JP5089287B2 - Method for producing low substituted hydroxypropylcellulose powder - Google Patents

Description

  The present invention relates to a low-substituted hydroxypropylcellulose which is added in order to impart disintegration or binding properties when producing a preparation in the pharmaceutical or food field. In particular, it relates to a material having excellent binding and disintegrating properties.

  In solid preparations such as the pharmaceutical or food field, preparations made only of the main drug do not provide sufficient disintegration even when the drug is administered. If the drug is not fully effective or has poor binding properties, tablets and granules When used as an agent, there is a problem that the shape cannot be maintained. In such a case, the disintegration property can be improved by adding a disintegrant such as low-substituted hydroxypropylcellulose, calcium salt of carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, and carboxymethyl starch. In order to improve the binding property, it can be improved by adding crystalline cellulose or adding a water-soluble binder. Low-substituted hydroxypropylcellulose is known as a unique additive having both the above-mentioned disintegration property and binding property.

  Since low-substituted hydroxypropylcellulose is nonionic, it has the advantage that it is unlikely to be altered by reaction with ionic drugs or the like. Patent Documents 1 and 2 describe that low-substituted hydroxypropylcellulose can be used as an additive for pharmaceuticals.

  As described in Patent Documents 1 to 4 and Patent Document 7, as a method for preparing alkali cellulose, there is a method in which a sheet-like pulp is immersed in an aqueous caustic soda solution and then pressed and manufactured. Soaked in an aqueous solution of caustic soda, an excessive amount of aqueous caustic soda solution is absorbed into the pulp, and even when pressed, only alkaline cellulose containing excess water or caustic soda can be produced, and the selectivity to side reactions is increased. The efficiency of the etherification reaction, which is a reaction, was low.

  Conventional low-substituted hydroxypropyl cellulose can be obtained by reacting alkali cellulose and propylene oxide as described in Patent Document 3. In the etherification reaction, the main reaction includes etherification of cellulose, and the side reaction includes a reaction of generating propylene glycol by the reaction of propylene oxide and water. The amount of propylene oxide used for the etherification reaction varies depending on the amount of aqueous caustic soda solution used as a reaction catalyst. If there is too much water or caustic soda in the alkali cellulose, there is a problem that the reaction efficiency decreases.

On the other hand, when manufacturing it by dripping or spraying and mixing a caustic soda aqueous solution to a powdery pulp, there exists an advantage which can adjust arbitrarily the amount of water or caustic soda in alkali cellulose.
Further, as described in Patent Document 3, when neutralizing the alkali remaining in the crude reaction product, the reaction product is poured into hot water containing acid to dissolve the crude reaction product. The resulting low-substituted hydroxypropylcellulose is in the form of a fiber as in the case of the raw material pulp and is excellent in cleaning properties and easy to refine, but on the other hand, it is inferior in grindability and powder with excellent fluidity. Can't get.

  Patent Document 2 discloses a method of partially neutralizing an alkali used as a reaction catalyst in water after completion of the etherification reaction and partially dissolving low-substituted hydroxypropyl cellulose to control the fibrous portion. Have been described. In this method, when the amount of remaining alkali is increased, the fibrous form is reduced by dissolution, and the resulting pulverized product has a high bulk density and good fluidity, but there is a problem that the cleaning property is reduced during purification. It is described that there is.

In Patent Document 3, by setting the water content of the washed dehydrate to 70 to 90% by mass, the pulverizability is improved, and the low-substituted hydroxypropylcellulose powder having a compressibility of 42% or less and an angle of repose of 48 ^° or less. It is described that the body can be obtained. Further, it is described that the pulverization is performed by an impact pulverizer such as a hammer mill.
However, the impact pulverizer is easily affected by the pulverized raw material, and the powder physical properties of the product are determined by the shape of the pulverized raw material. That is, as described in Patent Document 2, the amount of partial neutralization is increased or the reaction product is not passed through a dissolution step, and the reaction product is added to water or hot water containing an acid equivalent to caustic soda remaining in the crude reaction product. When pulverized with an impact pulverizer using raw materials in the fibrous form obtained by charging and neutralizing, the pulverized product obtained can only be a low-fluidity powder containing a lot of fibrous particles. It was. Moreover, since it grind | pulverized by giving high energy in a short time, it was a method with low throughput and low productivity.
In addition, low-substituted hydroxypropylcellulose produced by the method described above can be dissolved by reducing the amount of partial neutralization in order to increase the fluidity of the powder, thereby reducing the fibrous portion and reducing the binding properties. There was a problem. In addition, when the amount of partial neutralization is increased to increase the fiber portion in order to enhance the binding property, there is a problem that the fluidity is lowered.
What was obtained by controlling the water content of the washed dehydrated product of Patent Document 3 to 70 to 90% by mass is a powder in which particles in a fibrous form and spherical particles are mixed. Under the influence of the particles in the fibrous form, the fluidity is insufficient, and when tableting is performed by the direct compression method, the mass deviation of the tablet may be increased. Furthermore, since the binding property of the spherical particles is low, the binding property of the powder which is this mixture is insufficient.

In Patent Document 4, it is described that low substituted hydroxypropylcellulose having high fluidity can be obtained by completely dissolving the fibrous particles, but the binding ability of the powder obtained by this method is low. It was a thing.
Furthermore, Patent Document 2 describes that when the pulverization is performed by a ball mill instead of impact pulverization, the bonding property is inferior. In addition, those pulverized by a ball mill were inferior in swelling characteristics, which are important characteristics as a disintegrant.

Patent Document 5 describes a water-soluble cellulose ether having a low undissolved fiber content when it is dissolved in water by increasing the bulk density of the powdered pulp by using a vertical roller mill when pulverizing the pulp. Has been.
However, the water-soluble cellulose ether is different in that it does not include an essential neutralization step in the production of a water-insoluble low-substituted hydroxypropyl cellulose, and Patent Document 5 is an important characteristic of the low-substituted hydroxypropyl cellulose. No mention is made of binding and disintegration properties.

  Patent Document 6 describes a method for producing cellulose ether using a vertical roller mill, but this also relates to water-soluble cellulose ether and not to water-insoluble low-substituted hydroxypropyl cellulose.

Patent Document 7 describes a low-substituted hydroxypropyl cellulose having a volume increase rate of 100% or more when swollen at an angle of repose of 45 ^° or less, but the low-substituted hydroxypropyl cellulose has low binding properties. .
Japanese Patent Publication No. 48-38858 Japanese Patent Publication No.57-53100 Japanese Patent Laid-Open No. 10-305084 JP-A-11-322802 JP 2001-9316 A JP-A-9-76233 Japanese Unexamined Patent Publication No. 7-324101

  The present invention has been made to eliminate the above-mentioned drawbacks of the prior art, and provides a low-substituted hydroxypropylcellulose powder having high binding properties, good fluidity and excellent disintegration, and a method for producing the same. Objective.

