Method for producing low-substituted hydroxypropyl cellulose

Abstract

To provide a method for producing low-substituted hydroxypropyl cellulose having favorable disintegratability while maintaining sufficient compactibility.SOLUTION: A method for producing low-substituted hydroxypropyl cellulose having a hydroxypropoxy group content of 5 to 16 mass%, at least includes the steps of: bringing pulp into contact with and alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; dispersing the reaction product into water containing at least acid to partially solubilize the reaction product, and then neutralizing the reaction product with an additional amount of acid to precipitate crude low-substituted hydroxypropyl cellulose; using a screw press to remove liquid from the crude low-substituted hydroxypropyl cellulose to obtain purified low-substituted hydroxypropyl cellulose having a water content of 50 to 60 mass%; and drying and pulverizing the purified low-substituted hydroxypropyl cellulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing low-substituted hydroxypropyl cellulose having good disintegrability, which is added as a disintegrant or binder to solid preparations in the pharmaceutical or food fields. [Background technology]

[0002] Solid preparations such as pharmaceuticals or health foods disintegrate when the disintegrants contained therein absorb water and swell, and examples of disintegrants include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose and its calcium salts, and starch and its derivatives. In particular, in the pharmaceutical field, the number of newly developed drugs that are unstable is increasing, and the excipients that can be used are being restricted due to the possibility of drug interactions. Under these circumstances, low-substituted hydroxypropyl cellulose (hereinafter also referred to as "L-HPC") has been widely used as a nonionic disintegrant and binder, and is a preferred excipient.

[0003] Tablets, which are one of the dosage forms of solid pharmaceutical or food preparations, are solid preparations made by compressing powder into a specific shape and have advantages such as ease of handling. Tablets are the most widely used, accounting for approximately 50% of total production, particularly in the pharmaceutical field. Tablet manufacturing methods include dry direct compression, dry granulation, extrusion granulation, and wet granulation.

[0004] A known method for producing L-HPC is to disperse the reaction product of the etherification reaction of alkali cellulose in water containing 5 to 80% of the acid required to neutralize the total alkali content after the etherification reaction, thereby dissolving a portion of the L-HPC and controlling the formation of fibrous particles (Patent Document 1).It has been disclosed that L-HPC produced by this method has excellent binding properties and can be used in dry direct compression and wet granulation tableting to give tablets with high hardness. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 51-063927 Summary of the Invention [Problem to be solved by the invention]

[0006] However, when L-HPC obtained by the method described in Patent Document 1 is used for wet granulation and tableting, the binding ability is sufficient but the disintegration ability is sometimes insufficient, and further improvement in disintegration ability has been desired. The present invention has been made to overcome the drawbacks of the prior art, and aims to provide a method for producing L-HPC that has good disintegrability while maintaining sufficient binding properties. [Means for solving the problem]

[0007] As a result of extensive research to achieve the above object, the present inventors have surprisingly found that when L-HPC is produced, dehydration using a screw press to a moisture content of 50 to 60 mass % increases the swelling power and improves disintegration properties, while leaving the powder properties and binding properties almost unchanged, and have thus completed the present invention. According to the present invention, there is provided the following method for producing low-substituted hydroxypropyl cellulose. [1] contacting the pulp with an alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; a step of dispersing the reaction product in water containing at least an acid, partially dissolving the reaction product, and then neutralizing the resulting solution with the acid to precipitate crude low-substituted hydroxypropyl cellulose; a step of deliquoring the crude low-substituted hydroxypropyl cellulose using a screw press to obtain purified low-substituted hydroxypropyl cellulose having a water content of 50 to 60% by mass; drying and pulverizing the purified low-substituted hydroxypropyl cellulose; A method for producing low-substituted hydroxypropyl cellulose containing at least the above and having a hydroxypropoxy group content of 5 to 16 mass %. [2] The method for producing low-substituted hydroxypropyl cellulose according to [1], wherein the temperature at the inlet of the screw shaft of the screw press is 100 to 160°C. [Effects of the Invention]

[0008] The L-HPC obtained by the production method of the present invention has good disintegrability while maintaining sufficient binding properties, and therefore can shorten the disintegration time of solid preparations, enabling rapid onset of medicinal effects. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 2 is a schematic diagram showing an example of a screw press used in the liquid removal step. [Figure 2A] FIG. 2 is a front view of a schematic diagram showing an example of a jig used in measuring swelling force. [Figure 2B] FIG. 2 is a bottom view of a schematic diagram showing an example of a jig used in measuring swelling force. [Figure 3] FIG. 3 is a schematic diagram showing a swelling force measurement method using the jig of FIG. 2. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below. The method for producing L-HPC of the present invention includes at least the steps of contacting pulp with an alkali metal hydroxide solution to obtain alkali cellulose, reacting the alkali cellulose with propylene oxide to obtain a reaction product, dispersing the reaction product in water containing at least an acid, partially dissolving it, and then neutralizing it with the acid to precipitate crude L-HPC, removing the liquid from the crude L-HPC using a screw press to obtain purified L-HPC with a moisture content of 50 to 60% by mass, and drying and pulverizing the purified L-HPC. A screw press is a device that performs solid-liquid separation by using a compressive force generated by utilizing the volume change between the deliquified raw material inlet and the deliquified product outlet.

