A novel aldehyde containing polymer (ACP) is prepared by reaction of a polysaccharide with periodate to introduce aldehyde groups onto the C2 - C3 carbon atoms. By introduction of ether and ester groups onto the pendant primary hydroxyl solubility characteristics are modified. The ACP is utilized to absorb nitrogen bases such as urea in vitro or in vivo

Hsu, G. C.

Marsh, H. E., Jr.

Mueller, W. A.

English

NASA Technical Reports Server

United States Patent 1191 
Fletcher et al. 
[111 4,041,233 
1451 Aug. 9,1917 
[54] ALDEHYDE-CONTAINING 
UREA-ABSORBING POLYSACCHARIDES 
[76] Inventors: 
[21] Appl. NO.: 
[22] Filed: 
James C. Fletcher, Administrator of 
the National Aeronautics and Space 
Administration, with respect to an 
invention of; William A. Mueller, 
Glendale, Calif.; George C. Hsu, La 
Crescenta, Calif.; Harold E. Marsh, 
Jr., La Canada, Calif. 
666,992 
Mar. 15, 1976 
[51] Int. Cl.2 ........................ C08B 3/22; C08B 11/20; 
C08B 15/02; C08B 31/18 
[52] U.S. C1. ........................................ 536/56; 210/24; 
536/58; 536/84; 536/85; 536/105 
[58] Field of Search ....................... 536/56, 58, 84, 85, 
5 36/ 105 
1561 References Cited 
US. PATENT DOCUMENTS 
2,606,188 8/1952 Yelland ................................ 536/105 
2,648,629 8/1953 Dvonch et ai. ...................... 536/105 
3,033,851 5/1962 Schaefer et al. ..................... 536/105 
3,086,969 4/1963 Slager ................................... 536/105 
3,313,641 4/1967 Borchert .............................. 536/105 
3,634,395 1/1972 Walon .................................. 536/105 
FOREIGN PATENT DOCUMENTS 
253,034 7/1964 Australia .............................. 536/105 
703,933 2/1965 Canada ................................. 536/105 
7150/62 7/1962 Japan .................................... 536/105 
Primary Examiner-Ronald W. Griffin 
Attorney, Agent, or Firm-Monte F. Mote Wilfred 
Grifka; John R. Manning 
1571 ABSTRACT 
A novel aldehyde-containing polymer (ACP) is pre- 
pared by reaction of a polysaccharide with periodate to 
introduce aldehyde groups onto the C2 - Cj carbon 
atoms and by introduction of ether and ester groups 
onto the pendant primary hydroxyl to modify solubility 
characteristics. The ACP is utilized to absorb nitrogen 
bases such as urea in vitro or in vivo. 
7 Claims, No Drawings 
https://ntrs.nasa.gov/search.jsp?R=19770023292 2020-03-20T07:55:35+00:00Z
1 
4,041,233 
ALDEHYDE-CONTAINING UREA-ABSORBING 
POLYSACCHARIDES 
ORIGIN OF THE INVENTION 
The invention described herein was made in the per- 
formance of work under a NASA contract and is sub- 
ject to the provisions of Section 305 of the National 
Aeronautics and Space Act of 1958, Public Law 83-568 
(72 Stat. 435; 42 USC 2457). 
BACKGROUND O F  THE INVENTION 
1. Field of the Invention 
The present invention relates to a mofified polysac- 
charide, to methods of synthesis and to methods of use 
in absorbing basic compunds such as urea from solution. 
2. Description of the Prior Art 
A sizable fraction estimated 50,000 people who die of 
kidney failure each year in the United States are free of 
other complications and might be restored to useful life 
if their kidney function could be artifically. At present, 
artificial kidneys (using hemodialysis) and clinical pro- 
cedures have been developed to the point where long- 
term sustenance of life by periodic hemodialysis is prac- 
ticable in many cases. 
The limitations in using hemodialysis are the small 
number of patients who can be treated with a given 
kidney machine and the considerable expense of main- 
taining and staffing a kidney-treatment center. Obvi- 
ously, a desirable solution lies in the development of an 
artificial kidney which is inexpensive, portable and ca- 
pable of being operated outside the confines of a hospi- 
tal with a minimum of medical attention. Attainment of 
this solution will require increased efficiency of mass 
transfer and further optimization of design of artificial- 
kidney systems. 
In recent years, considerable attention has been fo- 
cused on methods of reducing the size of the artificial 
kidney. This requires miniaturization of the membrane- 
containing dialyzer and a significant reduction in the 
volume of dialyzing fluid. It is generally conceded that 
the toxin primarily responsible for the uremic syndrome 
has not yet been identified. Even though urea is not 
considered particularly toxic, its removal is one of the 
chief objectives on urea reomval is that, in the absence 
of more specific knowledge, dialysis based on this prin- 
ciple is obviously beneficial. At least two explanations 
suggest themselves: (a) Unidentified toxicants are re- 
moved along with the urea. (6) Urea produces toxic 
products. 
In order to increase the efficiency of hemodialysis, it 
is desirable to maintain the trans-membrane concentra- 
tion gradient of waste metabolites as high as possible. 
Low waste concentrations in the dialyzing fluid have in 
the past been maintained by two methods. The more 
widely used method is the continual dilution of the 
