Method of peritoneal dialysis using glucose polymer solutions

This invention relates to a new form of polymer, a method for its production and compositions containing it.

Maltodextrins (glucose polymers) are produced by the hydrolysis of pure starch isolated from various natural products, e.g. wheat, rice, tapioca etc. In a typical process a pure isolated starch is produced by a multi-stage separation process involving removal of protein, oil, fibre and glutens before being hydrolysed.

As no single number can adequately characterise the molecular weight of a polymer, such as a maltodextrin, various averages are used. The most commonly used are the weight average molecular weight ({overscore (M)}

w

) and the number average molecular weight ({overscore (M)}

n

):

{\overline{M}}_{w} = \frac{\sum n_{i} M_{i}^{2}}{\sum n_{i} M_{i}}

{\overline{M}}_{n} = \frac{\sum n_{i} M_{i}}{\sum n_{i}}

where n

i

is the number of molecules of molecular weight M

i

. {overscore (M)}

w

is particularly sensitive to changes in the high-molecular-weight content of the maltodextrin polymer whilst {overscore (M)}

n

is largely influenced by changes in the low molecular weight of the sample.

We have now found that it is possible to monitor starch hydrolysis and in particular to stop the hydrolytic action when the hydrolysate contains the maximum amount of molecules in the desired molecular weight range. The monitoring may be carried out by a technique known as size exclusion chromatography. Furthermore, fractionation of the starch hydrolysate can be monitored by size exclusion chromatography and a weight average molecular weight, a number average molecular weight and a molecular weight distribution of the products can be determined using chromatographic columns calibrated with dextran standards (Alsop et al Process Biochem 2 10-15 (1977) and Alsop et al J. Chromatography 246, 227-240, (1982)).

We have also found a method for optimising the yield of a glucose polymer with a preselected molecular weight range.

Glucose polymers are often characterised by the expression “degree of polymerisation” (DP). In this terminology a product may be described as having 20% of its weight comprising molecules with a DP greater than 10, ie. 20% has a molecular weight greater than 1656 (a polymer comprising 10 glucose units).

British Patent Application 2132914A describes a glucose polymer mixture having at least 15% by weight of glucose polymers of DP greater than 12 for use in continuous ambulatory peritoneal dialysis (CAPD). PCT/US Application 82/00774 describes a CAPD solution comprising glucose polymers of DP of at least 4.

European Patent Application 0076355 A2 discloses glucose polymer mixtures having at least 99% of glucose polymers of DP less than 12 for use in CAPD.

It has now surprisingly been found that certain polydisperse glucose polymer mixtures of high molecular weight are useful in medicine, e.g. in CAPD and in prevention of post-operative adhesions.

According to the invention we provide a glucose polymer mixture (I), wherein at least 50% by weight of the polymer is of molecular weight in the range 5000 to 30000.

We particularly prefer a glucose polymer (I), wherein at least 80% by weight of the polymer is of molecular weight in the range 5000 to 50,000.

We prefer the glucose polymer (I) to have a weight average molecular weight in the range of from 5000 to 100000, preferably of from 5000 to 50000, more preferably of from 12000 to 25000, and most preferably of from 14000 to 20000.

We prefer the glucose polymer (I) to have a number average molecular weight of less than 8000, preferably less than 5000, more preferably less than 4000 and most preferably less than 2900.

We prefer the content of mono-, di-, and tri-saccharide compounds present in the glucose polymer (I) to be less than 5% by weight, more preferably less than 2% and most preferably 0% by weight. By 0% we mean an amount which is undetectable by conventional methods.

We further prefer that the content of glucose polymers with molecular weight greater than 100000 in the glucose polymer (I) should be less than 5%, preferably less than 3% and most preferably less than 1% by weight.

We prefer the glucose polymers to be substantially free from endotoxins and nitrogenous contaminants arising from the original starch, or from the enzyme preparations used for its hydrolysis.

We particularly prefer the endotoxin level to be less than 0.25 endotoxin units/ml, more preferably less than 0.12 endotoxin units/ml and most preferably less than 0.06 endotoxin units/ml as determined by the Limulus Lysate Test (US Pharmacopoeia).

