JP2019181410A - Manufacturing method of multiple drug type composition - Google Patents

Abstract

To provide a manufacturing method of a multiple drug type composition capable of uniformly mixing a granular drug type and a high viscosity drug type while restraining a collapse of the granular drug type.SOLUTION: In a method for manufacturing a multiple drug type composition being an admixture of a granular drug type and a high viscosity drug type being 0.6-3.0 MPa in average collapse strength and 2.0 mm or less in an average particle diameter, the granular drug type and the high viscosity drug type are mixed so as to satisfy conditions I-III by using a mixer having a specific homogenizer 20. (The condition I) a clearance A between a fixed blade and a rotary blade 38 of the homogenizer 20, the average particle diameter B of the granular drug type and collapse time average compression strain C of the granular drug type satisfy A>B×(100-C)/100. (The condition II) the rotary blade 38 is rotated in the same direction as the inclination direction of a flow passage of the fixed blade. (The III) a shear speed between the fixed blade and the rotary blade 38 is 20,000 sor less.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a method for producing a multi-drug composition.

  As a method of manufacturing high-viscosity agent types such as dentifrices, conditioners, treatments, and skin creams, a method of uniformly mixing raw materials while applying high shearing force to the raw materials using a homogenizer having fixed blades and rotating blades Is known (Patent Document 1).

  In recent years, it has been proposed to add a granular dosage form such as a capsule containing an oily component (fragrance, active ingredient, etc.) to the dentifrice (Patent Document 2).

JP2015-144996A Japanese Patent No. 4902994

  However, since granular dosage forms such as capsules are designed to be easily disintegrated during use (during dentifrice etc.), when mixing high viscosity dosage forms such as dentifrices and granular dosage forms using a homogenizer There is a problem that the granular dosage form collapses.

  The present invention provides a method for producing a multi-drug composition capable of uniformly mixing a granular dosage form and a high viscosity dosage form while suppressing the collapse of the granular dosage form.

The present invention has the following aspects.
<1> A multi-drug composition that is a mixture of a granular dosage form having an average crushing strength of 0.6 to 3.0 MPa and an average particle diameter of 2.0 mm or less and a high viscosity dosage form is produced. A method for producing a multi-drug composition, wherein the granular dosage form and the high-viscosity dosage form are mixed so as to satisfy the following conditions I to III using a mixing apparatus equipped with the following homogenizer.
(Homogenizer)
A cylindrical fixed blade, and a rotary blade disposed coaxially with the fixed blade inside the fixed blade, the fixed blade is formed with a plurality of flow paths penetrating from the inside to the outside, The homogenizer, wherein the flow path of the fixed blade is inclined in the circumferential direction of the fixed blade from the inside toward the outside.
(Condition I)
The clearance between the fixed blade and the rotary blade of the homogenizer, the average particle size of the granular agent mold, and the average compressive strain during crushing of the granular agent mold satisfy the following formula.
A> B × (100-C) / 100
However, A is a clearance (mm) between a fixed blade and a rotary blade, B is an average particle diameter (mm) of a granule type, and C is an average compression strain at the time of collapse of a granule type ( %).
(Condition II)
The rotary blade is rotated in the same direction as the direction in which the flow path of the fixed blade is inclined in the circumferential direction of the fixed blade as it goes from the inside to the outside.
(Condition III)
The shear rate between the fixed blade and the rotary blade is 20,000 s ⁻¹ or less.
<2> The method for producing a multi-drug composition according to <1>, wherein the mixing device further includes a stirring tank having anchor blades.
<3> An external circulation line in which the mixing device is mixed in the agitation tank, then further mixed in the homogenizer, and returned to the agitation tank, the granular agent mold and the high viscosity agent mold discharged from the homogenizer. The method for producing a multi-dose composition according to <2>, further comprising:

  According to the method for producing a multi-drug composition of the present invention, the granular dosage form and the high viscosity dosage form can be uniformly mixed while suppressing the collapse of the granular dosage form.

It is a schematic block diagram which shows an example of a mixing apparatus. It is sectional drawing of the direction orthogonal to the central axis of a fixed blade and a rotary blade which shows an example of a homogenizer. It is sectional drawing of the direction in alignment with the central axis of a fixed blade and a rotary blade which shows an example of a homogenizer.

