JPH02167229A - Granular pharmaceutical of protein polysaccharide substance derived from coriolus versicolor quel. - Google Patents

Abstract

PURPOSE:To obtain a granular pharmaceutical, consisting of a protein polysaccharide substance derived from Coriolus versicolor Quel., disintegrating agent and additive acting as a binder, having a bulk density and solubility within specific ranges and capable of improving difficulty in drinking in administration without impairing pharmacological activity. CONSTITUTION:A granular pharmaceutical, obtained by granulating a protein polysaccharide substance derived from Coriolus versicolor Quel., e.g. a mixture of >=50 to <90wt.%, preferably >=75 to <90wt.% crestine, with >10 to <=50wt.%, preferably >10 to <=30wt.% additive (preferably white sugar, hydroxypropyl cellulose or starch), by a fluidized or extrusion granulating method, granulation method using a roller compactor or tableting machine or tumbling granulating method and having 0.30-0.80g/cm<3>, especially 0.35-0.75g/cm<3> bulk density and >=4 to <30min dissolution time in water in dissolution tests according to a paddle method.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a new orally administered preparation of a protein polysaccharide derived from Kawaratake that is used as an antitumor agent. 11. This invention relates to a granular preparation of protein polysaccharide derived from Kawaratake mushroom, which solves the problems of difficulty in taking it due to internal care and large volume.

(Prior art) In recent years, substances obtained from various mushrooms, bacterial cells, or metabolites produced by bacteria have been developed as excellent anti-J! It is known to have anti-inflammatory effects and protective effects against bacteria and viruses. For example, inventions related to polysaccharides extracted from the fruiting bodies of shiitake mushrooms (Japanese Patent Publication No. 47-37002, Japanese Patent Publication No. 49-484 @
), anti-I! whose active ingredient is ribopolysaccharide extracted from Mycobacterium tuberculosis! +4I Invention related to tumor agent
-1861'l@) has been proposed.

The present inventors also previously made inventions related to antitumor agents, hypoglycemic agents, etc. containing protein polysaccharides extracted from Kawaratake mushrooms as active ingredients (Japanese Patent Publications No. 51-36322, Japanese Patent Publications No. 52-443).
No. 80, Special Publication No. 55-23271 N, Special Publication No. 56-1
No. 4275, Special Publication No. 14276, Special Publication No. 14276, Special Publication No. 1987-
25312 @, Special Publication No. 57-40159, Special Publication No. 57
9-32480 N, JP-A-60-45532 fj
, JP-A No. 60-45533).

Among these, many of the substances with antitumor activity are known to exhibit activity when administered intradermally or intravenously.
It is also used clinically as an injection for intradermal or intravenous administration.

On the other hand, Krestin, a type of protein polysaccharide derived from Kawaratake, has been reported to exhibit medicinal efficacy when administered intravenously or intravenously, but it also exhibits antitumor activity when administered orally, and is clinically effective. It is used as an oral preparation.

Various possibilities have been proposed regarding the mechanism of Krestin's expression of the drug gh, among which it has been pointed out that Krestin's activation of immunocompetent cells existing in the gastrointestinal tract10 is important. The lectin-like activity of Krestin is thought to be important for this action, and the expression of this lectin-like activity depends on the state of Krestin dissolution, that is, the spread of Krestin molecules in the gastrointestinal tract. It is thought that the two-dimensional and three-dimensional spread of the molecule centering on the active site within the molecule of Krestin, which has lectin-like activity, and the state of the three-dimensional structure are important. It is also known that lectin-like activity can be inhibited depending on the substances that coexist when Krestin is dissolved, and it has a different mechanism of action and ability to express activity than other antitumor agents or low-molecular-weight drugs. are doing. As a dosage form for drugs with properties similar to Krestin, it is considered most desirable to take a solution in which Krestin is dissolved in water, but aqueous solutions have storage problems and
Many problems arise in actual clinical applications, such as transportation problems. Therefore, the Krestin ablation currently used clinically is a fine powder.

The clinical dose of Krestin is 3 g or more per day for cancer patients. The current Krestin powder is a fine powder and has a small bulk density, so it sticks to the mouth when taken, and the volume is too large to drink at once, so it is necessary to take it with water. I'm having problems.

Furthermore, due to its unique color tone and odor, there have been problems such as patients identifying the drug as Krestin and learning that they have cancer, so there has been a desire to develop a removal method suitable for Krestin. .

Generally, in order to simplify administration, fine powders are granulated using an appropriate binder or disintegrant, formed into tablets, or encapsulated in capsules. However, in the case of Krestin, as mentioned above, it is thought that the state of dissolution in the gastrointestinal tract after oral administration, that is, the spread of the molecular structure of Krestin, controls its drug activity, and the activity changes due to deletion. It is necessary to be especially careful about this.

For example, there are many granules, tablets, and capsules of Korean carrot extract and other Chinese herbal medicines on the market, but these drugs are mixtures of various polysaccharides and low-molecular substances, and are relatively water-soluble. In addition to excellent dispersibility, formulation design of such S products is relatively easy because the content of active ingredients contained in granules and tablets is low. However, special consideration is required when removing pharmaceuticals whose main component is protein, such as enzyme preparations and blood preparations. In other words, the activity of proteins or polysaccharides containing proteins often changes significantly depending on heat, pressure, or the substances they are mixed with.