  As a result of intensive investigations to achieve the above-mentioned object, the present inventors have added and mixed an aqueous caustic soda solution to powdered pulp in the production of low-substituted hydroxypropyl cellulose, and the mass ratio of caustic soda to anhydrous cellulose is 0.1. After producing an alkali cellulose of ~ 0.3 and then conducting an etherification reaction, neutralizing caustic soda with or without a dissolution step, washing and drying, and then compacting and grinding in a pulverization step, It has been found that a low-substituted hydroxypropylcellulose powder having high binding properties, good fluidity and excellent disintegration can be obtained.

The present invention is a method for producing a low-substituted hydroxypropylcellulose powder molar substitution per anhydrous glucose unit has a water swellable water-insoluble is 0.05 to 1.0, (1) powdered A step of adding an aqueous caustic soda solution in an amount so that the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3 and producing alkali cellulose, and (2) an etherification reaction of the obtained alkali cellulose. And a step of obtaining a crude reaction product, and (3) a step of neutralizing caustic soda contained in the obtained crude reaction product without passing through a dissolution step of dissolving a part or all of the crude reaction product, (4) Provided is a method for producing a low-substituted hydroxypropylcellulose powder comprising a subsequent washing / dehydrating step, (5) a drying step, and (6) a pulverizing step for performing compaction grinding. As a reference embodiment , specifically, a method for producing a low-substituted hydroxypropylcellulose powder having a water-insoluble and water-absorbing swellability, wherein the number of substituted moles per anhydroglucose unit is 0.05 to 1.0, 1) a step of adding an aqueous solution of caustic soda to the powdered pulp in an amount such that the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3 to produce alkali cellulose; and (2) of the obtained alkali cellulose. A step of obtaining a crude reaction product by performing an etherification reaction, a step of neutralizing caustic soda contained in the obtained crude reaction product, (4) a subsequent washing / dehydration step, and (5) Provided is a method for producing a low-substituted hydroxypropylcellulose powder comprising a drying step and (6) a grinding step of performing compaction grinding.
The washing / dehydrating step is preferably a step of performing dehydration with washing and a moisture content of 65% by mass or less .

The low-substituted hydroxypropyl cellulose powder of the present invention has high fluidity, excellent binding properties, and excellent swelling characteristics despite the fibrous form derived from the raw material pulp.
Moreover, since the low substituted hydroxypropyl cellulose powder of the present invention is excellent in binding and disintegrating properties, it has an advantage that the amount added in the tablet can be reduced and the size of the tablet can be reduced.

  The method of the present invention will be described below. First, any pulverization method may be used for powdered pulp used as a raw material. The average particle diameter is preferably 60 to 300 μm. It is industrially inefficient to prepare a powdered pulp of less than 60 μm, and if it exceeds 300 μm, the miscibility with aqueous caustic soda solution may be poor.

  The step of producing alkali cellulose is preferably performed by dropping or spraying a caustic soda aqueous solution into the powdered pulp and mixing. At this time, caustic soda acts as a catalyst for the etherification reaction. In the production of alkali cellulose, preferably, mixing is performed in an internal stirring type reactor, followed by etherification reaction, or alkali cellulose prepared in another mixer is charged into the reactor for etherification reaction. Any method may be used.

In addition, it was found that the amount of caustic soda in the alkali cellulose affects not only the reaction efficiency but also the swelling property and binding property of the final product. The optimum amount of caustic soda in the alkali cellulose is 0.1 to 0.3 in terms of a mass ratio of caustic soda to anhydrous cellulose (referred to excluding moisture in the pulp). If it is less than 0.1, the volume increase rate at the time of swelling characteristic, especially water absorption swelling becomes low, the disintegration property is lowered, and the binding property may be lowered. Moreover, when it exceeds 0.3, the swelling volume increase rate at the time of water absorption mentioned later and the swelling volume increase rate also become low, and binding property may also fall.
Caustic soda is preferably added as a 20 to 40% by weight aqueous solution.

  In the next step of performing the etherification reaction, alkali cellulose is charged into the reactor, and after purging with nitrogen, propylene oxide is charged into the reactor as an etherifying agent to perform the reaction. The charging ratio of propylene oxide is preferably about 0.1 to 1.0 mol with respect to 1 mol of anhydroglucose unit. The reaction temperature is about 40 to 80 ° C., and the reaction time is about 1 to 5 hours.

In addition, a dissolution process can be performed as needed after the process of performing an etherification reaction. The dissolution step is performed by dissolving a part or all of the crude reaction product after the etherification reaction in water or hot water. The amount of water or hot water used varies depending on the amount of dissolution of the crude reaction product, but the amount of water used to dissolve all of the crude reaction product is usually based on the low-substituted hydroxypropyl cellulose in the crude reaction product. The mass ratio is 0.5 to 10.
In consideration of the load in the washing / dehydration process described later and the further improvement of the low-substituted cellulose ether bondability, it is more preferable not to perform this dissolution process.

In the next neutralization step, the caustic soda used as a catalyst remains in the reaction product. Therefore, it is preferable to add the crude reaction product to water or hot water containing an equivalent amount of acid to the caustic soda. Do the sum. Further, the reaction product may be neutralized by adding water containing an equivalent amount of acid or hot water.
Examples of the acid to be used include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as formic acid and acetic acid.

In the next washing / dehydrating step, the obtained neutralized product is preferably dehydrated by a method selected from centrifugal separation, vacuum filtration, pressure filtration and the like while washing with water or hot water. The low-substituted hydroxypropylcellulose in the obtained dehydrated cake becomes a fibrous material in the same manner as the raw material pulp. Depending on the number of moles substituted in the dehydrated product that has undergone the dissolution step, the dehydration rate is generally 70 to 90% by mass, and the dehydration rate that does not pass through the dissolution step is usually 65% by mass or less. It can be reduced and productivity is improved. Furthermore, since there is no dissolution process, there is an advantage that the process can be simplified.
In addition, from the viewpoint of product binding, a product obtained by pulverization using a fiber-shaped product has a high specific surface area and a high binding property.

  The drying process for drying the dehydrate obtained above can be preferably performed at 60 to 120 ° C. using a dryer such as a fluidized bed dryer or a drum dryer.

