Hydroxypropyl methylcellulose phthalate and composition for hot melt extrusion

Abstract

To provide hydroxypropylmethylcellulose phthalate (HPMCP) which is excellent in flowability.SOLUTION: There are provided hydroxypropylmethylcellulose phthalate in which a volume fraction of spherical particles is 70.0% or more with respect to all the particles, when all the particles are classified into fine particles, spherical particles and fibrous particles by a dynamin image analysis method, wherein the spherical particles are composed of first spherical particles having a fiber length of 40 μm or more and an extension ratio that is a ratio between a fiber diameter and the fiber length of 0.5 or more, and second spherical particles having an extension ratio of less than 0.5 and an aspect ratio that is a ratio between a minimum Feret diameter and a maximum Feret diameter of 0.5 or more, and circularity that is a ratio between a peripheral length (PEQPC) of a circle having a same area as a projection area of the particles and a peripheral length (Preal) of actual particles of 0.7 or more.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to hydroxypropyl methylcellulose phthalate, a method for producing the same, and a composition for hot-melt extrusion. [Background technology]

[0002] Hydroxypropyl methylcellulose phthalate (hereinafter referred to as "HPMCP") is a methoxy group (-OCH 3 ), hydroxypropoxy group (-OC 3 H 6 OH) and carboxybenzoyl group (-COC 6 H 4 It is a cellulose derivative having the formula (COOH) and is produced by chemically modifying cellulose.

[0003] HPMCP is widely used, particularly in the pharmaceutical field, for example as an enteric polymer base for coating applications and for use in solid dispersions together with poorly water-soluble drugs.

[0004] Examples of methods for producing HPMCP include a method for producing a carboxylate-based cellulose derivative, which comprises carrying out an ester reaction between celluloses and a polyvalent carboxylic anhydride in an acetic acid solvent using an alkali metal carboxylate as a catalyst, using an amount of acetic acid solvent that is 1 to 2 times the weight of the celluloses, and stirring with a biaxial stirrer (Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 5-339301 Summary of the Invention [Problem to be solved by the invention]

[0006] In conventional methods for producing HPMCP, such as those described in Patent Document 1, water is added to a reaction solution to obtain a suspension in which HPMCP precipitates, and the HPMCP in the suspension is washed with water to remove impurities. The suspension contains a large amount of acetic acid, which was used as a solvent in the esterification reaction step. Acetic acid contained in the water used for washing is difficult to recover and is therefore discarded together with the water, but this causes an increase in the chemical oxygen demand (COD) of wastewater. Acetic acid also causes a decrease in the pH of the wastewater, and furthermore, acetic acid also causes odors. Therefore, when a suspension containing a large amount of acetic acid is subjected to a washing and recovery step, the water used for washing needs to be subjected to wastewater treatment such as biological treatment, and in order to reduce the load of wastewater treatment, it is desirable that the amount of acetic acid in the mixture subjected to the washing and recovery step is small.

[0007] In order to reduce the amount of acetic acid in the mixture to be subjected to the washing and recovery step, it may be possible to reduce the amount of acetic acid used in the esterification reaction step. However, as described in Patent Document 1, when the amount of acetic acid used is reduced, it may become difficult to uniformly dissolve celluloses at a high concentration in the acetic acid solvent. As described above, there is room for improvement in the conventional manufacturing method of HPMCP. In addition, there is room for improvement in the flowability of conventional HPMCP, in terms of handling issues such as clogging of the hopper, and hygiene issues caused by HPMCP remaining inside the hopper or piping. [Means for solving the problem]

[0008] As a result of extensive investigations aimed at solving the above problems, the present inventors have found that by removing acetic acid from a reaction solution containing HPMCP, the amount of acetic acid in the mixture subjected to the washing and recovery step can be reduced, and furthermore, HPMCP having excellent fluidity can be efficiently produced, thereby completing the present invention. In one embodiment of the present invention, there is provided hydroxypropyl methylcellulose phthalate, in which when all particles are classified into fine particles, spherical particles, and fibrous particles by dynamic image analysis, the volume fraction of the spherical particles to the total particles is 70.0% or more, The fine particles are particles having a fiber length of less than 40 μm, and the spherical particles are first spherical particles having a fiber length of 40 μm or more and an elongation ratio, which is a ratio of fiber diameter to fiber length, of 0.5 or more, and second spherical particles having an elongation ratio of less than 0.5, an aspect ratio, which is a ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5 or more, and a perimeter (P EQPC ) and the actual particle perimeter (P real and second spherical particles having a circularity of 0.7 or more, which is the ratio of the length of the fibrous particles to the length of the spherical particles, the fibrous particles being composed of long fibrous particles and short fibrous particles, the long fibrous particles being composed of first long fibrous particles having a fiber length of 200 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second long fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7, and the short fibrous particles being composed of first short fibrous particles having a fiber length of 40 μm or more and less than 200 μm, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second short fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7. Effect of the Invention

[0009] According to the present invention, since at least a part of acetic acid is removed from the reaction solution containing HPMCP, the amount of acetic acid in the mixture to be subjected to the washing and recovery step can be reduced, which is expected to reduce the burden on wastewater treatment, and the cost can be reduced by reusing the removed acetic acid. In addition, HPMCP with excellent flowability can be produced, which can improve the mixing uniformity of HPMCP and a drug in a composition for hot-melt extrusion and the formation of bridges in a hopper for a mixed powder of HPMCP and a drug, and is expected to improve the uniformity of the drug content, the mass ratio of HPMCP to the drug, and enable fixed-volume supply and continuous operation. [Brief description of the drawings]

[0010]

Figure 1

[0011] First, an esterification reaction step in which acetic acid is used as a solvent in the production method of HPMCP, and a reaction solution containing HPMCP is obtained by an esterification reaction between hydroxypropylmethylcellulose and phthalic anhydride will be described.