The following definitions of terms apply throughout this specification and the claims.
“Multi-dose composition” means a mixture of multiple dosage forms.
"Granular dosage form" means a granular solid agent.
The “high viscosity agent type” means a semi-solid agent or liquid agent having a viscosity at 25 ° C. of 20 Pa · s or more.
“Viscosity at 25 ° C.” is a measured value 3 minutes after the start of measurement, measured at 20 rpm and 25 ° C. using a single cylindrical rotary viscometer.
The “crushing strength” is a value obtained by measuring the test force (crush test force) when the granular dosage form is crushed according to JIS R 1639-5: 2007, and calculating from the following formula.
σ = 2.48 × P ₀ / (π × d ² )
However, sigma is the crushing strength (MPa), _{P 0} is the crush test force (N), d is the particle diameter of the particulate dosage form (mm).
The “average crushing strength” is a value obtained by calculating the crushing strength of 20 randomly selected granular dosage forms and arithmetically averaging them.
“Compressive strain at the time of crushing” is a value obtained by measuring the compression displacement (compression displacement at the time of crushing) when the granular dosage form is crushed when measuring the crushing test force, and calculating from the following formula.
ε = Δd / d × 100
Where ε is the compressive strain (%) during crushing, Δd is the compression displacement (μm) during crushing, and d is the particle size (μm) of the granule mold before compression.
“Average compressive strain at the time of crushing” is a value obtained by calculating the compressive strain at the time of crushing and calculating the arithmetic average of 20 randomly selected granular dosage forms.
“Particle size” is the maximum length value obtained in a granular dosage form.
The “average particle diameter” is a value obtained by arithmetically averaging the particle diameters of 10,000 granular dosage forms selected at random.
The “shear rate between the fixed blade and the rotating blade” is a value obtained from the following equation.
D = v / A
However, D is a shear rate (s ^<-1 >), v is the peripheral speed (mm / s) of a rotary blade, A is the clearance (mm) between a fixed blade and a rotary blade.
“˜” indicating a numerical range means that numerical values described before and after the numerical value range are included as a lower limit value and an upper limit value.
The dimensional ratios in FIGS. 1 to 3 are different from actual ones for convenience of explanation.

  The method for producing a multi-drug composition of the present invention is to mix a granular dosage form that easily disintegrates and a high-viscosity dosage form using a mixing device equipped with a homogenizer so as to satisfy conditions I to III described later. To produce a multi-dose composition that is a mixture of a granular dosage form and a high viscosity dosage form.

(Mixing device)
The mixing apparatus used in the production method of the present invention includes a homogenizer.
The mixing apparatus may further include a stirring tank having anchor blades as necessary.
The mixing apparatus is further provided with an external circulation line for returning the granular agent mold and the high-viscosity agent mold mixed in the stirring tank and then further mixed in the homogenizer and discharged from the homogenizer, if necessary, to the stirring tank. Also good.

FIG. 1 is a schematic configuration diagram illustrating an example of a mixing apparatus.
The mixing device 1 includes a stirring tank 10, a homogenizer 20 connected to the bottom of the stirring tank 10, and an external circulation line 40 that returns the granular agent mold and the high viscosity agent mold discharged from the homogenizer 20 to the stirring tank 10. .

The agitation tank 10 includes a tank body 12, an anchor blade 14 disposed inside the tank body 12, and a motor (not shown) that rotates the anchor blade 14.
The tank body 12 has a content outlet 12a at the bottom.
The anchor wing 14 has a center portion 16 and a U-shaped portion 18.

The central portion 16 includes a rotation shaft 16 a that is arranged in parallel with the height direction of the tank body 12, and a plurality of blades 16 b that protrude from the rotation shaft 16 a toward the side wall surface of the tank body 12.
The U-shaped portion 18 includes a U-shaped shaft 18a extending upward from the tip of the rotating shaft 16a along the side wall surface of the tank body 12, a plurality of blades 18b protruding from the U-shaped shaft 18a toward the rotating shaft 16a, and a U-shape. A plurality of blades 18c projecting from the shaft 18a toward the side wall surface of the tank body 12 and scraping off the side wall surface.
The central portion 16 and the U-shaped portion 18 are provided individually or together and rotatably in the same direction or in the opposite direction.

