JP2017071558A - Shock resistance-improving excipient for tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide excipients which are tablets molded with low pressure, having high hardness, and resistant to cracking, chipping or the like, as well as which have no cost problem of requiring large quantities of particles with special physical properties.SOLUTION: An excipient for tablets comprising mannitol is characterized by that the mannitol is obtained by mixing, at a ratio of 1:99 to 50:50, spherical crystalline particles obtained by spray drying and having a repose angle of 30 to 50 degrees with precipitated crystal particles obtained by crystallizing.SELECTED DRAWING: None

Description

  The present invention relates to an excipient mixed with mannitol having different particle shapes and characteristics. In addition, the present invention relates to a method that can reduce damage to the tablet during packaging or in the transportation stage, such as cracking or chipping of the tablet, and a tablet using the method.

  Mannitol is widely used as an excipient for tablets because of its stability, low calories, and low reactivity with pharmaceutical ingredients. However, mannitol crystallized from a saturated aqueous solution has a low bonding property between particles, and tablets using mannitol as an excipient are said to have low hardness. To obtain practical hardness, high molding pressure is required. Tableting and other binders were required. However, tableting at a high molding pressure leads to the consumption of the die of the tableting machine. When a large amount of binder is added, the disintegration effect is particularly adversely affected in the orally disintegrating tablet among tablets.

  Thus, mannitol for direct tableting that can obtain high hardness has been developed, but problems such as cracking and chipping increase with the use of tablet packaging machines, even for tablets with high hardness. It was.

  Furthermore, in view of such circumstances, the present applicant has obtained high tablet hardness as disclosed in International Publication No. 2008/146590 (Patent Document 1) and International Publication No. 2010/021300 (Patent Document 2). We have been developing spherical crystal particles of mannitol with special properties.

International Publication No. 2008/146590 International Publication No. 2010/021300

  However, there is still a demand for a solution to the problem that high hardness and low cracking and chipping are difficult to occur at a low molding pressure, and in order to obtain generally required tablet hardness, Patent Document 1 and Patent Document 2 The necessity of a large amount of particles having such special physical properties has been a problem from the viewpoint of cost.

  Therefore, the present inventors are not mannitol developed for direct tableting, and are obtained by a general crystallization method, using conventional precipitated crystallization particles of mannitol as a main component, and have high hardness, and In order to obtain excipients that can prevent tablet breakage and chipping, mannitol particles with various physical properties are blended, and mannitol obtained by a specific manufacturing method is mixed with the precipitated crystal particles of conventional mannitol at a specific ratio The present inventors have found that the problem can be solved by the agent, and have completed the present invention.

That is, the solution of the present invention is as follows.
First, a tableting excipient comprising mannitol, wherein the mannitol has an angle of repose obtained by spray drying of 30 to 50 degrees, and precipitated crystal particles, Is an excipient for tableting characterized by being mixed at a ratio of 1:99 to 50:50.
Second, the spherical crystal particles have an aspect ratio of 1.0 to 1.2, an oil absorption rate 1 according to Test Method A of 25 to 40%, an oil absorption rate 2 of 15 to 30%, and a loose bulk density of 0.4. The excipient for tableting according to the first aspect, characterized in that it has a particle size of ˜0.6 g / ml and an average particle size of 30-50 μm.
Third, the precipitated crystal particle is an excipient for tableting according to the first or second aspect, wherein the average particle size is 70 to 200 μm.
Fourthly, there is a method for decreasing the tablet drop breakage rate using the tableting excipient according to any one of the first to third.
Fifth, it is an orally disintegrating tablet having a reduced drop breakage rate using the tableting excipient according to any one of the first to third.

  Details of the present invention will be described below.

  In the present invention, the spherical crystal particles of mannitol are obtained by spray drying, and spray drying is a particle obtained by finely spraying a solution or suspension of mannitol in a hot air stream in a drying tower and evaporating the solvent. Is the way to get. The particles obtained by this method are characterized by having voids in the particles due to evaporation of the solvent, and the droplets sprayed in the drying tower are dried and granulated in the air, so that a spherical particle structure is formed. Therefore, particles having good fluidity can be obtained.

  Here, in the present invention, the spherical crystal particle means a particle containing a spherical structure obtained by spray drying. The shape of the particle itself may be spherical, or may be a particle shape in which several spherical structures are gathered.

