JP2009185009A - Pharmaceutical orally applicable composition for treating malignant tumor in the digestive tract - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition for oral administration for treating malignant tumor developed in the digestive tract which includes acetyl fucoidan as an active ingredient. <P>SOLUTION: Acetyl fucoidan manufactured using Cladosiphon okamuranus TOKIDA as a raw material is dissolved in water and orally administered, thereby in a mouse in which a colon 26 cell which is a cell line of a mouse colon cancer origin is transplanted the intestines to develop the colon cancer, the weight loss and expansion of weight of malignant tumor is made to be significantly (P=0.05) reduced. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to an oral pharmaceutical composition for treating malignant tumors, and more particularly to an oral pharmaceutical composition for treating gastrointestinal malignant tumors containing acetylfucoidan as an active ingredient.
The digestive tract is an organ that communicates with the outside world through the lips and anus, including the oral cavity, esophagus, stomach, and intestine. The surface of the digestive tract is covered with endothelium. Digestive enzymes are supplied from the digestive glands into the digestive tract to digest food. The inside of the digestive tract is outside the body. A gastrointestinal malignancy is a malignant tumor that has developed in the gastrointestinal tract.

  In the present specification, “malignant tumor” may be simply abbreviated as “tumor”. For example, the conventional expression “antitumor agent” means “antimalignant tumor agent”. In addition, “malignant tumor” means only solid cancer, and “cancer” is a different term in that it includes liquid cancer such as leukemia. However, in this specification, only solid cancer is discussed, so “malignant tumor”. “Cancer” is used as a synonym. For example, a malignant tumor that has developed in the large intestine is expressed as colon cancer according to conventional expressions.

If an antitumor agent that is not toxic even if taken orally and is not decomposed or absorbed in the digestive tract is orally administered, theoretically, the antitumor agent is affected with the malignant tumor in the digestive tract along with food. May be able to treat malignant tumors.
However, existing antitumor agents generally have strong antitumor activity and many are highly toxic, and many are not suitable for oral administration. In addition, the digestive tract has a strong foreign substance decomposing action due to changes in pH, digestive enzymes and resident bacterial flora, and a detoxifying action due to secretions and increased intestinal activity (diarrhea). Moreover, it is diluted with secretions such as digestive juice and food and drink. Therefore, even if administered orally, the affected area cannot be reached at a sufficient concentration at which the active ingredient of the drug exhibits a therapeutic effect. There have been no reports of antitumor agents that have actually demonstrated significant therapeutic effects by oral administration.

  Fucoidan is a general name for a sulfated polysaccharide having a molecular weight of several hundreds of thousands, which is abundant in mucus of brown algae such as kombu, wakame and mozuku. Since it is a polysaccharide obtained from nature, the type of fucoidan obtained varies depending on the raw material species and the sampling method. The main chain of the fucoidan polysaccharide has L-fucose linked by α- (1-2) or α- (1-4) bonds, and some hydroxyl groups are sulfated. It has not been. Fucoidan is not digested by human digestive enzymes.

As the fucoidan, U-fucoidan containing glucuronic acid, F-fucoidan composed only of sulfated fucose, G-fucoidan containing galactose and the like are known. Moreover, acetyl fucoidan in which a part of the hydroxyl group is acetylated is obtained from cultured Okinawa mozuku (Cladosiphon okamuranus TOKIDA) (for example, Patent Document 1).
Fucoidan has been found to have various physiological activities and has been actively studied since the 1970s.

Fucoidan has been reported to have antitumor activity. For example, hot water extract of Kagome kelp exhibits antitumor activity against various malignant tumor cells in in vitro test and antitumor activity against mouse colon cancer in mouse in vivo test by intravenous injection. showed that. In addition, it has been reported that a carcinogenesis-preventing action by azoxymethane was observed in a mouse in vivo test by oral administration (for example, see Patent Document 2).
Acetylfucoidan has also been reported to have antitumor activity in in vitro tests (see, for example, Patent Document 3).

  Regarding the activity of fucoidan, it has been shown that fucoidan having a lower molecular weight has stronger antitumor activity. For example, a fraction with a molecular weight of> 3000 to 5,000 that can be hydrolyzed under mild conditions using an organic acid as an acid catalyst for fucoidan has an effect of inhibiting cancer metastasis against B16 melanoma cells in a mouse in vivo test by intravenous injection. It is reported to show (for example, refer patent document 4).