dialyzed substances in a large reservoir fluid, usually 
100 to 300 liters. A second method of maintaining the 
gradient is to use the dialyzing fluid in a single-pass 
operation, where the waste-bearing effluent is dis- 
carded. Even then, more than 100 liters of fluid are 
required. The current research trend in obtaining low 
concentrations of wastes is to remove them selectively 
from the dialyzing fluid. Such an approach would allow 
the use of much smaller volumes of dialyzing fluid. 
Among all waste products, urea is by far the major 
waste metabolite which must be removed daily from the 
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body fluid. Three major methods of urea removal from 
dialysate have been reported. 
The first procedure utilizes an activated carbon bed 
which removes urea by absorption. However, the dem- 
onstrated capacity for urea is only 0.2-0.8 grams per 100 
grams of carbon. In another method urea is reduced by 
enzymatic hydrolysis either inside microcapsules or by 
the combination with other absorbents. A commercial 
apparatus utilizes sodium zirconium phosphate to re- 
move the ammonia produced by enzymatic decomposi- 
tion of urea in the presence of urease. However, the 
capacity of urea removal is limited by the reaction ex- 
tent of enzymatic decomposition. 
It has recently been reported that oxystarch has been 
used for binding urea in its transit through the gastroin- 
testinal tract (an in vivo application). Oxystarch is re- 
ceiving wide attention for its potential as an absorber in 
the gastointestinal tract. The disappointing aspect about 
this material is that it is useless in diaylsate because it 
dissolves in that fluid. Oxystarch absorbs urea at low 
pH but will dissolve if treated with alkali at pH 8. 
Therefore, oxystarch will dissolve into dialysate or 
leach into the blood if utilized for in vivo applications. 
SUMMARY OF THE INVENTION 
An improved nitrogen base absorbent is provided in 
accordance with this invention. The absorbent demon- 
strates a significant affinity for urea molecu!es while 
being insoluble in dialysate utilized in an artificial kid- 
ney system. The absorbent will find use generally in 
absorption of basic materials and particularly, ammonia, 
ammonium amine or amide compounds such as urea 
from solution. In vivo use by digestion of the material, 
and absorption of urea or other amide substituted me- 
tabolites while passing through the G.I. tract is also 
indicated. 
The absorbents of the invention have demonstrated 
absorption of at least 1% urea based on weight of absor- 
bent under physiological conditions (0.03M urea, pH 7). 
Some of the absorbents of the invention exhibit absorp- 
tion capacities comparing favorable with that of the 
commercially utilized urease-zirconium phosphate sys- 
tem which has a urea absorption of about 2%. 
The absorbents of this invention are prepared by 
modification of the primary hydroxyl group of the amy- 
lose unit of a polysaccharide to introduce from 0.05 to 
about 0.5 degree of subsititution of an ether or organic 
ester moiety and by specific vic-glycol oxidation of the 
C2 - C3 hydroxyl groups with a reagent such as perio- 
date to introduce from 10 to 35% by weight of aldehyde 
groups. 
The aldehyde groups are responsible for the absorp- 
tion capacity of the modified polysaccharide and the 
primary hydroxyl substitution provides the desired in- 
solubility characteristics while permitting the absorbent 
to be swellable such that the introduced aldehyde 
groups are available for absorption. 
DESCRIPTION OF THE PREFERRED 
EMBODIMENTS 
Polysaccharide materials for use in this invention 
have a molecular weight from 30,000 to 14,000,00 and 
may be derived from homopolysaccharide or hetero- 
polysaccharide sources, and are preferably homopoly- 
saccharides such as starch or cellulose. The fraction of 
interest is the amylose containing material of the for- 
mula: 
4,041,233 
3 
10 
The periodate reaction is specific for the oxidation of 
the C2 - C ,  hydroxyl groups to form a dialdehyde as 
follows: 
The oxidation is practiced at a pH of 4-5 and ambient 
temperature with from 0.5 to 1.5 moles of alkali metal 
periodate per mole of polysaccharide, typically equimo- 
lar sodium periodate. The oxidation may be practical 
before or after susbtitution of the primary hydroxyl. 
However, since the dialdehyde groups are subject to 
hemi-acetal shift during etherification or esterification it 
may be preferable to practice the subsititution step be- 
fore oxidation. 
The substitution step is practiced according to art- 
recognized etherification or esterification procedures 
except that the degree of substitution is controlled to 
introduce a small amount of substituent and to favor the 
susbstitution at the primary hydroxyl position. The 
primary hydroxyl groups are substituted to form an 
absorbent in which 0.05 to 0.5 of amylose units are of 
the formula: 
~ H , O R  
where R is aliphatic or aromatic ether or ester, prefer- 