We prefer the nitrogen content of the glucose polymers to be less than 0.01% w/w, more preferably less than 0.001% w/w and most preferably zero as determined by the Kjeldahl method (British Pharmacopoeia)

We also prefer the glucose polymers to be substantially free of undesirable metals, e.g. aluminium. Thus we prefer the level of aluminium to be less than 500 ppb, more preferably less than 200 ppb and most preferably less than 100 ppb.

We also prefer an aqueous solution comprising 10% w/v of the glucose polymer to be substantially clear and colourless. Thus we prefer such a solution to have a turbidity value of less than 30 EEL units (US Pharmacopoeia), more preferably less than 20 EEL units and most preferably less than 10 EEL units. We also prefer such a solution to have no substantially visible colour. We particularly prefer the solution to have a visible colour of less than 10 APHA Hazen units and more preferably less than 5 APHA Hazen units. The content of colour precursors such as 5-hydroxymethyl furfural can be measured by absorption of ultraviolet light of wavelength 275 or 284 nm. We prefer the absorbance to be less than 0.5, more preferably less than 0.25 and most preferably less than 0.15. The transmission of ultraviolet light measured at a wavelength of 430 nm is preferably greater than 90% and more preferably greater than 95%.

It is a further feature of this invention to provide a glucose polymer (I) having up to 20% by weight of glucose polymers with a molecular weight of from 800 to 10,000, preferably of from 1500 to 4000. We particularly prefer a glucose polymer (I) having up to 20% by weight of glucose polymers with a molecular weight of from 1500 to 2500, more preferably up to 10% by weight and most preferably up to 7% by weight.

According to the invention we also provide a method for the production of a glucose polymer (I), which comprises

a) fractional precipitation of an aqueous solution of a glucose polymer containing polymer (I) with a water miscible solvent, and/or

b) filtration of an aqueous solution of a glucose polymer containing polymer (I) through membranes possessing an appropriate molecular weight cut-off range. The molecular weight cut-off range may be determined empirically.

In process a) the process parameters used are interdependent and each parameter may vary depending upon the desired quality of the product, the desired molecular weight range, etc. The water miscible solvent may be an alcohol, eg an alkanol, such as ethanol. The solvent may be present in an aqueous solution which is mixed with an aqueous glucose polymer. The concentration of the solvent in the aqueous solution before mixing may be from 60 to 100%v/v, preferably from 75 to 90%v/v, and most preferably about 85%v/v.

The concentration of the aqueous glucose polymer solution before mixing may be from 0 to 80% w/v, preferably from 15 to 65% w/v, and most preferably from 30 to 40% w/V.

The fractionation may be carried out at a temperature of from 10 to 40° C. and more preferably from 20 to 30° C.

In process b) the type of membrane material used may vary with the particular molecular weight distribution which is desired. A chemically inert plastics material may be used for the membrane, eg. a cellulose acetate or polytetrafluoro-ethylene. We particularly prefer to use a material which is mechanically stable at high temperatures and pressures, eg. a polysulphone.

A series of membranes may be used consecutively such that both a high and a low molecular weight fractionation is carried out. The membrane fractionation may be carried out at elevated temperature sufficient to prevent bacteriological contamination. We prefer the fractionation to be carried out at a temperature of from 0 to 90° C., preferably from 20 to 80° C., and most preferably from 65° to 75° C.

The feed solution may be of a concentration of from 1.0 to 30.0% w/v, preferably from 5 to 15% w/v and most preferably about 10% w/v.

The glucose polymer starting material is preferably prepared by a method, e.g. hydrolysis, designed to optimise the proportion of polymer (I), and the progress of that method is preferably monitored by size exclusion chromotography. Any starch may be used in the hydrolysis but we prefer to use a cornstarch.

The molecular weight distribution of the fractions may be determined using the chromatographic techniques described by Alsop et al J. Chromatography 246, 227-240 (1982). The optical rotation of the various solutions produced may also be used to identify the concentrations of the polymer contained by the solutions.

The high molecular weight waste products from the fractionations may be further hydrolysed to produce further quantities of lower molecular weight products which can be fractionated. The low molecular weight waste products may be useful in the production of glucose syrups.

