JPH09176202A - Cellulose derivative, its manufacture and usage thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cellulose deriv. which neither decomposes in vivo nor causes diarrhea due to adsorbing protein and has high adsorbing capacity of uremia matter, and its usage. SOLUTION: This cellulose deriv. has more than one formylalkyl groups or formylbenzyl groups as substituents on its side chain. This compd. is manufactured by O-alkylation or O-benzylation of hydroxide group, which has been formed by hydrolyzing an acetyl group of cellulose acetate, by a haloalkyl or a halobenzyl both having an acetal group, then, an aldehyde group is formed on its side chain by hydrolyzing the acetal group by acid. A medicinal composition (adsorbent of uremia matter, medicine for nephritis and renal failure), food, and food additives contg. the cellulose deriv. as their effective component are prepared. The medicinal composition has high adsorbing characteristics to uremia matter such as urea and shows no protein adsorption which is considered as the cause of diarrhea.

Description

Detailed Description of the Invention

[Background of the Invention]

TECHNICAL FIELD The present invention has a substitution degree of 1 in a side chain.
It relates to a cellulose derivative having a larger formylalkyl group or formylbenzyl group. The present invention also provides
The present invention relates to a pharmaceutical composition containing the compound of the present invention, in particular, a novel therapeutic agent for nephritis and renal failure, and food and drink or food additives. The present invention also relates to methods of making the above compounds.

[0002]