[0012] Hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") is a non-ionic water-soluble cellulose ether. The HPMC may be synthesized by a known method or may be commercially available. From the viewpoint of obtaining HPMC with a low number of undissolved fibers, the DS of the methoxy group in HPMC is preferably 1.10 to 2.20, more preferably 1.30 to 2.10, even more preferably 1.60 to 2.00, and particularly preferably 1.80 to 2.00. From the viewpoint of obtaining HPMC with a low number of undissolved fibers, the MS of the hydroxypropoxy group in HPMC is preferably 0.10 to 1.00, more preferably 0.10 to 0.80, even more preferably 0.15 to 0.60, and particularly preferably 0.20 to 0.50. The DS of the methoxy group in HPMC represents the degree of substitution, and refers to the average number of methoxy groups per unit of anhydrous glucose. The MS of the hydroxypropoxy group in HPMC represents the molar substitution, and refers to the average number of moles of hydroxypropoxy groups per mole of anhydrous glucose. The DS of the methoxy group and the MS of the hydroxypropoxy group in HPMC can be calculated by converting the values ​​obtained by measuring according to the 17th Edition of the Japanese Pharmacopoeia.

[0013] From the viewpoint of kneadability in the esterification reaction step, the viscosity of a 2% by mass aqueous solution of HPMC at 20° C. is preferably 1.0 to 30.0 mPa s, and more preferably 2.0 to 20.0 mPa s. The viscosity of a 2% by mass aqueous solution of HPMC at 20° C. can be measured using an Ubbelohde viscometer by the method described in the “Hypromellose” section of the Japanese Pharmacopoeia, 17th Edition.

[0014] The amount of acetic acid used is preferably 3.5 to 10.0 mol, more preferably 4.5 to 7.0 mol, and even more preferably 5.0 to 6.5 mol, per mol of HPMC, from the viewpoint of dissolving HPMC and increasing the reaction rate.

[0015] The amount of phthalic anhydride used is not particularly limited as long as HPMCP having the desired degree of substitution is obtained, but from the viewpoint of reaction efficiency, it is preferably 0.2 to 3.0 mol, more preferably 0.4 to 1.8 mol, per mol of HPMC.

[0016] The esterification reaction may be carried out in the presence of a catalyst. From an economical viewpoint, the catalyst is preferably an alkali metal carboxylate such as sodium acetate. The catalyst may be used alone or in combination of two or more kinds, as necessary. In addition, a commercially available catalyst may be used. The amount of the catalyst used may be selected arbitrarily taking into consideration the degree of substitution of HPMCP, but from the viewpoint of reaction efficiency, it is preferably 0.1 to 3.0 mol, more preferably 0.3 to 2.0 mol, per mol of HPMC.

[0017] The esterification reaction may be carried out in the presence of a depolymerization agent. From an economical viewpoint, the depolymerization agent is preferably an alkali metal chlorate such as sodium chlorate. The depolymerization agent may be used alone or in combination of two or more kinds, as required. The depolymerization agent may be a commercially available product. The amount of the depolymerization agent used may be arbitrarily selected taking into consideration the desired degree of polymerization of HPMCP, but from the viewpoint of preventing a significant decrease in viscosity, it is preferably 0.01 to 0.20 mol, more preferably 0.02 to 0.10 mol, per mol of HPMC.

[0018] From the viewpoint of reaction efficiency, the esterification reaction is preferably carried out using a kneader reactor or the like. From the viewpoint of reaction rate, the reaction temperature in the esterification reaction step is preferably 60 to 120° C., more preferably 60 to 100° C. The reaction time in the esterification reaction step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of obtaining HPMCP with a desired degree of substitution.

[0019] Next, the water-adding step of adding water to the reaction solution containing HPMCP to obtain a water-added reaction solution will be described. By carrying out the water addition step, unreacted phthalic anhydride can be treated. The amount of water added is preferably an amount that does not cause HPMCP to precipitate, from the viewpoint of preventing a decrease in transportability due to precipitation of HPMCP, and specifically, is preferably 250 parts by mass or less, more preferably 1 to 200 parts by mass, and even more preferably 3 to 190 parts by mass, relative to 100 parts by mass of the starting material HPMC used in the esterification reaction. The temperature of the HPMCP-containing reaction solution to which water is added is preferably 60 to 100° C., from the viewpoint of performing an acetic acid removal step successively after the addition of water.

[0020] Next, an acetic acid removal step for obtaining a mixture having a reduced acetic acid content by removing at least a part of the acetic acid from the water-added reaction solution will be described. When sodium acetate is used as a catalyst, the following equilibrium is reached, and acetic acid derived from sodium acetate is not taken into consideration. CH 3 COONa+CH 3 COOH = CH 3 COOH+CH 3 COONa

[0021] The method for removing at least a portion of the acetic acid from the water-added reaction solution is not particularly limited, but from the viewpoint of efficiently removing and recovering acetic acid, it is preferable that the acetic acid removal step includes evaporating and recovering the acetic acid under heating and reduced pressure while stirring the water-added reaction solution. The acetic acid removal step can be carried out, for example, using an apparatus capable of stirring a highly viscous water-added reaction solution, and capable of ensuring a sealed state in which heating and decompression or decompression can be performed. Examples of the apparatus include a reactor capable of heating and decompression equipped with a rotating agitator blade, a reactor capable of heating and decompression equipped with a rotating and revolving agitator blade, and the like. A preferred example is a reactor capable of heating and decompression equipped with a rotating and revolving agitator blade, such as a 5L vertical kneader reactor (Trimix TX-5 type, manufactured by Inoue Seisakusho Co., Ltd.) having three frame-shaped agitator blades that revolve while rotating. From the viewpoint of uniformity of agitation in the acetic acid removal step, the peripheral speed of the rotating motion of one agitator blade is preferably 0.01 to 2.00 m / s. When the revolving motion is also used, the peripheral speed of the revolving motion of one agitator blade is preferably 0.001 to 2.00 m / s. In this specification, the "circumferential speed in the rotational motion" refers to the speed of the fastest part of one agitator blade that rotates on its own axis (i.e., the outermost periphery of one agitator blade) in the device used. The "circumferential speed in the revolutionary motion" refers to the speed of the fastest part of one agitator blade that revolves on its own axis (i.e., the outermost periphery of one agitator blade) in the device used.

[0022] The acetic acid removal temperature in the acetic acid removal step is preferably 60 to 100° C. from the viewpoint of evaporating acetic acid. The degree of reduced pressure in the acetic acid removal step is preferably −0.10 to −0.02 MPaG from the viewpoint of evaporating acetic acid. The reduced pressure in the acetic acid removal step can be performed using an aspirator or the like. The acetic acid removal time in the acetic acid removal step is preferably 0.1 to 5 hours from the viewpoint of productivity.