  In addition, fluidity can be expressed in terms of angle of repose. The angle of repose is an angle of a mountain formed when the powder is naturally dropped on the disk, and is measured by a powder tester PT-X (manufactured by Hosokawa Micron Corporation) set as follows. The sample hopper is oscillated with a setting of a vibration width of 1 mm, passed through a mesh having a mesh opening of 710 μm, a discharge funnel, and a nozzle (inner diameter 7.8 mm), and dropped onto a disk of an angle of repose sample table to form a mountain. The angle of the peak of the powder formed under these conditions is expressed as a measured value as a result of image analysis by the powder tester PT-X.

  In the present invention, since the spherical crystal particles of mannitol and the precipitated crystal particles are mixed, the spherical crystal particles are uniformly distributed in the precipitated crystal particles when the two kinds of particles are mixed. Is important. For these reasons, the angle of repose is preferably 30 to 50 degrees, more preferably 35 to 45 degrees in the spherical crystal particle according to the present invention.

  In addition, the spherical crystal particles have a higher sphericity and a hollow structure having many voids, but the finer particles can achieve the effect of the present invention more remarkably. This is because the hollow structure is more likely to be plastically deformed, so that at the time of tableting, not only between adjacent particles on the particle surface, but also an inside surface of the hollow structure gives an adhesive surface between the particles, so that tabletability is improved. This is thought to be due to improvement. Further, the finer the particles, the larger the specific surface area. This characteristic also contributes to an increase in the adhesion surface between the particles, and the tablet hardness tends to increase.

  Therefore, the aspect ratio representing the sphericity of the spherical crystal particles is preferably 1.0 to 1.2, and the oil absorption 1 representing the voids of the particles is 25 to 40 as measured by the method described below. %, And the oil absorption 2 is preferably 15 to 30%.

  The aspect ratio in the present invention is a ratio between the major axis and the minor axis of a particle and serves as a standard indicating sphericity. The ratio of the major axis to the minor axis is determined by taking a photograph of the sample particles with an electron microscope (TM-3000, manufactured by Hitachi High-Technologies Corporation) at an enlargement ratio of about 200 times. Measure the length (major axis) and the length (minor axis) of the minor axis perpendicularly drawn from the midpoint of the major axis, find the ratio of the major axis to the minor axis for each, and show the average value of 30 is there.

  If the aspect ratio is 1.0 to 1.2, the flowability of the spherical crystal particles becomes more preferable, the mixing with the precipitated crystal particles becomes uniform, and the particles with high sphericity are mixed with the precipitated crystal particles. The obtained excipient can be uniformly mixed with other components and is excellent in content uniformity.

  In addition, the oil absorption rate by the test method A in this invention is as follows. Place 30g of medium chain fatty acid triglyceride (Coconard MT, manufactured by Kao Corporation) and 15g of mannitol sample into a 100mL glass beaker, gently mix the oil and powder sample with a spatula so as not to crush the powder, It puts into drying machine (VOS-300D, the product made by EYELA), and decompresses to 0.67 Pa at room temperature, and impregnates oil for 3 hours.

  Next, the sample is transferred to a centrifuge tube (having a hole at the bottom) covered with a filter cloth having an opening of 45 μm (325 mesh), and the centrifuge (Hokusan Co., Ltd., H-500R) is set to 1300 G for 10 minutes. Centrifuge. The weight (weight a) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured value of the centrifuge tube containing the sample after centrifugation and the weight of the centrifuge tube tare, and the value calculated by the following equation 1 is the oil absorption rate 1 And

  Oil absorption 1 (%) = [(weight a-15) / 15] × 100 (formula 1)

  Further, the centrifuge tube containing the sample after centrifugation is put into a 100 mL glass beaker, 20 g of n-hexane is added from above the powder sample, and the centrifuge is set to 1300 G and centrifuged for 10 minutes. Next, the weight (weight b) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured value of the centrifuge tube containing the sample after centrifugation and the centrifuge tube tare weight, and the value calculated by the following equation 2 is obtained. Oil absorption rate is 2.

  Oil absorption 2 (%) = [(weight b−15) / 15] × 100 (Formula 2)

  Moreover, it is preferable that the average particle diameter of a spherical crystal particle is 30-50 micrometers. When the average particle size is smaller than 30 μm, segregation is likely to occur when the mixture is obtained, and when the mixture is tableted as it is, fine particles enter the clearance between the millstones in the tableting machine, and the tableting trouble is disturbed. Easy to happen. On the other hand, when the average particle size is larger than 50 μm, the hardness of the resulting tablet slightly decreases. This is considered to be caused by the fact that the number of contact points between the particles increases the number of binding points.