2. Description of the Related Art Dialysis therapy enables long-term survival of patients with chronic renal failure and has brought great gospel to many patients with chronic renal failure, but on the other hand, it is a therapeutic method that must be continued for a lifetime unless kidney transplantation is performed. , It is a great mental and physical burden for patients with chronic renal failure. In addition to dialysis, treatments for chronic renal failure include symptomatic treatments with antihypertensive agents, diuretics, and drugs, and diet therapy with a low-protein diet, but all are limited to passive therapy. Adsorption of uremic substances that accumulate in the body in chronic renal failure, such as urea, in the intestinal tract or stomach and excretion in the feces can suppress the progress of renal failure and prolong the dialysis induction period. Be expected. In order to achieve such an object, an active carbon oral adsorbent has been developed so far, and its usefulness has been reported (Japanese Patent Publication No. 62-29368; Japanese Patent Publication No. 63-
60009; Kidney and Dialysis, 21, 199 (1986); J
pn. J. Nephrol, 33, 507 (199
1); Kidney Int. , 40, 461 (19
91); Clinical dialysis, 2,415 (1986); Clinical dialysis, 2,563 (1986)). However, although oral adsorbents made of activated carbon are highly stable, their adsorbability for urea and ammonia is low, and further, their drawbacks such as constipation and the development of digestive system symptoms such as anorexia have been pointed out. ing. Further, as a material other than activated carbon, oxidized starch (DAS) (Proc. Eur. Dial.
Trans. Assoc. , 10, 136 (197)
3); Trans. Am. Soc. Artif. In
t. Organs, 20, 161 (1974); Kid
eye Int. , 10, S273 (1976); artificial organ, 12, 662 (1983)), oxidized cellulose (DAC) (Kidney Int., 10, S26).
6 (1976)) was studied as an oral adsorbent, but it was pointed out that diarrhea occurs due to side reactions (adsorption) with enzymes and proteins in the intestinal tract due to surface-active formyl groups. There is. In order to overcome these drawbacks, albumin-treated oxidized starch (albumin-treated DAS) is surface-treated with respect to active formyl groups.
(Artificial Organs, 11, 40 (1982); Journal of Artificial Dialysis Research, 16, 411 (1983); Research Report, Institute for Advanced Polymer Materials, 151, 51 (1986)) and Chitosan-Coated Oxidized Cellulose (Chitosan DAC) (Japan) Journal of Chemistry,
1,104 (1990); The Chemical Society of Japan, 6,486.
(1995); Japanese Pharmacology Journal, 106, 113 (1
995); Journal of Japanese Pharmacology, 106, 123 (199).
5); Chitin and Chitosan Research, 1, 183 (199)
5)) was developed and in-vitro in Chitosan DAC
The effectiveness was shown in the nitrogen adsorption test in o and the renal failure pathological model. However, as a result of studies by the present inventors, it has a demerit as an oral adsorbent that it decomposes at physiological pH to produce glyoxal having mutagenicity. On the other hand, a method for producing a cellulose derivative having an aldehyde group in its side chain has been reported (Japanese Patent Laid-Open No. Sho 63-63).
-35603), oxidized starch and oxidized cellulose do not decompose under physiological pH conditions, and no harmful substances such as glyoxal are produced. However,
The one produced by the conventional method has a substitution degree of 0.8,
The specification also describes that a cellulose derivative having an aldehyde group with a substitution degree of 1 or more in the side chain is difficult to separate and purify, and no specific production example thereof is shown. Further, although this report makes a general statement that a polymer having an aldehyde group as a functional group may adsorb biological waste, a specific example of the above-mentioned cellulose derivative having an aldehyde group having a substitution degree of 1 or more is described. There is no description of experimental facts.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a cellulose derivative which is not decomposed in vivo, does not cause diarrhea due to protein adsorption and has a high ability to adsorb uremic substances. . The present invention also provides the use of the compound of the present invention, specifically a pharmaceutical composition containing the compound, in particular, a therapeutic agent for nephritis and renal failure, and a food or drink or a food additive. Further, the present invention aims to provide a method for producing the above compound.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted diligent research in accordance with the above-mentioned object, and as a result, for the first time, found a cellulose derivative having a formylalkyl group or formylbenzyl group whose degree of substitution is greater than 1 in the side chain. As well as preparing
The inventors have found that these compounds do not decompose in vivo and have high adsorption ability for urea, which is a uremic substance, and have completed the present invention. That is, the compound according to the present invention is a cellulose derivative having a formylalkyl group or a formylbenzyl group whose degree of substitution is greater than 1 in the side chain. In addition, the method for producing the above-mentioned compound according to the present invention comprises the steps of hydrolyzing the acetyl group of cellulose acetate, converting the resulting hydroxyl group to O-alkylated or O-benzylated with an alkyl halide or benzyl halide having an acetal group, and further acetal. It is characterized in that the group is hydrolyzed with an acid to form an aldehyde group in the side chain. Furthermore, the pharmaceutical composition according to the present invention, in particular, a therapeutic agent for nephritis / renal failure as a uremic substance adsorbent comprises the above compound as an active ingredient. Furthermore, the food or drink or food additive according to the present invention contains the above cellulose derivative. <Effect> As described above, the compound of the present invention (cellulose derivative) hydrolyzes the acetyl group of cellulose acetate, and the generated hydroxyl group is O-alkylated or O- with a halogenated alkyl or benzyl halide having an acetal group. It can be produced by benzylation and further hydrolyzing the acetal group with an acid to generate an aldehyde group in the side chain. The compound of the present invention which can be produced by this method is not only a cellulose derivative having a side chain with an aldehyde substitution degree of more than 1, which is conventionally considered to be difficult to separate and purify, but, surprisingly, a cellulose having an aldehyde group in a conventional side chain. Compared with the above, not only was the adsorbing ability for urea, which is a uremic substance, dramatically improved, but the activity for adsorbing proteins, which is considered to be the cause of diarrhea, was low. Such a large improvement in the adsorption capacity for urea and protein is completely unexpected, and the compound of the present invention is particularly useful as an adsorbent for uremic substances.