In order to provide appropriate removal of these substances, there are various problems that have not been seen in the case of conventional low molecular weight compounds and synthetic drugs. For example, when making granules, there are problems such as reduction in activity due to various heat treatments and deactivation due to insolubilization. As a method to solve these problems, it is possible to mix large amounts of various saccharides, amino acids, and inorganic compounds to stabilize the active ingredient, protein or polysaccharide containing protein. Therefore, the content of active ingredients such as proteins and protein-containing polysaccharides must be reduced.

Until now, there have been almost no studies or technical reports on the relationship between the removal of a protein-bound polysaccharide, such as Krestin, and its activity.

Krestin has an average molecular weight of 100,000 or more, its composition is not a simple polysaccharide, but a protein polysaccharide with proteins bound to it, and the dosage form required for its activity is relatively large. Therefore, it is important to formulate a drug by solving the contradictory issues of not changing the medicinal efficacy and not increasing the dosage amount.

In other words, since Krestin is a high-molecular-weight polysaccharide bound to proteins, the mechanism by which it exerts its drug efficacy when administered orally has to be considered. In such cases, difficult technical issues remain that cannot be solved by the simple application of conventional formulation techniques.

In other words, it is important to establish a formulation form and formulation method that solves the problems of fine powder and large volume, which make it difficult to swallow when administering medication, and that does not impair biological activity. be. In other words, in order to solve the difficulty of swallowing due to fine powder, it is necessary that the particles have a specific particle size or a specific particle size distribution, which solves the problem of the large volume of medication making it difficult to swallow. In order to achieve this, it is necessary to increase the bulk density of the particles as much as possible. Furthermore, as mentioned above, such particles must be able to dissolve quickly in the gastrointestinal tract after administration and exhibit the characteristic action of Krestin.

An example of a method for powdering a protein polysaccharide or protein such as Krestin is a spray drying method, a method for producing powder using a so-called spray dryer.

The powder obtained by this method can be heated under the immediate conditions of drying.
The pharmacological activity of Krestin may be impaired depending on the operating conditions of the spray dryer, such as the wind speed, solution supply rate, etc., but by adjusting the hot air temperature, weight, and solution supply rate, the pharmacological activity can be maintained without compromising the pharmacological activity. Crestin can be powdered.

Krestin powder obtained by such a spray drying method is a hollow particle with a diameter of 1 to 100 mm,
Although the surface area is large, the air adsorbed on the surface of the particles and the air contained therein prevents contact with water (wetting), suppressing dissolution. Further, the bulk density of the powder obtained by this spray drying method is usually less than 0.309/cJ, and when this fine powder is administered, the above-mentioned problems occur.

Therefore, we have carefully studied not only the method of powdering Krestin but also the method of granulating it, and investigated the characteristics and pharmacological activity of the obtained particles. We have repeatedly considered this issue in order to resolve the issue.

In other words, as a result of various studies on how to increase the bulk density without changing the properties of the powder, we found that the spray-dried powder is compressed using a tablet machine (slug machine) or roller compactor, and then pulverized (hereinafter referred to as "heavy"). It has been found that it is useful to prepare the powder (abbreviated as powder).

Furthermore, using this heavy powder, we investigated the possibility of ablation to facilitate drug administration without changing the bioavailability of the drug.

A method of granulating U1 fine powder by mixing it with suitable additives such as disintegrants, binders, excipients, etc. is known as a grinding method that is easy to administer. Since the mechanism of action, that is, the dissolution and fractional state in the gastrointestinal tract, influences the pharmacological activity of the drug, a wide range of studies including evaluation of drug efficacy are required. It has been found that in addition to the physical properties of the granules, such as their solubility in water, particle size, and bulk density, the type and content of additives added during granulation are important factors.

On the other hand, granulation methods include extrusion granulation, fluidized granulation, rolling granulation, etc., and it is also necessary to select additives and consider granulation conditions corresponding to each manufacturing method.

The present inventors used spray-dried powder, a heavy powder made by making it heavy with a roller compactor or tablet machine (slug machine), or Krestin powder obtained by freeze-drying or evaporating to dryness, as a granulation raw material. As a result of examining additives, particle size, granulation density, solubility, and manufacturing method, as well as the expression of pharmacological activity in animal experiments, and ease of administration in clinical settings, we found that 50% by weight or more and less than 90% by weight. A granular preparation containing Krestin and having a specific particle size distribution granulated by the granulation method, extrusion granulation method, or rolling granulation method has high dissolution in water and is not suitable for living organisms. The pharmacological activity when administered is not impaired at all, and it is difficult to swallow, which is seen in Krestin spray-dried powder and current Krestin commercial products. Based on these findings, the present invention was completed.