[0023] The evaporated acetic acid can be recovered by a cold trap or the like connected to the device. The cold trap is preferably cooled by ice cooling or the like. The recovered acetic acid may contain water.

[0024] The ratio of the acetic acid removed in the acetic acid removal step to the acetic acid added as a solvent is called the acetic acid removal rate. From the viewpoint of the fluidity of HPMCP, the acetic acid removal rate is preferably 10.0% or more, more preferably 20.0 to 95.0%, further preferably 40.0 to 90.0%, and particularly preferably 70.0 to 85.0%. In addition, the removal rate of acetic acid in the acetic acid removal step is defined by the following formula, taking into consideration that the removed acetic acid is a mixture diluted with water or the like added in the water addition step. Acetic acid removal rate (%) = {(C × D / 100) / A} × 100 In the formula, "A" represents the mass ratio of acetic acid used as a solvent to the starting material HPMC, "C" represents the mass ratio of the recovered material containing acetic acid (including water added in the water addition step) to the starting material HPMC, and "D" represents the concentration of acetic acid in the recovered material containing acetic acid (including water added in the water addition step).

[0025] The mixture with a reduced acetic acid content to be subjected to the washing and recovery step is preferably in a solid state from the viewpoint of the fluidity of HPMCP. When the mixture with a reduced acetic acid content is in a high viscosity liquid state or the like, a solid mixture can be obtained by cooling it to room temperature.

[0026] Between the acetic acid removal step and the washing and recovery step described below, from the viewpoint of efficiently washing the mixture having a reduced content of solid acetic acid, a crushing step may be carried out in which the solid mixture is crushed to obtain a crushed mixture having a reduced content of acetic acid. The grinding can be carried out using a grinder, which may include high-speed rotary grinders such as a hammer mill or a pin mill, high-shear devices such as a homomixer or a high-shear mill, roll grinders such as a roller mill, media grinders such as a vibration mill or a planetary mill, and fluid grinders such as a jet mill. In the case where the mixture with the reduced acetic acid content is a non-sticky solid, the pulverization may be performed as it is (dry pulverization), or in the case where the mixture with the reduced acetic acid content is a sticky solid, water may be added to the mixture before pulverization (wet pulverization). In general, when the mixture with the reduced acetic acid content is in a solid state, the removal rate of acetic acid is high, and the lower the acetic acid content, the weaker the adhesion. From the viewpoint of the pulverization property of HPMCP, the temperature of the water to be added is preferably 5 to 40°C. The amount of water to be added is preferably 100 to 1000 parts by mass with respect to 100 parts by mass of the mixture from which the solid acetic acid has been removed.

[0027] Next, a washing and recovery step in which the mixture having a reduced acetic acid content is washed to recover hydroxypropyl methylcellulose phthalate will be described.

[0028] The washing and recovery method is not particularly limited, and examples include a method in which the mixture with a reduced acetic acid content is mixed with water to obtain a water-containing mixture, the water-containing mixture is subjected to centrifugation, filtration, decantation, or the like to obtain crude HPMCP, the obtained crude HPMCP is dispersed in water, stirred with a stirrer, and the water used for washing is separated by centrifugation, filtration, or the like; a method in which water is continuously poured over the mixture with a reduced acetic acid content or the crude HPMCP; and a method in which part of the liquid in the water-containing mixture is repeatedly replaced with water. The aqueous mixture of the mixture with a reduced acetic acid content and water is preferably in the form of a suspension from the viewpoint of cleaning properties.

[0029] From the viewpoint of efficiently removing impurities contained in the HPMCP, the temperature of the water used for washing is preferably 5 to 40° C. The amount of water used for washing varies depending on the washing method, but for example, when washing is performed after obtaining crude HPMCP by centrifugation or filtration, from the viewpoint of obtaining HPMCP with few impurities, the amount of water used is preferably 200 to 20,000 parts by mass per 100 parts by mass of the mixture with a reduced acetic acid content. The amount of water used for washing may be adjusted so as to be within the above range, together with the amount of water added in the water adding step.

[0030] The obtained HPMCP may be dried as necessary. From the viewpoint of preventing aggregation of HPMCP, the drying temperature is preferably 40 to 100° C., more preferably 40 to 80° C. From the viewpoint of preventing aggregation of HPMCP, the drying time is preferably 1 to 20 hours, more preferably 3 to 15 hours. The resulting HPMCP may be sieved, if necessary, to obtain a desired average particle size.

[0031] The viscosity at 20°C of a methanol / methylene chloride mixed solution (mass ratio 1:1) containing 10 mass% HPMCP is preferably 10.0 to 300.0 mPa s, more preferably 15.0 to 250.0 mPa s, and even more preferably 15.0 to 220.0 mPa s. The viscosity at 20°C of a methanol / methylene chloride mixed solution (mass ratio 1:1) containing 10 mass% HPMCP can be measured using an Ubbelohde viscometer by the method described in the "Hypromellose phthalate" section of each pharmaceutical article in the 17th edition of the Japanese Pharmacopoeia.

[0032] The DS of the methoxy group in HPMCP is preferably 1.10 to 2.20, more preferably 1.30 to 2.10, even more preferably 1.60 to 2.00, and most preferably 1.80 to 2.00. The MS of the hydroxypropoxy group in HPMCP is preferably 0.10 to 1.00, more preferably 0.10 to 0.80, even more preferably 0.15 to 0.60, and most preferably 0.20 to 0.50. The DS of the carboxybenzoyl group in HPMCP is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.40 to 0.80. The DS of the methoxy group and carboxybenzoyl group in HPMCP and the MS of the hydroxypropoxy group can be calculated from the values ​​obtained by the method described in the pharmaceutical articles "hypromellose" and "hypromellose phthalate" in the 17th revised Japanese Pharmacopoeia. The DS of the methoxy group and carboxybenzoyl group in HPMCP represents the degree of substitution, and refers to the average number of methoxy groups and carboxybenzoyl groups per unit of anhydrous glucose. The MS of the hydroxypropoxy group in HPMCP represents the molar substitution, and refers to the average number of moles of hydroxypropoxy groups per mole of anhydrous glucose.