[Specific description of the invention]

BEST MODE FOR CARRYING OUT THE INVENTION

<Cellulose Derivative> The compound of the present invention is a cellulose derivative having a formylalkyl group or a formylbenzyl group having a degree of substitution of more than 1 in the side chain, and therefore, a polysaccharide in which D-glucopyranose is β-1,4-glucoside linked. Is a compound having a structure having a formylalkyl group or a formylbenzyl group in the hydroxyl group of cellulose.
As the alkyl group of the formylalkyl group, a lower alkyl group, specifically, an alkyl group having 1 to 4 carbon atoms, particularly a methyl group is preferable. Therefore, preferred specific examples of the cellulose derivative according to the present invention include compounds having a structure in which formylmethyl, formylethyl, formylpropyl, formylbutyl or formylbenzyl is bonded to the hydroxyl group of cellulose. The compound of the present invention as described above has a high urea adsorption ability, is not decomposed at pH of a living body like chitosan DAC, and is used in the treatment of nephritis / renal failure without causing diarrhea due to protein adsorption. Effective as an oral adsorbent. Further, since the compound of the present invention is not decomposed in the living body but is excreted outside the body as it is, there is no fear of side effects.

<Production Method of Cellulose Derivative> The cellulose derivative according to the present invention can be produced by any purposeful production method. One preferable method is to hydrolyze the acetyl group of cellulose acetate, The resulting hydroxyl group is O-alkylated or O with an alkyl halide having an acetal group or a benzyl halide.
-Benzylation, and the acetal group is further hydrolyzed with an acid to form an aldehyde group on the side chain. Specifically, this method can be carried out as follows, for example. First, a cellulose derivative having an acetal group in its side chain, which is a precursor of the cellulose derivative of the present invention having a formylalkyl group or a formylbenzyl group whose degree of substitution is greater than 1, is prepared. This precursor compound can be prepared by a known method, for example, J. Appl.
Poly. Sci. , 45, 417 (1992). That is, 1 part by weight of cellulose acetate is dissolved in 30 to 120 parts by weight, preferably 50 to 60 parts by weight of an organic solvent such as dimethyl sulfoxide, and 2 to 9 parts by weight of an alkali such as sodium hydroxide.
Preferably 6 to 7 parts by weight are added. Next, 10 to 30 parts by weight, preferably 15 to 25 parts by weight of alkyl halide or benzyl halide having an acetal group is added. This reaction solution is 20 ° C to 90 ° C, preferably 60 ° C.
At ~ 75 ° C for 10 to 30 hours, preferably 15 to 20
By stirring for a period of time, hydrolysis of the acetyl group and progress of O-alkylation or O-benzylation proceed, and a cellulose derivative as a precursor having an acetal group in the side chain can be prepared. The alkyl halide or benzyl halide having an acetal group used at this time is represented by the following formula (I)

Embedded image Wherein X is chloro, bromo, iodo, A is a chemical bond, alkylene, preferably C1-C3 lower alkylene or phenyl, and each R ¹ is individually methyl or ethyl, or taken together. It is a group forming a C1-C4 alkylene], preferably bromoacetaldehyde dimethyl acetal. The cellulose derivative of the present invention having a formylalkyl group or a formylbenzyl group having a degree of substitution of more than 1 in its side chain has a suitable acid content of 10 parts by weight per 1 part by weight of the cellulose derivative having an acetal group in its side chain, which is obtained by the above-mentioned technique. It can be obtained by heating to 100 to 100 parts by weight, preferably 20 to 50 parts by weight and usually refluxing for 10 to 30 minutes. As the above-mentioned acid, for example, 0.05 to
A 0.4N hydrochloric acid aqueous solution, a 0.05-0.4N sulfuric acid aqueous solution, and a 1.0-4.0N acetic acid aqueous solution can be used.

Examples of the formyl side chain of the cellulose derivative of the present invention having a formylalkyl group or formylbenzyl group, which is the final product thus obtained, include:
Formylmethyl, formylethyl, formylpropyl,
Formyl butyl and formyl benzyl are mentioned. The degree of substitution of the final product, the cellulose derivative of the present invention having a formylalkyl group or a formylbenzyl group in the side chain, is determined by the reduction method using sodium borohydride (Japan).
n Analyst, 15, 176 (1966)), and has more than 1 formylalkyl group or formylbenzyl group per unit structure as shown in the examples below. At this time, the substitution degree (DS) of the formylalkyl group or the formylbenzyl group is, for example, when the formylalkyl group is a formylmethyl group, the blank hydrogen generation amount is VB (ml), and the sample hydrogen generation amount is V (m).
l), when the sampling amount is W (g), the equation W
xDS / (42 xDS + 162) = (VB-V) / 2
It is obtained as 2400 solutions.