[0011] [Step for obtaining alkali cellulose] In this step, alkali cellulose is obtained by contacting a raw pulp with an alkali metal hydroxide solution, either by immersing a pulp sheet or chips in the alkali metal hydroxide solution and squeezing it, or by adding or spraying the alkali metal hydroxide solution onto a pulp powder in an internally stirred reactor.

[0012] The pulp may be either wood pulp or non-wood pulp such as linter pulp, but wood-derived pulp is preferred from the viewpoint of being GMO (genetically modified organism)-free, etc. The wood species that can be used include conifers such as pine, spruce, and hemlock, and broad-leaved trees such as eucalyptus and maple.

[0013] The alkali metal hydroxide solution is not particularly limited as long as it can convert pulp into alkali cellulose, but an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution is preferred for economic reasons. The concentration of the alkali metal hydroxide in the alkali metal hydroxide solution is preferably 20 to 60 mass %.

[0014] [Step of Reacting Alkali Cellulose with Propylene Oxide to Obtain a Reaction Product] Next, in this step, the alkali cellulose obtained in the previous step is reacted with propylene oxide to obtain a reaction product. The reaction in this step may be carried out by adding the alkali cellulose obtained in the previous step together with propylene oxide to a separate reactor, or, if an internally stirred reactor was used in the previous step, by subsequently adding propylene oxide to the same reactor and carrying out the reaction. The amount of propylene oxide added is preferably 0.05 to 0.5 parts by mass per part by mass of anhydrous cellulose. The propylene oxide may be added in any manner, such as by adding a predetermined amount of propylene oxide all at once, by adding it in several portions, or by adding it continuously. The reaction temperature in this step is preferably 40 to 80°C. The reaction time in this step is preferably 1 to 5 hours. This step is preferably carried out under a nitrogen atmosphere.

[0015] [Precipitation process] In this step, the reaction product obtained in the previous step is dispersed in water containing at least an acid, and the mixture is mixed to dissolve a portion of the L-HPC. The amount of acid is preferably 5 to 80%, more preferably 10 to 60%, and even more preferably 10 to 40% of the equivalent amount required to neutralize the alkali metal hydroxide present with the reaction product. Further, acid is added to the solution containing a portion of the L-HPC to completely neutralize the remaining alkali metal hydroxide, resulting in the precipitation of crude L-HPC. The equivalent required to neutralize the alkali metal hydroxide present with the reaction product is the equivalent required to neutralize the alkali metal hydroxide in the alkali metal hydroxide solution used in contact with the pulp (hereinafter, simply referred to as "neutralization equivalent"). The acid to be used may be a mineral acid such as hydrochloric acid, sulfuric acid, or nitric acid, or an organic acid such as formic acid or acetic acid, but from the viewpoint of corrosiveness and toxicity, hydrochloric acid or acetic acid is preferred.

[0016] [Deliquoring process] Next, in this step, the crude L-HPC obtained in the previous step is deliquified using a screw press to obtain purified L-HPC. In order to remove by-products formed in the previous step, the crude L-HPC obtained in the previous step is preferably mixed with water before being subjected to this step. From the viewpoint of extractability of by-products such as salts and propylene glycols, the temperature of the water mixed with the crude L-HPC is preferably 20 to 100°C, more preferably 30 to 90°C. After mixing the crude L-HPC with water, the mixture may be heated to preferably 20 to 100°C, more preferably 30 to 90°C. If necessary, a washing step may be carried out before the deliquor step to wash the crude L-HPC obtained in the previous step to obtain washed L-HPC. In the washing step, the crude L-HPC is washed with, for example, water using a continuous horizontal vacuum filter, a horizontal table filter, or a horizontal belt filter. The washed L-HPC may be mixed with water again and the washing step may be repeated multiple times. The temperature of the water used in the washing step is preferably 60 to 100°C in view of the purpose of the washing step. The water content of the mixture of crude L-HPC and water before the deliquoring step is preferably 80 to 98 mass %, more preferably 85 to 95 mass %, from the viewpoint of fluidity. The moisture contents of crude L-HPC, washed L-HPC, and purified L-HPC were measured using a heat-drying moisture meter (MX-50, A&D) on 5 g of sample at a heating temperature of 105°C for 120 minutes. Note that the moisture content is not the ratio of water to L-HPC, but the ratio of water to the total of water and L-HPC.