Before, during and/or after the fractionation of process a) or b) the polymer may be purified. The purification may be to remove undesirable colour or to remove contaminants, for example proteins, bacteria, bacterial toxins, fibres or trace metals, eg aluminium. Any conventional purification technique may be applied, for example, filtration and/or absorption/adsorption techniques such as ion exchange or charcoal treatment.

The product of the fractionation of process a) or b) may be packaged and transported as a syrup or solution, for example an aqueous solution. However, we prefer the product to be in a solid form, preferably a powder, and most preferably spray dried granules.

The glucose polymer (I) is useful in a wide variety of medical indications, e.g. peritoneal dialysis, as a nutritional agent or for the prevention of post-operative adhesions etc.

According to the invention we also provide a pharmaceutical composition comprising a glucose polymer (I), wherein at least 50% of the polymer is of a molecular weight in the range 5000 to 30000, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Any composition for use in CAPD preferably comprises physiologically acceptable electrolytes, eg. sodium, potassium, calcium and magnesium in order to prevent the transfer of desirable electrolytes from the serum to the peritoneum. The amounts may vary depending upon the requirements of any individual patient and are generally sufficient to provide an osmolarity of from about 240 to 275 mOsm/liter (see Example A).

According to the invention we also provide a physiologically acceptable polysaccharide (II) with an osmolarity of less than 160 mOsm/liter, preferably less than 110 mOsm/liter more preferably less than 90 mOsm/liter and most preferably less than 20 mOsm/liter, which is capable of being used in solution in the dialysis of normal human serum. By normal human serum we mean serum with an osmolarity of between 280 and 290 mOsm/liter at 37° C. The polysaccharide (II) preferably has the molecular weight and other parameters described above with respect to glucose polymer (I). Any suitable polysaccharide may be used but we prefer the polysaccharide to be a glucose polymer (I).

The polysaccharide (II) may be prepared by any of the processes hereinbefore described or by conventional processes known per se.

We also provide a composition capable of dialysing normal human serum comprising a polysaccharide (II) and having an osmolarity somewhat greater than normal serum. The osmolarity of the composition is preferably less than 400 mOsm/liter, more preferably less than 350 mOsm/liter and most preferably less than 330 mOsm/liter at 37° C. We particularly prefer a composition with an osmolarity less than 300 mOsm/liter at 37° C.

The composition may be in solid form, eg suitable for extemporaneous production of a solution, or it may be a liquid, eg in the form of an aqueous solution. The composition preferably includes pharmacologically acceptable electrolytes. Such electrolytes may include appropriate ions, eg of sodium, potassium, calcium, magnesium and chloride; buffers, eg. lactate, acetate or bisulphite; or other additives, such as amino acids, polyols or insulin.

The polymer (I) and the polysaccharide (II) are advantageous over the prior art. The long term use of high osmolarity glucose solutions in peritoneal dialysis can result in irreversible changes to the peritoneal membrane due to the continuous high pressure differentials across the peritoneum. When a glucose solution with a low osmolarity is used in CAPD for greater than four hours glucose may be lost from the peritoneum to the serum, this is undesirable, particularly in diabetic patients. The present invention provides a method of applying an osmotic pressure over the peritoneum for greater than four hours without causing damage to the peritoneum whilst preventing appreciable loss of polysaccharide to the serum from the peritoneum and maintaining the flow of water from the serum to the peritoneum.

BRIEF DESCRIPTION OF DRAWINGS

The invention will now be described by way of example only and by reference to the attached drawings in which

FIG. 1

is a flow diagram of the process described in Example 1;

FIG. 2

is a flow diagram of the process described in Example 2;

FIG. 3

is a flow diagram of the process described in Example 3;

FIG. 4

is a flow diagram of the process described in Example 4; and

FIG. 5

is a flow diagram of the process described in Example 5.

In the Examples OR means optical rotations.

The molecular weight distribution of the starch hydrolysate starting material which was used in Examples 1 and 2 is shown in Table 1. The starting material was found to have an {overscore (M)}

w

of 6309 and an {overscore (M)}

n

of 401.

EXAMPLE 1

Ethanol Fractionation

The fractionation procedure used to isolate the required molecular weight distribution of a maltodextrin syrup is given in FIG.