[0033] The cumulative 50% particle size D in the particle size distribution of HPMCP 50 From the viewpoint of the flowability of HPMCP, the thickness is preferably 50 to 700 μm, more preferably 100 to 600 μm, and even more preferably 300 to 500 μm. The cumulative 90% particle size of the HPMCP particle size distribution D 90 and cumulative 10% particle size D 10 Particle size ratio (D 90 / D 10 From the viewpoint of the flowability of HPMCP, the particle size ratio (D 90 / D 10 ) represents the width of the particle size distribution. D in the particle size distribution of HPMCP 10 , D 50 , D 90 was measured at a dispersion pressure of 2 bar using a dry laser diffraction particle size distribution analyzer (Mastersizer 3000, Malvern Instruments). Dry laser diffraction particle size distribution analyzers are devices that eject a powder sample with compressed air, irradiate it with laser light, and measure the diameter of a volume-equivalent sphere based on the diffraction intensity. Examples of such devices include the Mastersizer manufactured by Malvern Instruments in the UK and the HELOS device manufactured by Sympatec in Germany.

[0034] From the viewpoint of handling, the loose bulk density of HPMCP is preferably 0.30 to 0.60 g / cm 3 , more preferably 0.35 to 0.55 g / cm 3 , and more preferably 0.40 to 0.53 g / cm 3 Loose bulk density refers to the bulk density in a loosely packed state, and is measured by uniformly dispensing a sample into a cylindrical container 5.03 cm in diameter and 5.03 cm in height (volume 100 mL) from 23 cm above, leveling the top surface, and weighing the sample.

[0035] The outflow rate of HPMCP, which can be measured by the outflow rate measurement method from an orifice described in the Reference Information of the Japanese Pharmacopoeia, 17th Edition, is preferably 1.50 to 3.50 g / sec, more preferably 1.60 to 3.00 g / sec, from the viewpoint of handling. As described in the Reference Information of the Japanese Pharmacopoeia, 17th Edition, the outflow rate is highly dependent on the measurement method used, so when comparing outflow rates, it is necessary to compare outflow rates measured under the same conditions. Details of the measurement conditions will be described in detail in the Examples.

[0036] In this specification, HPMCP is classified into four types of particles: "long fiber particles", "short fiber particles", "spherical particles" and "fine particles". Figure 1 shows a flow chart summarizing the method of classifying "total particles" of HPMCP into four types of particles: "fine particles", "long fiber particles (LF1 and LF2)", "short fiber particles (SF1 and SF2)" and "spherical particles (S1 and S2)". The volume fraction of each particle in HPMCP can be calculated by measuring the following shape parameters such as fiber length (LEFI), fiber diameter (DIFI), elongation ratio, aspect ratio and circularity by dynamic image analysis. Dynamic image analysis is a method of continuously taking images of particles dispersed in a fluid such as a gas or a solvent, and performing binary analysis to determine particle size and particle shape. For example, it can be measured using a dynamic image analysis type particle size distribution measuring device QICPIC / R16 (manufactured by Sympatec Co., Ltd.).

[0037] The total particles A are divided into particles C with a fiber length (Length of Fiber: LEFI) of 40 μm or more and fine particles B with a fiber length of less than 40 μm. LEFI is defined as the length between both ends of a particle, which is the longest path from one side of the particle outline to the other side. Note that the detection limit of the QICPIC / R16 equipped with the M7 lens is 4.7 μm, so particles less than 4.7 μm are not detected. However, the volume of particles with a LEFI less than 4.7 μm accounts for a very small proportion of the total volume of the HPMCP, so it can be ignored for the purposes of this invention.

[0038] Particle C with a LEFI of 40 μm or more has a fiber diameter ( Di ameter of Fi The elongation ratio, which is the ratio of fiber diameter (DIFI:DIFI) to LEFI (DIFI / LEFI), is 0.5 or more, and the elongation ratio (D) is less than 0.5. DIFI is defined as the short diameter of the particle and is calculated by dividing the projected area of ​​the particle by the sum of the lengths of all the fiber branches.

[0039] Particles D with a LEFI of 40 μm or more and an elongation ratio of less than 0.5 are divided into particles E with an aspect ratio, which is the ratio (Fmin / Fmax) of the minimum Feret diameter (Fmin) to the maximum Feret diameter (Fmax), of less than 0.5, and particles F with an aspect ratio of 0.5 or more. The aspect ratio of all particles is greater than 0 and less than 1. The Feret diameter is the distance between two parallel tangents that sandwich a particle, and the maximum Feret diameter (Fmax) is the distance between two tangents that sandwich a particle, and is greater than 0. o From 180 o The minimum Feret diameter (Fmin) is the distance between the two tangents that sandwich the particle, and is 0 o From 180 o This refers to the minimum diameter when the direction is changed to the maximum.

[0040] Fibrous particles E having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5 are divided into first long fibrous particles (LF1) having a LEFI of 200 μm or more and first short fibrous particles (SF1) having a LEFI of less than 200 μm.

[0041] Particles F with LEFI of 40 μm or more, elongation of less than 0.5, and aspect ratio of 0.5 or more are divided into second spherical particles (S2) with circularity of 0.7 or more and fibrous particles G with circularity of less than 0.7. Circularity is calculated by dividing the perimeter (P) of a circle having the same area as the projected area (Ap) of the particle. EQPC ) and the actual particle perimeter (P real ) and is defined by the following formula. For any particle, the circularity is greater than 0 and less than 1. The smaller the circularity, the more irregular the particle shape. EQPC is the equivalent circle diameter (Diameter of a C ircle of Eq ual P It is defined as the diameter of a circle having an area equal to the projected area of ​​a particle, i.e., the projected area of ​​the particle, and is also called the Heywood diameter.

[0042]

number

[0043] Fibrous particles G having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, and a circularity of less than 0.7 are divided into second long fibrous particles (LF2) having a LEFI of 200 μm or more and second short fibrous particles (SF2) having a LEFI of less than 200 μm.

[0044] The volume of the particles in HPMCP (V m ) can be calculated by the following formula, assuming that the microparticle is a sphere with a diameter of EQPC: V m =(π / 6)×(EQPC) 3 ×N m Here, N m is the number of particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of particles.

[0045] In this specification, particles having a LEFI of 40 μm or more, excluding fine particles having a LEFI of less than 40 μm from all particles, are classified and distinguished from one another as "long fiber particles," "short fiber particles," and "spherical particles" based on the above-mentioned particle shape parameters, namely, LEFI, elongation ratio, aspect ratio, and circularity.