Moreover, it was shown that the partial degradation product obtained by hydrolyzing fucoidan obtained from Okinawa Mozuku under conditions using an acid catalyst has an immune function regulating action (see, for example, Patent Document 5).
Determine the structure of partial degradation products obtained by the enzyme that hydrolyzes fucoidan, and some of these partial degradation products exhibit antitumor activity against various malignant tumor cells in in vitro tests (For example, refer to Patent Document 6).

However, the cancer metastasis-suppressing action and the azoxymethane-preventing action on B16 melanoma cells described above are the cancer-preventing action of cells on the process of adhesion of tumor cells to normal cells or the process of precancerous lesions of normal cells by carcinogens. Thus, it is not an antitumor effect that directly acts on the developed malignant tumor cells to inhibit growth.
No fucoidan derivative has been reported that exhibits antitumor activity by oral administration.
A method of releasing a drug from an administered preparation at a desired site in the digestive tract when orally administered is known (see, for example, Patent Document 7).

Japanese Patent No. 3371124 JP 2001-226408 A JP 2007-51081 A JP 2005-263812 A JP 2007-39341 A JP 2001-224394 A JP 2001-326057 A

Fucoidan and acetyl fucoidan, or a partially decomposed product thereof are saccharides, and are not absorbed into the body even if administered orally. Therefore, it cannot be expected that the therapeutic effect shown by intravenous administration into the body is reproduced by oral administration.
Since saccharides act as allergens in the body, serious allergic reactions can occur when intravenously administered fucoidan and acetylfucoidan or their partial degradation products.

Fucoidan or acetylfucoidan is a food and is characterized by no toxicity when administered orally. When fucoidan or acetylfucoidan is used as an antitumor agent, the characteristics of fucoidan or acetylfucoidan cannot be utilized without oral administration.
The objective of this invention is providing the pharmaceutical composition which treats the malignant tumor which developed in the digestive tract by oral administration.

  In order to solve such a problem, the present inventors used a mouse in which colon 26 cells, which are cell lines derived from mouse colon cancer, were transplanted into the intestine and developed colon cancer. As a result of the search for substances having therapeutic effects, it was found that by orally administering acetylfucoidan, the growth of Colon 26 cells in mice in the acetylfucoidan administration group was significantly suppressed as compared with the control group. As a result of continuous research, the present invention has been completed.

The oral pharmaceutical composition for gastrointestinal malignancy treatment according to the present invention comprises acetylfucoidan as an active ingredient.
Furthermore, the acetyl fucoidan of the present invention comprises L-fucose having 1 mol of sugar component, 0.03 to 0.10 mol of D-xylose, and 0.2 to 0.4 mol of D-glucuronic acid. A polysaccharide composed of a ratio, wherein the polysaccharide is converted into L-fucose, 0.1 to 0.3 residue acetyl group, and 0.2 to 0.4 residue sulfate group. Including.

  Furthermore, the acetyl fucoidan according to the present invention is obtained by homogenizing a cultured Okinawa mozuku and water containing at least one acid selected from 0.01 to 0.2 mol / L hydrochloric acid, sulfuric acid and oxalic acid at 10 to 35 ° C. Extract, remove insolubles, neutralize to obtain an extract, and evaporate water from the extract to pulverize, or filter the precipitate formed by adding methanol or ethanol to the extract. It is manufactured by taking, drying and pulverizing

  The acetyl fucoidan of the present invention is prepared by further dissolving the acetyl fucoidan powder in water, adding barium chloride or barium acetate to form a precipitate, removing the precipitate by filtration, and removing the filtrate from a cation exchange resin. Is a sodium salt type or potassium salt type acetylfucoidan obtained by desalting with water, eluting with water, neutralizing the eluate with sodium hydroxide or potassium hydroxide and then pulverizing.

  The pharmaceutical composition for oral administration of the present invention is a liquid, suspension, or jelly composition produced by dissolving or suspending acetylfucoidan in water. Since acetyl fucoidan is a viscous polysaccharide, it may become a jelly when dissolved or suspended in water.

Moreover, it is preferable that the pharmaceutical composition for oral administration of this invention is a powder, a paste, or a tablet.
The solid preparation of the present invention is preferably further encapsulated or subjected to a coating treatment on the surface.
For the treatment of malignant tumors that develop in the oral cavity, pharynx, esophagus, etc., it is preferable to use oral preparations.
Encapsulated preparations and coating preparations can be produced using known methods.