The pulverization step is carried out by compacting and grinding the dried product obtained by the above method.
For the compaction grinding, a pulverizer such as a roller mill, a ball mill, a bead mill, or a stone mill pulverizer can be used. A roller mill is a crusher in which a roller or ball rolls while compressing and shearing the material to be crushed by the centrifugal force and gravity load associated with its rotational movement. IS Mill manufactured by Ishikawajima-Harima Heavy Industries, Ltd. VX mill manufactured by MS, MS roller mill manufactured by Masuno Seisakusho Co., Ltd. can be used. The ball mill is a pulverizer using steel balls, magnetic balls, cobblestones and the like as pulverization media, and a ball mill manufactured by Kurimoto Tekko Co., Ltd., a tube mill manufactured by Otsuka Tekko Co., Ltd., a planetary ball mill manufactured by FRITSCH, etc. can be used. The bead mill is similar to the ball mill. However, the bead mill manufactured by Ashizawa Seisakusho Co., Ltd. can be used. For example, a bead mill manufactured by Ashizawa Seisakusho can be used. The stone mill type crusher is a machine that can grind powder by rotating the stone mill at a high speed with a narrow clearance. For example, a serendipeater manufactured by Masuko Sangyo Co., Ltd. can be used.
In particular, a roller mill with less metal foreign matter, a small installation area, and high productivity is preferable.

  In addition, it has been said that the low-substituted hydroxypropyl cellulose produced by conventional impact pulverization is expressed by the entanglement of the fibrous form. For this reason, if the amount of fibrous particles is increased in order to enhance the bonding property, the fluidity is lowered. However, the low-substituted hydroxypropylcellulose powder of the present invention surprisingly showed high binding properties even though the fibrous form disappeared by compaction and grinding.

Preparation of powder physical properties of products in the prior art is performed by partially neutralizing caustic soda used as a reaction catalyst in water after completion of the etherification reaction, as described in Patent Document 2 and Patent Document 3, This was performed by partially dissolving propylcellulose and controlling the amount of fibrous particles. In Patent Document 4, a powder having high fluidity is prepared by completely dissolving low-substituted hydroxypropylcellulose. And any crushing has been performed by using an impact crusher such as an impact mill using an impact force.
The impact pulverizer is easily affected by the pulverized raw material, and the powder physical properties of the product are determined by the shape of the pulverized raw material. That is, the amount of partial neutralization is increased as described in Patent Document 2 or Patent Document 3, or the equivalent amount of acid to caustic soda remaining in the reaction product without passing through the dissolving step according to one embodiment of the present invention. When the raw material in a fibrous form obtained by neutralizing the reaction product in water containing hot water or hot water is used, the obtained pulverized product is low in fluidity containing a lot of fibrous particles. Only powder was obtained.

  According to the present invention, the fibrous particles as the pulverized raw material are repeatedly compacted and milled, and the primary particles can be reduced by the disappearance of the fibrous and hollow tubular form derived from the raw material pulp. Therefore, the specific surface area increases. Moreover, the fibrous form derived from raw material pulp disappears, and a powder having a uniform particle shape is obtained.

Next, preferably, the desired low-substituted hydroxypropylcellulose powder can be obtained by sieving the pulverized product according to a conventional method. A sieve having an opening of about 75 to 180 μm can be used.
The average particle size of the low-substituted hydroxypropylcellulose powder of the present invention is preferably about 10 to 100 μm, more preferably about 20 to 60 μm. If it is less than 10 μm, the agglomeration may increase due to micronization and the fluidity of the powder may be reduced, and if it exceeds 100 μm, the mixing property with the drug may be reduced and non-uniform.

The specific surface area of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 1.0 m ² / g or more. If it is less than this, there is a possibility that high binding properties cannot be obtained.
In general, it is known that the higher the specific surface area of the powder, the higher the binding property of the powder. Specific surface area analysis is a method of adsorbing molecules with a known adsorption area on the surface of powder particles at the temperature of liquid nitrogen, and obtaining the specific surface area of the sample from the amount. BET method based on low-temperature low-humidity physical adsorption of inert gas Can be used. For example, it can be measured using MICROMERITICS GEMINI 2375 (manufactured by Shimadzu Corporation).
In general, the specific surface area can be increased by reducing the average particle size, but if the average particle size becomes too small as described above, the cohesiveness of the powder increases and the fluidity of the powder decreases. There is a fear. In the present invention, a powder having a high specific surface area can be obtained by compaction grinding, although it has an average particle diameter that provides fluidity of the powder.

The elastic recovery rate is an index indicating the compression moldability of the powder. The powder can be obtained from the following formula from the tablet thickness when the tablet diameter is 11.3 mm and compression molding is performed with a tablet mass of 480 mg and a compression pressure of 50 MPa using a flat plate having a flat contact surface.
Elastic recovery rate = {(Tablet thickness after 30 seconds−Minimum tablet thickness) / (Minimum tablet thickness)} × 100
Here, "minimum tablet thickness" refers to the lowest point when the powder is compressed with an upper punch using a flat punch with a fixed lower punch, that is, the thickness when the tablet is most compressed, “Tablet thickness after 30 seconds” refers to the tablet thickness 30 seconds after the upper eyelid is opened upward.
The elastic recovery rate of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 7% or less, and is a plastic deformation body similar to crystalline cellulose widely used as a binder, and forms a dense molded body upon compression. It was found that it was a powder. The powders prepared by the methods described in Patent Document 2 and Patent Document 5 were powders having a high elastic recovery rate and strong elastic deformation properties.

As a method for measuring the swelling property of the low-substituted hydroxypropylcellulose powder of the present invention, for example, the low-substituted hydroxypropylcellulose powder is formed into a tablet having a flat surface with a diameter of 15 mm at a tableting pressure of 1 t, and water is dropped therein. Thus, the swelling volume increase rate and swelling volume increase rate when the tablet swells can be evaluated. When using alkali cellulose having a mass ratio of caustic soda to anhydrous cellulose of 0.1 to 0.3, the swelling volume increase rate is preferably 300% or more, and the swelling volume increase rate is preferably 100% / min or more. .
The swelling volume increase rate is obtained by forming a powder into a tablet having a flat surface with a diameter of 15 mm at a tableting pressure of 1 t, and then attaching a ridge with a conduit instead of the upper ridge, through which water is applied to the tablet in a state where it enters the mortar. Is added as a swelling volume increase rate when the tablet absorbs water for 10 minutes. Water is added dropwise at a rate of 1 ml / min for 10 minutes. The increase in volume can be determined by the following equation from the change in tablet thickness.
Swelling volume increase rate = (difference in tablet thickness before and after water addition / tablet thickness before water addition) × 100
In the above formula, “the difference in tablet thickness before and after water addition” is obtained by subtracting the tablet thickness before water addition from the tablet thickness after water addition for 10 minutes.
The swelling volume increase rate of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 300% or more from the viewpoint of swelling characteristics which are important characteristics as a disintegrant. When the swelling volume increase rate is less than 300%, the disintegration time may be extended when the preparation is formulated.
The swelling volume increase rate means the initial swelling rate 30 seconds after the start of water addition when the swelling volume increase rate is measured under the same conditions as in the above method, and can be determined from the following equation.
Swelling volume increase rate = (difference in tablet thickness before and after initial water addition / tablet thickness before water addition) × 100 / 0.5
In the above formula, “the difference in tablet thickness before and after initial water addition” is obtained by subtracting the tablet thickness before water addition from the tablet thickness 30 seconds after the start of water addition.
The swelling volume increase rate of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 100% / min or more from the viewpoint of swelling characteristics which are important characteristics as a disintegrant. When the swelling volume increase rate is less than 100% / min, the disintegration time may be extended when the preparation is formulated.