<Use of Cellulose Derivative> The final product, the cellulose derivative of the present invention having a formylalkyl group or a formylbenzyl group in its side chain, has a solute concentration in the rat gastrointestinal tract as shown in Examples described later. Adsorption test method using equivalent artificial digestive tract fluid (Journal of the Chemical Society of Japan, 6,
486 (1995)), shows a high urea adsorption capacity of 10 to 20 mg per 1 g of the compound of the present invention.

Pharmaceutical composition / uremic substance adsorbent (nephritis / kidney
Dysfunction drug) Since the compound of the present invention has a high urea adsorption ability, it is effective as a pharmaceutical for mammals, particularly for humans. In particular, these compounds can be administered to patients for use in the treatment of nephritis / renal failure. The compound of the present invention as a pharmaceutical or a uremic substance adsorbent can be administered by any purposeful administration route, preferably oral administration. The compounds of the invention are pharmaceutically acceptable tablets for mammals, preferably humans, alone or preferably according to standard practice,
It can be formulated in a form that can be taken by a usual medicinal product such as pills, granules, emulsions, solutions, suspensions and sugar-coated tablets.
Further, it may be contained in a capsule and taken. To manufacture these preparations, solvents (corn oil, propylene glycol, macrogol, etc.) commonly used in medicine, solubilizers (hardened castor oil, polyethylene glycol, triethanolamine, sodium carbonate, sodium citrate, etc.) , Isotonic agents (sodium chloride, glycerin, etc.), preservatives (paraoxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenylethyl alcohol, benzalkonium chloride, phenol, cresol, thimerosal, dehydroacetic acid, sorbic acid, etc.), Antioxidants (sulfite, ascorbic acid, thioglycerol, butylhydroxyanisole, dibutylhydroxytoluene, ascorbic acid palmitate, dl-
α-tocopherol, etc.), excipients (lactose, glucose,
Corn starch, sorbit, etc.), binders (dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, etc.),
Lubricants (talc, magnesium stearate, polyethylene glycol, etc.), disintegrants (starch, sodium alginate, non-gelatin, calcium carbonate, calcium citrate, dextrin, etc.), emulsifiers (sodium lauryl sulfate, benzalkonium chloride, lauryl amino) Propionic acid), a stabilizer, etc. can be added. Further, it is expected that the compound of the present invention can be a more effective uremic substance adsorbent by formulating it in a form in which an appropriate swelling agent is mixed at the time of administration. As the swelling agent, for example, sucrose fatty acid ester, polysorbate, macrogol and the like can be used, but the swelling agent is not limited thereto.

The dose of the compound of the present invention is determined in consideration of the results of animal experiments and various situations so that the total dose does not exceed a certain amount. The specific dosage is the administration method,
It goes without saying that it may vary depending on the condition of the patient or animal (eg, age, weight, sex, concomitant drug, degree of illness), and the appropriate amount and frequency of administration under certain conditions generally follow the above guidelines. It will be determined by the titration test of a specialist. Specifically, the compound of the present invention is usually administered to each person at a rate of 1 to 15 g / dose, about 1 to 4 times a day. The fact that the cellulose derivative of the present invention having a formylalkyl group or a formylbenzyl group in the side chain has high adsorption properties for uremic substances such as urea, and exhibits almost no protein adsorptivity that is considered to be the cause of diarrhea. That was totally unexpected.