FIG. 2 is a cross-sectional view (II-II cross-sectional view of FIG. 3) in a direction orthogonal to the central axis of the fixed blade and the rotary blade of the homogenizer 20. FIG. 3 is a cross-sectional view (III-III cross-sectional view of FIG. 2) in a direction along the central axis of the fixed blade and the rotary blade of the homogenizer 20.
The homogenizer 20 includes a fixed portion 22, a rotating portion 32, and a motor (not shown) that rotates the rotating portion 32.

The rotating unit 32 includes a rotating shaft 34, a disk-shaped rotating disk 36 provided at the upper end of the rotating shaft 34, and a rotating blade 38 extending upward from the outer peripheral edge of the rotating disk 36.
The fixed portion 22 is disposed so as to cover the upper end of the rotary blade 38, and has a ring-shaped top plate 24 having an opening 24a formed in the center, and a cylindrical first fixed blade extending downward from the outer peripheral edge of the top plate 24. 26, a cylindrical second fixed blade 28 extending downward from the inner peripheral edge of the top plate 24, and an opening 30a that is disposed below the rotating disk 36 and serves as a bearing for the rotating shaft 34 of the rotating portion 32, It has a disk-shaped bearing plate 30 to which the lower end of the first fixed blade 26 is fixed at the outer peripheral edge.
The rotary blade 38 is disposed inside the first fixed blade 26 and outside the second fixed blade 28. Further, the first fixed blade 26, the rotary blade 38 and the second fixed blade 28 are arranged coaxially with the central axis of the rotary shaft 34.

The 1st fixed blade 26 is provided with the wall-shaped blade | wing 26a along the circumferential direction at intervals in several places, such as a circumference, and has a comb-tooth shape. As for the number of the blade | wings 26a, 10-60 are preferable. If the number of the blades 26a is within the above range, the effect of the present invention is easily exhibited.
A plurality of flow paths 26b penetrating from the inside to the outside of the first fixed blade 26 are formed between the two adjacent blades 26a. The minimum width of the flow path 26b is preferably equal to or greater than the average particle size of the granular dosage form from the viewpoint of suppressing the collapse of the granular dosage form and ensuring the flow rate. The minimum width of the flow path 26b is preferably equal to or less than the circumferential length of the blades 26a from the viewpoint of efficiently applying a shearing force to each dosage form between the first fixed blade 26 and the rotary blade 38.
The flow path 26b is inclined in the circumferential direction of the first fixed blade 26 (clockwise direction in FIG. 2) as it goes from the inside to the outside. The inclination angle of the flow path 26b is preferably 30 to 60 degrees with the radial direction of the first fixed blade 26 as a reference (0 degree). If the inclination angle of the flow path 26b is within the above range, the effects of the present invention are easily exhibited.

The 2nd fixed blade 28 is provided with the wall-shaped blade | wing 28a in alignment with the circumferential direction at intervals in several places, such as the circumference, and has a comb-tooth shape. The number of blades 28a is preferably 10-60. If the number of the blades 28a is within the above range, the effect of the present invention is easily exhibited.
A plurality of flow paths 28b penetrating from the inside to the outside of the second fixed blade 28 are formed between two adjacent blades 28a. The minimum width of the flow path 28b is preferably equal to or greater than the average particle size of the granular dosage form from the viewpoint of suppressing the collapse of the granular dosage form and ensuring the flow rate. The minimum width of the flow path 28b is preferably equal to or less than the circumferential length of the blade 28a from the viewpoint of efficiently applying a shearing force to each dosage form between the second fixed blade 28 and the rotary blade 38.
The flow path 28b is inclined in the circumferential direction of the second fixed blade 28 (clockwise direction in FIG. 2) as it goes from the inside to the outside. The flow path 28 b is inclined in the same direction as the flow path 26 b of the first fixed blade 26. The inclination angle of the flow path 28b is preferably 30 to 60 degrees with the radial direction of the second fixed blade 28 as a reference (0 degree). If the inclination angle of the flow path 28b is within the above range, the effect of the present invention is easily exhibited.

The rotary blade 38 is configured such that blades 38a extending in the radial direction are provided at a plurality of positions on the circumference and spaced apart from each other, and have a comb shape. The number of blades 38a is preferably 10-60. If the number of blades 38a is within the above range, the effect of the present invention is easily exhibited.
A plurality of flow paths 38b penetrating from the inside to the outside of the second fixed blade 28 are formed between two adjacent blades 38a. The minimum width of the flow path 38b is preferably equal to or greater than the average particle size of the granular dosage form from the viewpoint of suppressing the collapse of the granular dosage form and ensuring the flow rate. The minimum width of the flow path 38b is that the blade 26a is effective in that shear force is efficiently applied to each dosage form between the first fixed blade 26 and the rotary blade 38 and between the second fixed blade 28 and the rotary blade 38. Or less in the circumferential direction and less than or equal to the circumferential length of the blade 28a.
The flow path 38 b is formed along the radial direction of the rotary blade 38.