(Means for solving the problems) The granular preparation of the present invention comprises 50% protein polysaccharide derived from Kawaratake.
Consisting of more than 90% of Shidejima and less than 90% of Shigedejima, and its bulk density is 0.
．． 30 to 0.80 g/J, and its dissolution time in water is 4 minutes or more and less than 30 minutes in dissolution test 1 according to the Badl method. Furthermore, when the dissolution time in Elution Test 2 was within 15 minutes, the particle size distribution was such that it passed through the No. 10 sieve, the amount remaining on the No. 12 sieve was 5% by weight or less of the total weight, and the total amount passing through the No. 200 sieve was 5% by weight or less of the total weight. It is preferable that the amount is 10% by weight or less.

The protein polysaccharide derived from Kawaratake of the present invention is present in the granular preparation in an amount of 5.1% or more and less than 90% by weight, preferably 75% or more and less than 90% by weight.

The protein polysaccharide derived from Kawaratake of the present invention refers to the mycelium, cultured product (
It is an extract of broth or fruiting body using hot water or alkaline aqueous solution, containing about 18 to 38% protein and having a molecular weight of 5,000 or more (as measured by ultracentrifugation).

More specifically, the protein polysaccharide according to the present invention is disclosed in, for example, Japanese Patent Publication No. 51-36322 and Japanese Patent Publication No. 56-14274.
Q Publication (U, S, Patent No. 4202969
), Special Publication No. 56-14276 (U, S, Pate
nt No. 4140578), Special Publication No. 1983-3928
Publication No. 8 (U, S, Patent No. 426850
5) and u, s, patent No. 405131
It is a substance obtained by the tail method described in 4 etc., and is a mycelium obtained by culturing basidiomycetes belonging to the genus Kawaratake,
Broth or extract of fruiting bodies in hot water or alkaline aqueous solution, containing about 18 to 38% protein, with a molecular weight of 5,000 h or less (as measured by ultracentrifugation);
For example, the molecular weight is 5,000 to 300,000 (Ultracentrifugal valve aX standard method).

Among the protein polysaccharides derived from Kawaratake mushroom of the present invention, one protein polysaccharide derived from Kawaratake mycelium [FERM-P2412] is commercially available under the trade name Krestin [Recent new drug, Volume 28, pages 14-16 (1
977〉, and Volume 29, pages 96-101 (197
8〉, Pharmaceutical Handbook 6th edition, 1346 pages (1978)
May) Published by Yakugyo Jihosha, Medical Drugs Japan Pharmaceutical Collection 7th Edition 2
Page 40 (see 1983, published by Yakuguri Jihosha), some of its properties are as follows.

The sugar moiety of the main fraction is β-D-glucan, and the structure of this glucan moiety is 1→3, 1→4. It is a polysaccharide containing a protein with a nitrogen content of 3 to 6% and a branched structure containing 1→6 bonds, and the protein is composed of acidic amino acids such as aspartic acid and glutamic acid, and valine and leucine. There are many neutral amino acids such as , and there are few basic amino acids such as lysine and arginine. Soluble in water, almost insoluble in methanol, pyridine, chloroform, bempine, and hexane. It gradually decomposes from about 120°C.

As mentioned above, the Krestin® is an anti-l1IS
It has already been provided to society as a drug, has extremely low toxicity,
It is a safe substance.

There are various methods for pulverizing Krestin, but the spray-drying method described below allows for easy pulverization without impairing the activity of individual particles. A spray drying method is preferable.

[Spray drying method] Krestin aqueous solution (solid content concentration: 10%) was dried using a spray dryer (Niyoshi!, ASO410 type).
Hot air inlet temperature 140~180℃, outlet temperature 70~12
0℃, hot air 6M 37 minutes, atomizer rotation speed 10.0
A spray-dried powder is obtained by spray drying under the conditions of 00 to 20.00 rpm and a feed rate of 5 to 101/min of the Krestin aqueous solution. The key density of the spray-dried powder obtained is 0.15-0.30 g/cm3.

In addition to the above-mentioned spray-dried powder, the starting material of the present invention, the white polysaccharide derived from Kawaratake, may include a heavy powder obtained by compacting the spray-dried powder using a roller compactor or a slug machine.

[Pelletization method using Ll-Lar compactor] Spray-dried powder is prepared using a U-Lar compactor at a roll pressure of 0.3~
Compress to 4 tons/crR1 preferably to 0.5 and 3 tons/α to make it heavy, and use a granulator to granulate it (heavy powder)
This is the way to do it. This method can be repeated, e.g. 2 to 7 times.
It is preferable to carry out the process twice, preferably 3 to 6 times, and the pressure in this case is preferably 0.5 to 1.4 tons/ca.

[Granulation method using a tablet machine (slug machine) 1 tablet'g
This is a method in which spray-dried powder is compressed using a slug machine (M) at a compression pressure of 2 to 15 tons to make it heavier. The obtained suspended product is granulated using a flour mill (heavy powder)
do.

If necessary, additives may be added to the protein polysaccharide derived from Kawaratake and used as a heavy powder.

Further, the heavy powder to which additives have been added may be used as it is as a granular preparation.

