U membrane and others

were investigated in an in vitro perfusion test. The removal of cytokines with BG-U is mainly conducted by adsorption as shown in the graph: the green bar was the major portion of total removed amount with BG-U. As for removal of IL-6, the adsorbed amount with BG-U exceeded the total amounts with both polysulfone membranes.

Excwllent quality know as biocompatible membrane

Touma studied on the biocompatibility of BG-U membrane based upon the time course of WBC count, Platelet count and Complement fragment C3a in comparison with Cellulose Tri-acetate membrane, FB, and the previous PMMA membrane, BK-U.

As shown with blue line, the changes on these biocompatibility parameters of BG-U were more stable than that of FB and almost the same as BK-U. So the biocompatibility of BG-U membrane is judged as the superior level as previous PMMA membrane which has obtained a reputation by its excellent biocompatibility in a long period of its history.

Modified from Touma S, Kidney & Dialysis, Suppl.,132-134, 1997

n=4, crossover

n=4, crossover

n=4, crossover

BGFBBKU

700

600

500

400

300

200

100

0

C3a

(ng/

mL)

8,000

6,000

4,000

2,000

WBC

(/mm

3 )

30

25

20

15

10

Plat

.(10

4 /mm

3 )

pre 15min 30min post

Unique Adsorption of Proteins

Adsorption of 125I-labeled plasma proteins on the various membranes

For the 6 kinds of dialyzers, Birk et al., conducted the adsorption experiment of plasma protein in vitro with radio-isotope labelling. The PMMA membrane showed the maxi-mum amount of protein adsorption per unit surface area.

Furthermore, as a result of analyzing the molecular weight of the adsorbed proteins, compared with other mem-brane materials, PMMA adsorbed higher molecular weight proteins (HMW proteins) than albumin, shown in blue bars. When the PMMA membrane was used, the removability by adsorption tended to increase for proteins with higher mo-lecular weights.

Adsorption of plasma proteins with mini-module

The below figure shows the internal data for adsorption of plasma proteins with mini-module with 3 kinds of synthetic membranes. On the X axis, plasma proteins in the order of iso-electric point are shown. For example, the adsorptive ratio of β2-MG on BK and BG membranes are in the high level. But towards the target proteins with more cationic iso-electric point, BG membrane adsorbed more of them than BK membrane such as PF-4, lysozyme and somatostatin. So these data suggest the adsorption of cationic proteins are enhanced by the electric interaction with the BG membrane.

PMMA BG PMMA BK

PS

100

80

60

40

20

0

Adso

ptive

Rat

io (%

)

Retinol

Binding

Fibrin

ogen

(5.8)

α1-micr

oglob

lin(5.

89)

β2-micr

oglob

lin(6.

07)

IgG (6

.5)

Factor

D (7)

PF-4 (8

.65)

β-throm

boglo

blin(8.

93)

Protein

(5.14

)

lysozy

me (9.0

5)

somato

statin

(9.16

)

C3a (9.

92)

Birk, H-W. et al., Artificial Organs,19(5),411-415, 1995

HMW proteins>65kDLMW proteins<65kD

The possibility in removal of HCV particles in HD patients over hemodialysis therapy

In worldwide HD patients, the positive rate of anti-HCV antibody seems to be high. But the number of HCV RNA in blood is lower and the liver disorder is slight. It is due to extracorporial treatment through dialyzer use every 2 days. Kuramochi reported that the viral particles reduced in the blood through dialyzer, above all, through PMMA mem-brane. The viral particles were not detected in the filtrate or dialysate, and were rather thought to be adsorbed on the dialyzer membrane surface.

600

400

200

0

HC

V R

NA

(KU

/mL)

PS

EVAL

PAN

PMMA

CDA

CTA

Kuramochi and Shima J Artif Organs 4 ; 146-149, 2001

Kato A. et.al., Artificial Organs 25(6);441-447, 2001*p=0.047 as compared to scores at the beginning, §p=0.049 as compared to scores at 2 months

An Example of QOL Improvement

Excellent Clinical Benefits to Renal Failure Patients

3.5

3.0

2.5

2.0

1.5

1.0

Cross over

Pre 1M 2M 3M 4M 5M 6M

Itchin

g sc

ales

Group 2 (n=8)PMMA membrane Conventional membrane

PMMA membraneGroup 1 (n=9)

Conventional membrane *§

120

100

80

60

40

20

0

Chan

ge o

f % h

istam

ine

rele

ase

Pre

Post

With Polysulfone

With BG

Fraction from

patients was solely

incubated

Yamada S. et al., Kidney and Dialysis,suppl,; 167-171, 2003

*

**

Inlet of dialyzer

Outlet of dialyzer

* P<0.05

** P<0.01

Pre: Before incubationPost: After incubation without fibers

Efficacy in amelioration of renal itching in hemodialysis patients (cross over study)

In group 1, one month after changing to BG membrane, the pruritus score was decreased to 1.9 ±0.4 which is sig-nificantly lower compared to those at 2 months when the conventional membranes were used (§p=0.049).