The clearance between the first fixed blade 26 and the rotary blade 38 is appropriately set so as to satisfy the condition I described later.
The clearance between the second fixed blade 28 and the rotary blade 38 is appropriately set so as to satisfy the condition I described later.

  A discharge line 42 for discharging the multi-drug composition from the mixing device 1 is branched from the middle of the external circulation line 40. A three-way valve 44 is provided at a branch point where the discharge line 42 branches from the external circulation line 40.

(Granule type)
Examples of the granular dosage form include capsules, microgel particles, granules and the like.
Examples of capsules include those in which oily components (fragrances, active ingredients, etc.) are encapsulated in the film.
Examples of the microgel particles include hydrogel particles obtained by dispersing a gel containing a gelling agent, an oil component, and a surfactant in water and gelling the mixture.
Examples of the granule include granule zeolite, water-insoluble granules granulated using abrasive silica and a water-insoluble binder.

  The average crushing strength of the granular dosage form is 0.6 to 3.0 MPa, preferably 0.6 to 2.0 MPa, and more preferably 1.0 to 1.5 MPa. If the average crushing strength of the granular dosage form is equal to or greater than the lower limit of the above range, the granular dosage form will not easily collapse when the high viscosity dosage form and the granular dosage form are mixed using the homogenizer 20. If the average crushing strength of the granular dosage form is not more than the upper limit of the above range, the granular dosage form tends to collapse when the multi-drug composition is used (such as during dentifrice).

  The average particle size of the granular dosage form is 2.0 mm or less, preferably 0.2 to 2.0 mm, more preferably 0.5 to 2.0 mm, and even more preferably 0.5 to 1.5 mm. When the average particle size of the granular dosage form is not less than the lower limit of the above range, the granular dosage form tends to collapse when the multi-drug composition is used (such as during dentifrice). If the average particle diameter of the granular dosage form is not more than the upper limit of the above range, the granular dosage form will not easily collapse when the high viscosity dosage form and the granular dosage form are mixed using the homogenizer 20.

(High viscosity agent type)
Examples of the high-viscosity agent type include dentifrices, conditioners, treatments, and skin creams.
Examples of raw materials for dentifrices include abrasives, foaming agents, wetting agents, binders, and fragrances.

  The viscosity at 25 ° C. of the high viscosity agent type is preferably 20 to 200 Pa · s, more preferably 40 to 130 Pa · s. If the viscosity at 25 ° C. of the high-viscosity agent type is within the above range, it is easy to uniformly mix the granular agent type and the high-viscosity agent type using a mixing device equipped with a homogenizer.

(Multi-drug composition)
A multi-dose composition is a mixture of a specific granular dosage form and a high viscosity dosage form with an average crushing strength and average particle size within a specific range.
The multi-drug composition may contain a granular dosage form other than the specific granular dosage form, if necessary. Moreover, the multi-drug composition may contain a dosage form other than the granular dosage form and the high viscosity dosage form, if necessary.
The compounding quantity of a granule type | mold is 0.1-5.0 mass parts normally with respect to 100 mass parts of a high viscosity agent type | mold.

(Mixing method)
The high-viscosity agent mold may be prepared in advance in a separate stirring tank, may be prepared in the stirring tank 10 before the granular dosage form is added, or may be prepared simultaneously with mixing with the granular dosage form.
The high-viscosity agent mold or its raw material and the granular agent mold are put into the stirring tank 10, stirred by the anchor blade 14, and premixed. The peripheral speed of the anchor blade 14 is preferably 0.6 to 3.6 m / s, and more preferably 1.0 to 3.0 m / s. By premixing the high viscosity agent mold and the granular agent mold with the anchor blade 14, the high viscosity agent mold and the granular agent mold in the agitation tank 10 can be supplied to the homogenizer 20 without any bias. The entire mold and granule mold can be mixed evenly.