The oral pharmaceutical composition for treating gastrointestinal malignant tumors comprising acetylfucoidan of the present invention as an active ingredient has an effect of treating malignant tumors developed in the gastrointestinal tract by oral administration. Moreover, since it is an oral administration agent, a patient can be treated at home and the burden on the patient can be reduced.
Acetyl fucoidan is an edible polysaccharide made from cultured Okinawa mozuku, and has no toxicity. Therefore, it has no side effects like conventional chemotherapeutic agents and can reduce the burden of side effects on patients.
Since cultured Okinawa Mozuku is used as a raw material, it can be mass-cultured and manufactured at low cost.

Acetylfucoidan is a polysaccharide, is a stable compound that dissolves in water and has no side effects, and is easy to formulate, store and handle. Since acetyl fucoidan is water-soluble, it can be administered by oral administration as a liquid preparation dissolved in water or suspended in water. This method can reduce the burden on the patient compared to administration by injection or infusion, for example. On the other hand, a solid preparation can prescribe a larger amount of active ingredient than a liquid preparation, and a drug delivery system can be used.
By encapsulating or coating the solid preparation of the oral pharmaceutical composition for gastrointestinal malignant tumor treatment of the present invention, the active ingredient can be transported to the affected area using a known drug delivery system, and acetylfucoidan A unique flavor can be prevented.

  Acetylfucoidan is a polysaccharide and is not absorbed into the body even when administered orally. The oral pharmaceutical composition for treatment of malignant tract tumor of the present invention showed the effect of treating a malignant tumor that developed in the intestine with Colon 26 cells. Therefore, it is considered that the antitumor action was exhibited. Incidentally, acetylfucoidan is not digested by digestive enzymes, but may be partially degraded in the digestive tract.

  Patent Document 5 reports that an oligosaccharide component obtained by partially decomposing acetylfucoidan derived from Okinawa mozuku with an acid has various immune function regulating effects in an in vitro test. The test conditions of Example 1 of the present invention described below are conditions under which the activity shown in the in vitro test may be reflected in the therapeutic effect.

Since it is desirable that the acetylfucoidan of the present invention is not digested or partially decomposed to be transported to the affected area of the malignant tumor, the preparation is encapsulated or coated to provide a known drug delivery system corresponding to the affected area. It is desirable to transport to the affected area using For example, enteric encapsulation or coating using an enteric film material is preferred for the treatment of malignant tumors that develop in the rectum or large intestine.
For the treatment of malignant tumors that develop in the oral cavity, pharynx, esophagus, etc., it is preferable to use oral preparations. The preparation for oral administration can be easily produced by, for example, kneading with arabic gum.

Since the acetyl fucoidan of the present invention has a unique flavor, it is preferably encapsulated or coated with a sugar coating for easy ingestion. When formulating a plurality of purposes, capsule materials or coating materials having properties corresponding to the purposes can be used in layers.
Hereinafter, embodiments of the present invention will be described in detail with reference to examples, but these are for explaining the present invention and do not limit the scope of rights of the present invention. It goes without saying that various changes or modifications can be made to these embodiments without departing from the spirit of the present invention.

(1) Production of Acetyl Fucoidan The acetyl fucoidan used in the present invention can be suitably used, for example, acetyl fucoidan produced from Okinawa Mozuku described in Patent Document 1, Okinawa in which the cell wall is broken using a mixer or a homogenizer. Mozuku is dispersed in water with 0.01 to 0.2 mol / L acid added. Okinawa mozuku may be a freshly collected wet algal body or a dried Okinawa mozuku. Moreover, although the said acid is not specifically limited, A sulfuric acid, hydrochloric acid, and oxalic acid can be mentioned as a preferable specific example. An insoluble matter is removed from the dispersion and neutralized to obtain an extract, and water is evaporated from the extract to form a powder, or a precipitate formed by adding methanol or ethanol to the extract is filtered. Crude fucoidan was produced by taking, drying and pulverizing. This fucoidan is light brown.

White fucoidan can be produced by dissolving the above crude fucoidan in a barium chloride solution or a barium acetate solution and then filtering through a diatomaceous earth layer.
Fucoidan produced by the above method is barium salt type. In order to convert to the sodium or potassium salt form, it can be produced by desalting with a cation exchange resin, neutralizing with sodium hydroxide or potassium hydroxide solution, and pulverizing. Yield from moist Mosella is 2.0%.