The additive of the present invention acts as a disintegrant and a binder. The content of the additive in the granular preparation is more than 10% and less than 50% by weight, preferably more than 10% and less than 25%.

If the amount of additive exceeds 50% by market weight, it is not preferable because the area for each injection becomes large and it becomes difficult to drink.

Examples of additives include sugars such as glucose, mannose, and sucrose, sugar alcohols such as mannitol, cellulose compounds such as Avicel and hydroxypropyl cellulose, starches, agar, gelatin, gum arabic, and polyvinylpyrrolidone. Among these, saccharides, cellulose compounds and starches are preferred. In particular, white sugar,
Hydroxypropyl cellulose and starch are preferred because they can improve the disintegration or solubility of the granular preparation compared to spray-dried powder without impairing the pharmacological activity of the protein polysaccharide derived from Kawaratake.

The density of the granular preparation of the present invention is 0.30-0.80 g
/d, preferably 0.35 to 0.759/ctl. Granular preparations with a bulk density of less than 0.309/d are difficult to swallow, and when dispersed in water, the particles stick together to form large gel-like particles that have poor solubility. It is difficult to produce granular formulations with bulk densities exceeding 0.803/d.

The complete dissolution time of the soluble fraction in water in the dissolution test (dissolution test 1) according to the Badl method of the granular preparation of the present invention in water is 4 minutes or more and less than 30 minutes, preferably 4 to 20 minutes.Complete dissolution time If the time is longer than 30 minutes, the drug's bio-
Availability (bioavailability) tends to decrease and antitumor activity decreases.

Furthermore, put 1 g of the granular preparation of the present invention into a beaker, and add 100 ad! of water to it! The dissolution time is within 15 minutes, preferably within 10 minutes (dissolution test 2), which measures the time for complete dissolution of the soluble fraction by adding a stirring bar with a length of 3 minutes and stirring at 200 rpm+. It is preferable that If the dissolution time exceeds 15 minutes, when dispersed in water, the particles will stick together and form a large gel-like mass, resulting in poor solubility and increased stickiness in the mouth, making it difficult to drink.

The particle size distribution of the granular preparation of the present invention is as follows:
The amount remaining on the sieve is 5% by weight or less of the total weight, and the amount passing through the No. 200 sieve is 10 times or less of the total weight, and preferably there are some that do not pass through the 12 sieve and those that pass 200. It is preferable to have a particle size distribution in which the amount of particles is small. This is because the particles remaining on the No. 12 sieve and the
This is because the fine powder that passes through the No. 0 sieve is the main cause of difficulty in drinking. In particular, if the amount passing through the No. 200 sieve exceeds 10 of the total weight, it will be difficult to drink, and
The fine powder acts as an adhesive, and a part of the granular preparation becomes a large gel-like lump with poor solubility.

The granular preparation of the present invention is produced by using a starting material consisting of a protein polysaccharide derived from Kawaratake mushroom and an additive by: ■ Fluid granulation method, ■ Extrusion granulation method, ■ Rolling granulation method, ■ Using a roller converter. Granulation method: (1) Granulation using a tablet machine or a combination of two or more methods.

(1) Fluidized granulation method involves mixing heavy powder and additives,
Sugars such as glucose, mannose and white sugar, cellulose compounds such as hydroxypropyl cellulose, gelatin,
This is a method in which a solution containing a binder such as gum arabic or polyvinyl vinyl 1 coliton is sprayed onto a mixture of heavy powder and additives floating in a fluidized bed to form granules. As the binder, hydroxypropylcellulose is preferred, and as the solvent, water and/or alcohols can be used. The concentration of the binder in the solution is 10 w/v% or more, preferably 8
The amount of solution to be sprayed is 50 to 2,000 m, preferably 100 to 1,500 m per 1 kg of the mixture of the heavy powder and the additive.

7 le call Examples include building alcohol and n-propertool.

(2) Extrusion granulation is a method in which a heavy powder or spray-dried powder and additives are mixed, a solution in which a binder is dissolved is added, and after kneading, the mixture is extruded through a screen and granulated.

As the binder, those mentioned above can be used, among which hydroxypropylcellulose is preferred, and as the solvent, water and/or alcohols can be used.

IIlr of the binder in solution! 1 is 1 ow/v% or less,
Preferably it is 8w/v% or less, and the solution used for kneading is 100 to 1% per 1 kg of the mixture of heavy powder and additives.
0QOd, preferably 300-800d.

(3) Rolling granulation is a method in which spray-dried powder, heavy powder, or a mixture of these and additives is added to the granulation cores, which are moistened by spraying a solution containing a binder, etc. cloth,
This is a method of applying vibration or rotational motion to these particles and granulating them into dense spherical particles by transfer.

In the case of water droplets, granulation cores are used, and sugar is usually used as the granulation cores. Hydroxypropyl cellulose is used as the binder, and water and/or alcohols are used as the solvent. The granulation conditions during centrifugal granulation are:
500 rpm, preferably 100-250 rpm.