  The premixed granular dosage form and the high viscosity dosage form are supplied to the inside of the second fixed blade 28 of the homogenizer 20. The granular agent mold and the high viscosity agent mold supplied to the inside of the second fixed blade 28 flow into the flow path 38b of the rotary blade 38 through the flow path 28b of the second fixed blade 28. By rotating the rotary blade 38, centrifugal force is applied to the granular agent mold and the high viscosity agent mold, and the granular agent mold and the high viscosity agent mold are discharged from the flow path 26b of the first fixed blade 26 to the outside. At this time, a high shear force is applied to the granular agent type and the high-viscosity agent die that flow between the rotating rotary blade 38 and the first fixed blade 26 and between the rotating rotary blade 38 and the second fixed blade 28. The granular dosage form is uniformly dispersed in the high viscosity dosage form.

  The granular agent mold and the high viscosity agent mold mixed by the homogenizer 20 and discharged from the homogenizer 20 are returned to the upper part of the stirring tank 10 through the external circulation line 40. By circulating the granular agent mold and the high viscosity agent mold between the stirring tank 10 and the homogenizer 20 by the external circulation line 40, the high viscosity agent mold and the granular agent mold in the stirring tank 10 can be supplied to the homogenizer 20 without bias. Therefore, the entire high viscosity agent mold and granule dosage mold in the stirring tank 10 can be mixed evenly.

(Condition I)
In the present invention, the clearance between the first fixed blade 26 and the rotary blade 38 of the homogenizer 20, the average particle size of the granular agent mold, and the average compressive strain at the time of crushing of the granular agent mold are granular so as to satisfy the following formula: The dosage form and the high viscosity dosage form are mixed.
In addition, the granular agent mold and the high viscosity agent so that the clearance between the second fixed blade 28 and the rotary blade 38, the average particle diameter of the granular agent mold, and the average compressive strain at the time of crushing of the granular agent mold satisfy the following formula: Mix with mold.
A> B × (100-C) / 100
However, A is a clearance (mm) between a fixed blade and a rotary blade, B is an average particle diameter (mm) of a granule type, and C is an average compression strain at the time of collapse of a granule type ( %).

  “B × (100−C) / 100” represents the particle size in the compression direction of the granular dosage form at the time of crushing. If the clearance A between the fixed blade and the rotary blade is larger than the particle size in the compression direction of the granule mold at the time of crushing, the granule mold is sandwiched between the fixed blade and the rotary blade and compressed and deformed. However, the granular dosage form is difficult to disintegrate.

(Condition II)
In the present invention, the direction in which the flow path 26b of the first fixed blade 26 is inclined in the circumferential direction of the first fixed blade 26 from the inner side toward the outer side (hereinafter also referred to as “inclination direction of the flow path”). And the rotary blade 38 is rotated in the same direction (the clockwise direction in FIG. 2) as the inclination direction of the flow path 28b of the second fixed blade 28.

By rotating the rotary blade 38, circumferential force and centrifugal force are applied to the granular agent mold and the high-viscosity agent mold. Therefore, the flow direction of the granular agent mold and the high-viscosity agent mold is the rotational direction of the rotary blade 38 and the rotation. The direction gradually increases from the blade 38 to the outside.
Therefore, when the rotary blade 38 is rotated in the clockwise direction, the flow directions of the granular agent mold and the high viscosity agent mold are substantially the same as the inclination direction of the flow path 26b of the first fixed blade 26. Therefore, the granular agent mold and the high-viscosity agent mold that have flowed between the rotating rotary blade 38 and the first fixed blade 26 smoothly flow into the flow path 26 b of the first fixed blade 26. As a result, it is difficult for excessive shearing force to be applied to the granular dosage form and the high-viscosity dosage form, and the granular dosage form is unlikely to collapse.
On the other hand, when the rotary blade 38 is rotated in the counterclockwise direction, the flow direction of the granular agent mold and the high viscosity agent mold is a direction intersecting the inclination direction of the flow path 26b of the first fixed blade 26. Therefore, when the granular agent mold and the high viscosity agent mold flowing between the rotating rotary blade 38 and the first fixed blade 26 flow into the flow path 26b of the first fixed blade 26, the granular agent mold and the high viscosity agent. Excessive shear force is applied to the mold, and the granular dosage form tends to collapse.