1

. The precise technique to be used will of course be varied to take account of the quality and molecular weight distribution of the maltodextrin used as the starting material.

Aqueous ethanol (33 l at 85%v/v) was added, with stirring, to 37 l of a maltodextrin syrup (at 116° OR=23 kg, dissolved maltodextrins). After settling the resulting Syrup I (5 l at 92° OR) was drawn from the bottom outlet of the fractionator.

Aqueous ethanol (40 l at 85% v/v) was added, with stirring, to the Supernatant I. After settling the Supernatant II (84 l at 13.5° OR) was decanted.

Aqueous ethanol (75 l at 85% v/v) and pyrogen free water (25 l) were added, with stirring, to the Syrup II (46 l at 50.25° OR ). After settling the Supernatant III (103 l at 3.5° OR ) was decanted.

Aqueous ethanol (54 l at 85% v/v) and pyrogen free water (14 l) were added, with stirring, to the resulting Syrup III (13 l at 104° OR ). After settling the Supernatant IV (69 l at 3.4° OR ) was decanted.

Aqueous ethanol (48 l at 85% v/v) and pyrogen free water (12 l) were added with stirring, to the resulting Syrup IV (12 l at 98° OR ). After settling the required maltodextrin fraction, Syrup V, (10.51 at 102.4° OR =5.5 kg dissolved maltodextrins) was drawn off. This represents 23.9% recovery of the maltodextrins present in the initial syrup. 3.8 kg of Syrup V was dissolved in pyrogen free water (25 l) and refluxed with stirring in the presence of 0.4 kg of activated carbon (Norit UK, GSX grade). The carbon was removed by filtration and the resulting syrup was used to prepare peritoneal dialysis solutions.

The {overscore (M)}

w

of the product maltodextrin after carbon treatment was 18949 and the {overscore (M)}

n

was 6316. The molecular weight distribution is shown in Table 2, 61% of the product lies within the range 5000 to 30000.

EXAMPLE 2

Ethanol Fractionation

The procedure of Example 1 was repeated using the quantities shown in FIG.

2

. However, the carbon treatment was carried out by adding the activated carbon (Norit UK, grade GSX 5 kg) to the alcoholic Syrup V. The alcohol was removed by steam distillation and the carbon by depth filtration (Carlson Ford grade NA90). The resulting syrup was then spray dried.

The {overscore (M)}

w

of the product maltodextrin was 12027 and the {overscore (M)}

n

was 3447. The molecular weight distribution is shown in Table 3, 60% of the product lies within the range 5000 to 30000.

The {overscore (M)}

w

of the product maltodextrin after carbon treatment was 12027 and the {overscore (M)}

n

was 3447. The molecular weight distribution is shown in Table 3, 60% of the product lies within the range 5000 to 30000.

EXAMPLE 3

Ethanol Fractionation

The molecular weight distribution of the starting material is shown in Table 4. The starting material had an {overscore (M)}

w

of 11534 and an {overscore (M)}

n

of 586.

The procedure of Example 1 was repeated using the quantities shown in FIG.

3

. However, the carbon treatment was carried out by adding the activated carbon (Norit UK, Grade GSX 60 kg) to the alcoholic syrup IV. The activated carbon was filtered off by depth filtration (Carlson Ford Grade ‘O’ pads). A further carbon treatment was carried out on the syrup VI (15 kg Norit UK Grade GSX, filtered off using Carlson Ford Grade NA90 pads) during ethanol removal by steam distillation. The ethanol-free syrup was spray dried.

The {overscore (M)}

w

of the product maltodextrin was 21838 and the {overscore (M)}

n

was 7105. The molecular weight distribution is shown in Table 5, 58% of the product lies within the range 5000 to 30000.

EXAMPLE 4

Ethanol Fractionation

The molecular weight distribution of the starting material is shown in Table 6. The starting material had an {overscore (M)}

w

of 12636 and an {overscore (M)}

n

of 639.

The procedure of Example 1 was repeated using the quantities shown in FIG.