  Here, the above average particle diameter represents the median diameter of the powder, and can be known with a laser diffraction particle size distribution meter. As a laser diffraction particle size distribution analyzer, Microtrac MT3000 manufactured by Microtrac Bell Co., Ltd. can be used as a suitable example. As a method for measuring water-soluble mannitol, wet method in which isopropanol is used as a solvent and dispersed in the solvent. It is better to measure in the state.

  The spherical crystal particles of the present invention preferably have a loose bulk density of 0.4 to 0.6 g / ml. The spherical crystal particles of the present invention have a structure having many voids, but it is difficult to obtain particles having a loose bulk density lower than 0.4, and particles having a loose bulk density of less than 0.6 do not have the effects of the present invention because there are few voids.

  The loose bulk density in the present invention is a packing density in a state where powder is naturally dropped in a predetermined container, and is measured by the following method using a powder tester PT-X (manufactured by Hosokawa Micron Corporation).

  Place the sample container (volume: 100 mL) on the measuring platform, and the sample hopper vibrates with the setting of the vibration width of 1 mm, drop the sample through the mesh of 710 μm mesh, fill the sample container in the heap, and the upper part of the sample container In, cut with a spatula and measure the weight. The same operation is repeated three times for one type of sample, and the average value is defined as the loose bulk density.

  Next, the precipitated crystal particles of the present invention can be obtained by a crystallization method from a saturated aqueous solution conventionally known by those skilled in the art.

  In other words, after preparing saturating solution by dissolving mannitol in water, alcohol or other solvent, heating or cooling can cause supersaturation, with or without seed crystals added, crystals can be precipitated, and crystal growth Steps may be taken and controlled to obtain crystals in the solvent. Thereafter, the crystal is recovered by separating only the crystal from the solvent by filtration or centrifugation, and the recovered crystal is dried to obtain precipitated crystal particles. The crystal form of the obtained precipitated crystal particles may be any of α, β, and γ, but β-type crystals are the most stable and are generally readily available. In addition, the crystal shape is needle-like, and is often a cluster of elongated crystals precipitated in the solvent during crystallization and crystals oriented in the long side direction. Those that have not been refined are referred to as precipitated crystal particles of the present invention.

  The average particle size of the precipitated crystal particles is preferably 70 to 200 μm. When the average particle size is less than 70 μm, the fluidity is poor and the working efficiency of mixing and the like is poor, and when the average particle size is greater than 200 μm, the hardness of the resulting tablet decreases as with the spherical crystal particles.

  Moreover, it is preferable that the angle of repose of the precipitated crystal particles is 35 to 55 degrees. This is because the crystals of mannitol precipitated from the solution are needle-like long and thin polyhedrons, and when it exceeds 55 degrees, the fluidity is very poor and the particles segregate during mixing, which is not preferable.

  In the present invention, spherical crystal particles and precipitated crystal particles as described above are mixed at a specific ratio to obtain an excipient. The mixing ratio of spherical crystal particles: precipitated crystal particles is 1:99 to 50:50, preferably 30:70 to 50:50, by mass ratio. Even with the addition of a very small amount of spherical crystal particles, it is possible to reduce the cracking and chipping of the tablet, which is the effect of the present invention. However, since the spherical particles are appropriately present between the precipitated crystal particles, the fineness of the spherical crystal particles can be reduced. It is considered that the crystals contribute to the effect of reducing tablet breakage and chipping.

  In addition, when the spherical crystal particles: the precipitated crystal particles are mixed in a larger proportion than the 50:50 ratio, it is possible to reduce tablet breakage and chipping due to the characteristics of the spherical crystal particles. It was surprising that when there are many precipitated crystal particles in the form, it is possible to remarkably reduce tablet breakage and chipping by simply adding a small amount of spherical crystal particles.

  In addition, as a use mode of the excipient of the present invention, a mixture of spherical crystal particles and precipitated crystal particles is used as it is as an excipient, and a pharmacologically active ingredient or other excipient which is a raw material for other tablets. It may be directly tableted by mixing with a disintegrant, a lubricant, etc., but it is preferably used as an excipient for tablets after granulating after mixing spherical crystal particles and precipitated crystal particles. . This prevents the spherical crystal particles from being unevenly distributed in the mixture of spherical crystal particles and precipitated crystal particles having different shapes and sizes, and the effect of the present invention can be further obtained by uniformly presenting the spherical crystal particles. This is because it becomes a state.