(4) The granulation method using a roller compactor means that a mixture of starting raw material powder and additives is prepared using a roller compactor at a pressure of 0.3 to 4 tons/cm, preferably 0.5 to 4 tons/cm.
This is a method in which the material is compressed at 3 tons/α to make it heavier, and then granulated using a granulator. This method can be repeated for example 2~
It is preferable to carry out 7 times, preferably 3 to 6 times, and the roll pressure in this case is O. S~1.4 tons/α is preferable.

In the granulation method using a roller compactor, additives include binders, disintegrants, and lubricants. binder,
As the disintegrant, those mentioned above are used, and as the lubricant, talc, magnesium stearate, calcium stearate, corn starch, etc. are exemplified. The content of lubricant is not more than 5% by weight of the total m, preferably not more than 3% by weight. Two or more types of lubricants can also be used in combination.

(5) The granulation method using a tablet machine is a slug machine that is used to compress a mixture of starting materials and additives into tablets at a pressure of 2 to 1.
This is a method in which the material is shrunk at 5 tons to make it heavy, and the obtained heavy material is granulated using a granulator.

Additives for water droplets include binders, disintegrants, and lubricants. Although these additives are mentioned above, coloring agents, fragrances, flavoring agents, excipients, stabilizers, etc. can also be added to the granular preparation of the present application, as necessary.

(Effects of the Invention) The granular preparation of the present invention has no difference in pharmacological activity from conventional solution preparations or fine powder preparations, and has no problems with the stability of solution preparations, especially storage problems and fine powder preparations. This solution solves a number of problems that arise when using a powder preparation, such as difficulty in swallowing when administering medication, such as sticking in the mouth and the large volume making it difficult to swallow at once, and is excellent for actual clinical application. be.

(Examples) Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

The method for measuring each parameter is as follows.

can be used.

Bulk measuring device (iii
1 (manufactured by Wa Gakkiki Co., Ltd.) was fixed on a horizontal, vibration-free table, a washed and dried receiver whose weight was accurately measured was attached to the bottom of the funnel, and the sample was allowed to fall naturally from the top of the funnel. The sample is placed in a receiver, the upper mountain part of the receiver is removed with a sliding knife without causing any vibration to the receiver, the weight of the receiver containing the sample is accurately measured, and the following formula is calculated. The bulk density was measured using

C (ρ: bulk density, WF: weight of the receiver containing the sample, W,
: Weight of empty receiver, Wo: Inner volume of receiver) The measurement of one degree of bulk was carried out at 18 to 28° C. under the condition of 55 to 65% R11.

Dissolution Test 1 Using a 6-unit automatic dissolution test system (manufactured by Toyama Sangyo Co., Ltd.), the dissolution test was carried out using a mutatis mutandis method of the Badl method among the dissolution test methods specified in the 11th revised Japanese Pharmacopoeia General Test Methods.

That is, 900 ml of degassed purified water was placed in a tester and heated to 37°C, and the temperature of the test solution was maintained at 37 ± 1°C.
Add 1 g of 0I to the test liquid at approximately the midpoint between the inner wall of the tester and the stem of the paddle for 2 to 3 seconds, and immediately after the addition, increase the stirring speed [1
The paddle was stirred at 100 rpm.

After the start of stirring, sampling was performed at 1 minute intervals for 10 minutes, and at 2 minute intervals from 10 to 30 minutes, and the absorbance at 280 nm was measured. The sample whose absorbance was measured was returned to the tester before the next sampling. Measurement is 6
Samples were run at the same time.

When the increase in absorbance in successive samplings was 0.01 or less on average when using a cell with a ratio of 11:111 as a light transmitting part, it was determined that the soluble fraction was completely dissolved.

Iron loss 1 (2) As mentioned above, diameter 6 (1” 70m N capacity ffi 20
0m+7) Put 1g of the sample in a beaker, add 10m of degassed purified water (25±1°C), and add a 3cm long sample to this.
A stirrer was added and the mixture was stirred at a stirring speed of 200 rpm.

This test was carried out simultaneously in three beakers, each with 5
The mixture was stirred for 10 minutes, then 15 minutes. Immediately after stirring, pour this solution into a white resin vat (size: 200 x 180
tm or higher, and the solution was spread uniformly and observed.

When no insoluble matter or gel-like substance was observed and the whole solution was found to be homogeneous, it was determined that the entire amount was dissolved.

Anti-ff! 1×106 Sarcoma 180 tumors were implanted subcutaneously in the axillary region of 710 ICR mice with tumor active IF, and samples (
(as protein polysaccharide derived from Kawaratake) as body weight I K'S
000119 per day was administered orally once a day for 20 consecutive days, and 2 days after the end of administration, the tumor was sacrificed and the tumor part was removed.
the! The weight of the tumor is T, and the weight of the tumor in the control group in which physiological saline was administered instead of the sample is C and L.
Antitumor activity (%) was determined by the formula (1-)xlOO.

Example 1 Krestin aqueous solution (solid content concentration 10%) was prepared by Nirosha'! I (ASO410 type machine) using a spray dryer,
Spray dry to obtain a fine powder. That is, hot air (inlet temperature 150°C, outlet temperature 90°C, hot air f
While blowing air at 16 M''/min), apply 6.
The mixture was fed at 6 N/min to obtain a tarespoon spray-dried powder. The yield of the obtained powder was 95%, the bulk density was 0.199/cIj, and the average particle size was 15-.