[0046] <Long fiber particles> Particles that meet either of the following definitions LF1 or LF2 are classified as "long fibrous particles". do. LF1: Particles with an elongation ratio less than 0.5, an aspect ratio less than 0.5, and a LEFI (fiber length) greater than or equal to 200 μm. LF2: Particles having an elongation ratio less than 0.5, an aspect ratio greater than or equal to 0.5, a circularity less than 0.7 and a LEFI (fiber length) greater than or equal to 200 μm. The volume of long fibrous particles in HPMCP (V LF ) can be calculated by the following formula by assuming that the long fibrous particle is a cylinder with a base diameter of DIFI and a height of LEFI. V LF =(π / 4) × (DIFI) 2 ×(LEFI)×N LF Here, N LF is the number of long fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of long fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of long fibrous particles. The volume of each of the particles satisfying the definitions of LF1 and LF2 is calculated by the above formula, and the sum of these volumes is the volume of the long fibrous particles in HPMCP.

[0047] <Short fiber particles> Particles that meet either definition SF1 or SF2 below are classified as "short fibrous particles". SF1: Particles having an elongation ratio of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (fiber length) of 40 μm or more and less than 200 μm. SF2: Particles having an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, a circularity of less than 0.7 and a LEFI (fiber length) of 40 μm or more and less than 200 μm. The volume of short fibrous particles in HPMCP (V SF ) can be calculated by the following formula by assuming the short fibrous particles as cylinders with a base diameter of DIFI and a height of LEFI, similarly to the above long fibrous particles. V SF =(π / 4) × (DIFI) 2 ×(LEFI)×N SF Here, NSF is the number of short fiber particles in a sample, DIFI is the median DIFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of short fiber particles, and LEFI is the median LEFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of short fiber particles. The volume of each of the particles satisfying the definitions of SF1 and SF2 is calculated by the above formula, and the sum of these volumes is the volume of the short fiber particles in HPMCP.

[0048] <Spherical particles> Particles that meet either definition S1 or S2 below are classified as "spherical particles". S1: Particles having an elongation ratio of 0.5 or more and a LEFI (fiber length) of 40 μm or more. S2: Elongation ratio less than 0.5, aspect ratio more than 0.5, circularity more than 0.7 and 40 Particles with a LEFI (fiber length) of 1 μm or more. The volume of spherical particles in HPMCP (V S ) can be calculated by the following formula, assuming that the spherical particles are spheres with a diameter of EQPC. VS =(π / 6)×(EQPC) 3 ×N S Here, NS is the number of spherical particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of spherical particles. The volume of each particle that satisfies the definitions of S1 and S2 above is calculated using the above formula. The sum of these values ​​is the volume of the spherical particles in HPMCP.

[0049] The volume fraction of each type of particle in HPMCP is the volume V defined above. m , V LF , V SF and V S can be calculated using the following formulas. Volume fraction of fine particles = {V m / (V m +V LF +V SF +V S )}×100 Volume fraction of long fiber particles = {V LF / (V m +V LF +V SF +V S )}×100 Volume fraction of short fiber particles = {V SF / (V m +V LF +V SF +V S )}×100 Volume fraction of spherical particles = {V S / (V m +V LF +V SF +V S )}×100

[0050] The volume fractions of various particles (long fiber particles, short fiber particles, spherical particles, and fine particles) were measured using a quantitative feeder VIBRI / L, an airflow type disperser RODOS / L, and a dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec Co., Ltd.) equipped with an M7 lens at a frame rate of 500Hz, an injector of 4mm, and a dispersion pressure of 1bar. The captured particle images were analyzed using analysis software WINDOX5 Version:5.9.1.1 to determine the number-based median EQPC, number-based median LEFI, number-based median DIFI, elongation ratio, aspect ratio, and circularity of various particles, and were calculated using the above-mentioned formula based on these values. Note that M7 was used as the classification during the analysis.

[0051] From the viewpoint of obtaining an HPMCP having excellent fluidity, the volume fraction of spherical particles in the HPMCP is 70.0% or more, preferably 75.0 to 99.0%, and more preferably 83.0 to 97.0%. The volume fraction of the long fibrous particles in the HPMCP is preferably 30.0% or less, more preferably 1.0 to 25.0%, and even more preferably 3.0 to 20.0%, from the viewpoint of the fluidity of the HPMCP. The volume fraction of short fibrous particles in HPMCP is preferably 2.5% or less, more preferably 0.0 to 1.5%, and even more preferably 0.0 to 0.5%, from the viewpoint of the fluidity of HPMCP. From the viewpoint of the fluidity of HPMCP, the volume fraction of the fine particles in HPMCP is preferably 2.5% or less, more preferably 0.0 to 1.5%, and even more preferably 0.0 to 0.5%.

[0052] Next, a composition for hot-melt extrusion containing at least the above-mentioned hydroxypropyl methylcellulose phthalate and a drug will be described. Use of the above-mentioned HPMCP having good fluidity can improve the uniformity of mixing of the HPMCP and the drug in the composition for hot-melt extrusion and the formation of bridges in the mixed powder of HPMCP and the drug in a hopper, and can be expected to improve the uniformity of the drug content, the mass ratio of HPMCP to the drug, and enable fixed-volume supply and continuous operation.

[0053] The drug is not particularly limited as long as it is an orally administrable drug, and examples of the drug include central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussives and expectorants, antihistamines, antipyretic analgesics and anti-inflammatory drugs, diuretics, autonomic nervous system acting drugs, antimalarials, antilagragulants, psychotropic drugs, vitamins and their derivatives, etc.

[0054] Central nervous system drugs include diazepam, idebenone, paracetamol, naproxen, piroxicam indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, and chlordiazepoxide. Examples of cardiovascular drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedivine, atenolol, spironolactone, metoprolol, vindolol, captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, and alprenolol hydrochloride.

[0055] Respiratory medications include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin. Examples of gastrointestinal drugs include benzimidazole drugs having antiulcer effects, such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl, and 5-aminosalicylic acid.

[0056] Examples of the antibiotics include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, and erythromycin. Antitussives and expectorants include noscapine hydrochloride, carbetapentane citrate, isoaminyl citrate, and dimemorfan phosphate. Antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride. Examples of the antipyretic, analgesic and anti-inflammatory agents include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin and ketoprofen.

