JPH09313573A - Crushing method of adhesive/cohesive drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent fixing of a drug in a crusher and to improve crushing efficiency by crushing an adhesive/cohesive drug at a temperature not higher than specific one. SOLUTION: When an adhesive/cohesive drug with about 3-3.5MPa of tensile strength is to be pulverized, for instance, drug powder with the average particle diameter of about 5-200μm is preliminarily dipped into liquid nitrogen to be sufficiently cooled, then continuously fed through a supply port to a crusher together with liquid nitrogen. The crusher is kept in a temperature not higher than about -10 deg.C, for instance from -10 to -100 deg.C, during crushing. The process is repeated until the powder comes to be a desired size. Adhesive/ cohesive drugs to which this crushing method applies are, for instance, diethyl 4-[(2R, 4S)-1,2,4,5-tertrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiep in-2- carboxamide]benzyl phosphate etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for pulverizing a drug having adhesiveness / cohesiveness. It also relates to a fine powder of a pharmaceutical product obtained by the method of the present invention.

[0002]

2. Description of the Related Art Conventionally, the particle size of pharmaceutical powder has been
It is known as a factor that greatly affects the compounding properties and pharmacokinetics in drug formulation design, and is appropriately prepared in the manufacturing process to obtain a desired drug formulation depending on its properties and drug efficacy. However, for adherent / cohesive drugs, the crushed material or crushed material adheres to the vessel wall in the crusher, or becomes a block and sticks, causing blockage, so it is not possible to obtain the desired crushed product. It was impossible. On the other hand, the low-temperature pulverization method is conventionally a technique for pulverizing an elastic substance such as plastic or rubber by utilizing low-temperature brittleness, and a technique for pulverizing a heat-labile drug or pharmaceutical composition without denaturing ( Japanese Patent Laid-Open No. 61-236721). However, a method for pulverizing adherent / cohesive drugs has not been established.

[0003]

[Problems to be Solved by the Invention]
Since cohesive drugs cannot be pulverized into fine particles, the desired pharmacological or pharmaceutical function cannot be obtained.
There are many cases where it cannot be commercialized. Therefore, there has been a strong demand for a method of avoiding sticking in the crusher and efficiently crushing the adherent / cohesive drug.

[0004]

Means for Solving the Problems As a result of various studies on methods for preventing clogging of adherent / cohesive drugs in a crusher, the present inventors have found that these drugs are fixed by crushing at low temperature. The present invention has been completed by discovering that the phenomenon of occurrence of crushing can be avoided and that crushing can be performed without blocking in the crusher. That is, the present invention is (1) a pulverizing method characterized by pulverizing an adhesive / cohesive drug at about -10 ° C or lower. The present invention also provides (2) diethyl 4-[(2R, 4S)-having an average particle size of about 2 to 20 μm.
1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-
Carboxamide] benzyl phosphate powder and (3) N- (1-naphthalenesulfonyl)-(3S) -L-isoleucine-L-tryptophanal powder having an average particle size of about 1 to 5 μm.

The adhesive / cohesive drug in the present invention is
Generally, it refers to a drug having a high tensile strength at the time of compression molding, more specifically, a drug having a tensile strength in the range of about 2 to 5 MPa (megapascal). Although there are various methods for testing the tensile strength, the tensile strength in a compression tensile test at room temperature is adopted here. Specifically, using a molded product obtained by compression-molding an adhesive / cohesive drug alone, as a sample, the Journal of Pharmaceutical Sciences 5
The tensile strength was determined according to the test method reported in Volume 9, No. 5, pages 687 to 691. As a sample in this case, 200 mg of the drug is 98 MPa and the diameter is 8.0 mm.
The tablets obtained by compression molding are used. The adhesive / aggregating drug which is particularly focused on in the pulverization method of the present invention has, for example, a melting point of 100 ° C. or higher, preferably 150 ° C.
As above, melting point is relatively high, stable to heat,
Examples include a drug having physical properties such as a low water content (preferably 0.5% or less), almost no hygroscopicity, and a crystalline substance having a small residual solvent (preferably 0.5% or less). Further, a relatively low molecular weight compound having a molecular weight of 1000 or less is also a preferable target. Specific examples of such a drug include, for example, (2R, 4S)-(-)-N- [4-
(Diethoxyphosphoryl) phenyl] -1,2,4,5-
Tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide (JP-A-4-364719) and N- (1-naphthalene sulfonyl)-(3S) -L- Isoleucyl-L
-Tryptophanal (JP-A-7-101924).