The low-substituted hydroxypropylcellulose powder of the present invention has a high fluidity and is a powder having an angle of repose, which is one of the indices of the fluidity of the powder, preferably 42 ^° or less. The angle of repose refers to an angle formed between a generatrix of a cone deposited by dropping a sample on a plane and a horizontal plane. For example, by using a powder tester PT-D type (manufactured by Hosokawa Micron Corporation), a sample is allowed to flow out on a metal disk-shaped table having a diameter of 80 mm until a certain angle is reached from a height of 75 mm. It can be calculated by measuring the angle with the table. It can be said that the smaller the angle, the better the powder.

Moreover, it can evaluate by tablet hardness when a sample powder is compression-molded with a flat powder having a tablet diameter of 11.3 mm, a tablet mass of 480 mg, and a compression pressure of 150 MPa as an index of binding. The tablet hardness using the low-substituted hydroxypropylcellulose powder of the present invention is preferably 35 kgf or more, particularly preferably 40 kgf or more. Tablet hardness can be evaluated by, for example, tableting under the above conditions using a tableting tester (manufactured by Sankyo Powtech). In addition, since the tablet hardness obtained by the water | moisture content of sample powder changes, it is preferable to carry out by making the water | moisture content of sample powder constant. For example, it is preferable to adjust the moisture content of the sample powder to 2 to 4% by mass.
Furthermore, it can be evaluated by the loose bulk density of the low-substituted hydroxypropylcellulose powder. For example, it can be calculated by measuring the mass when a 100 ml container is lightly filled (meaning without tapping) using a powder tester (manufactured by Hosokawa Micron). The loose bulk density of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 0.3 to 0.5 g / ml, particularly preferably 0.35 to 0.45 g / ml. If the loose bulk density is less than 0.3 g / ml, the fluidity of the powder may be lowered, which may be unfavorable for handling, and if it exceeds 0.5 g / ml, the binding property may be lowered.

The low-substituted hydroxypropylcellulose powder of the present invention can be used as a binder or disintegrant for solid preparations such as tablets or granules. Tablets can be obtained by any production method such as a dry direct tableting method, a wet stirring granulation tableting method, a fluidized bed granulation tableting method, and a dry granulation tableting method.
Here, the dry direct tableting method is a method in which a low-substituted hydroxypropylcellulose powder and a drug, other excipients, lubricants, etc. are dry-mixed and then tableted, and there is no granulation step. The process can be simplified and the method is highly productive. With the wet stirring granulation tableting method, after granulating the low-substituted hydroxypropyl cellulose powder and drug, other excipients, etc. using water or a water-soluble binder solution using a high-speed stirring granulator, This is a method in which the powder obtained by drying and a lubricant are mixed and then tableted, and the drug content is highly uniform. The fluidized bed granulation tableting method is a method of granulating a low-substituted hydroxypropylcellulose powder and drugs, other excipients, etc. using a fluidized bed granulator using water or a water-soluble binder solution, and then drying. In this method, the powder obtained and the lubricant are mixed and then tableted, and the drug content uniformity is high as in the wet stirring granulation tableting method. The dry granulation tableting method is a method in which a low-substituted hydroxypropylcellulose powder and drug, other excipients, etc. are granulated by compression and tableted. Effective for drugs that are sensitive to water and solvents. It is a simple method. In addition, the present invention can also be applied to a rapidly disintegrating tablet in the oral cavity that rapidly disintegrates in the oral cavity with no water or a small amount of water that has been actively developed in recent years. This method is an effective dosage form for elderly people and children with low swallowing ability.
Furthermore, the low-substituted hydroxypropylcellulose of the present invention can also be used as a binder or disintegrant for granules. The granule can be obtained by any production method such as wet stirring granulation, fluidized bed granulation, and dry granulation.
In addition, it is also possible to spheroidize a columnar granule or a granulated product after extrusion granulation by a malmerizer by extrusion granulation. In addition, layering can be performed by spraying the binder solution while spraying a mixed powder of low-substituted hydroxypropylcellulose powder, drug powder and other excipients on a spherical core made of sugar or the like.

The drug used in the preparation using the low-substituted hydroxypropylcellulose powder of the present invention is not particularly limited, and is a central nervous system drug, a circulatory system drug, a respiratory system drug, a digestive system drug, an antibiotic. Substances and chemotherapeutic agents, metabolic drugs, vitamin drugs and the like.
Examples of central nervous system drugs include diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, etenzamide, ketoprofen and the like.
Examples of circulatory drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedibin, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbitol nitrate and the like.
Examples of respiratory drugs include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin and the like.
Digestive drugs include 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl] penimidazole and 5-methoxy-2-[(4-methoxy -3,5-dimethyl-2-pyridyl) methylsulfinyl] benzimidazole and other benzimidazole drugs having antiulcer activity, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid and the like.
Antibiotics and chemotherapeutic agents include cephalexin, cefaclor, cefradine, amoxicillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, erythromycin stearate, lincomycin, doxycycline, trimethoprim / sulfamethoxazole and the like.
Examples of metabolic drugs include serrapeptase, lysozyme chloride, adenosine triphosphate, glibenclamide, potassium chloride and the like.
Examples of vitamin drugs include vitamin B1, vitamin B2, vitamin B6, vitamin C, and the like.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to a following example.
[Example 1]
806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor, and 303 g of 26% caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes. The mass ratio of caustic soda to anhydrous cellulose was 0.105. Alkali cellulose was obtained. Next, nitrogen substitution was performed, 123 g of propylene oxide (0.164 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. As a result, 1232 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.28 was obtained. The etherification efficiency was 61.4%.
Next, neutralization was performed by adding 236 g of 50% by mass of acetic acid to a 10 L internal stirring reactor. This neutralized product was washed and dehydrated with hot water at 90 ° C. using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 58.2% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated by the following methods, and the results are shown in Table 1. . An electron micrograph of the obtained powder is shown in FIG. FIG. 1 shows that a fibrous form having a smooth surface derived from raw pulp disappears by compaction and is a powder composed of particles having a constant shape and voids.