Since the produced acetylfucoidan uses natural products as raw materials, the components of acetylfucoidan obtained by the raw materials and the collection method vary. The acetyl fucoidan according to the present invention comprises 0.03 to 0.10 mol of D-xylose and 0.2 to 0.4 mol of D-glucuron with respect to 1 mol of L-fucose. An acid, and 0.1 to 0.3 residue acetyl group and 0.2 to 0.4 residue sulfate group in terms of L-fucose, and an average molecular weight It was in the range of 500,000 to 600,000.
(Production Example 1)

  To 50 g of fresh dried Okinawa mozuku, 2 L of 0.1 molar hydrochloric acid was added and stirred at room temperature for 3 hours, followed by filtration through a diatomaceous earth layer to obtain a light brown transparent liquid. 0.1 mol sodium hydroxide was added to this solution for neutralization, and 2 times the amount of ethanol was added for precipitation. The resulting precipitate was taken out and dried under reduced pressure to give 22 g of light brown acetylfucoidan. Got.

  10 g of the above acetylfucoidan is dispersed in 500 mL of 0.1 molar barium chloride solution, dissolved by stirring for 1 hour, filtered through a layer of diatomaceous earth, and precipitated by adding ethanol to 7.7 g of acetylfucoidan. Got. This acetyl fucoidan was passed through a cation exchange resin (Amberlite IR-120, Spellco) column, the eluate was neutralized with sodium hydroxide, and freeze-dried to obtain 4.5 g of sodium-type acetyl fucoidan. It was. According to the component analysis of this production example, the total sugar is 67.0% (weight / weight, the same applies hereinafter), the uronic acid content is 13.2%, the sulfuric acid is 12.0%, the ash content is 22.3%, and the water content is It was 3.0%.

(2) Tumor cells In the present invention, development research on methods for treating malignant tumors by oral administration was performed using Colon 26 cells, which are cell lines derived from mouse colon cancer.
(Production Example 2)

(Adjustment of Colon 26 cells)
Colon 26 cells, which are cell lines derived from mouse colon cancer, were placed in a plastic dish (Asahi Techno Glass) in a cell culture medium (RPMI1640 Invitrogen Japan) with 10% fetal calf serum (Invitrogen Japan) and 100 μg / mL kanamycin. After addition, the cells were cultured at 37 ° C. for 48 hours in air containing 5% carbon dioxide gas. The monolayer cultured cells attached to the bottom surface were washed once with phosphate buffered saline, then cultured with 1 mL of cell separation solution (Sigma-Aldrich Japan) for 24 hours, floating cells were collected, and cell culture medium (RPMI1640) was suspended in a medium supplemented with 100 μg / mL kanamycin and adjusted to a cell density of 5 × 10 ⁷ cells / mL.

(3) Administration test Male BALB / c mice at 9 laps of age were acclimated for 1 lap until the start of the test, and then bred in a plastic breeding box. The test animals were fasted for 24 hours and then anesthetized by adding isoflurane to a mixed gas of oxygen and laughing gas. A midline incision was made in the abdomen, and Colon 26 cell suspension was injected 5 times into the small intestine with microneeds. After the surgery, the animals were reared for 2 weeks, divided into a control group in which normal water was drunk and a test group in which 5% acetylfucoidan was dissolved in normal water, and changes in body weight were recorded.
On day 15, the animals were sacrificed, the abdomen was opened, and the tumor size was measured. Thereafter, the lesions were excised and examined for tumor invasion by staining with hematoxylin and eosin and for the presence of apoptotic cells by immunohistochemical staining.

(4) Immunohistochemical analysis Fragmented DNA generated in the course of apoptosis was labeled with biotin-labeled nucleotides using a kit and then reacted with HRP-labeled streptavidin for staining and detection. There are Klenow Kits using the ISEL method and TdT Kits using the TUNEL method. In the present invention, TdT Kit is used.

(Dosage test)
A group of 10 9-year-old male BALB / c mice (purchased from CLEA Japan) 4 groups (40 mice) were acclimatized for 1 week until the start of the test, and then each group was placed in a plastic breeding box In the environment of temperature 21 ± 2 ° C., humidity 45 ± 10 ° C., illumination for 12 hours, and dark room for 12 hours, the animals were bred with normal food (MF, manufactured by Oriental Yeast Co., Ltd.).
After the test animals were fasted for 24 hours, anesthesia was introduced by adding 5% isoflurane to a mixed gas of 30% oxygen and 70% laughing gas, and isoflurane was 2% during the operation. In the operation, the abdomen was incised centrally, and 30 μL of Colon 26 cell suspension having a cell density of 5 × 10 ⁶ cells / mL was injected 5 times into the small intestine with a microneedle (100 μL, Terumo). After transplanting Colon 26 cells, the wound was sutured with nylon thread.
After the surgery, the animals were reared for 2 weeks, divided into a control group in which normal water was drunk and a test group in which 5% acetylfucoidan was dissolved in normal water, and changes in body weight were recorded.
On day 15, the animals were sacrificed by pentobarbital overdose and opened.