5

. The carbon treatment was carried out by adding activated carbon (Norit UK, Grade GSX, 20 kg) to the alcoholic syrup IV. The carbon was filtered by depth filtration (Carlson Ford Grade ‘O’ pads). Ethanol was removed from the final syrup (syrup V) by steam distillation and the aqueous product ion exchanged (mixed bed system), and spray dried. The mixed bed resin was Duolite A1725 in the hydroxyl form and C225H in the chloride form. (Duolite is a trade mark).

The {overscore (M)}

w

of the product maltodextrin was 22020 and The {overscore (M)}

n

was 7767. The molecular weight distribution is shown in Table 7, 60% of the product lies within the range 5000 to 30000.

EXAMPLE 5

Membrane Fractionation

a) A high molecular weight fractionation was carried out by passing 1.9 kg of starch hydrolysate, (molecular weight distribution, see Table 8), as a 10% w/v solution (20 liters) through a series of membranes. Polysulphone membranes with an approximate molecular weight cut-off of 20,000 and an area of 0.216 m

2

were used. The feed flowrate was 6.6 liters/min at a temperature of 70° C. The total solids level of the retained liquid was maintained at 10% w/v and the low molecular weight species were washed through the membrane. After 6.5 hours the concentration of carbohydrate in the permeate product stream leaving the ultrafiltration module was low, eg 0.5% w/v, (see Table 9) and the process was terminated. The high molecular weight residues were recovered from the membrane (0.2 kg, 10.5%) and the permeative low molecular weight product was isolated from the permeate (1.70 kg, 89.5%).

The molecular weight distribution of the product is shown in Table 10.

b) A low molecular weight fractionation was carried out by passing 0.64 kg of the low molecular weight product from Example 3a) as a 3.2% w/v solution (20 liters) through a series of membranes. Polysulphone membranes with an approximate molecular weight cut-off of 2,000 and an area S of 0.18 m

2

were used. The feed flowrate was 6.6 liters/min at a temperature of 70° C. The total solids level of the retained liquid was maintained at approximately 4.0% w/v and the low molecular weight species were washed through the membrane. After 95 minutes the concentration of carbohydrate in the permeate stream was zero (see Table 11) and the process was terminated. The undesired permeate product was recovered (0.465 kg, 73%) and the desired retained product was 0.166 kg (26%).

The molecular weight distribution of the product is shown in Table 12, 55% of the product lies within the range 5000 to 30000.

EXAMPLE 6

a) Membrane Fractionation

The procedure for Example 5a) was repeated using 2.0 kg of starch hydrolysate. Membranes were used with a cut-off value of 25000 an area of 0.144 m

2

. After 5.5 hours the concentration of the carbohydrate in the permeate was undetectable (see Table 13). The high molecular weight residues were recovered from the membrane (0.384 kg, 19.2%) and the permeative low molecular weight product was isolated from the permeate (1.613 kg, 80.6%). The molecular weight distribution of the permeate is given in Table 14. {overscore (M)}

w

was found to be 4906 and {overscore (M)}

n

determined as 744.

b) Ethanol Fractionation

1.7 kg of maltodextrin from Example 6a) in 53 liters of pyrogen free water was mixed with 132.5 liters of aqueous ethanol (85% v/v).

The syrup from the fractionation had an {overscore (M)}

w

of 19712 and an {overscore (M)}

n

of 4798. The molecular weight distribution is shown in Table 15, 55% of the product lies within the range 5000 to 30000.

EXAMPLE 7

Ethanol Fractionation

The procedure of Example 3 was carried out. Syrup V was isolated and the molecular weight distribution determined.

The {overscore (M)}

w

of the product maltodextrin was 20211 and the {overscore (M)}

n

was 2890. The molecular weight distribution is shown in Table 16, 50% of the product lies within the range 5000 to 30000.

EXAMPLE A

Two examples of peritoneal dialysis solutions are shown below. The ionic electrolytes behave ideally and therefore 1 mOsm/l is equivalent to 1 mmol/l.