[0017] A screw press is a device that separates solids and liquids using a compressive force generated by utilizing the volumetric change between the deliquified raw material inlet and the deliquified product outlet. Figure 1 shows a schematic diagram of an example of a screw press used in the deliquifying process. The screw press 1 comprises a substantially cylindrical filter cylinder 2 having slits or perforations formed by punching or the like for discharging the liquid, and a screw disposed concentrically within the filter cylinder 2. The screw comprises a screw shaft 4 and screw blades 3 welded to its periphery. The volume of the screw shaft 4 gradually increases from the deliquified raw material inlet 5 to the deliquified product outlet 8. The screw shaft 4 can control temperature by passing a liquid or a gas from the temperature-adjusting liquid inlet 6 to the temperature-adjusting liquid outlet 10. The screw shaft 4 also comprises a straight section 12 without screw blades 3 in a section preceding the deliquified product outlet 8, in order to extend the residence time of the deliquified raw material A within the apparatus and thereby enhance dehydration performance. Specifically, deliquified raw material A, transported from the deliquified raw material inlet to the deliquified product outlet due to volumetric changes, remains in the straight section 12, which lacks screw blades. This applies pressure to the deliquified raw material A, which is subsequently transported from the deliquified raw material inlet 5, from the deliquified product outlet 8, further reducing the moisture content of the deliquified product B. The length of the straight section 12 is called the straight length (or plug length), and this length can be adjusted by moving the screw, which is horizontally movable along the main shaft. The deliquified product outlet 8 is equipped with a truncated cone-shaped back pressure plate 11 concentrically arranged on the screw shaft 4. The opening of the back pressure plate 11 is adjustable. Furthermore, pressure can be applied from the deliquified product outlet 8 to the deliquified raw material inlet 5 using an air cylinder 9 (hereinafter also referred to as "back pressure"). The compressed liquid C, the liquid component compressed by the screw press 1, passes through the perforations of the filter cylinder 2 and is discharged from the compressed liquid outlet 7. Examples of the screw press include the FKC screw press (manufactured by Fukoku Kogyo Co., Ltd.), the ISGKV hybrid press-fit screw press (manufactured by Ishigaki Co., Ltd.), and the YSP screw press dehydrator (manufactured by Yamato Sangyo Co., Ltd.).

[0018] A method for deliquoring crude L-HPC or washed L-HPC using a screw press will be described based on the screw press 1 illustrated in FIG. First, if necessary, select a screw that will achieve the desired compression ratio. The compression ratio of a screw is the ratio of the area between the thickest part of the screw shaft 4 and the inner diameter of the filter cylinder 2 to the area between the thinnest part of the screw shaft 4 and the inner diameter of the filter cylinder 2. Next, the desired screw rotation speed, straight length, back pressure plate opening, back pressure, and screw shaft inlet temperature are set. After setting, the screw press 1 is operated to rotate the screw shaft 4. After the screw rotation speed reaches the desired speed, a mixture of crude L-HPC and water or washed L-HPC is introduced as deliquified raw material A through the deliquified raw material inlet 5. The deliquified raw material A supplied through the deliquified raw material inlet 5 undergoes gravity filtration through the holes in the filter tube 2 directly below the deliquified raw material inlet 5, resulting in solid-liquid separation of a portion of the liquid component. The partially solid-liquid separated deliquified raw material A is transported by the rotating screw to the deliquified product discharge section 8. During this process, deliquification occurs due to volume changes between the deliquified raw material inlet 5 and the deliquified product discharge section 8. The deliquified product B is in the form of a wet powder or wet lump and falls from the deliquified product discharge section 8 by its own weight or after being roughly crushed by collision with the back pressure plate 11. The compressed liquid C, which is the liquid component obtained by solid-liquid separation, is discharged through the holes in the filter cylinder 2 and recovered from the compressed liquid discharge section 7.

[0019] The screw shaft inlet temperature is preferably 100 to 160° C., more preferably 110 to 150° C., and even more preferably 115 to 145° C. If the screw shaft inlet temperature is less than 100° C., purified L-HPC with a moisture content of 50 to 60% by mass may not be obtained, whereas if it exceeds 160° C., L-HPC may dry, adhere, and solidify on the surface of the screw shaft, and the overdried adhered product may peel off irregularly and become mixed into the product as foreign matter, potentially causing a decrease in quality.

[0020] The compression ratio is preferably 1.1 to 2.0, more preferably 1.2 to 1.8, from the viewpoint of obtaining purified L-HPC with a low water content.

[0021] The straight length is preferably 100 to 150 mm, more preferably 120 to 150 mm, from the viewpoint of obtaining purified L-HPC with a low water content.

[0022] The back pressure is preferably 0 to 0.5 MPa, more preferably 0.1 to 0.4 MPa, from the viewpoint of obtaining purified L-HPC with a low water content. The opening of the back pressure plate is not particularly limited, but is preferably 20 mm or more from the viewpoint of the dischargeability of purified L-HPC.