There are no particular restrictions on the shape (shape, size, etc.) of these pharmaceuticals used in the crushing method of the present invention, and there is no particular limitation as long as they are suitable for the crusher used, but in the case of fine crushing Is preferably coarsely pulverized in advance so as to have a particle diameter of about 2 to 100 times the target fine powder.
The model of the crusher used in the crushing method of the present invention is not particularly limited, and an impact crusher such as a hammer mill or a disc mill,
Those falling within the range of a dry fine pulverizer such as a jet pulverizer can be preferably used. Further, in terms of material, it is preferable that the metal is a metal that does not cause brittle damage under cooling from −10 ° C. or lower to about −200 ° C. The crushing method in the present invention is
After cooling the sample to be crushed (crushed material) and the crushing chamber, the crushed material is crushed under cooling to -10 ° C or lower. The pulverizing step is performed according to a pulverizing means known per se except that the pulverizing step is performed under cooling, and the pulverizing conditions are appropriately selected according to the characteristics of the pulverizer and the pulverizing material used. As a cooling method for the crushed material, the crushed material and a refrigerant (liquid nitrogen, dry ice, etc.) are mixed at an appropriate mixing ratio, immersed in a liquid refrigerant such as liquid nitrogen, or low-temperature vaporized gas such as carbon dioxide or nitrogen. The method of exposing to the inside can be mentioned. Also. Similarly, in the crusher, a solid, liquid or gaseous refrigerant such as low temperature vaporized gas of dry ice or liquid nitrogen may be appropriately supplied into the crushing chamber for cooling. In addition,
The refrigerant to be used is preferably one that can be easily removed from the pulverized product to a pharmaceutically acceptable range in the pulverizing step or after pulverizing, or is harmless per se.

As a cooling method during pulverization, the cooled pulverized material is mixed with a refrigerant and supplied to the pulverizer, or the refrigerant is mixed into the inflow gas into the crushing chamber, or the refrigerant is continuously used as the inflow gas. In general, the method of supplying into the crushing chamber is general and effective, but the method is not necessarily limited to these, and any method capable of maintaining the desired temperature in the crushing chamber may be used. At this time, the temperature of the crushed material in the crushing chamber may be controlled by appropriately adjusting the supply amount of the cooling medium according to the characteristics of the crushed material, the crushing amount, and the crusher used. The temperature in the grinding chamber during grinding is about -10 to -200 ° C,
It is preferably kept in a cooled state of about -10 to -100 ° C. It is also within the scope of the present invention to repeatedly or in combination pulverize by the above-mentioned pulverization method or to carry out closed-circuit pulverization until the desired particle size is obtained, depending on the characteristics of the pulverized material and the amount of pulverization. Further, when the obtained pulverized product has a possibility of absorbing moisture, it is desirable to raise the temperature of the pulverized product to room temperature under dehumidification by a method such as blowing dry air to the pulverized product recovery unit in advance. Such a fine powder of a drug obtained by the pulverization method of the present invention has a smaller particle size and a larger surface area than conventional products, and is useful for formulation design such as formulation miniaturization and rapid dissolution, and is also useful in a living body. It can also be expected to be useful in terms of pharmacokinetics, such as improvement of absorption rate.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION As a concrete example of the pulverization method of the present invention, for example, in the case of pulverizing an adhesive / cohesive drug having a tensile strength of about 3 to 3.5 MPa, for example, an average particle diameter of about 5
The drug powder of 200 μm (laser diffraction particle size measuring device) was immersed in liquid nitrogen in advance and sufficiently cooled, and then continuously supplied to the inside of the apparatus through the powder supply port of the crusher together with the liquid nitrogen, and the inside of the crushing chamber was- Grinding is performed while maintaining the temperature at 10 to -100 ° C. If necessary, this operation is carried out by using a pulverized product having a desired particle size (for example, an average particle size of about 1 to 20 μm and a pulverized material of about 12.
5 v / v% or less) to obtain a fine powder of the drug.