The average particle diameter was measured using HELOS & RODOS (manufactured by Sinpack), which is a laser diffraction particle size distribution measurement.
The specific surface area was measured using MICROMERITICS GEMINI 2375 (manufactured by Shimadzu Corporation).
The loose bulk density was measured from above (23 cm) by passing the sample through a JIS 24-mesh sieve into a 100 cc cylindrical container (made of stainless steel) having a diameter of 5.03 cm and a height of 5.03 cm using a powder tester (manufactured by Hosokawa Micron). It was calculated by filling lightly evenly (meaning without tapping), grinding the upper surface and measuring the mass.
The angle of repose was calculated by using a powder tester (manufactured by Hosokawa Micron Co., Ltd.) to flow out from a height of 75 mm on an 80 mm disk-shaped table and measuring the angle between the deposited powder and the table.
The elastic recovery rate is calculated from the tablet thickness when the sample powder is compression-molded with a tableting tester (manufactured by Sankyo Powtech Co., Ltd.) with a tablet diameter of 11.3 mm, a tablet mass of 480 mg, and a compression pressure of 50 MPa. I asked for it.
Elastic recovery rate = {(Tablet thickness after 30 seconds−Minimum tablet thickness) / (Minimum tablet thickness)} × 100
The binding was measured by tablet hardness when the powder was compression-molded with a tableting tester (manufactured by Sankyo Powtech Co., Ltd.) with a flat plate having a tablet diameter of 11.3 mm, a tablet mass of 480 mg, and a compression pressure of 150 MPa.
As the swelling volume increase rate, the volume increase rate after 10 minutes when the tablet swelled by water absorption was measured by molding the powder into a tablet having a flat surface with a diameter of 15 mm at a tableting pressure of 1 t, and dropping the water there. did.
The swelling volume increase rate is determined by molding the powder into a tablet having a diameter of 15 mm at a tableting pressure of 1 t, and dropping the water into it to increase the swelling volume from the volume change after 30 seconds when the tablet swells. The rate was calculated.

Next, ascorbic acid direct compression tablets were produced using the obtained powder under the following conditions.
Tablet composition Ascorbic acid granulated powder VC-97 (manufactured by BASF Takeda Vitamin Co., Ltd.) 90 parts by mass
10 parts by mass of low-substituted hydroxypropylcellulose
Magnesium stearate 0.5 parts by mass tableting machine Rotary tableting machine (manufactured by Kikusui Seisakusho)
Tablet size Diameter: 8 mm, curved surface radius: 6.5 mm, tablet weight: 200 mg
Tableting pressure Main pressure: 0.5t Preload: 0.2t
Tableting speed 40rpm
The tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Example 2]
806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor and 504 g of 26 mass% caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes, so that the mass ratio of caustic soda to anhydrous cellulose was 0.175. Of alkali cellulose was obtained. Next, nitrogen substitution was performed, and 143 g of propylene oxide (0.190 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. 1453 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.29 was obtained. The etherification efficiency was 53.6%.
Next, 394 g of 50% by mass of acetic acid was added to a 10 L internal stirring reactor and mixed for neutralization. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 60.5% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Example 3]
806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor and 808 g of 26 mass% caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes. Of alkali cellulose was obtained. Next, nitrogen substitution was performed, and 173 g of propylene oxide (0.230 parts by mass with respect to cellulose) was added thereto, and the reaction was carried out at a jacket temperature of 60 ° C. for 1.5 hours. Hydroxypropoxyl per anhydroglucose unit 1787 g of a hydroxypropylcellulose crude reaction product having a group substitution mole number of 0.30 was obtained. The etherification efficiency was 46.4%.
Next, 629 g of 50% by mass of acetic acid was added to a 10 L internal stirring type reactor, and neutralized by mixing. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 62.2% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown in Table 1. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Example 4]
8.6 kg of powdery pulp (anhydrous equivalent 8 kg) was charged into a 130 L internal stirring reactor, and 35 kg of 35% by weight caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes, and the mass ratio of caustic soda to anhydrous cellulose Of 0.151 was obtained. Next, nitrogen substitution was performed, 1.6 kg of propylene oxide (0.2 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours. 13.7 kg of a crude reaction product of hydroxypropyl cellulose having a propoxyl group substitution mole number of 0.35 was obtained.
Next, 11.8 kg of 50% by mass of acetic acid was added to the internal stirring reactor and mixed for neutralization. This neutralized product was washed with hot water at 90 ° C. using a batch vacuum filter. The water content of the dehydrated product was 59.5% by mass. The dehydrated product was dried with a fluidized bed dryer at an intake air of 80 ° C. until an exhaust temperature of 60 ° C. The etherification reaction efficiency was 57.6%.
The dried product was pulverized and dehydrated with an IS-250 manufactured by Roller Mill IHI at a pressure of 3 MPa, a table rotation speed of 120 rpm, a classification rotation speed of 300 rpm, an air volume of 11 Nm ³ / min, and a supply time of 5 kg / hr. The obtained pulverized product was sieved with a sieve having an opening of 75 μm to obtain the desired low-substituted hydroxypropylcellulose powder.
The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown in Table 1. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[ Reference Example 5]
806 g of powdery pulp (750 g in anhydrous conversion) was charged into a 10 L internal stirring reactor, and 303 g of 26% by mass caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes. The mass ratio of caustic soda to anhydrous cellulose was 0.105. Of alkali cellulose was obtained. Next, nitrogen substitution was performed, 81.8 g of propylene oxide (0.109 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1 hour, and hydroxypropoxyl per anhydroglucose unit. 1190.8 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.20 was obtained. The etherification efficiency was 65.0%.
Next, 2250 g of hot water of 50 ° C. and 59 g of glacial acetic acid were put into a 10 L batch kneader, and 1190.8 g of the above-mentioned crude reaction product was added in total for dissolution. It took 20 minutes for complete dissolution. Then, neutralization was performed by adding 118 g of 50% by mass acetic acid at a rate of 20 g / min. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 62.2% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 75 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown in Table 1. .
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Comparative Example 1]
806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor, 300 g of 13 mass% caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes, and the mass ratio of caustic soda to anhydrous cellulose was 0.052. Of alkali cellulose was obtained. Next, nitrogen substitution was carried out, and 146 g of propylene oxide (0.195 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. 1252 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.28 was obtained. The etherification efficiency was 50.9%.
Next, 117 g of 50% by mass of acetic acid was added to a 10 L internal stirring reactor and mixed for neutralization. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 50.1% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Comparative Example 2]
806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor, and 761 g of 35% by weight caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes. The mass ratio of caustic soda to anhydrous cellulose was 0.355. Of alkali cellulose was obtained. Next, nitrogen substitution was performed, and 161 g of propylene oxide (0.214 parts by mass with respect to cellulose) was added thereto, and the reaction was carried out at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. 1728 g of a hydroxypropylcellulose crude reaction product having a group substitution mole number of 0.28 was obtained. The etherification efficiency was 43.5%.
Next, 800 g of 50% by mass of acetic acid was added to a 10 L internal stirring reactor and mixed for neutralization. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 65.2% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Comparative Example 3]
806 g of powdery pulp (750 g in anhydrous conversion) was charged into a 10 L internal stirring reactor, 844 g of 43% by weight caustic soda was charged into the reactor and mixed at 45 ° C. for 30 minutes, and the mass ratio of caustic soda to anhydrous cellulose was 0.484. Of alkali cellulose was obtained. Next, nitrogen substitution was carried out, and 165 g of propylene oxide (0.220 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. 1815 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.27 was obtained. The etherification efficiency was 42.3%.
Next, 1088 g of 50% by mass acetic acid was added to a 10 L internal stirring reactor and mixed to effect neutralization. This neutralized product was washed with hot water at 90 ° C. and dehydrated using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 66.8% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having an opening of 180 μm to obtain the desired low-substituted hydroxypropylcellulose powder. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1.