FIG. 1 shows a graph showing changes in body weight between the control group and the acetylfucoidan administration group. As shown in FIG. 1, weight loss was significantly suppressed in the acetylfucoidan-administered group compared with the control group (P = 0.05).
FIG. 2A shows a lesion photograph of a representative example of the control group, and FIG. 2B shows a lesion photograph of a representative example of the acetylfucoidan administration group. As shown in FIGS. 2A and 2B, the growth of malignant tumors was suppressed in the acetylfucoidan administration group compared to the control group.
Tumors were removed and tumor size was measured. FIG. 3 shows a graph in which the tumor was removed and the tumor size was measured.
The volume of the malignant tumor was calculated according to the following formula: tumor volume [mm ³ ] = length [mm] × width [mm ² ] × 1/2
As shown in FIG. 3, in the acetylfucoidan administration group, the volume of the malignant tumor was significantly reduced (P = 0.05) compared to the control group.

(1) Hematoxylin / eosin staining of tissue The excised tissue was fixed with a 4% paraformaldehyde solution at room temperature for 10 minutes. Serial sections were prepared with fixed tissues, and the tissues were stained with hematoxylin and eosin. FIG. 4 shows a photograph of the hematoxylin / eosin staining of the tissue in the control group, and FIG. 5 shows a photograph of the tissue staining in the acetylfucoidan administration group. As shown in FIG. 4, in the control group, malignant tumor cells inoculated into the intestinal epithelium strongly infiltrate the normal tissue. As shown in FIG. 5, in the acetylfucoidan administration group, a boundary line is formed at the ▲ mark. Infiltration of normal tissue by malignant tumor cells inoculated into the intestinal epithelium is suppressed.

(Immunohistochemical analysis)
The fixed tissue sections were washed 3 times with phosphate buffered saline, permeated for 30 minutes using DEAE cellulose (Cytopore GE Healthcare Healthcare Bioscience), and 40% methanol solution of 3% hydrogen peroxide. The TACS 2 TdT-DAB kit (Trevigen Apoptic Cell System) is a DNA kit for immersing in DNA for 5 minutes to erase the endogenous peroxidase block and labeling the fragmented DNA generated during the apoptosis with biotin-labeled nucleotides. Apoptotic cells were labeled with TACS by incubation with a labeling solution (manufactured) for 1 hour at 37 ° C., and normal nuclei were stained with methyl green.

  FIG. 6 shows a photograph of immunohistochemical staining of the tumor in the control group, and FIG. 7 shows a photograph of immunohistochemical staining of the tumor in the acetylfucoidan administration group. The arrow indicates apoptotic staining positive cells indicating apoptosis. As shown in FIG. 6, the control group shows few apoptosis staining positive cells showing apoptosis, but as shown in FIG. 7, the acetylfucoidan administration group has apoptosis staining positive cells showing apoptosis, especially normal cells. It is often seen at the boundary of malignant tumor cells.

(Manufacture of jelly-form preparation)
In the preparation tank, sodium acetylfucoidan (10 g) produced in Production Example 1 was added to purified water (100 g) at room temperature, and dissolved by stirring at 60 to 80 ° C. To this was added kappa carrageenan (0.4 g), iota carrageenan (0.9 g), locust bean gum (0.4 g), dextrin (5 g), sodium polyacrylate (4 mg), at 80 to 90 ° C. Stir to dissolve. Further, D-sorbitol (56 g), glycerin (27 g), propyl paraoxybenzoate (0.5 g), and a fragrance (a trace amount) were added, and purified water was appropriately added to adjust to a total of 198 g. This was heated at 80 to 90 ° C. for 1 hour to sterilize to produce a jelly-form preparation.