[0057] Diuretics include caffeine. Autonomic nervous system agonists include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine, and the like. Antimalarial agents include quinine hydrochloride and the like. Antidiarrheal agents include loperamide hydrochloride. Psychotropic drugs include chlorpromazine and the like. Examples of vitamins and derivatives thereof include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

[0058] In particular, the solubility of poorly water-soluble drugs can be improved by using the HPMCP of the present invention as a carrier for a solid dispersion of poorly water-soluble drugs. Poorly water-soluble drugs refer to drugs that are described as "slightly soluble," "extremely soluble," or "almost insoluble" in water as described in the 17th revised Japanese Pharmacopoeia. "Slightly soluble" refers to the degree to which the drug dissolves in 100 mL or more but less than 1000 mL within 30 minutes when 1 g or 1 mL of a solid drug is placed in a beaker, water is added, and the drug is vigorously shaken for 30 seconds every 5 minutes at 20±5°C. "Extremely soluble" refers to the degree to which the drug dissolves in 1000 mL or more but less than 10,000 mL within 30 minutes. "Almost insoluble" refers to the degree to which the drug dissolves in 1000 mL or more but less than 10,000 mL within 30 minutes. In addition, in the above pharmaceutical tests, the fact that a poorly water-soluble drug is soluble means that the drug is soluble or miscible in water, and that no fiber or the like is detected or, if detected, only a very small amount.

[0059] Examples of poorly water-soluble drugs include azole compounds such as itraconazole, ketoconazole, fluconazole, and metconazole; dihydropyridine compounds such as nifedipine, nitrendipine, amlodipine, nicardipine, nilvadipine, felodipine, and efonidipine; propionic acid compounds such as ibuprofen, ketoprofen, and naproxen; indole acetic acid compounds such as indomethacin and acemetacin; as well as griseofulvin, phenytoin, carbamazepine, and dipyridamole.

[0060] The mass ratio of HPMCP to drug is not particularly limited, but from the viewpoint of storage stability in the amorphous state, it is preferably 1:0.1 to 1:10, more preferably 1:0.2 to 1:5.

[0061] Furthermore, the composition for hot-melt extrusion may contain additives such as a plasticizer and a surfactant in order to improve moldability during hot-melt extrusion. Examples of the plasticizer include higher alcohols preferably having 10 to 20 carbon atoms, such as cetyl alcohol and stearyl alcohol; polyhydric alcohols preferably having 2 to 6 valences, such as mannitol, sorbitol, and glycerin; beeswax; alkylene glycols, such as triethyl citrate, polyethylene glycol, and propylene glycol; triacetin, dibutyl sebacate, glycerin monostearate, and monoglycerin acetate. The content of the plasticizer in the composition for hot-melt extrusion is preferably 0.1 to 30% by mass from the viewpoint of storage stability.

[0062] Examples of surfactants include anionic surfactants such as sodium lauryl sulfate, nonionic surfactants such as diglycerides, poloxamer, polyoxyethylene sorbitan fatty acid esters (Tween 20, 60, 80), glycerin fatty acid esters, and propylene glycol fatty acid esters, and natural surfactants such as lecithin and sodium taurocholate. The content of the surfactant in the composition for hot-melt extrusion is preferably 0.1 to 10% by mass from the viewpoint of storage stability.

[0063] The composition for hot melt extrusion can be prepared by mixing HPMCP, a drug, and, if necessary, a plasticizer and a surfactant to obtain a composition for hot melt extrusion. The prepared composition for hot melt extrusion is fed from a hopper of a hot melt extruder and extruded into a desired shape, such as a circle, a square, a column, a film, or the like, to obtain a molded product.

[0064] The hot melt extruder is not particularly limited as long as it is an extruder that heats HPMCP and a drug in a system, melts and kneads them by applying shear force with a piston or screw, and then extrudes them from a die, but in order to obtain a more uniform extrusion product, a twin-screw extruder is preferable.Specific examples include Capilograph (single-screw piston type extruder) manufactured by Toyo Seiki Co., Ltd., Nano-16 (twin-screw type extruder) manufactured by Leistritz, Mini Lab (twin-screw type extruder) and Pharma Lab (twin-screw type extruder) manufactured by Thermo Fisher Scientific. The heat-melting temperature is not particularly limited, but is preferably a temperature at which the composition for hot-melt extrusion can be melted and extruded without difficulty, and at which decomposition of the drug and HPMCP due to heat can be avoided as much as possible. The heat-melting temperature is preferably 50 to 250°C, more preferably 60 to 200°C, and even more preferably 90 to 190°C, taking into consideration the melting points of the drug and HPMCP and the melting point of the composition for hot-melt extrusion. The hot melt extrusion conditions may be appropriately determined according to the properties of the composition for hot melt extrusion in accordance with a conventional method.

[0065] The hot-melt extrusion product after extrusion is cooled naturally at room temperature (1 to 30°C) or by cold air after the die discharge outlet. In order to minimize thermal decomposition of the drug and, in the case of an amorphous drug, to suppress recrystallization, it is desirable to cool the product to preferably 50°C or below, more preferably below room temperature (30°C or below).

[0066] The hot melt extrusion product after cooling may be pelletized to 0.1 to 5 mm by a cutter as necessary, or may be further pulverized to adjust the particle size until it is in a granular or powder form. For pulverization, an impact pulverizer such as a jet mill, knife mill, or pin mill is preferred because the product temperature is less likely to become high due to the structure of the equipment. If the inside of the cutter or pulverizer becomes too hot, the HPMCP will soften due to the heat and the particles will stick together, so it is preferable to pulverize under cold air. EXAMPLES

[0067] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples in any way. In the acetic acid removal step, the concentration of acetic acid in a mixture containing at least the removed acetic acid and water was measured by liquid chromatography under the following conditions. Equipment: Shimadzu Liquid Chromatograph LC-20AB Column: ODS-3 (inner diameter 4.6 mm, length 15 cm, particle size 5 μm, manufactured by GL Science) Column temperature: 30℃, constant Detector: UV-visible spectrophotometer (measurement wavelength: 215 nm, SPD-20AV, Shimadzu Corporation) Mobile phase: A 0.02 mol / L aqueous solution of potassium dihydrogen phosphate was adjusted to pH 2.8 by adding phosphoric acid. Flow rate: 1mL / min

[0068] The measurement sample was prepared by diluting a mixture containing at least the acetic acid removed in the acetic acid removal step and water 500 times by volume with water, and then further diluting the diluted product 6.25 times by volume with the mobile phase.