(Condition III)
The shear rate between the first fixed blade 26 and the rotary blade 38 and the shear rate between the second fixed blade 28 and the rotary blade 38 are 20,000 s ⁻¹ or less, and 5,000 to 20,000 s ^{−. 1} is preferable, and 10,000 to 15,000 s ⁻¹ is more preferable. If the shear rate is equal to or higher than the lower limit of the above range, the granular dosage form is easily dispersed uniformly in the high viscosity dosage form. If the shear rate is less than or equal to the upper limit of the above range, it is difficult to apply excessive shearing force to the granular dosage form and the high viscosity dosage form, and the granular dosage form is unlikely to collapse.

(Mechanism of action)
In the manufacturing method of the multi-drug composition of the present invention described above, the granular dosage form and the high viscosity agent type are mixed using the mixing apparatus equipped with the homogenizer, so that the granular dosage form and the high viscosity type are mixed. The dosage form can be mixed uniformly.
In addition, for the following reasons, although the granular agent mold and the high viscosity agent mold are mixed using a mixing apparatus equipped with a homogenizer, the collapse of the granular agent mold can be suppressed.
i) Since the average crushing strength of the granular dosage form is 0.6 MPa or more and the average particle diameter of the granular dosage form is 2.0 mm or less, the high viscosity dosage form and the granular dosage form are mixed using a homogenizer. In particular, the granular dosage form does not easily collapse.
ii) In order to satisfy the condition I, that is, the clearance between the fixed blade and the rotary blade is made larger than the particle size in the compression direction of the granular agent mold at the time of crushing, Therefore, even if the granule mold is sandwiched between the fixed blade and the rotary blade and compressed and deformed, the granule mold is unlikely to collapse.
iii) Since the rotary blade is rotated in the same direction as the inclination direction of the flow path of the fixed blade so as to satisfy the condition II, and the granular agent mold and the high viscosity agent mold are mixed, the rotating rotary blade The granular agent mold and the high-viscosity agent mold that flowed between the blade and the fixed blade smoothly flow into the flow path of the fixed blade. As a result, it is difficult for excessive shearing force to be applied to the granular dosage form and the high-viscosity dosage form, and the granular dosage form is unlikely to collapse.
iv) Since the shear rate between the fixed blade and the rotary blade is relatively low so as to satisfy the condition III, excessive shearing force is hardly applied to the granular agent mold and the high viscosity agent mold, and the granular agent The mold is difficult to collapse.

(Other embodiments)
The method for producing the multi-drug composition of the present invention uses a mixing apparatus equipped with the above-described homogenizer, and the average crushing strength and the average particle diameter are in a specific range so as to satisfy the above-described conditions I to III. Any method may be used as long as it is a method of mixing the granular dosage form and the high-viscosity dosage form.
For example, a mixing device that does not include an external circulation line may be used.
As the mixing device, a device provided with a stirring tank having a stirring blade other than the anchor blade may be used.
As a mixing device, a device not equipped with a stirring tank may be used.
A homogenizer that does not have the second fixed blade 28 may be used.
As the homogenizer, a homogenizer having a second rotary blade arranged inside the second fixed blade 28 and coaxially with the second fixed blade 28 may be used.
A homogenizer having three or more combinations of fixed blades and rotary blades may be used.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

(viscosity)
The viscosity at 25 ° C. of the high-viscosity agent type is measured at 20 rpm at 25 ° C. using a single cylindrical rotary viscometer (manufactured by Toki Sangyo Co., Ltd., TVB10H). did.

(Particle size)
The particle size of the granular dosage form was determined by measuring the maximum length of the granular dosage form using an image analysis particle size distribution meter (manufactured by Jusco International, FF-30micro).
The average particle diameter of the granular dosage form was obtained by arithmetically averaging the particle diameters of 10,000 randomly selected granular dosage forms.

(Average crushing strength)
About 20 granular dosage forms randomly selected from the high viscosity dosage form 10 minutes after adding the granular dosage form to the high viscosity dosage form, a small tabletop testing machine (EZ-SX, manufactured by Shimadzu Corporation) The crush test force was measured under the conditions of a test speed of 1 mm / min in accordance with JIS R 1639-5: 2007, the crushing strength was determined, and the average crushing strength was determined as the average crushing strength.

(Average compression strain during crushing)
10 minutes after adding the granular dosage form to the high-viscosity dosage form, when measuring the crushing test force of 20 granular dosage forms randomly selected from within the high-viscosity dosage form, The compressive strain at the time of crushing was measured, and the arithmetic average was taken as the average compressive strain at the time of collapse.