(Manufacture of enteric capsule preparations)
Enteric hard capsule of Japanese Pharmacopoeia No. 1 produced by molding and processing hydroxyalkyl cellulose (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) that does not dissolve at acidity of pH 3.0 or less but dissolves at neutral to weak alkalinity. 0.15 g of a mixed powder of 10 parts by weight of sodium-type acetylfucoidan powder prepared in Production Example 1 and 5 parts by weight of carboxymethylcellulose calcium was filled in, and the fitting part was sealed with an enteric base material to enter the enteric composition. An albumin hard capsule preparation was produced.

  Sodium-type acetylfucoidan (25.6% by weight), lactose (48.4% by weight), crystalline cellulose (20.0% by weight), low-substituted hydroxypropylcellulose (LH-21) (5) produced in Production Example 1 0.0 wt%) and magnesium stearate (1.0 wt%) were tableted to prepare tablets.

To the tablet produced in claim 6, Eudragit E (trade name, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, Degussa Japan Co., Ltd., 7 parts by weight), ethanol (70 parts by weight), water (as an inner layer) A solution composed of 19.5 parts by weight) and talc (3.5 parts by weight) was applied by spraying continuously at 50 ° C.
After spraying, the core is dried, and then, as an upper layer, Eudragit S (trade name, methacrylate-methyl methacrylate copolymer, Degussa Japan Co., Ltd., 7 parts by weight) and ethanol (70 parts by weight) A solution consisting of water (18.8 parts by weight), talc (3.5 parts by weight) and polyethylene glycol 6000 (0.7 parts by weight) was applied by spraying continuously at 50 ° C. Enteric coated tablets were prepared.

It is a graph which shows the change of the body weight of a control group and an acetyl fucoidan administration group. A is a lesion photograph of a representative example of the control group, and B is a lesion photograph of a representative example of the acetylfucoidan administration group. It is the graph which extracted the tumor and measured the tumor size. It is a photograph of hematoxylin and eosin staining of the tissue of the control group. It is a photograph of hematoxylin and eosin staining of the tissue of the acetylfucoidan administration group. It is a photograph of immunohistochemical staining of a tumor in a control group. It is a photograph of the immunohistochemical staining of the tumor of an acetylfucoidan administration group.

Claims (8)

  An oral pharmaceutical composition for treating gastrointestinal malignancies comprising acetylfucoidan as an active ingredient.   The acetylfucoidan is composed of L-fucose having 1 mol of sugar component, 0.03 to 0.10 mol of D-xylose, and 0.2 to 0.4 mol of D-glucuronic acid. Wherein the polysaccharide contains 0.1 to 0.3 residue acetyl groups and 0.2 to 0.4 residue sulfate groups in terms of L-fucose. The oral pharmaceutical composition for gastrointestinal malignant tumor treatment according to claim 1.   The acetyl fucoidan is homogenized from cultured Okinawa Mozuku and extracted with water containing at least one acid selected from 0.01 to 0.2 mol / L hydrochloric acid, sulfuric acid and oxalic acid at 10 to 35 ° C. The product is removed and neutralized to obtain an extract, and water is evaporated from the extract to form a powder, or methanol or ethanol is added to the extract and the resulting precipitate is filtered and dried. The oral pharmaceutical composition for treating gastrointestinal malignant tumor according to claim 2, wherein the composition is produced by pulverization.   The acetyl fucoidan is prepared by dissolving the acetyl fucoidan according to claim 2 in water, adding barium chloride or barium acetate to form a precipitate, removing the precipitate by filtration, and removing the filtrate using a cation exchange resin. 2. A sodium salt type or a potassium salt type acetylfucoidan obtained by desalting, eluting with water, and neutralizing the eluate with sodium hydroxide or potassium hydroxide and then pulverizing. 4. An oral pharmaceutical composition for treating gastrointestinal malignant tumor according to 3.   5. The composition according to claim 1, wherein the composition is a liquid, suspension, or jelly composition produced by dissolving or suspending the acetyl fucoidan in water. The oral pharmaceutical composition for gastrointestinal malignant tumor treatment as described.   5. The oral pharmaceutical composition for treating gastrointestinal malignant tumor according to any one of claims 1 to 4, wherein the acetylfucoidan is powder, kneaded product, or tablet.   The oral pharmaceutical composition for treating gastrointestinal malignant tumor according to claim 6, wherein the powder, paste or tablet is further encapsulated or coated on the surface.   5. The oral pharmaceutical composition for treating gastrointestinal malignant tumor according to any one of claims 1 to 4, wherein the acetylfucoidan is formulated for oral administration.