[Comparative Example 4]
The sheet-like pulp was dipped in a 43% caustic soda solution and then pressed to obtain alkali cellulose containing 22.2% by mass of caustic soda and having a mass ratio of caustic soda to anhydrous cellulose of 0.484. The obtained alkali cellulose was cut into chips of about 1 cm square, and 350 g of alkali cellulose in terms of cellulose was charged into a reactor having a capacity of 5 L, followed by nitrogen substitution. 79 g of propylene oxide (0.226 parts by mass with respect to cellulose) was added thereto, and the reaction was carried out at a jacket temperature of 45 ° C. for 2 hours and at 65 ° C. for 30 minutes, and the hydroxypropoxyl group substitution moles per anhydroglucose unit was 0. 857 g of a crude reaction product of .27 hydroxypropylcellulose was obtained. The etherification efficiency was 42.0%.
Next, as in Patent Document 2 and Patent Document 3, a part of the crude reaction product was dissolved in hot water, neutralized (partial neutralization method), and the resulting dried product was subjected to impact pulverization. Produced.
1750 g of water at 50 ° C. and 52 g of glacial acetic acid were put into a 5 L batch kneader, and the total amount of 857 g of the above-mentioned crude reaction product was added for dissolution. It took 30 minutes to dissolve completely. Thereafter, 633 g of 33% acetic acid was added at a rate of 20 g / min for neutralization precipitation.
This neutralized product was washed with hot water at 90 ° C. at a rotation speed of 3000 rpm using a batch centrifuge. The water content of the dehydrated product was 75.4% by mass. The dehydrated product was dried in a blowing oven at 80 ° C. for a whole day and night.
The obtained dried product was pulverized using a Victory Mill with a high-speed rotary impact pulverizer having a screen with an aperture of 0.3 mm, and the pulverized product was sieved with a sieve having an aperture of 75 μm to achieve the desired low degree of substitution. Hydroxypropyl cellulose powder was obtained. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1. Further, an electron micrograph of the obtained powder is shown in FIG. FIG. 2 shows that the raw material pulp-derived surface is a powder having a smooth fibrous form and spherical dense particles produced by the dissolving process.

[Comparative Example 5]
After complete dissolution described in Patent Document 4, neutralization was performed, and a sample was prepared by impact pulverization of the obtained dried product.
Into a 5 L batch kneader, 2450 g of water at 50 ° C. was put, and 857 g of the crude reaction product reacted in the same manner as in Comparative Example 4 was added to dissolve (complete dissolution). It took 1 hour to completely dissolve. Thereafter, 793 g of 33% acetic acid was added at a rate of 20 g / min for neutralization precipitation.
This neutralized product was washed with hot water at 90 ° C. and dehydrated at a rotation speed of 3000 rpm using a batch centrifuge. The water content of the dehydrated product was 80.1% by mass. The dehydrated product was dried in a blowing oven at 80 ° C. for a whole day and night.
The obtained dried product was pulverized using a Victory Mill with a high-speed rotary impact pulverizer having a screen with an aperture of 0.3 mm, and the pulverized product was sieved with a sieve having an aperture of 75 μm to achieve the desired low degree of substitution. Hydroxypropyl cellulose powder was obtained. The average particle size, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown in Table 1. .
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1. Moreover, the electron micrograph of the obtained powder was shown in FIG. FIG. 3 shows that there are few fibrous particles produced by the dissolving step, and the powder is composed of spherical fine particles.

[Comparative Example 6]
A low-substituted hydroxypropylcellulose powder was obtained in the same manner as in Example 2 except that a high-speed rotary impact pulverizer Victory Mill having a screen with a mesh opening of 0.3 mm was used. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, binding property, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated in the same manner as in Example 1, and the results are shown in Table 1. It is shown in 1.
Further, ascorbic acid direct compression tablets were prepared in the same manner as in Example 1, and the tablet hardness, disintegration time (test solution: water) and tablet mass deviation in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 1. Moreover, the electron micrograph of the obtained powder was shown in FIG. FIG. 4 shows that the surface derived from the raw material pulp is a powder having a smooth fibrous form.

FIG. 5 shows the results of examining the influence of the mass ratio of caustic soda to anhydrous cellulose in alkali cellulose on the swelling characteristics. FIG. 5 shows the measurement time from the start of water addition on the horizontal axis and the swelling volume increase rate on the vertical axis.
It turns out that an Example has a larger swelling volume increase rate and a larger swelling volume increase rate than a comparative example.

  As is apparent from Table 1, when caustic soda having a predetermined mass ratio and using compaction milling has a large specific surface area and a low elastic recovery rate, it has a high binding property and is formulated. Tablets with high tablet hardness are obtained. Moreover, since the swelling volume increase rate and the swelling volume increase rate were high, a preparation with a short disintegration time was obtained when it was formulated. On the other hand, a powder that does not use a predetermined caustic soda mass ratio even when using compaction milling is inferior in specific surface area, binding property, swelling volume increase rate, tablet hardness and disintegration time which are important as disintegrants. This is shown in the results of Comparative Examples 1 to 3. Moreover, in the result of Comparative Examples 2-3, it is inferior also to the swelling volume increase rate which is an important swelling characteristic as a disintegrating agent. Even if a specific caustic soda mass ratio is used, the powder obtained by impact grinding instead of compaction grinding is inferior in specific surface area, fluidity, binding properties, tablet hardness and disintegration time, and tablet mass deviation Is shown in the result of Comparative Example 6. In Comparative Example 4, since sheet-like pulp is used, alkali cellulose containing excess caustic soda is used, and the swelling volume increase rate is inferior. Further, since an impact pulverizer was used, the specific surface area was small, the elastic recovery rate was large, and the bonding property was low. On the other hand, Comparative Example 5 had a low repose angle and excellent fluidity because there were few fibrous forms due to complete dissolution, but the bondability was low.