1

2

Sodium (mO sm/1)

131

138

Potassium (mO sm/1)

0

0

Calcium (mO sm/1)

1.8

1.78

Magnesium (mO sm/1)

0.75

0.75

Chloride (mO sm/1)

91

90

Lactate (mO sm/1)

45

45

Acetate (mO sm/1)

—

—

Bisulphite (mO sm/1)

—

—

Total Electrolyte

269.6

275.5

Osmolarity (mO sm/1)

Glucose polymer (I) (mO sm/1)

12.9

12.9

(50 g/l)

(50 g/l)

Total Osmolarity

282.5

288.4

TABLE 1

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

165

0.00

167

2.50

172

5.00

178

7.50

184

10.00

191

12.50

199

15.00

207

17.50

216

20.00

226

22.50

237

25.00

249

27.50

262

30.00

276

32.50

291

35.00

307

37.50

326

40.00

346

42.50

366

45.00

391

47.50

419

50.00

446

52.50

488

55.00

532

57.50

598

60.00

681

62.50

837

65.00

1099

67.50

1570

70.00

2328

72.50

3436

75.00

4915

77.50

6789

80.00

7135

82.50

12074

85.00

13825

87.50

20735

90.00

27447

92.50

37044

95.00

53463

97.50

199559

100.00

TABLE 2

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

296

0.00

1231

2.50

1756

5.00

2279

7.50

2795

10.00

3291

12.50

3771

15.00

4246

17.50

4722

20.00

5203

22.50

5696

25.00

6196

27.50

6718

30.00

7247

32.50

7809

35.00

8378

37.50

8986

40.00

9607

42.50

10272

45.00

10960

47.50

11695

50.00

12472

52.50

13295

55.00

14184

57.50

15126

60.00

16162

62.50

17274

65.00

18499

67.50

19872

70.00

21352

72.50

23122

75.00

25084

77.50

27319

80.00

30070

82.50

33400

85.00

37527

87.50

42867

90.00

50412

92.50

61686

95.00

82648

97.50

288182

100.00

TABLE 3

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

183

0.00

484

2.50

874

5.00

1292

7.50

1695

10.00

2082

12.50

2460

15.00

2836

17.50

3215

20.00

3595

22.50

3986

25.00

4382

27.50

4786

30.00

5204

32.50

5627

35.00

6072

37.50

6519

40.00

6994

42.50

7473

45.00

7982

47.50

8499

50.00

9048

52.50

9611

55.00

10212

57.50

10836

60.00

11502

62.50

12208

65.00

12955

67.50

13777

70.00

14637

72.50

15626

75.00

16708

77.50

17905

80.00

19298

82.50

20957

85.00

22960

87.50

25476

90.00

29002

92.50

34287

95.00

44550

97.50

299523

100.00

TABLE 4

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

146

0.00

157

2.50

173

5.00

192

7.50

213

10.00

235

12.50

259

15.00

285

17.50

313

20.00

343

22.50

378

25.00

411

27.50

450

30.00

489

32.50

536

35.00

583

37.50

636

40.00

695

42.50

755

45.00

837

47.50

920

50.00

1036

52.50

1161

55.00

1350

57.50

1590

60.00

1919

62.50

2393

65.00

3094

67.50

4176

70.00

5731

75.00

7802

75.00

10354

77.50

13393

80.00

17014

82.50

21436

85.00

27030

87.50

34348

90.00

44586

92.50

60087

95.00

89965

97.50

578156

100.00

TABLE 5

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

1394

2.50

2060

5.00

2644

7.50

3199

10.00

3751

12.50

4299

15.00

4856

17.50

5421

20.00

6003

22.50

6597

25.00

7208

27.50

7841

30.00

8497

32.50

9175

35.00

9881

37.50

10615

40.00

11385

42.50

12189

45.00

13033

47.50

13924

50.00

14870

52.50

15874

55.00

16947

57.50

18096

60.00

19333

62.50

20685

65.00

22167

67.50

23793

70.00

25616

72.50

27661

75.00

29973

77.50

32624

80.00

35745

82.50

39445

85.00

44003

87.50

49720

90.00

57401

92.50

68831

95.00

90432

97.50

TABLE 6

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

146

0.00

156

2.50

175

5.00

197

7.50

223

10.00

250

12.50

279

15.00

311

17.50

345

20.00

381

22.50

420

25.00

462

27.50

506

30.00

555