500g of the resulting spray-dried powder and 150g of white sugar!
? and 150 g of corn starch were mixed, and 500 d of a 3W ha% hydroxybutyl cellulose solution dissolved in ethanol was added, and the mixture was kneaded using a kneader until it became a uniform paste.

Next, extrusion granulation was performed using a No. 16 sieve (manufactured by Tokyo Screen Co., Ltd.), and after completion of the extrusion granulation, ventilation drying was performed at 60°C. This granulated product #
The portions that passed through the 312@ sieve but did not pass through the 200 bow sieve were collected to obtain 512 g of a granular preparation.

The amount of additive in the obtained granular formulation was 38.6% by weight,
The particle size distribution is as follows: No particles remain on the No. 10 sieve, and no particles remain on the No. 10 sieve.
The amount remaining on the No. 200 sieve was 0.5% by weight of the total weight, the amount of sieve passing through the No. 200 sieve was 1.3% by weight of the total weight, the density was 0.359/J, and the elution test 1 The dissolution time according to the dissolution test 2 was 4 minutes, and the dissolution time according to dissolution test 2 was within 5 minutes.

The anti-FF11! of the obtained granular formulation! Tumor activity is 90.1%
Met.

The antitumor activity of Krestin's current commercially available product and Krestin spray-dried powder is 83.8% and 80.0%, respectively.
Met.

Examining the quality of medication in actual clinical applications, 10
Krestin spray-dried powder, Krestin's current commercially available product, Krestin's granular preparation of the present invention, and Nonbarrel 101 (manufactured by U India Sangyo Co., Ltd.) were distributed to a panel of people with 19 doses each, and they were easy to swallow when taken with water. We conducted a thorough evaluation. Here, 1 point was given to Frespoon spray-dried powder, which is the raw material of this granular preparation, and 10 points were given to Non-Barrel 101■, which has a reputation for ease of drinking.The relative ease of drinking was given as a score and totaled. . As a result, the current Krestin product received 20 points, and this granular formulation received 73 points.

Furthermore, we investigated how the fine powder that passes through a No. 200 sieve affects drinkability. When fine powder that passes through a No. 200 sieve is added to the granular preparation of the present invention, the amount of both is 20%.
, 5% by weight, 10% by weight, 15% by weight, and 20% by weight were measured for drinkability using the above method, and the results were 73 points, 70 points, 62 points, 45 points, and 38 points, respectively. Met.

Yuklestin (Lot! IIQ 95^) passes through a No. 10 sieve and a No. 12 sieve, and the proverb that passes through a 200-bow sieve is 19,9.
It is 11i%.

The bulk density is 0.499/c1j, the dissolution time in dissolution test 1 is 2 minutes, and the dissolution time in dissolution test wA2 is 1
It took more than 5 minutes.

Comparative Example 2 Krestin spray-dried powder passed through a No. 200 sieve,
Or so; the tsfi degree was 0.199/cr&, and the dissolution times in dissolution tests 1 and 2 were 30 minutes or more and 15 minutes or more.

Loss 10 Raw 2 Krestin spray-dried powder obtained in the same manner as in Example 1 was made into a heavy mass using a roller compactor and then crushed. Heavy powder obtained by repeating these steps 5 times (bulk density 0
．． 649/cd) 5QOg and white 1825g,
3 w/v% hydroxypropylcellulose solution 2 mixed with corn starch 259 and dissolved in ethanol
50 ae was added and kneaded, extrusion granulation was performed using a No. 16 sieve (manufactured by Tokyo Screen Co., Ltd.), and then fluidized bed drying was performed at 80° C. to produce granules. Of this granular material, the part that passed through a No. 12 sieve but did not pass through a No. 200 sieve was collected to obtain 390 g.

When the obtained granular preparation is sieved through a No. 10 sieve, there is no substance remaining on the sieve, and what remains on the No. 12 sieve is 0.5% by weight of the total weight, and those that pass through a 200-bow sieve are It was 1.0% by weight of the total weight.

Furthermore, the additive content in the obtained granular preparation was 10.3% by weight, and its bulk density, dissolution time in dissolution test 1, dissolution time in dissolution test 2, and anti-III tumor activity were each 0.56 g.
, /J, 10 minutes, within 10 minutes, and 93.1%.

The ease of drinking was measured in the same manner as in Example 1, and the result was 80 points.

800 g of Krestin spray-dried powder obtained in the same manner as in Example 1 and 200 g of mannitol were mixed until uniform.