1) Orally disintegrating tablet [Example 6]
Using the low-substituted hydroxypropylcellulose obtained by the method described in Example 1, an intraoral rapidly disintegrating tablet was prepared under the following conditions.
Tablet composition Erythritol (250 μm sieved product) 70 parts by mass
Low substituted hydroxypropylcellulose 30 parts by weight
Magnesium stearate 0.5 parts by weight Tableting machine Single tableting machine Tableting tester (manufactured by Sankyo Powtech)
Tablet size Diameter: 11.3 mm, flat tableting pressure 10, 25, 50 MPa
The tablet hardness, oral disintegration time, and ingestion feeling of the obtained tablets were evaluated. In the oral disintegration time, four healthy adults did not chew the tablet in the oral cavity, measured the time until the tablet was completely dissolved or disintegrated in a state of being lightly contained in the mouth, and the average value was calculated. Table 2 shows the results of tablet hardness and oral disintegration time.

[Comparative Example 7]
An intraoral quick disintegrating tablet was prepared in the same manner as in Example 6 except that the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 4 was used. The obtained tablets were evaluated in the same manner as in Example 6, and the results are shown in Table 2.

  In Example 6, the tablet hardness was higher than that in Comparative Example 7, and the disintegration time in the oral cavity was short. Further, in Example 6, none of the tablets was rough and creamy, while in Comparative Example 7, paper was included in the mouth, and the feeling of taking was poor.

2) Wet stirring granulation [Example 7]
Using the low-substituted hydroxypropyl cellulose obtained by the method described in Example 4, a powder having the following composition was charged into a vertical granulator FM-VG-05 (manufactured by POWREC), and the main shaft was 600 rpm and the chopper was rotated at 1000 rpm. Premixing was carried out for 1 minute, and 55 g of water was added and mixed for 5 minutes to perform wet stirring granulation.
Tablet composition Ethenzamid 210g (70 parts by weight)
200 # lactose 60g (20 parts by mass)
Low substituted hydroxypropylcellulose 30g (10 parts by mass)
The granulated product was sieved with a sieve having an opening of 1180 μm, dried in a fluidized bed dryer at an intake air of 60 ° C. and a flowing air amount of 70 m ³ / hr, and dried until the exhaust temperature reached 45 ° C.
Table 3 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
The average particle diameter, loose bulk density, and angle of repose of the obtained granules were measured in the same manner as in the low-substituted hydroxypropylcellulose powder, and the compacted bulk density and compressibility were measured by the following methods. did.
In other words, the firm bulk density is the bulk density when tapping is applied to the loose bulk density to make it densely packed. Tapping is a light impact on the bottom by repeatedly dropping the sample-filled container from a certain height. To close-pack the sample. Therefore, when measuring the loose bulk density, after measuring the loose bulk density, weigh the upper surface and then put a cap (equipment of a powder tester manufactured by Hosokawa Micron Co., Ltd.) on the container. And tapping with a tap height of 1.8 cm is performed 180 times. After the tapping is completed, the cap is removed, and the powder is ground on the upper surface of the container and weighed. These operations can be measured by using a powder tester (PT-D) manufactured by Hosokawa Micron.
The degree of compression is a value indicating the degree of sag, and is obtained by the following equation.
Compressibility (%) = [(hardened bulk density−loose bulk density) / hardened bulk density] × 100

Next, 0.5 part by mass of magnesium stearate was added to 100 parts by mass of the granule, and then mixed to obtain a powder for tableting. Using this powder, continuous tableting was performed under the following conditions.
Tablet press Rotary tablet press (manufactured by Kikusui Seisakusho)
Tablet size Diameter: 8 mm, radius of curvature: 6.5 mm, tablet weight: 200 mg
Tableting pressure Main pressure: 1t, Preload: 0.2t
Tableting speed 40rpm
Capping occurs after the tablet hardness and the friability test of the obtained tablet according to the following methods according to the tablet hardness, disintegration time in the Japanese pharmacopoeia disintegration test (test solution: water), and the Japanese Pharmacopoeia friability test. The capping occurrence rate and tablet mass deviation were evaluated by measuring the number of tablets.
In the friability test, the mass reduction rate after 20 tablets were tested at 25 rpm for 16 minutes using the friability tester described in the Japanese Pharmacopoeia was calculated from the following formula.
[{(Tablet weight before test) − (Tablet weight after test)} / (Tablet weight before test)] × 100
The capping occurrence rate was calculated from the number of tablets in which the tablet was broken into two layers after the friability test was performed.
For the tablet mass deviation, the coefficient of variation (CV value) was calculated by measuring the mass of 20 tablets.
Table 4 shows the obtained results.

[Comparative Example 8]
Wet granulation was carried out in the same manner as in Example 7, except that the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 4 was used. Table 3 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
Next, continuous tableting was carried out in the same manner as in Example 7, and the evaluation was performed. The results are shown in Table 4.

[Comparative Example 9]
Wet granulation was carried out by the same method as in Example 7 except that microcrystalline cellulose Ceolus PH-101 (manufactured by Asahi Kasei Chemicals) was used instead of the low-substituted hydroxypropyl cellulose. However, since microcrystalline cellulose has lower water retention than low-substituted hydroxypropylcellulose, the amount of water was reduced to 36 g. Table 3 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
Next, continuous tableting was carried out in the same manner as in Example 7, and the evaluation was performed. The results are shown in Table 4.

  In Example 7, the loose bulk density was high and heavy compared to Comparative Examples 8 and 9, and granules with excellent fluidity were obtained due to the low degree of compression and angle of repose.

  In Example 7, an excellent preparation with high tablet hardness and low tablet mass deviation was obtained as compared with Comparative Example 8. In Comparative Example 9 using microcrystalline cellulose, capping occurred, the tablet friability was high, and the tablet hardness was low, but Example 7 was an excellent formulation in all evaluation items. .