[0023] The screw rotation speed is preferably 0.5 to 6 rpm, more preferably 1 to 4 rpm, from the viewpoint of obtaining purified L-HPC with a low water content while maintaining high production efficiency.

[0024] The water content of the purified L-HPC obtained after the deliquoring step is 50 to 60% by mass, preferably 50 to 57% by mass, and more preferably 50 to 55% by mass. If the water content of the purified L-HPC is less than 50% by mass, the deliquored product will be too hard and will have poor grindability, whereas if it exceeds 60% by mass, disintegrability will not improve.

[0025] [Drying and grinding process] Finally, the purified L-HPC is dried and then pulverized to obtain L-HPC. Drying is carried out using a dryer such as a tray dryer, a fluidized bed dryer, a grooved agitator dryer, a cylindrical agitator dryer, or a rotary dryer equipped with a steam pipe. The drying temperature is preferably 60 to 120°C, more preferably 80 to 100°C. The pulverization is carried out using an impact pulverizer such as a hammer mill, impact mill, or victory mill, or a compaction pulverizer such as a roller mill or ball mill. From the viewpoint of energy efficiency, an impact pulverizer is preferred. Furthermore, it is preferable to sieve the pulverized L-HPC by a standard method to remove insufficiently pulverized coarse powder. The sieve mesh size is preferably 45 to 250 μm, more preferably 75 to 150 μm.

[0026] [Low-substituted hydroxypropyl cellulose (L-HPC)] The degree of substitution of L-HPC obtained by the production method of the present invention will be described below. The hydroxypropoxy group content of L-HPC is 5 to 16% by mass, preferably 6 to 15% by mass, and more preferably 7 to 14% by mass. If the hydroxypropoxy group content is less than 5% by mass, the swelling property after water absorption will be low, while if it exceeds 16% by mass, the water solubility of L-HPC will be high, resulting in insufficient disintegration properties when used in solid preparations. The hydroxypropoxy group content can be measured by the quantitative method listed in the section on "Low-substituted hydroxypropyl cellulose" in the 18th edition of the Japanese Pharmacopoeia.

[0027] The volume-based average particle size of L-HPC measured by dry laser diffraction is preferably 10 to 100 μm, more preferably 30 to 80 μm, and even more preferably 40 to 70 μm, from the viewpoints of disintegration and binding properties. The average particle size refers to the diameter corresponding to the 50% cumulative value of the volume-based cumulative distribution curve, and can be measured, for example, using a laser diffraction particle size distribution analyzer, Mastersizer 3000 (manufactured by Malvern).

[0028] From the viewpoint of fluidity and binding properties, the bulk density of L-HPC is preferably 0.2 to 0.6 g / mL, more preferably 0.3 to 0.5 g / mL. The bulk density of L-HPC can be measured by the method described in the 18th Edition of the Japanese Pharmacopoeia, Section 3.01, "Measurement of Bulk Density and Tapped Density," Section 1.3, "Method Using a Container." For example, the measurement can be performed using a powder property evaluation device, Powder Tester Model PT-S (manufactured by Hosokawa Micron Corporation).

[0029] The binding strength of L-HPC is preferably 100 N or more, more preferably 150 N or more, from the viewpoint of tablet hardness or the occurrence of capping. Here, the binding property of L-HPC refers to the hardness of a tablet produced by compressing 450 mg of L-HPC, which has been conditioned to a loss on drying (moisture content) of 2.8 to 3.8% by mass, in a single-punch tablet press using a 12 mm diameter circular flat punch at a tableting pressure of 10.0 kN (approximately 88.5 MPa). The loss on drying of L-HPC can be measured by the method described in the section "General Test Methods: Loss on Drying Test Method" of the 18th Edition of the Japanese Pharmacopoeia. The hardness of a tablet can be measured by applying a load at a constant rate in the diametric direction of the tablet and measuring the maximum breaking strength when the tablet breaks, for example, using a tablet hardness tester TBH 125 (manufactured by ERWEKA).

[0030] From the viewpoint of disintegration, the swelling power of L-HPC is preferably 54 N or more, more preferably 56 N or more. The upper limit is not particularly limited, but is 100 N. The higher the swelling power, the shorter the disintegration time of tablets or granules and the more rapidly the drug is released, resulting in superior efficacy. The swelling power can be measured, for example, using a texture analyzer TA-XT plus (manufactured by Stable Micro Systems). Details of the measurement method are described in the Examples.