In group 2, the BG membrane gradually and significantly reduced pruritus score from 2.8 ±0.2 to 1.9 ±0.4 3 months later (*p=0.047). The degree of pruritus did not worsen dur-ing the next 3 months despite returning to the conventional dialyzers.

Confirmation of removal of pruritus generating substances assayed with mast cells

This shows the results when the fraction from patients’ blood which has activity for histamine release from mast cells was coincubated with hollow fibers for 3 hours.

With BG membrane the activity was massively reduced compared with that of polysulfone membrane.

These data suggest the adsorption of the sustances gen-erating pruritus and correspond well to the observation of clinical amelioration in pruritus with BG membrane.

Advanced Technical Data

BG-U Series

Type BG-1.3U BG-1.6U BG-1.8U BG-2.1U

Housing Material Polystyrene

Fibers Material Poly (methylmethacrylate), PMMA

Inner diameter (µm) 200

Membrane thickness (µm) 30

Effective surface area (m2) 1.3 1.6 1.8 2.1

Potting Material Polyurethane

Sterilization Gamma-ray Irradiation

Blood Volume (mL) 76 94 112 126

Clearance in vitro (mL/min)*

Urea 184 189 191 192

Creatinine 182 188 188 191

Phosphate 154 165 172 179

Vitamin B12 106 118 123 133

Inulin 60 67 72 81

UFR in vitro {mL/hr, at 13.3kPa (100mmHg)}** 2,600 3,200 3,600 4,100

Max. TMP {kPa (mmHg)} 66 (500)

* Clearances were measured with aqueous solution. QB: 200mL/min, QD: 500mL/min, QF: 10mL/min, Temp.: 37°C** UFRs were measured data with bovine blood. (Ht 30 ±2%, TP 6g/dL) QB: 200mL/min, TMP: 13.3kPa (100mmHg), Temp.: 37°C Allowable ranges: Blood volume; ±13%. Clearances, Urea; ±6%, Creat.; ±6%, Others; ±13%, UFR in vitro; ±15%“Instructions for Use” should be read thoroughly prior to the use of these medical devices.Specifications and designs are subject to change without notice for improvements.

ClearanceBG-1.3UQB 300 400 500UR; Urea 234 267 289CR; Creatinine 228 253 269PO4; Phosphate 186 206 216VB12; Vitamin B12 119 123 129IN; Inulin 63 63 64

BG-1.6UQB 300 400 500UR; Urea 249 283 310CR; Creatinine 247 276 298PO4; Phosphate 202 221 236VB12; Vitamin B12 134 140 146IN; Inulin 73 74 79

BG-1.8UQB 300 400 500UR; Urea 258 301 321CR; Creatinine 250 285 300PO4; Phosphate 217 236 253VB12; Vitamin B12 142 152 155IN; Inulin 80 83 86

350

300

250

200

150

100

50

0200 400

350

300

250

200

150

100

50

0200 400

350

300

250

200

150

100

50

0200 400

350

300

250

200

150

100

50

0200 400

BG-2.1UQB 300 400 500UR; Urea 265 312 335CR; Creatinine 262 300 318PO4; Phosphate 223 248 268VB12; Vitamin B12 155 169 172IN; Inulin 86 90 99

BG-1.3U BG-1.6U BG-1.8U BG-2.1U

UFR

Measured data with aqueous solution

BG-1.3U BG-1.6 BG-1.8U BG-2.1U

Printed in Japan 0501 G

EU Representative:Toray Europe Ltd.Medical Department7, Old Park Lane, London W1K 1AD, U. K.TEL: 44-20 7663 7749 / FAX: 44-20 7663 7714

Exporter:Toray Medical Co., Ltd.International Business DivisionARCA Central 21F., 2-1, Kinshi 1-chome, Sumida-ku, Tokyo 130-0013, JAPANTEL: (03)5610-6535 / FAX: (03)5610-6545 / E-MAIL: TMC_INTL_FL@tmc.toray.co.jp

Manufacturer:Toray Industries, Inc.2-1, Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo 103-8666, JAPANTEL: (03)3245-5111 / FAX: (03)3245-5555