(Particulate dosage form disintegration)
The multi-drug composition was sampled from the stirring tank, and the number of undisintegrated granular dosage forms was visually counted. The sampling amount is calculated from the theoretical number of granular dosage forms per unit mass of the multi-drug composition determined from the input amounts of the high-viscosity dosage form and granular dosage form, and the theoretical number of granular dosage forms in the sample is 20 It was set to a constant amount of about 100. The same operation was repeated 10 times, and the arithmetic average was obtained to obtain the actual number of granular dosage forms in the sample. Using the measured number of granular dosage forms in the sample and the theoretical number of granular dosage forms in the sample, the residual rate of the granular dosage forms was determined from the following formula.
Residual rate (%) = (actual number of granular dosage forms) / (theoretical number of granular dosage forms) × 100
The disintegration property of the granular dosage form was evaluated according to the following criteria.
○: Remaining rate 90% or more.
X: Remaining rate is less than 90%.

Example 1
As the mixing apparatus, the mixing apparatus 1 shown in FIG. 1 was used.
As the homogenizer, the homogenizer 20 shown in FIGS. 2 and 3 was used.
As a granular dosage form, a capsule having an average crushing strength of 0.6 MPa, an average particle diameter of 1.9 mm, and an average compressive strain at the time of crushing of 71% was used.
As the high viscosity agent type, a paste dentifrice having a viscosity at 25 ° C. of 55.0 Pa · s was used.

99.5 parts by mass of the high viscosity agent type is charged into the stirring tank 10 of the mixing apparatus 1, and 0.5 parts by mass of the granular type is charged while the anchor blade 14 is rotated at a peripheral speed of 1.0 m / s. And premixed.
The homogenizer 20 is driven at the clearance shown in Table 1, the homogenizer mode shown in Table 1, and the shear rate shown in Table 1 to further mix the granular agent mold and the high viscosity agent mold, and at the same time, the granular agent mold discharged from the homogenizer 20 And the high viscosity agent mold was returned to the upper part of the stirring tank 10 through the external circulation line 40.
Anchor blade until the total volume of the granular agent type and the high viscosity agent type returned to the agitation tank 10 through the external circulation line 40 is the same as the capacity of the high viscosity agent type charged in the agitation tank 10 14 and the homogenizer 20 were continued to obtain a multi-drug composition.
After mixing, the multi-drug composition was sampled from the stirring tank 10 to evaluate the disintegration property of the granular dosage form. The results are shown in Table 1.

(Examples 2-3)
A multi-drug composition was obtained in the same manner as in Example 1 except that the shear rate was changed to the value shown in Table 1. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 1.

(Examples 4 to 6)
As the granular dosage form, a capsule having an average crushing strength of 2.4 MPa, an average particle diameter of 1.0 mm, and an average compressive strain at the time of crushing of 73%, the first fixed blade 26 and the rotary blade 38 are used. A multi-drug composition was obtained in the same manner as in Examples 1 to 3, except that the clearance between and was changed to the value shown in Table 1. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 1.

(Examples 7 to 9)
Examples 1 to 3 were used except that capsules having an average crushing strength of 2.4 MPa, an average particle diameter of 1.0 mm, and an average compressive strain at the time of crushing of 73% were used as the granular dosage form. Similarly, a multi-drug composition was obtained. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 2.

(Examples 10 to 12)
As the granular dosage form, a capsule having an average crushing strength of 1.1 MPa, an average particle diameter of 0.5 mm, and an average compressive strain at the time of crushing of 80%, the first fixed blade 26 and the rotary blade 38 are used. A multi-drug composition was obtained in the same manner as in Examples 1 to 3, except that the clearance between and was changed to the value shown in Table 2. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 2.

(Comparative Examples 1-3)
A multi-drug composition was obtained in the same manner as in Examples 1 to 3, except that the clearance between the first fixed blade 26 and the rotary blade 38 was changed to the values shown in Table 3. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 3.

(Comparative Example 4)
A multi-drug composition was obtained in the same manner as in Example 1 except that the shear rate was changed to the values shown in Table 3. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 3.

(Comparative Example 5)
Except for using a capsule having an average crushing strength of 0.1 MPa, an average particle size of 1.0 mm, and an average compressive strain at the time of crushing of 57%, the same procedure as in Example 1 was used. Thus, a multi-drug composition was obtained. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 3.