[0031] Next, we will explain how to produce tablets by wet granulation using L-HPC as a disintegrant. For example, L-HPC, an excipient such as lactose, a binder such as hydroxypropyl methylcellulose, and an active ingredient such as a drug used in pharmaceuticals are charged into a wet agitation granulator, water is added, and the mixture is granulated. The granules are then dried using a fluidized bed dryer to obtain granules. Subsequently, a lubricant such as magnesium stearate is mixed with the granules, and the mixture is compressed at a predetermined pressure using a tablet press such as a rotary tablet press to produce tablets.

[0032] The average particle size of the granulated product varies depending on the application, but when used for tablets, from the viewpoints of tableting properties and tablet mass variation, it is preferably 60 to 300 μm, more preferably 70 to 200 μm, and even more preferably 80 to 150 μm. The average particle size of the granulated product can be measured using a laser diffraction particle size distribution analyzer (Mastersizer 3000, manufactured by Malvern) by a dry method according to the Fraunhofer diffraction theory, at a dispersion pressure of 2 bar and a scattering intensity of 2 to 10%, as the diameter corresponding to the 50% cumulative value on the volume-based cumulative particle size distribution curve. The bulk density of the granulated product is preferably 0.2 to 0.7 g / mL, more preferably 0.3 to 0.6 g / mL, from the viewpoint of tableting properties and tablet mass variation. Here, the bulk density of the granulated product can be measured by the method described in Section 3.01, "General Test Methods for Bulk Density and Tapped Density Measurement, 1.3, Method 3 (Method Using a Container)" of the 18th Edition of the Japanese Pharmacopoeia. For example, it can be measured using a powder property evaluation device, Powder Tester Model PT-S (manufactured by Hosokawa Micron Corporation).

[0033] The tablet hardness is preferably 60 to 300 N, more preferably 80 to 200 N, from the viewpoint of preventing cracking or chipping during filling, transportation, or when the tablet is removed from the PTP sheet. The tablet hardness can be measured using a tablet hardness tester (TBH 125, manufactured by ERWEKA) by applying a load in the diameter direction of the tablet at a rate of 1 mm / sec and measuring the maximum breaking strength when the tablet breaks. From the viewpoint of efficacy, the disintegration time of the tablet is preferably within 90 seconds, more preferably within 85 seconds. The disintegration time of the tablet can be measured using a disintegration tester (NT-400, manufactured by Toyama Sangyo Co., Ltd.) in accordance with the disintegration test method of the 18th Edition of the Japanese Pharmacopoeia (test liquid: water, no auxiliary disc). [Example]

[0034] EXAMPLES The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0035] Example 1 The wood-derived sheet pulp was immersed in a 43% by mass aqueous solution of sodium hydroxide at 35°C for 5 seconds, and then squeezed to remove excess sodium hydroxide solution, yielding alkali cellulose containing 22.0% by mass of sodium hydroxide (the mass ratio of sodium hydroxide to anhydrous cellulose in the alkali cellulose was 0.479). This alkali cellulose was pulverized using a slitter cutter, and 100 parts by mass of anhydrous cellulose was charged into an internally stirred pressure reactor. After the atmosphere inside the reactor was thoroughly replaced with nitrogen gas, 27 parts by mass of propylene oxide was charged and reacted at 50°C for 3 hours to obtain a reaction product. Next, 500 parts by mass of 45°C warm water and 18.0 parts by mass of acetic acid (25% of the neutralization equivalent) were placed in a kneader, and 100 parts by mass of the reaction product as anhydrous cellulose was dispersed therein. The mixture was then mixed at a jacket temperature of 45°C for 40 minutes to dissolve a portion of the L-HPC. After that, 53.9 parts by mass of acetic acid (75% of the neutralization equivalent) was added to completely neutralize the mixture, and crude L-HPC was precipitated. Next, 100 parts by mass of crude L-HPC was mixed with 1,900 parts by mass of hot water at approximately 90°C and dehydrated using a vacuum filter. After that, 1,900 parts by mass of hot water at approximately 90°C was added, and the mixture was mixed again and dehydrated in the same manner. This dispersion and dehydration procedure was repeated three times to wash the crude L-HPC, yielding washed L-HPC with a water content of 89.8% by mass. Next, the washed L-HPC was deliquored using a screw press (SHX-200, manufactured by Fukoku Kogyo Co., Ltd.) under the following conditions: screw shaft inlet temperature 120°C (steam was supplied at a vapor pressure of 0.1 MPa), compression ratio 1.47, straight length 130 mm, back pressure 0.3 MPa, back pressure plate opening 20 mm, and screw rotation speed 2 rpm, to obtain purified L-HPC with a water content of 58.5% by mass. The purified L-HPC was then dried in a tray dryer at 80°C for 18 hours, and the dried product was crushed in an impact crusher (Victory Mill VP-1, manufactured by Hosokawa Micron Corporation) and sieved through a sieve with 90 μm openings to obtain L-HPC. The hydroxypropoxy group content of the obtained L-HPC was measured, and the average particle size, bulk density, binding ability, and swelling power were measured as described below. The results are shown in Table 1.