[0069] The flow rate of HPMCP was measured using a flow tester BEP2 (Copley Scientific) under the following conditions, and the average of two measurements was calculated. Orifice diameter: 8mm Amount of HPMCP: 30g Standing time: 30 seconds Container: Cylindrical (diameter 57 mm)

[0070] Example 1 A 5 L vertical kneader reactor (Trimix TX-5, Inoue Seisakusho) equipped with three frame-shaped stirring blades that revolve while rotating on their own axis was charged with 600.0 g of HPMC having a methoxy group DS of 1.88, a hydroxypropoxy group MS of 0.24, and a viscosity of a 2 mass% aqueous solution at 20°C of 6.0 mPa s, 960.0 g of glacial acetic acid, 498.0 g of phthalic anhydride, 253.0 g of sodium acetate, and 9.5 g of sodium chlorate, and the mixture was stirred at 85°C for 4.5 hours, to obtain 2,320.5 g of a reaction solution containing HPMCP. Next, in the same reactor, 27.0 g of water was added to the reaction solution containing HPMCP while maintaining the temperature at 85° C., and the mixture was stirred to obtain 2347.5 g of a water-added reaction solution. The equivalent relationship in the esterification reaction is shown in Table 1.

[0071] [Table 1]

[0072] Next, in the same reactor, the internal pressure of the kneader reactor was reduced to -0.09 MPaG using an aspirator (A-1000S, manufactured by Tokyo Rikakikai Co., Ltd.), and acetic acid was recovered using an ice-cooled cold trap while stirring at 85°C for 30 minutes. The recovered acetic acid contained water, and the amount of the recovered material containing at least acetic acid and water was 253.8 g. Then, the internal temperature of the kneader reactor was cooled to room temperature, whereby the amount of acetic acid was reduced, and a sticky solid mixture containing HPMCP was obtained. The peripheral speed of the rotational motion of the frame-shaped agitating blade in the esterification reaction step, the water addition step, and the acetic acid removal step was 0.050 m / s, the peripheral speed of the revolution motion was 0.019 m / s, and the ratio of the peripheral speed of the rotational motion to the peripheral speed of the revolution motion was 2.6. The peripheral speed of the rotational motion was the same for all three frame-shaped agitating blades that revolved while rotating on their own axes.

[0073] Next, 300 parts by mass of water at 20°C was added to 100 parts by mass of the sticky solid mixture, and the mixture was pulverized in a homomixer (Homomixer MARKII 2.5 type, manufactured by Primix Corporation, rotor diameter 30.0 mm) rotating at 8000 rpm and a peripheral speed of 12.57 m / sec to obtain a suspension of the pulverized mixture. The pulverized mixture was then filtered to obtain crude HPMCP. The crude HPMCP was then washed by repeating the procedure of dispersing in water, stirring, and filtering 10 times. The temperature of the water used for washing was 20°C, and the amount of water used for washing was 500 parts by mass per 100 parts by mass of the solid mixture with a reduced acetic acid content. The mixture was then dried at 80°C for 2 hours, and sieved through a sieve with 0.5 mm openings to obtain HPMCP. Table 2 shows the mass ratio of glacial acetic acid used as a solvent to HPMC (A), the mass ratio of water added in the water addition step after the esterification reaction step to HPMC (B), the mass ratio of the recovered material containing at least acetic acid and water in the acetic acid removal step to HPMC (C), the concentration of acetic acid in the recovered material containing at least acetic acid and water (D), the acetic acid removal rate, and the state of the mixture with a reduced acetic acid content subjected to the washing and recovery step. Table 3 also shows various physical properties of the obtained HPMCP.

[0074] Example 2 The acetic acid content was reduced and a non-sticky solid mixture containing HPMCP was obtained in the same manner as in Example 1, except that the stirring time in the acetic acid removal step was 60 minutes and the amount of the recovered material containing at least the removed acetic acid and water was 775.0 g. Next, the solid mixture with reduced acetic acid content was pulverized at 4000 rpm and a peripheral speed of 55.79 m / s using a Feather Mill FM-1F (manufactured by Hosokawa Micron Corporation, rotor diameter 266.4 mm) equipped with a knife-type pulverizing blade and a screen with an opening of 0.8 mm. Next, 300 parts by mass of water at 20°C was added to 100 parts by mass of the pulverized mixture with reduced acetic acid content and mixed to obtain a water-containing mixture of the pulverized mixture with reduced acetic acid content and water, and the water-containing mixture was then filtered to obtain crude HPMCP. The crude HPMCP was then washed by repeating the procedure of dispersing in water, stirring, and filtering 10 times. The temperature of the water used for washing was 20°C, and the amount of water used for washing was 500 parts by mass per 100 parts by mass of the solid mixture with a reduced acetic acid content. The crude HPMCP was then washed, dried, and sieved in the same manner as in Example 1 to obtain HPMCP. The results are shown in Tables 2 and 3.

[0075] Example 3 HPMCP was obtained by the same operation as in Example 1, except that the amount of water added to the reaction solution containing HPMCP was 1104.0 g, the stirring time in the acetic acid removal step was 60 minutes, and the amount of the recovered material containing at least acetic acid and water was 1230.2 g. In the acetic acid removal step, the content of acetic acid was reduced, and a sticky solid mixture containing HPMCP was obtained. The results are shown in Tables 2 to 3.

[0076] Example 4 HPMCP was obtained by the same operation as in Example 2, except that the amount of water added to the reaction solution containing HPMCP was 1104.0 g, the stirring time in the acetic acid removal step was 120 minutes, and the amount of the recovered material containing at least acetic acid and water was 1719.5 g. In the acetic acid removal step, the content of acetic acid was reduced, and a non-sticky solid mixture containing HPMCP was obtained. The results are shown in Tables 2 and 3.

[0077] Comparative Example 1 The same procedure as in Example 1 was carried out, except that the amount of water added to the reaction solution containing HPMCP was 1104.0 g, and the water-added reaction solution was fed to the homomixer without carrying out the acetic acid removal step, to obtain HPMCP. The results are shown in Tables 2 and 3.