  The spherical crystal particles and the precipitated crystal particles can be mixed by any method as long as the powder can be uniformly mixed, and a tumbler mixer, a V mixer, or the like can be used. The spherical crystal particles and the precipitated crystal particles may be granulated by a conventionally known method such as an agitation granulator, a fluidized bed granulator / dryer or an extrusion granulator. It is preferable to perform granulation while spraying the adhesive as a binder, since the spherical crystal particles are fixed in a state of being uniformly dispersed between the precipitated crystal particles and cause appropriate aggregation.

  Hereinafter, the contents of the present invention will be described in detail based on examples, but the technical scope of the present invention is not limited to the following examples.

  Create tablets using only precipitated crystal particles as excipients and tablets using spherical crystal particles mixed with precipitated crystal particles, and compare the degree of tablet cracking and chipping that are the effects of the present invention did.

  The comparison method was as follows. 45 tablets divided into 15 tablets each time, dropped from a height of 1.5 m onto a marble plane, and divided by the total number of tablets used in the test. The drop breakage rate was used. Find the drop breakage rate of the tablet when only the precipitated crystal particles as the control are used as excipients, compare with the test section of the same hardness, and how much drop breakage when the spherical crystal particles and precipitated crystal particles are mixed It was calculated | required with the following formula | equation whether the rate was improved.

  Drop breakage improvement rate (%) = [1- (Example drop breakage rate / Control drop drop breakage rate)] × 100

  However, when the molding pressure is set so that the tablet has a high hardness and only the precipitated crystal particles as a control are used as an excipient, capping, etc., in which cracking or the like has already occurred during tableting may occur. Under the conditions that occurred, it was assumed that the total damage was assumed to be 100%, and in the test group with the same target hardness, the above formula was used to improve the drop damage rate of the tablet when spherical crystal particles and precipitated crystal particles were mixed. I asked for it.

[Control Example 1]
As the precipitated crystal particles, Mannitol S manufactured by Mitsubishi Corporation Foodtech was used. Table 1 shows the physical properties such as the average particle diameter of the powder. A tablet was prepared using only the precipitated crystal particles as an excipient. Tablets were prepared by using a fluidized bed granulator with a hydroxypropylcellulose (“HPC-SSL” manufactured by Nippon Soda Co., Ltd.) 8% solution as a binder, After uniformly mixing 99 parts by mass of the excipient granulated product that has been granulated by spraying so that the solid content becomes 1% and 1 part by mass of the disintegrant (“Collidon CL-F” manufactured by BASF Japan) The mixture and 1 part by mass of magnesium stearate as a lubricant are mixed and punched using a single-punch tableting machine (“NS-T100” manufactured by Nano Seeds Co., Ltd.) so that the weight is 180 mg in the shape of φ8 mm round corners. Locked. The tableting pressure was set to the tableting conditions for producing tablets by appropriately changing the load and thickness at the time of tableting so that the hardness was 5 kgf. The tablet hardness was measured using a hardness meter (“TH-303MP” manufactured by Toyama Sangyo Co., Ltd.) for 5 tablets from the tablets obtained by tableting, and an average value was adopted.

  Table 2 shows the hardness and drop breakage rate of the obtained tablets.

  Manitite Q manufactured by Mitsubishi Corporation Foodtech Co., Ltd. as spherical crystal particles obtained by spray drying, and Mannit S same as Control Example 1 as precipitated crystal particles were mixed at a ratio of 1:99 as an excipient. Used to make tablets. Table 1 shows the physical properties such as the average particle size of the Mannit Q used. Tablets were obtained by granulating excipients in the same manner as in Control Example 1, and then mixing with other tablet raw materials and tableting. Table 2 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 5:95. Table 2 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 1 except that the ratio of spherical crystal particles to precipitated crystal particles was 10:90. Table 2 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 30:70. Table 2 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 1 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 50:50. Table 2 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

[Control Example 2]
Mannitite S of a lot different from that of Control Example 1 was used as the precipitated crystal particles, and granulated in the same manner as in Control Example 1 to obtain an excipient granulated product. 98.5 parts by mass of this excipient granulated product, 1 part by mass of disintegrant (Kollidon CL-F), and 0.5 parts by mass of silicon dioxide (“Aerosil 200” manufactured by Nippon Aerosil Co., Ltd.) as a water-conducting agent are uniformly mixed. After that, this mixture was mixed with 1 part by mass of magnesium stearate as a lubricant, and tableting was performed using a single tableting machine as in Control Example 1. The tableting pressure was set to the tableting conditions for producing tablets by appropriately changing the load and thickness at the time of tableting so that the hardness was 5 kgf. The physical properties of the used Mannit S are shown in Table 3, and the hardness and drop breakage rate of the obtained tablets are shown in Table 4.