[0036] <Measurement of average particle size> The average particle diameter was measured using a laser diffraction particle size distribution analyzer, Mastersizer 3000 (manufactured by Malvern), in a dry method according to the Fraunhofer diffraction theory, at a dispersion pressure of 2 bar and a scattering intensity of 2 to 10%, as the diameter corresponding to the 50% cumulative value on the volume-based cumulative distribution curve.

[0037] <Measurement of bulk density> The bulk density was measured using a powder property evaluation device, Powder Tester PT-S Model (manufactured by Hosokawa Micron Corporation), in accordance with the method described in the section "General Test Methods 3.01 Bulk Density and Tapped Density Measurement Method 1.3 Method 3 (Method Using a Container)" of the 18th Edition of the Japanese Pharmacopoeia.

[0038] <Binding Measurement> The binding strength was evaluated by storing L-HPC in a desiccator (relative humidity: approximately 11%) at 25°C containing saturated aqueous lithium chloride solution for one week to adjust the moisture content to 2.8 to 3.8% by mass. After that, the L-HPC was compressed into 450 mg tablets at a tableting pressure of 10 kN (approximately 88.5 MPa) using a tabletop tablet press HANDTAB-200 (Ichihashi Seiki Co., Ltd.) equipped with a 12 mm diameter circular flat punch. The hardness of the tablets was measured using a tablet hardness tester TBH 125 (ERWEKA) by applying a load in the diameter direction of the tablet at a rate of 1 mm / sec, and the maximum breaking strength at which the tablet broke was measured.

[0039] <Measurement of swelling force> To measure the swelling force, we used a swelling force measuring jig 20 manufactured in-house, as shown in Figure 2. The swelling force measuring jig is composed of a first acrylic tube 21, a second acrylic tube 22, and an 18-mesh (opening size 850 μm) plain woven wire mesh 23. The first acrylic tube 21 had an inner diameter of 26 mm, an outer diameter of 30 mm, and a length of 60 mm. The second acrylic tube 22 had an inner diameter of 26 mm, an outer diameter of 30 mm, and a length of 10 mm, and had four 4 mm diameter circular holes 24 drilled on the side and four 8 mm diameter semicircular grooves 25 on the bottom, as shown in Figure 2. The 18 mesh (opening size 850 μm) plain woven wire mesh 23 was cut into a circle with a diameter of 31 mm. A swelling force measuring jig was prepared by sandwiching an 18 mesh (opening size: 850 μm) plain woven wire mesh 23 between a first acrylic tube 21 and a second acrylic tube 22, and bonding them together with adhesive applied from the outside. Fig. 3 shows a method for measuring swelling force using the swelling force measuring jig 20 shown in Fig. 2. The swelling force was measured using a texture analyzer TA-XT plus (manufactured by Stable Micro Systems) 32. The swelling force measuring jig 20 was placed in the center of a stainless steel Petri dish 31 (outer diameter 75 mm, inner diameter 74 mm, height 20 mm). Filter paper 34 (diameter 25.5 mm), sample 35 (1.00 g), and measurement probe 36 (25 mm Cyl. Perspex) were placed on wire mesh 23 of jig 20. Calibration was performed by applying a 1000 g load three times. Measurement was then started under the conditions of measurement program HLDD, pretest speed 2.0 mm / sec, test speed 1.0 mm / sec, force 20 g, and trigger force 5 g. 25°C water 33 was poured up to near the interface between sample 35 and measurement probe 36. The time when the sample began to absorb water was defined as 0 minutes, and the value after 10 minutes was measured as the swelling force. Each measurement was carried out three times, and the average value and standard deviation were calculated.

[0040] Using the L-HPC obtained above, granules and tablets were prepared by the wet stirring granulation and tableting method described below, and various physical properties were measured. 210 g (70 parts by weight) of acetaminophen (fine powder grade, Yamamoto Chemical Industry Co., Ltd.) as the active ingredient, 66 g (22 parts by weight) of lactose (Pharmatose 200M, DFE Pharma) as the excipient, 15 g (5 parts by weight) of L-HPC as the disintegrant, and 9 g (3 parts by weight) of hydroxypropyl methylcellulose as the binder were charged into a wet agitation granulator (VG-05, Powrex Corporation) and premixed for 1 minute at a main blade rotation speed of 450 rpm and a cross screw rotation speed of 3000 rpm. Subsequently, 57 g (19 parts by weight) of water was added to the same apparatus, and the mixture was kneaded for 5 minutes at a main blade rotation speed of 450 rpm and a cross screw rotation speed of 3000 rpm. The mixture was then sieved through a JIS test sieve with 1 mm openings to obtain a wet granule. This was placed in a fluidized bed granulation dryer (Multiplex MP-01, manufactured by Powrex Corporation) and dried at an intake air temperature of 80°C and an air volume of 0.6 to 0.8 m 3The mixture was dried at a rate of 1 / min until the exhaust temperature reached 45°C, and then sieved through a JIS test sieve with 500 µm openings to obtain granules. The average particle size and bulk density of the obtained granules are shown in Table 1. Next, 200 g (100 parts by mass) of the resulting granules were mixed with 1.0 g (0.5 parts by mass) of magnesium stearate (vegetable grade, manufactured by Taihei Chemical Industry Co., Ltd.) as a lubricant, and compressed using a rotary tablet press VIRGO (manufactured by Kikusui Seisakusho) at a tableting pressure of 12.0 kN (approximately 239 MPa) and a tableting speed of 20 rpm to obtain tablets with a diameter of 8 mm, a curvature radius of 12 mm, and a tablet mass of 200 mg. The tablet hardness and disintegration time of the resulting tablets were measured for six tablets each, and the average values ​​and standard deviations are shown in Table 1.