Foods and Food Additives As described above, the compound of the present invention has a high urea adsorbing ability, and in addition to a uremic substance adsorbent as a medicine, it was incorporated into a food or drink or a food additive. It can also be applied for use as a health food or a food additive having a form, that is, a substance adsorbing uremic substances. In order to obtain a food or drink or food additive containing the cellulose derivative of the present invention, an appropriate amount of powder or liquid may be added in accordance with the type or form of the base food or food additive. Examples of basic foods include ordinary solid foods (eg biscuits, breads), liquid foods (eg soft drinks, drinks) or semi-liquid foods (eg custard pudding, jelly), and basic food additives. Examples of the product include ordinary preservatives, antioxidants, sweeteners,
Colorants, emulsifiers, seasonings, spices, acidulants and the like can be mentioned. In order to obtain further effects, it is desirable that the intake amount of the cellulose derivative of the present invention is about 1 to 15 g at a time.

[0012]

[Examples] The following shows production examples and pharmacological test results of the compounds of the present invention, but the present invention is not limited to these Examples. Example 1 Cellulose acetate (Wako Pure Chemical Industries, Ltd .; 5 g) was dissolved in dimethyl sulfoxide (300 ml), sodium hydroxide (29 g) was added, and the mixture was stirred at 50 ° C. for 1 hr. Bromoacetaldehyde dimethyl acetal (46 ml) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. Bromoacetaldehyde dimethyl acetal (8 ml) was added 3 times every 1 hour, and the mixture was stirred at 70 ° C. for 20 hours. The precipitated floating substance was collected by filtration, dissolved in water and then neutralized with dilute hydrochloric acid. The obtained solution was dialyzed with a dialysis membrane for 2 days and then freeze-dried to obtain 4.0 g of a cellulose derivative having an acetal group in its side chain. A cellulose derivative having an acetal group on its side chain (4.
0 g) was dissolved in 150 ml of 0.05N hydrochloric acid water,
Heated to reflux for minutes. The reaction solution is poured into acetone, the precipitated solid is collected by filtration, washed with a large amount of water and acetone, and a cellulose derivative having a formylmethyl group in its side chain (Compound 1)
2.9g was obtained. The substitution degree of the formylalkyl group of Compound 1 was measured by the following method. 0.1 g of the compound 1 was taken, an aqueous boric acid solution (3 ml; boric acid 0.1 g / ion-exchanged water 10 ml) and ion-exchanged water (1 ml) were added and the lid was closed, and the gas buret and the reaction vessel were connected. Sodium borohydride solution (3 ml; sodium borohydride 0.1 g / 0.1N sodium hydroxide aqueous solution 10 m
l) was added to the dropping funnel and added dropwise to the sample suspension. Ion-exchanged water (3 ml) was put into the dropping funnel to wash out the sodium borohydride solution. It was washed again with ion-exchanged water (2 ml). The reaction solution was stirred for 2 hours using a magnetic stirrer while keeping the inside of the flask slightly depressurized from the atmosphere. A 2N aqueous sulfuric acid solution (3 ml) was added, and the mixture was stirred for 5 minutes. The amount of hydrogen (Vml) generated after stopping the magnetic stirrer was read. On the other hand, a blank experiment was carried out by the same operation for the compound to which Compound 1 was not added, and the generated hydrogen amount (VBml) was read.
Substitution degree was calculated by substituting V and VB into the above equation. The substitution degree of the formylalkyl group of Compound 1 was 1.8.

Example 2 Cellulose acetate having a formylmethyl group in its side chain (compound 2) using 20 g of cellulose acetate, 1.2 l of dimethyl sulfoxide, 116 g of sodium hydroxide and 280 ml of bromoacetaldehyde dimethyl acetal as in the case of Compound 1. Was obtained. As a result of measuring the substitution degree using the same method as for Compound 1, the substitution degree of the formylalkyl group of Compound 2 was 3.0.

Example 3 Cellulose acetate (600 g), dimethyl sulfoxide (36 l), sodium hydroxide (4.2 kg) and bromoacetaldehyde dimethyl acetal (10.5 l) were used in the same manner as in Compound 1 to prepare a cellulose derivative having a formylmethyl group in the side chain (compound). 595 g of 3) was obtained. As a result of measuring the substitution degree using the same method as for Compound 1, the substitution degree of the formylalkyl group of Compound 3 was 1.8.