  Mannite Q of a lot different from that of Example 1 was used as spherical crystal particles obtained by spray drying, and Mannite S of the same lot as that of Control Example 2 was used as precipitated crystal particles, and mixed at a ratio of 10:90. Used as an excipient. Table 3 shows the physical properties of the used spherical crystal particles and precipitated crystal particles. Tablets were obtained by granulating excipients in the same manner as in Control Example 2, and then mixing with other tablet materials to make tablets. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 6 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 30:70. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 6 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 50:50. Table 4 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

[Control 3]
Tablets were obtained in the same manner as in Control Example 2, except that Mannit S of a lot different from Control Examples 1 and 2 was used as the precipitated crystal particles, and the target hardness as a tablet condition was changed to 8 kgf. All the tablets obtained were capped and the hardness could not be measured. Therefore, the drop breakage rate was set to 100% as described above. Table 5 shows the physical properties of the used Mannit S.

  The same lot of Mannit Q as in Example 6 was used as spherical crystal particles, and Mannit S from the same lot as Control Example 3 was used as the precipitated crystal particles, which were mixed at a ratio of 50:50 and used as an excipient. Table 5 shows the physical properties of the used spherical crystal particles and precipitated crystal particles. Tablets were obtained by granulating excipients in the same manner as in Control Example 3, and then mixing with other tablet raw materials for tableting. Table 6 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

[Control 4]
Tablets were obtained in the same manner as in Control Example 2, except that PEARLITO 160C manufactured by Rocket Frere was used as the precipitated crystal particles. Table 7 shows the physical properties of the used PEARLITO 160C, and Table 8 shows the hardness and drop breakage rate of the obtained tablets.

  As the spherical crystal particles obtained by spray drying, Mannit Q of the same lot as in Example 1 was used, and PEARLITL 160C as in Control Example 4 was used as the precipitated crystal particles, mixed at a ratio of 30:70 and used as an excipient. . Table 7 shows the physical properties of the used spherical crystal particles and precipitated crystal particles. The tablets were obtained in the same manner as in Control Example 2, after granulating the excipient, and then mixing with other tablet materials to make tablets. Table 8 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 10 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 50:50. Table 8 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

[Control 5]
Tablets were obtained in the same manner as in Control Example 4 except that the target hardness as tablet conditions was changed to 8 kgf. The precipitated crystal particles used are the same as in Control Example 4. Table 9 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  The same lot of Mannit Q as in Example 1 was used as spherical crystal particles, and Mannit S from the same lot as Control Example 4 was used as the precipitated crystal particles, which were mixed at a ratio of 30:70 and used as an excipient. Tablets were obtained by granulating excipients in the same manner as in Control Example 5, and then mixing with other tablet raw materials and tableting. Table 9 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

  A tablet was obtained in the same manner as in Example 12 except that the ratio of the spherical crystal particles to the precipitated crystal particles was 50:50. Table 9 shows the hardness, drop breakage rate, and drop breakage improvement rate of the obtained tablets.

From the above results, the tablet using the mannitol tableting excipient of a specific mixing ratio according to the present invention is remarkably compared to the tablet using the excipient consisting only of the precipitated crystal particles as a control. It can be seen that the drop breakage improvement rate is improved.

Claims (5)

  A tableting excipient comprising mannitol, characterized in that the mannitol has a repose angle of 30 to 50 degrees obtained by spray drying, and a precipitated crystal obtained by crystallization An excipient for tableting, wherein the particles are mixed in a ratio of 1:99 to 50:50.   The spherical crystal particles have an aspect ratio of 1.0 to 1.2, an oil absorption 1 according to Test Method A of 25 to 40%, an oil absorption 2 of 15 to 30%, and a loose bulk density of 0.4 to 0.6 g. The tableting excipient according to claim 1, wherein the average particle size is 30 to 50 µm.   The excipient for tableting according to claim 1 or 2, wherein the precipitated crystal particles have an average particle size of 70 to 200 µm.   The tablet fall breakage rate reduction method using the excipient | filler for tableting as described in any one of Claims 1-3. An orally disintegrating tablet having a reduced drop breakage rate using the tableting excipient according to any one of claims 1 to 3.