[0041] Example 2 L-HPC was obtained in the same manner as in Example 1, except that the screw press operating conditions were changed to a screw shaft inlet temperature of 133°C (steam was supplied at a steam pressure of 0.2 MPa) to obtain purified L-HPC with a water content of 53.3% by mass. The hydroxypropoxy group content, average particle size, bulk density, binding ability, and swelling power of the obtained L-HPC were measured in the same manner as in Example 1. The results are shown in Table 1. Next, the L-HPC obtained above was used to perform wet granulation in the same manner as in Example 1 to obtain a granulated product. The average particle size and bulk density of the obtained granulated product were measured in the same manner as in Example 1. The results are shown in Table 1. Subsequently, the granules obtained above were used to obtain tablets by tableting in the same manner as in Example 1. The tablet hardness and disintegration time of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

[0042] Example 3 L-HPC was obtained in the same manner as in Example 2, except that the operating conditions of the screw press were changed to a straight length of 150 mm to obtain purified L-HPC with a water content of 50.4% by mass. The hydroxypropoxy group content, average particle size, bulk density, binding ability, and swelling power of the obtained L-HPC were measured in the same manner as in Example 1. The results are shown in Table 1. Next, the L-HPC obtained above was used to perform wet granulation in the same manner as in Example 1 to obtain a granulated product. The average particle size and bulk density of the obtained granulated product were measured in the same manner as in Example 1. The results are shown in Table 1. Subsequently, the granules obtained above were used to obtain tablets by tableting in the same manner as in Example 1. The tablet hardness and disintegration time of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

[0043] Example 4 100 parts by mass of wood-derived powdered pulp as anhydrous cellulose was charged into an internally stirred pressure reactor, and while mixing, 75 parts by mass of a 35% by mass aqueous sodium hydroxide solution was charged. The mixture was mixed for 30 minutes at a jacket temperature of 45°C to obtain alkali cellulose containing 15.0% by mass of sodium hydroxide (the mass ratio of sodium hydroxide to anhydrous cellulose in the alkali cellulose was 0.281). Next, the inside of the vessel was thoroughly purged with nitrogen gas, and then 19 parts by mass of propylene oxide was charged, and the mixture was reacted for 2 hours with stirring at a jacket temperature of 60°C to obtain a reaction product. Next, 350 parts by mass of 45°C warm water and 12.6 parts by mass of acetic acid (30% of the neutralization equivalent) were placed in a kneader, and 100 parts by mass of the reaction product as anhydrous cellulose was dispersed therein. The mixture was then mixed at a jacket temperature of 45°C for 40 minutes to dissolve a portion of the L-HPC. After that, 29.5 parts by mass of acetic acid (70% of the neutralization equivalent) was added to completely neutralize the mixture, and crude L-HPC was precipitated. Subsequently, the crude L-HPC was washed in the same manner as in Example 1 to obtain washed L-HPC with a water content of 89.0 mass %. Next, the washed L-HPC was dehydrated in the same manner as in Example 2 to obtain purified L-HPC with a water content of 54.0% by mass, and then L-HPC was obtained in the same manner as in Example 1. The hydroxypropoxy group content of the obtained L-HPC was measured, and the average particle size, bulk density, binding ability, and swelling power were measured as described below. The results are shown in Table 1. Next, using the L-HPC obtained above, wet granulation was carried out in the same manner as in Example 1, except that the amount of water added was 60 g (20 parts by mass), to obtain a granulated product. The average particle size and bulk density of the obtained granulated product were measured in the same manner as in Example 1. The results are shown in Table 1. Subsequently, the granules obtained above were used to obtain tablets by tableting in the same manner as in Example 1. The tablet hardness and disintegration time of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