32.50

603

35.00

662

37.50

721

40.00

792

42.50

875

45.00

971

47.50

1099

50.00

1269

52.50

1496

55.00

1827

57.50

2320

60.00

3043

62.50

4107

65.00

5556

67.50

7396

70.00

9581

75.00

12065

75.00

14880

77.50

18153

80.00

21986

82.50

26590

85.00

32293

87.50

39532

90.00

49285

92.50

63509

95.00

89961

97.50

439968

100.00

TABLE 7

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

1586

2.50

2290

5.00

2882

7.50

3443

10.00

3991

12.50

4545

15.00

5110

17.50

5694

20.00

6302

22.50

6931

25.00

7587

27.50

8263

30.00

8965

32.50

9692

35.00

10441

37.50

11218

40.00

12030

42.50

12878

45.00

13761

47.50

14691

50.00

15671

52.50

16705

55.00

17805

57.50

18982

60.00

20244

62.50

21615

65.00

23120

67.50

24766

70.00

26584

72.50

28624

75.00

30930

77.50

33568

80.00

36623

82.50

40240

85.00

44626

87.50

50148

90.00

57346

92.50

67788

95.00

86399

97.50

TABLE 8

Starch Hydrolysate

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

146

0.00

160

2.50

176

5.00

195

7.50

217

10.00

240

12.50

264

15.00

291

17.50

322

20.00

354

22.50

390

25.00

428

27.50

470

30.00

511

32.50

558

35.00

605

37.50

657

40.00

714

42.50

772

45.00

852

47.50

934

50.00

1050

52.50

1185

55.00

1398

57.50

1688

60.00

2104

62.50

2708

65.00

3617

67.50

4870

70.00

6517

75.00

8552

75.00

10946

77.50

13729

80.00

17036

82.50

21022

85.00

25964

87.50

32324

90.00

40911

92.50

53516

95.00

76329

97.50

356145

100.00

TABLE 9

Pressure

Permeate Flow

Feed Soln

Permeate

in

out

Temp

Rate

Concn

Conc

Time

Bar

° C.

1/min

% w/v

% w/v

0

4.6

3.4

64

on total recycle

1

″

″

64

190

10.5

7

1.5

″

″

68

192

10

6.5

2

″

″

71

198

9

5

3

″

″

69

166

8

3.5

4

″

″

69

165

6.75

2.25

6

″

″

70

148

6

1

6.5

″

″

65

140

8

0.5

TABLE 10

Permeate (Ex 5(a))

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

146

0.00

169

2.50

205

5.00

247

7.50

285

10.00

323

12.50

362

15.00

403

17.50

444

20.00

488

22.50

533

25.00

581

27.50

630

30.00

681

32.50

734

35.00

787

37.50

845

40.00

906

42.50

966

45.00

1038

47.50

1117

50.00

1196

52.50

1303

55.00

1423

57.50

1567

60.00

1758

62.50

2003

65.00

2308

67.50

2720

70.00

3287

72.50

4080

75.00

5156

77.50

6535

80.00

8280

82.50

10326

85.00

12731

87.50

15631

90.00

19283

92.50

24378

95.00

32986

97.50

93587

100.00

TABLE 11

Pressure

Permeate Flow

Feed Soln

Permeate

in

out

Temp

Rate

Concn

Conc

Time

Bar

° C.

1/min

% w/v

%. w/v

0

5.4

4.6

70

390

3.25

1.75

15

mins

5.4

4.6

70

400

3.5

1.5

35

mins

5.4

4.6

71

300

5.0

2.0

60

mins

5.4

4.6

70

280

4.25

1

95

mins

5.4

4.6

69

280

3.0

0

TABLE 12

Retentate (Ex 5(b))

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

186

0.00

834

2.50

1339

5.00

1837

7.50

2410

10.00

3090

12.50

3869

15.00

4717

17.50

5613

20.00

6540

22.50

7492

25.00

8458

27.50

9433

30.00

10414

32.50

11398

35.00

12385

37.50

13374

40.00

14384

42.50

15406

45.00

16449

47.50

17519

50.00

18611

52.50

19754

55.00

20917

57.50

22167

60.00

23437

62.50

24832

65.00

26283

67.50

27852

70.00

29576

72.50

31415

75.00

33457

77.50

35747

80.00

38449

82.50

41731

85.00

45703

87.50

50765

90.00

57945

92.50

69100

95.00

90766

97.50

410452

100.00

TABLE 13

Pressure

Permeate Flow

Feed Soln

Permeate

in

out

Temp

Rate

Concn

Conc

Time

Bar

° C.