3) Fluidized bed granulation [Example 8]
Using the low-substituted hydroxypropylcellulose obtained by the method described in Example 1, a powder having the following composition was charged into a fluidized bed granulator multiplex MP-01 (manufactured by POWREC), intake air 60 ° C., fluidized air Granulation was carried out by spraying 60 g of a 5 mass% aqueous solution of an amount of 50 m ³ / hr, an exhaust temperature of 30 to 35 ° C., and a hydroxypropylmethylcellulose TC-5R (manufactured by Shin-Etsu Chemical Co., Ltd.) at a rate of 10 g / min.
Tablet composition Acetaminophen 80 g (40 parts by mass)
200 # Lactose 28g (14 parts by mass)
Corn starch 12g (6 parts by mass)
80 g (40 parts by mass) of low-substituted hydroxypropylcellulose
Table 5 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
Next, 0.5 part by mass of magnesium stearate was added to 100 parts by mass of the granule, and then mixed to obtain a powder for tableting. Using this powder, continuous tableting was carried out in the same manner as in Example 7. The tablet hardness of the obtained tablets, the disintegration time in the Japanese Pharmacopoeia disintegration test (test solution: water), and the tablet mass deviation were evaluated. The results are shown in Table 6.

[Comparative Example 10]
Fluidized bed granulation was carried out by the same method as in Example 8 except that the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 4 was used. Table 5 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
Next, continuous tableting was carried out in the same manner as in Example 8, and the evaluation was performed. The results are shown in Table 6.

[Comparative Example 11]
Fluidized bed granulation was carried out by the same method as in Example 8 except that the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 5 was used. Table 5 shows the average particle diameter, loose bulk density, compacted bulk density, degree of compression, and angle of repose of the obtained granules.
Next, continuous tableting was carried out in the same manner as in Example 8, and the evaluation was performed. The results are shown in Table 6.

  In Example 8, the loose bulk density was high and heavy compared to Comparative Examples 10 and 11, and granules with excellent fluidity were obtained due to the low degree of compression and angle of repose.

  Example 8 was a preparation having a higher tablet hardness and a smaller tablet mass deviation than Comparative Examples 10 and 11.

4) Extrusion granulation [Example 9]
Using the low-substituted hydroxypropyl cellulose obtained by the method described in Example 4, a powder having the following composition was charged into a vertical granulator FM-VG-05 (manufactured by POWREC), and the main shaft was 600 rpm and the chopper was rotated at 1000 rpm. Premixing was carried out for 1 minute, and 50 g of water was added and mixed for 5 minutes to perform wet stirring granulation.
Tablet composition Aspirin 279 g (93 parts by mass)
Low substituted hydroxypropylcellulose 15g (5 parts by mass)
Hydroxypropylmethylcellulose TC-5E 6g (2 parts by mass)
Next, extrusion granulation of the wet powder was carried out using an extrusion granulator Dome Gran (Dalton Co., Ltd.) 1.0 mmφ screen, and the granulation rate converted to solid content is shown in Table 7. Moreover, the obtained extruded granulated product was spheroidized at 750 rpm using a Malmerizer (Dalton). Thereafter, drying was performed with a fluidized bed dryer at an intake air temperature of 60 ° C. and a flowing air amount of 70 m ³ / hr until the exhaust temperature reached 45 ° C. The granule strength of the obtained granules and the disintegration time (test solution: water) in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 7.
The granule strength is determined by the following formula using a Japanese Pharmacopoeia friability tester, 10 g of granules are charged therein, 20 glass beads with a diameter of 5 mm are put, and the test is performed at 25 rpm for 4 minutes. Calculated from
[{(Granule mass before test) − (granule mass after test)} / (granule mass before test)] × 100

[Comparative Example 12]
Extrusion granulation was carried out by the same method as in Example 9 except that the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 4 was used, and the granulation rate converted to solid content is shown in Table 7. Indicated. The obtained wet granulated product was spheroidized and dried in the same manner as in Example 9.
The granule strength of the obtained granules and the disintegration time (test solution: water) in the Japanese Pharmacopoeia disintegration test were measured. The results are shown in Table 7.

  Example 9 was an excellent preparation with a high granulation rate and high productivity as compared with Comparative Example 12, and a high granule strength of the obtained granule.

5) Dry granulation [Example 10]
Using the low-substituted hydroxypropylcellulose obtained by the method described in Example 4 and using a roller compactor MINI (manufactured by Freund Corporation), a powder having the following composition was used, and the roll pressure was 4 MPa, the roll rotation speed was 5 rpm, and the screw rotation speed was 12 rpm. And dry granulation was performed.
Tablet composition Ascorbic acid 50 g (10 parts by mass)
200 # lactose 245g (49 parts by mass)
Corn starch 105g (21 parts by mass)
Low substituted hydroxypropylcellulose 100g (20 parts by mass)
Magnesium stearate 2.5 g (0.5 parts by mass)
The granulated product was sieved with a sieve having an opening of 250 μm, and the granulated product was subjected to continuous tableting under the following conditions.
Tablet press Rotary tablet press (manufactured by Kikusui Seisakusho)
Tablet size Diameter: 8 mm, radius of curvature: 6.5 mm, tablet weight: 200 mg
Tableting pressure Main pressure: 1t, Preload: 0.2t
Tableting speed 40rpm
Table 8 shows the results of evaluating the tablet hardness of the obtained tablets and the disintegration time (test solution: water) in the Japanese Pharmacopoeia disintegration test.

[Comparative Example 13]
Except for using the low-substituted hydroxypropylcellulose obtained by the method described in Comparative Example 4, dry granulation was performed by the same method as in Example 10, and continuous tableting was performed by the same method as in Example 10. Carried out. Table 8 shows the results of evaluating the tablet hardness of the obtained tablets and the disintegration time (test solution: water) in the Japanese Pharmacopoeia disintegration test.

  Example 10 was a preparation having high tablet hardness while having the same disintegration time as compared with Comparative Example 13.

The electron micrograph of the powder obtained in Example 1 is shown. The electron micrograph of the powder obtained in Comparative Example 4 is shown. The electron micrograph of the powder obtained in Comparative Example 5 is shown. The electron micrograph of the powder obtained in Comparative Example 6 is shown. The swelling volume increase rate with progress of time of the powder obtained in Examples 1-3 and Comparative Examples 1 and 3 is shown.

Claims (2)

A method for producing a low-substituted hydroxypropyl cellulose powder having a water-insoluble and water-absorbing swelling property, wherein the number of substituted moles per anhydroglucose unit is 0.05 to 1.0,
(1) A step of adding alkaline caustic soda solution to powdered pulp in an amount such that the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3 to produce alkali cellulose;
(2) performing a etherification reaction of the obtained alkali cellulose to obtain a crude reaction product;
(3) a step of neutralizing caustic soda contained in the obtained crude reaction product without undergoing a dissolution step of dissolving a part or all of the crude reaction product;
(4) Subsequent cleaning / dehydration process,
(5) a drying step;
(6) A method for producing a low-substituted hydroxypropylcellulose powder comprising a pulverization step of performing compaction grinding. The method for producing a low-substituted hydroxypropylcellulose powder according to claim 1, wherein the washing / dehydrating step is a step of washing and dehydrating the water content to 65% by mass or less.