[0044] Comparative Example 1 L-HPC was obtained in the same manner as in Example 1, except that the washed L-HPC was dehydrated using a V-type disc press (Asahi Press C-25, manufactured by Asahi Koki Co., Ltd.) instead of the screw press to obtain purified L-HPC with a water content of 77.9% by mass. The hydroxypropoxy group content, average particle size, bulk density, binding ability, and swelling power of the obtained L-HPC were measured in the same manner as in Example 1. The results are shown in Table 1. Next, the L-HPC obtained above was used to perform wet granulation in the same manner as in Example 4 to obtain a granulated product. The average particle size and bulk density of the obtained granulated product were measured in the same manner as in Example 1. The results are shown in Table 1. Subsequently, the granules obtained above were used to obtain tablets by tableting in the same manner as in Example 1. The tablet hardness and disintegration time of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

[0045] Comparative Example 2 L-HPC was obtained in the same manner as in Example 1, except that the screw press operating conditions were changed to a screw shaft inlet temperature of 90°C (hot water was supplied) and a screw rotation speed of 3 rpm to obtain purified L-HPC with a water content of 66.1% by mass. The hydroxypropoxy group content, average particle size, bulk density, binding ability, and swelling power of the obtained L-HPC were measured using the same methods as in Example 1. The results are shown in Table 1. Next, the L-HPC obtained above was used to perform wet granulation in the same manner as in Example 4 to obtain a granulated product. The average particle size and bulk density of the obtained granulated product were measured in the same manner as in Example 1. The results are shown in Table 1. Subsequently, the granules obtained above were used to obtain tablets by tableting in the same manner as in Example 1. The tablet hardness and disintegration time of the obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.

[0046] [Table 1]

[0047] To more accurately evaluate the performance of L-HPC as a disintegrant, it is preferable to make the physical properties (average particle size and bulk density) of the granules uniform, so the amount of water added during wet agitation granulation was finely adjusted. That is, in Examples 1 to 3, 19 parts by mass of water was added per 100 parts by mass of the charged powder, and in Comparative Examples 1, 2, and Example 4, 20 parts by mass of water was added and wet agitation granulation was performed, thereby obtaining granules with approximately the same average particle size and bulk density.

[0048] Examples 1 to 4, in which the water content of purified L-HPC was 50 to 60% by mass, had similar hydroxypropoxy group contents, average particle sizes, and bulk densities to those of Comparative Examples 1 and 2, in which the water content of purified L-HPC exceeded 60% by mass, and maintained good binding properties of 150 N or more. However, surprisingly, the swelling force increased to 54 N or more. It was revealed that the increased swelling force improved the disintegration time of the tablets to 90 seconds or less, even though the tablet hardness was similar, demonstrating excellent disintegrability. The mechanism behind the increase in swelling force has not yet been clarified. Furthermore, Examples 1 to 3 show that the lower the moisture content of purified L-HPC, the greater the swelling force and the shorter the disintegration time of the tablets. Furthermore, Example 4, which used powdered pulp as the raw material, shows that when the moisture content of purified L-HPC is 50 to 60 mass%, the swelling force is 54 N or more and the disintegration time is 90 seconds or less, regardless of the shape of the raw material pulp. [Explanation of symbols]

[0049] 1. Screw press 2 Filter cylinder 3 screw blades 4 screw shaft 5 Dehydrated raw material input section 6 Temperature control liquid inlet 7. Squeezed liquid discharge section 8 Dehydrated product discharge section 9 Air Cylinder 10 Temperature control liquid outlet 11 Back pressure plate 12 Straight section A. Crude L-HPC and water mixture or washed L-HPC B Dehydrated product (purified L-HPC) C. Pressed liquid D Temperature control liquid to be added E Discharged temperature control liquid 20 Swelling force measurement jig 21 First Acrylic Tube 22 Second acrylic tube 23 18 mesh (opening 850 μm) plain woven wire mesh 24 Circular hole 25 Semicircular groove 31 Stainless steel petri dish 32 Texture Analyzer 33 water 34 filter paper 35 samples 36 Measuring Probes

Claims

1. contacting the pulp with an alkali metal hydroxide solution to obtain alkali cellulose; reacting the alkali cellulose with propylene oxide to obtain a reaction product; a step of dispersing the reaction product in water containing at least an acid, partially dissolving the reaction product, and then neutralizing the resulting solution with an acid to precipitate crude low-substituted hydroxypropyl cellulose; a step of deliquoring the crude low-substituted hydroxypropyl cellulose using a screw press to obtain purified low-substituted hydroxypropyl cellulose having a water content of 50 to 60% by mass; drying and pulverizing the purified low-substituted hydroxypropyl cellulose; A method for producing low-substituted hydroxypropyl cellulose having a hydroxypropoxy group content of 5 to 16 mass %, which contains at least

2. 2. The method for producing low-substituted hydroxypropyl cellulose according to claim 1, wherein the screw shaft inlet temperature of the screw press is 100 to 160°C.

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