(Comparative Example 6)
A multi-drug composition was obtained in the same manner as in Example 1 except that the homogenizer mode was changed to the mode shown in Table 3 and the shear rate was changed to the value shown in Table 3. The disintegration property of the granular dosage form was evaluated. The results are shown in Table 3.

  “P” of the homogenizer mode in the table is a pumping mode (a mode in which the rotary blade is rotated in the same direction as the inclination direction of the flow path of the fixed blade), and “H” is a homogenizing mode (the flow of the fixed blade flow path). Mode in which the rotary blade is rotated in the direction opposite to the tilt direction).

In Examples 1 to 12, since the conditions I to III were satisfied, the collapse of the granule dosage form was suppressed.
In Comparative Examples 1 to 3, the granular agent mold has a small average compressive strain at the time of crushing, and the clearance between the first fixed blade 26 and the rotary blade 38 is narrow. Increased.
In Comparative Example 4, since the shear rate between the first fixed blade 26 and the rotary blade 38 was high, the condition III was not satisfied, and the number of disintegrating granular dosage forms increased.
In Comparative Example 5, since the average crushing strength of the granular dosage form was low, more granular dosage forms were disintegrated.
In Comparative Example 6, since the rotary blade was rotated in the direction opposite to the inclination direction of the flow path of the fixed blade, the condition II was not satisfied and the number of collapsible granular dosage forms increased.

  The method for producing a multi-drug composition of the present invention is a method for producing a high-viscosity dosage form (dentist, conditioner, treatment, skin cream, etc.) containing granular dosage forms (capsules, microgel particles, granules, etc.). Useful as.

  DESCRIPTION OF SYMBOLS 1 Mixing apparatus, 10 Stirrer tank, 12 Tank main body, 12a Discharge port, 14 Anchor blade, 16 Center part, 16a Rotating shaft, 16b Blade, 18 U-shaped part, 18a U-shaped shaft, 18b Blade, 18c Blade, 20 Homogenizer, 22 fixed part, 24 top plate, 24a opening, 26 first fixed blade, 26a blade, 26b flow path, 28 second fixed blade, 28a blade, 28b flow path, 30 bearing plate, 30a opening, 32 rotating part, 34 rotation Shaft, 36 rotating disc, 38 rotating blade, 38a blade, 38b flow path, 40 external circulation line, 42 discharge line, 44 three-way valve.

Claims (3)

It is a method for producing a multi-drug composition that is a mixture of a granular dosage form having an average crushing strength of 0.6 to 3.0 MPa and an average particle diameter of 2.0 mm or less and a high viscosity dosage form. ,
The manufacturing method of the multi-drug type composition which mixes the said granule dosage form and the said high viscosity agent type | mold so that the following conditions I-III may be satisfied using the mixing apparatus provided with the following homogenizer.
(Homogenizer)
A cylindrical fixed blade, and a rotary blade arranged coaxially with the fixed blade inside the fixed blade;
The fixed blade is formed with a plurality of flow paths penetrating from the inside to the outside,
The homogenizer, wherein the flow path of the fixed blade is inclined in the circumferential direction of the fixed blade from the inside toward the outside.
(Condition I)
The clearance between the fixed blade and the rotary blade of the homogenizer, the average particle size of the granular agent mold, and the average compressive strain during crushing of the granular agent mold satisfy the following formula.
A> B × (100-C) / 100
However, A is a clearance (mm) between a fixed blade and a rotary blade, B is an average particle diameter (mm) of a granule type, and C is an average compression strain at the time of collapse of a granule type ( %).
(Condition II)
The rotary blade is rotated in the same direction as the direction in which the flow path of the fixed blade is inclined in the circumferential direction of the fixed blade as it goes from the inside to the outside.
(Condition III)
The shear rate between the fixed blade and the rotary blade is 20,000 s ⁻¹ or less.   The manufacturing method of the multi-drug type composition of Claim 1 with which the said mixing apparatus was further equipped with the stirring tank which has an anchor wing | blade.   The mixing device further includes an external circulation line for returning the granular agent mold and the high-viscosity agent mold mixed in the stirring tank and then further mixed by the homogenizer and discharged from the homogenizer to the stirring tank. Moreover, the manufacturing method of the multi-drug type composition of Claim 2.

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