Using a centrifugal granulator CF-3603 type (manufactured by Freund Sangyo Co., Ltd.), spray air pressure 1.5D/J, rotor rotation speed 1
Non-barrel 101■ (32-42 mesh) (manufactured by Freund Sangyo Co., Ltd.) 50G9 was charged into this centrifugal granulator as a granulation core at a rate of 20ONJl/min along the 70RPJ slit air line and an air temperature of 27-35°C. While spraying 700 ae of a 3w/v% hydroxypropylcellulose aqueous solution as a binder liquid onto the core, a mixed powder of Krestin and Mantonil, which had been previously TA!4, was sprinkled onto the core, and a granular preparation was formed by rolling granulation using meteoric motion. The prepared granular preparation was dried at 60°C to obtain 1015 g of a granular preparation that passed through a 12-bow sieve but did not pass through a No. 42 sieve.The particle size distribution of the obtained granular preparation was 10 There is nothing on the No. 12 sieve, and the total weight is 0.
, 1% by weight, the amount passing through the No. 200 sieve is 0 of the total weight.
．． It was 1% by weight. The maximum number of additives in this granular preparation is 4.
7.0% by weight, its bulk density is 0.46SF/c+J
The dissolution time for dissolution test 1 was 4 minutes, the dissolution time for dissolution test 2 was within 5 minutes, and the antitumor activity was 88.5%. The ease of drinking was measured in the same manner as in Example 1, and the result was 90 points.

笈亙dan 1 Krestin spray-dried powder 16009, white sugar 32
09, after mixing and homogenizing magnesium stearate 309, roller compactor T F -M 1ni (7O
(manufactured by Indo Sangyo Co., Ltd.) to form a plate-shaped solid (flake), which was pulverized and granulated using a granulator equipped with a 24-mesh wire mesh. This process was repeated five times with the roll load current ranging from 0.8 to 2.2 to obtain 1905 g of granules.

Diurnal hydro-tosibrovir cellulose 50g isobu 0
It was dissolved in building alcohol to make 1000d.

On the other hand, after putting 1800 g of the granules obtained earlier into a multipurpose formulation machine kneader (manufactured by Hata Tekkosho Co., Ltd.),
After kneading, extrusion granulation machine EXKS model (manufactured by Fuji Paudal Co., Ltd.) (1 screen hole) was extrusion granulated. The particles were sized using a granule (manufactured by Powdal).

The obtained particles were sieved, and the granular preparations that passed through No. 12 sieve but did not pass through No. 42 sieve were collected and dried at 60°C in a tray hot air dryer.
, and dried for 5 hours to obtain a granular formulation of 14109. The particle size distribution of the obtained granular preparation is such that there is no particle present on the No. 10 sieve, 0.1% by weight of the total weight is present on the No. 12 sieve, and 0.1% of the total weight is present on the No. It was 0.1% by weight.

The resulting granular formulation had a bulk density of 0.58 g/cII at 1120.0% by weight of the additive, the dissolution time for dissolution test 1 was 6 minutes, the dissolution time for dissolution test 2 was within 10 minutes, and the anti-I
l! Tumor activity was 90.0%. The ease of drinking was measured in the same manner as in Example 1, and the result was 92 points.

1600g of spray-dried Krestin powder, 320g of corn starch, 30g of magnesium stearate
After mixing and homogenizing g, use a roller compactor TF-Min.
+ (manufactured by Freund Sangyo Co., Ltd.) to form a plate-shaped solid (flake), which was pulverized and granulated using a granulator equipped with a 24-mesh wire mesh. This process was repeated five times with the roll load current ranging from 0.8 to 2.2 to obtain 18759 granules.

It was dissolved in diurnal hydroxypropylcellulose-snol to give a concentration of 1000 d. On the other hand, after putting 1,800 g of the previously obtained granules into a universal formulation machine kneader (manufactured by Hata Tekkosho Co., Ltd.), ! After kneading, 975 d of an ethanol solution of human Oxib Ovir cellulose prepared in 1 was added, and after kneading, extrusion granulation was carried out through extrusion granulation 11EXKs type (manufactured by Fuji Paudal Co., Ltd.) screen hole 1a+. This granulated material was sized using a spherical sizing machine Marmerizer Model 0-230 (manufactured by Fuji Baudal Co., Ltd.).

The obtained granules are sieved, passing through a No. 12 sieve, but passing through a No. 42 sieve.
Collect the granular preparations that do not pass through the No. sieve and dry them in a tray hot air dryer for 6 minutes.
It was dried at 0° C. for 5 hours to obtain a granular preparation of 14509. The particle size distribution of the obtained granular preparation is as follows: those present on the No. 10 sieve are 0.1% of the total weight, those present on the No. 12 sieve are 0.1% of the total weight, and those that pass through the No. 200 sieve are It was 0.1% by weight. The additive 61 in the obtained granular preparation is 2
At 0.0% by volume, the scraping density is 0.559/cJ, the dissolution time for dissolution test 1 is 10 minutes, the dissolution time for dissolution test 2 is within 10 minutes, and the pile! The tumor activity was 85.5%.

The ease of drinking was measured in the same manner as in Example 1, and the result was 88 points.

X raw shellfish I Krestin heavy powder 480 obtained by the same method as Example 2
g and 120 g of white sugar were placed in a fluidized granulator FLO-1 model (Freund Sangyo Co., Ltd.'fJ), stirred for 2 minutes, and reduced to 3 w/v%.
Ethanol solution of hydroxypropyl cellulose 250
At was sprayed for 30 minutes and dried for 20 minutes.