1/min

% w/v

% w/v

0.75

4.7

3.3

67

225

9.5

5.0

1.25

4.7

3.8

68

184

10.5

5.5

2.50

4.8

3.2

70

150

9.0

4.0

3.50

4.8

3.2

70

144

8.0

1.5

4.50

4.8

3.2

69

130

6.5

0.5

5.50

4.8

3.2

69

123

6.0

0

TABLE 14

Permeate (Ex 6)

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

146

0.00

170

2.50

207

5.00

251

7.50

293

10.00

335

12.50

378

15.00

423

17.50

469

20.00

516

22.50

566

25.00

616

27.50

660

30.00

720

32.50

773

35.00

827

37.50

882

40.00

939

42.50

1004

45.00

1070

47.50

1135

50.00

1226

52.50

1320

55.00

1418

57.50

1567

60.00

1717

62.50

1947

65.00

2218

67.50

2566

70.00

3056

72.50

3718

75.00

4671

77.50

5959

80.00

7656

82.50

9753

85.00

12271

87.50

15332

90.00

19237

92.50

24688

95.00

34400

97.50

98105

100.00

TABLE 15

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

170

0.00

845

2.50

1292

5.00

1674

7.50

2044

10.00

2429

12.50

2841

15.00

3283

17.50

3754

20.00

4269

22.50

4805

25.00

5361

27.50

5958

30.00

6583

32.50

7232

35.00

7937

37.50

8666

40.00

9447

42.50

10273

45.00

11129

47.50

12062

50.00

13024

52.50

14053

55.00

15147

57.50

16281

60.00

17537

62.50

18860

65.00

20264

67.50

21839

70.00

23542

72.50

25408

75.00

27488

77.50

29900

80.00

32694

82.50

36020

85.00

40183

87.50

45419

90.00

52731

92.50

64063

95.00

85249

97.50

349210

100.00

TABLE 16

Molecular Weight Distribution

MOLECULAR

INTEGRAL

WEIGHTS

DISTRIBUTION

147

0.00

354

2.50

627

5.00

918

7.50

1243

10.00

1602

12.50

1996

15.00

2431

17.50

2908

20.00

3428

22.50

3990

25.00

4591

27.50

5232

30.00

5924

32.50

6653

35.00

7417

37.50

8230

40.00

9092

42.50

9990

45.00

10946

47.50

11966

50.00

13032

52.50

14178

55.00

15407

57.50

16704

60.00

18105

62.50

19643

65.00

21999

67.50

23093

70.00

25087

72.50

27332

75.00

29844

77.50

32692

80.00

35966

82.50

39805

85.00

44449

87.50

50079

90.00

57437

92.50

67881

95.00

86087

97.50

331467

100.00

Number	Name	Date
2823128	Toulmin	Feb 1958
4182756	Ramsay et al.	Jan 1980
4357323	Soma et al.	Nov 1982
4514560	Shinohara et al.	Apr 1985
4886789	Milner	Dec 1989

Number	Date	Country
0 153 164	Aug 1985	EP
WO 8203329	Oct 1982	WO

	Number	Date	Country
Parent	07/779129	Oct 1991	US
Child	07/954686		US

	Number	Date	Country
Parent	06/875461	Jun 1996	US
Child	07/779129		US

Method of peritoneal dialysis using glucose polymer solutions

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

Parent Case Info

US Referenced Citations (5)

Foreign Referenced Citations (2)

Non-Patent Literature Citations (3)

Continuations (1)

Continuation in Parts (1)

Entry
Alexander et al., Chemical Abstracts, vol. 98, 1983 No. 149608 K.*
Chemical Abstracts vol. 85, 1976, p. 410 (Reference No. 141580f).
Chemical Abstracts vol. 99, 1983, p. 619 (Reference No. 105608b).