Reference Example 1: Method for producing cellulose derivative having aldehyde group in side chain by conventional method (Reference Example Compound 1) Methylcellulose (4000 cp: Wako Pure Chemical Industries, Ltd.) (5 g) was added to dimethyl sulfoxide (300 ml). )
Dissolve in, add sodium hydroxide (28g), 40 ℃
For 3 hours. Allyl chloride (30 ml) in the reaction solution
Was added and the mixture was stirred at 70 ° C. for 4 hours. The reaction solution was fractionated with chloroform / water, the chloroform layer was washed 3 times with water and once with saturated saline, and then the chloroform layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, methanol was added to obtain a film-like substance.
The film-like substance was dissolved in chloroform (100 ml), methanol (400 ml) was added, and the precipitated solid was filtered to obtain a cellulose derivative having an allyl group in its side chain. A cellulose derivative having an allyl group on this side chain is chloroform / methanol (500 m
1/100 ml) and add ozone gas at -78 ° C to 8
Bubble for 0 minutes. After bubbling oxygen gas for 1 hour to remove excess ozone from the reaction solution, the mixture was stirred at room temperature for 13 hours. Dimethyl sulfide (4 ml) was added to the reaction solution, and the mixture was further stirred at room temperature for 11 hours. A film-like substance was obtained by distilling off the solvent under reduced pressure. By washing this with methanol, 2.14 g of a cellulose derivative having an aldehyde group on the side chain (Reference Example compound 1) was obtained. As a result of measuring the substitution degree using the same method as for Compound 1, the substitution degree of the formylalkyl group of Reference Example Compound 1 was 0.7.

Reference Example 2: Method for producing oxidized cellulose (DAC) (Reference Example compound 2) Sodium periodate (9.63 k) was added to pure water (96 l).
g) was added little by little and dissolved. Acetic acid (1.92 kg)
Was added, cellulose (4.95 kg) was added little by little, and the mixture was stirred at 25 ° C. for 40 hours. The reaction solution was filtered with a centrifuge and washed thoroughly with pure water until the filtrate had no residual iodic acid. After confirming the residual iodic acid, it was dehydrated until no filtrate came out from the centrifugal separator. The residue was ground with a hammer mill and the fluid phase was dried to obtain Reference Example compound 2 (3.4 kg). As a result of measuring the substitution degree using the same method as for Compound 1, the number of aldehydes per unit structure of Reference Example Compound 2 was 1.8.

Test Example 1: in using artificial digestive tract fluid
Vitro adsorption test (1) Test method An artificial digestive tract fluid corresponding to the solute concentration in the rat digestive tract was prepared and 10 mg / d of the compound of the present invention and Reference Example compound 1 were prepared.
An adsorption test was carried out by shaking at 37 ° C. for 18 hours after each addition at a concentration of 1. The artificial digestive tract fluid has the following composition. Urea 100 mg / dl 28% aqueous ammonia solution 100 μl / ml Uric acid 15 mg / dl Creatinine 7 mg / dl Ferrous sulfate heptahydrate 4 mg / dl Bovine serum albumin 400 mg / dl Sodium chloride 800 mg / dl Potassium chloride 20 mg / dl Anhydrous sodium hydrogen phosphate 115 mg / dl Anhydrous potassium dihydrogen phosphate 20 mg / dl pH is set to 7.4 After shaking, the supernatant is recovered by centrifugation and the supernatant is obtained. Each solute concentration in each was measured by the following method. -Urea nitrogen: urease / indophenol method (urea nitrogen B-Test Wako; Wako Pure Chemical Industries, Ltd.)-Albumin: pyrogallol red method (micro TP-
Test Wako; Wako Pure Chemical Industries, Ltd.) The value obtained by subtracting the concentration of each solute in the supernatant when the sample was not added from the concentration of each solute when the sample was not added was the adsorption rate of the compound of the present invention for each solute. And (2) Results Table 1 shows the results of the adsorption test. From the results in Table 1, it is clear that the compounds of the present invention have high adsorption properties for urea which is a uremic substance, and bovine serum albumin (BS
It is clear that it has almost no adsorptive capacity to A), ie, almost no protein adsorption as a side reaction that is considered to be the cause of diarrhea.