Of the obtained granular preparations, only those that passed through a No. 30 sieve (500μ) but did not pass through a No. 200 sieve were collected and weighed at 480 g.
I got it. The resulting granular preparation remained on No. 10 and No. 12 sieves, and the amount that passed through No. 200 sieve was 0.3% by weight of the total weight. Furthermore, the amount of additive in the obtained granular preparation was 21.0% by weight, the bulk density of this granular preparation was 0.47'J/cl, and the dissolution time in dissolution test 1 was 7 minutes. The dissolution time in dissolution test 2 was within 10 minutes, and the antitumor activity was 80.7%. The ease of drinking was measured in the same manner as in Example 1, and the result was 77 points.

On the other hand, both portions passing through a No. 200 sieve were collected to obtain 91 g.

The size of this fraction is W! Degree is 0.32g/-7, dissolution test 1
The dissolution time of anti-Il! and 2 was 30 minutes or more and 15 minutes or more, respectively. m activity was 74.5%. The ease of drinking was measured in the same manner as in Example 1, and the result was 16 points.

Example 7 Really! Krestin spray-dried powder 4515y obtained in the same manner as in Example 1, corn starch 500g
and 60 g of magnesium stearate using a slug tablet press NT-ESS'! I! (manufactured by Hata Tekkosho Co., Ltd.). At this time, the diameter of the punch tip of the tableting machine was 20M, and the tableting pressure was 5 to 8 tons. - The punch length of the punch was 12A.
m, and the thickness of the prepared tablets was 2.6 to 2.8 m.

This slug tablet was crushed using a granulator equipped with a 32-mesh wire mesh to obtain a heavy powder. This heavy powder was sieved through No. 30 and No. 200 sieves;
The fractions that did not pass through the @ sieve were collected to obtain a granular preparation of 30459. The particle size distribution of the obtained granular preparation was as follows: nothing remained on the No. 10 sieve and No. 12 sieve, and the amount that passed through the No. 200 sieve was 0.8% of the total weight. The additive content in the granular formulation was 11.1 u%. The bulk density of this granular formulation was 0.459/':j, the dissolution time of dissolution test II41 was 5 minutes, the dissolution time of dissolution test 2 was within 5 minutes, and the anti-Illfs activity was 87.8%. there were. The ease of drinking was determined by GCill in the same manner as in Example 1, and the result was 63 points.

1600 g of spray-dried Krestin powder obtained in the same manner as in Example 1, 320 g of white sugar, and 309 magnesium stearate were subjected to a roller compactor TF-Mini (manufactured by Freund Sangyo Co., Ltd.) to make them heavier.

At this time, the feed screw type is B type, and the 0-hole is D.
Compression was performed using a PS type at a linear pressure of 0.9 tons/cIR. The compression molded product was pulverized using a granulator equipped with a 24-mesh wire mesh.

This process was repeated five times under conditions such that the small load on the mill was the same. However, the material was pulverized using a granulator equipped with a 32-mesh wire mesh after 5 times of heavy-duty. Yield after 5 treatments is 18
It was 609. Add this heavy powder to 3o@ (500%
> and a No. 200 sieve, and the fractions that passed through the No. 30 sieve but did not pass through the No. 200 sieve were collected. 1209!
? A granular formulation of was obtained. The amount of additive was 17.5% by weight.

The particle size distribution of the obtained granular preparation was such that nothing remained on the No. 10 sieve and No. 12 sieve, the amount passing through the No. 200 sieve was 1.3% by weight of the total weight, and the bulk density was 0.56 Lj/
With ctl, the dissolution time according to dissolution test 1 was 8 minutes, and the dissolution time according to dissolution test wA2 was within 10 minutes, and anti-fi! 'f
The fl activity was 82.3%. Drinking and drinking
:tIji As a result of measurement in the same manner as in Example 1, it was 70 points.

Generation J manpower = fJ: Month 11 Mt. Takeshi

Claims (5)

[Claims] (1) Protein polysaccharide derived from Kawaratake mushroom 50% by weight or more 90%
% by weight and more than 10% by weight but not more than 50% by weight of additives, has a bulk density of 0.30 to 0.80 g/cm^3, and has a dissolution time in water of 4 minutes or more in an elution test according to the Badl method. A granular formulation characterized in that it is less than a minute. (2) It has a particle size distribution in which the amount that passes through the No. 10 sieve and remains on the No. 12 sieve is 5% by weight or less of the total weight, and the amount that passes through the No. 200 sieve is 10% by weight or less of the total weight. The granular preparation according to claim 1. (3) Protein polysaccharide derived from Kawaratake is 75% by weight or more9
A granular formulation according to claim 1, which contains less than 0% by weight. (4) The granular preparation according to claim 1, wherein the protein polysaccharide derived from Kawaratake mushroom is Krestin. (5) The granulation according to claim 1 is characterized in that the granulation is carried out by a fluidized granulation method, an extrusion granulation method, a granulation method using a roller compactor, a granulation method using a tablet machine, or a rolling granulation method. Granular formulation.