ably alkyl of 1 to 6 carbon atoms, phenyl or alkylated 
phenyl, substituted alkyl such as carboxyalkyl of alkan- 
oyl of 1-6 carbon atoms such as 
where n is 0 to 4. 
Etherification is effected by treatment with alkali 
such as 530% NaOH followed by an alkylation reagent 
such as an alkyl or aryl halide at room or elevated tem- 
perature. Esterification can be practiced by soaking the 
cellulose in a dilute solution of sulfuric acid in glacial 
acetic acid which is then added to a mixture of acetic 
anhydride and acetic acid or by suspension in pryidine 
with excess of acetic, propionic or butyric anhydride. 
Specific examples of practice follow: 
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The absorbents were tested for urea absorption in 65 
Two gram samples of the various products were 
isotonic dialysate as follows: 
stirred with 100 ml of the following solution: 
1 
4 
1 liter distilled water 
4.5 grams sodium acetate trihydrate 
5.8 grams sodium chloride 
2.0 grams urea 
Urea concentration of the solution was measured by a 
spectrophotometric method involving formation of a 
colored reaction product of urea and p-dime- 
thylaminobenzaldehyde as described in Handbook of 
Analytical Chemistry, L. Meites ed., McGraw-Hill, 
1963, P. 46-48. The samples were suspended in the urea 
test solution and stirred with a magnetic stirring bar. 
After the desired time had elasped, the mixture was 
filtered to remove suspended material and the urea 
concentration in the filtrate determined. 
Absorbents were prepared by etherification or esteri- 
fication of cellulose, followed by oxidation of the etheri- 
fied sample with aqueous sodium periodate at pH 4-5 
and ambient termperature. 
EXAMPLE 1 
Carboxymethyl cellulose (D.S. 0.15) was stirred with 
an equimolar quantity of 6% sodium periodate solution 
in water at room temperature until reaction was com- 
plete as evidenced by lack of color formation with 
maganous ion-phosphoric acid mixture. Time required 
was 36 hours. The resulting solid was washed until free 
of iodate. It was then tested for urea absorption and 
showed a urea pickup of 2% by weight after 16 hours. 
EXAMPLE 2 
Cellulose filter pulp (4 g) was suspended in 20% so- 
dium hydroxide for a few minutes. It was then filtered 
and washed with water until neutral. The water was 
exchanged with dioxane, the dioxane-wet pulp was 
washed with pyridine and suspended in fresh pyridine. 
A 20% molar excess of p-toluene sulfonychloride was 
added, and the mixture stirred for 4 hours at room tem- 
perature, and allowed to stand overnight. The solid was 
filtered and washed, suspended in methanol, and a 2 
molar excess of sodium methoxide was added. The 
mixture was refluxed for 1 hour, and then filtered and 
washed with dilute acid and finally with water. It was 
then reacted with sodium periodate as in Example 1, 
filtered, washed, and dried. The material showed a urea 
absorption of 1.5 wt%. 
Example 3 
Cellulose filter pulp 4 (g) was suspended in pyridine 
and an excess of acetic anhydride added. The mixture 
was allowed to stand 3 days at room temperature, fil- 
tered, and washed. The solid was then reacted with 
sodium periodate and thoroughly washed. The resultant 
material had a urea absorption of 1.5%. 
It is to be realized that only preferred embodiments of 
the invention have been described and that numerous 
substitutions, alterations and modifications may be 
made without departing from the spirit and scope of the 
invention as defined in the following claims: 
What is claimed is: 
1. A modified polysaccharide containing 10% to 35% 
by weight of C2 - Cs aldehyde groups and in which 0.05 
to 0.5 of the amylose units are of the formula: 
4,041,233 
6 5 
7. A method of producing a modified polysaccharide 
0 
II 
comprising the steps in sequence: 
~ H , O R  
10 where R is the residue of an ether or ester moiety. 
2. A polysaccharide according to claim 1 in which R 
is an alkyl of 1 to 6 carbon atoms, phenyl, alkylated 
phenyl, carboxyalkyl of 1 to 6 carbon atoms or the ester 
residue of an alkanonic acid of 1 to 6 carbon atoms. 
is carboxymethyl. 
is methyl. 
3. A polysaccharide according to claim 2 in which R l5 
4. A polysaccharide according to claim 2 in which R 
modifying 0.05 to 0.5 of the primary hydroxyl groups 
of the amylose units to introduce an ether or ester 
group thereon; and 
oxidizing the Cz - C3 hydroxyl groups of the amylose 
units to dialdehyde groups at pH 4-5 with 0.5 to 1.5 
moles of an alkali metal periodate per mole of poly- 
saccharide to introduce from 10% to 35% be 
weight of Cz - C1 aldehyde groups to form amylose 
units of the formula: 
~ H , O R  
20 
5. A polysaccharide according to claim 1 having a 
6. A polysaccharide according to claim 5 selected 
molecular weight from 30,000 to 14,000,000. 
from starch or cellulose. 
where R is the residue of an ether or ester moiety. * * * * *  
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Aldehyde-containing urea-absorbing polysaccharides

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