[Table 1]

Test Example 2: Solubility Measurement Test (1) Test Method Inventive Compound 3 (3 g) and Reference Example Compound 2 (3 g)
Were suspended in phosphate buffer (30 ml) and the pH was adjusted to 7. with sodium hydrogen carbonate using an automatic titrator.
Adjusted to 4. This suspension was stirred at 37 ° C. for 6 hours and then centrifuged at 3000 rpm for 10 minutes to separate the precipitate and the supernatant. In addition to the pure water (10
ml) was added and the mixture was centrifuged at 3000 rpm for 10 minutes. Each of the precipitate and the supernatant was freeze-dried, and the ratio of the solubilized component and the insoluble component to water was measured. (2) Results Table 2 shows the results of the solubility measurement test. From the results in Table 2, it is clear that the compound of the present invention hardly decomposes at physiological pH.

[Table 2]

Formulation Example The compound 3 obtained in the above Production Example was made into tablets and capsules according to the usual method using the following ingredients. (1) Capsule (for oral administration) Compound 3 150 mg Lactose 30 mg Microcrystalline cellulose 30 mg Magnesium stearate 10 mg 1 capsule 220 mg (2) Tablet (for oral administration) Compound 3 100 mg Microcrystalline cellulose 60 mg Starch 30 mg Lactose 10 mg Magnesium stearate 10 mg 1 capsule 210mg

Production Example of Foods and Beverages According to a usual method, the compound 3 obtained in the above production example was used to produce a cookie by using the following components. Flour 120 g Sugar 50 g Butter 20 g Shortening 10 g Egg 70 g Baking powder 3 g Vanilla essence 1 g Compound 3 26 g

[0021]

The compound of the present invention (cellulose derivative) is
It can be manufactured by the manufacturing method of the present invention as described above. The compound of the present invention is not only a cellulose derivative having an aldehyde substitution degree of a side chain of more than 1 which is conventionally considered to be difficult to separate and purify, but also urea which is a uremic substance as compared with a conventional cellulose having an aldehyde group in the side chain. In addition to the dramatic improvement in the adsorption capacity for the, the protein adsorption activity, which is considered to be the cause of diarrhea, is low. Such a large improvement in the adsorption capacity for urea and protein is completely unexpected, and is particularly useful as an adsorbent for uremic substances.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Kozo Sato 1-2-2 Sojamachi, Maebashi City, Gunma Prefecture Kirin Brewery Co., Ltd.

Claims (12)

[Claims] 1. A cellulose derivative having a formylalkyl group or a formylbenzyl group whose side chain has a degree of substitution of more than 1. 2. The alkyl group of the formylalkyl group is C1 to C1.
The cellulose derivative according to claim 1, which is a C4 lower alkyl group. 3. The cellulose derivative according to claim 2, wherein the lower alkyl group is a methyl group. 4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 as an active ingredient. 5. An adsorbent for uremic substances, which comprises the compound according to any one of claims 1 to 3 as an active ingredient. 6. The adsorbent according to claim 5, wherein the uremic substance is urea. 7. A therapeutic agent for nephritis or renal failure, which comprises the compound according to any one of claims 1 to 3 as an active ingredient. 8. A food or drink or a food additive containing the compound according to any one of claims 1 to 3. 9. An acetyl group of cellulose acetate is hydrolyzed, the resulting hydroxyl group is O-alkylated or O-benzylated with an alkyl halide having an acetal group or a benzyl halide, and the acetal group is hydrolyzed with an acid. The method for producing a compound according to claim 1, wherein an aldehyde group is generated in the side chain. 10. The method according to claim 9, wherein the generated hydroxyl group is treated with an alkyl halide having an acetal group. 11. An alkyl halide is a halogenated C1 to C1.
The production method according to claim 10, which is C4 alkyl. 12. The method according to claim 10, wherein the alkyl halide having an acetal group is bromoacetaldehyde dimethyl acetal.