[0078] [Table 2]

[0079] [Table 3]

[0080] By carrying out the acetic acid removal process, it is possible to obtain HPMCP with a volume fraction of spherical particles of 70.0% or more, and with a good particle size ratio (D 90 / D 10), loose bulk density, and outflow velocity were also shown. In addition, it is expected that the burden on wastewater treatment will be reduced and costs will be reduced by reusing the recovered acetic acid. In addition, it is expected that the mixing uniformity of HPMCP and the drug in the composition for hot-melt extrusion and the formation of bridges in the hopper of the mixed powder of HPMCP and the drug can be improved, and it is expected that the uniformity of the drug content and the mass ratio of HPMCP to the drug can be improved, and that quantitative supply and continuous operation can be achieved. The scope of the claims as originally filed for the original application of this application (Patent Application No. 2020-166788) is as follows: [Claim 1] An esterification reaction step of performing an esterification reaction between hydroxypropyl methylcellulose and phthalic anhydride using acetic acid as a solvent to obtain a reaction solution containing hydroxypropyl methylcellulose phthalate; a water addition step of adding water to the reaction solution to obtain a water-added reaction solution; an acetic acid removing step of removing at least a portion of the acetic acid from the water-added reaction solution to obtain a mixture having a reduced acetic acid content; a washing and recovering step of washing the mixture to recover the hydroxypropyl methylcellulose phthalate; A method for producing hydroxypropyl methylcellulose phthalate comprising at least [Claim 2] The method for producing hydroxypropyl methylcellulose phthalate according to claim 1, wherein the amount of acetic acid removed in the acetic acid removal step is 10.0% or more relative to the amount of acetic acid used as the solvent. [Claim 3] The method for producing hydroxypropyl methylcellulose phthalate according to claim 1 or claim 2, wherein the acetic acid removal step comprises evaporating the acetic acid under heating and reduced pressure while stirring the water-added reaction solution. [Claim 4] Hydroxypropyl methylcellulose phthalate, in which when all particles are classified into fine particles, spherical particles, and fibrous particles by dynamic image analysis, the volume fraction of the spherical particles to the total particles is 70.0% or more, The fine particles have a fiber length of less than 40 μm, The spherical particles are composed of first spherical particles having a fiber length of 40 μm or more and an elongation ratio, which is a ratio of fiber diameter to fiber length, of 0.5 or more, and second spherical particles having an elongation ratio of less than 0.5, an aspect ratio, which is a ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5 or more, and a perimeter (P EQPC ) and the actual particle perimeter (P real and a second spherical particle having a circularity of 0.7 or more, The fibrous particles are composed of long fibrous particles and short fibrous particles, the long fibrous particles are composed of first long fibrous particles having a fiber length of 200 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second long fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7; The short fibrous particles are hydroxypropyl methylcellulose phthalate particles consisting of first short fibrous particles having a fiber length of 40 μm or more and less than 200 μm, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second short fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7. [Claim 5] In the particle size distribution of the hydroxypropyl methylcellulose phthalate, the cumulative 50% particle diameter D 50 is 50 to 700 μm, and the cumulative 90% particle diameter D 90 and cumulative 10% particle size D 10 Particle size ratio (D 90 / D 10 5. The hydroxypropyl methylcellulose phthalate according to claim 4, wherein the molecular weight of the hydroxypropyl methylcellulose phthalate is 40.0 or less. [Claim 6] A composition for hot-melt extrusion comprising at least the hydroxypropyl methylcellulose phthalate according to claim 4 or 5 and a drug. [Explanation of symbols]

[0081] A: Whole particle B: Fine particles C: Particles with LEFI (fiber length) of 40 μm or more D: Particles with LEFI of 40 μm or more and elongation ratio of less than 0.5 E: Particles with LEFI of 40 μm or more, elongation ratio of less than 0.5, and aspect ratio of less than 0.5 F: Particles with LEFI of 40 μm or more, elongation ratio of less than 0.5, and aspect ratio of 0.5 or more G: LEFI is 40μm or more, elongation ratio is less than 0.5, aspect ratio is 0.5 or more, and circularity is Particles with a circularity of less than 0.7 S1: First spherical particle S2: Second spherical particle LF1: First long fiber particle LF2: Second long fiber particle SF1: First short fiber particle SF2: Second short fiber particles LEFI: Fiber length elongation: elongation ratio aspectratio: Aspect ratio circularity: circularity

Claims

1. Hydroxypropyl methylcellulose phthalate, in which when all particles are classified into fine particles, spherical particles, and fibrous particles by dynamic image analysis, the volume fraction of the spherical particles to the total particles is 70.0% or more, The fine particles are particles having a fiber length of less than 40 μm, The spherical particles include first spherical particles having a fiber length of 40 μm or more and an elongation ratio, which is a ratio of fiber diameter to fiber length, of 0.5 or more, and second spherical particles having an elongation ratio of less than 0.5, an aspect ratio, which is a ratio of a minimum Feret diameter to a maximum Feret diameter, of 0.5 or more, and a perimeter (P ＥＱＰＣ ) and the actual particle perimeter (P ｒｅａｌ and a second spherical particle having a circularity of 0.7 or more, the circularity being a ratio of The fibrous particles are composed of long fibrous particles and short fibrous particles, the long fibrous particles are composed of first long fibrous particles having a fiber length of 200 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second long fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.7; The short fibrous particles are hydroxypropyl methylcellulose phthalate particles consisting of first short fibrous particles having a fiber length of 40 μm or more and less than 200 μm, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5, and second short fibrous particles having an aspect ratio of 0.5 or more and a circularity of less than 0.

7.

2. In the particle size distribution of the hydroxypropyl methylcellulose phthalate, the cumulative 50% particle diameter D ５０ is 50 to 700 μm, and the cumulative 90% particle diameter D ９０ and cumulative 10% particle diameter D １０ Particle size ratio (D ９０ / D １０ 2. The hydroxypropyl methylcellulose phthalate according to claim 1, wherein the molecular weight of the hydroxypropyl methylcellulose phthalate is 40.0 or less.

3. A composition for hot melt extrusion comprising at least the hydroxypropyl methylcellulose phthalate according to claim 1 or 2 and a drug.

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