[0009]

The present invention will be described in more detail with reference to the following examples, but these examples do not limit the present invention. Example 1 (2R, 4S)-(−)-N- [4- (diethoxyphosphoryl) phenyl] -1,2,4,5 with a mass median diameter of 105 μm (measured with a laser diffraction particle sizer) -Tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide (tensile strength: 3.2 MPa) 50 g was immersed in liquid nitrogen and cooled,
In order to cool the inside of the apparatus, it was continuously supplied together with liquid nitrogen from a powder supply port of a jet mill (70AS type jet mill: Paulex Co., Ltd.) and pulverized. During crushing, the inside of the crushing chamber was kept at -10 to -40 ° C, and nitrogen gas (nitrogen pressure for crushing 6.0 kgf / cm ² ) was used as the crushing air stream.
As a result, a crushed product having a mass median diameter of 6 μm was obtained without causing clogging.

Example 2 Mass median diameter 8 μm (measured with a laser diffraction particle size analyzer) according to Example 1 N- (1-naphthalene sulfonyl)-
(3S) -L-isoleucyl-L-tryptophanal (tensile strength: 3.3 MPa) was cryogenically ground system GO.
Using BLIN (Nara Machinery Co., Ltd.), rotation speed 1
As a result of low temperature pulverization at 6200 rpm and screen hole diameter of 3 mm, the median diameter of mass was 2μ without causing blockage.
It was possible to obtain a pulverized product of m. The temperature inside the grinding chamber during grinding was kept at -10 to -20 ° C. Example 3 (2R, 4S)-(-)-N was prepared in the same manner as in Example 1 except that a disc mill was used instead of the jet mill of Example 1 and the inside of the grinding chamber was maintained at about -100 ° C. -[4- (Diethoxyphosphoryl) phenyl] -1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-
As a result of pulverizing 5-oxo-3-benzothiepine-2-carboxamide, a pulverized product having a mass median diameter of 20 μm was obtained without causing clogging.

Comparative Example 1 As a comparative control experiment of Example 1, only the material to be pulverized was supplied from the powder supply port, and pulverization was tried at room temperature. The other conditions were the same as in Example 1. As a result, remarkable adhesion was observed on the powder supply nozzle and the wall surface of the crushing chamber, which clogged and crushing became impossible. Comparative Example 2 As a comparative control experiment of Example 2, only the object to be pulverized was supplied from the powder supply port, and pulverization was tried at room temperature. The other conditions were the same as in Example 2. As a result, remarkable adhesion was observed at the powder supply nozzle portion, and the powder supply nozzle portion was clogged, making crushing impossible.

[00012]

According to the crushing method of the present invention, by keeping the inside of the crusher under cooling to -10 ° C or less, a force is applied to the particles by the collision between the particles and the wall surface and between the particles during the crushing, that is, the particles are hardened. By avoiding the phenomenon of sticking, it becomes possible to continuously pulverize the pulverization target substance having the adhesion / cohesiveness, which has been impossible to pulverize due to the conventional clogging, by using various pulverizers that are usually used. Further, it is possible to repeatedly pulverize or perform closed circuit pulverization by the present pulverization method, and thereby it becomes possible to obtain a drug having adherence / aggregation of particles finer than the particle size which has hitherto been the limit. The fine powder of the drug obtained by the present invention is
Since it has a smaller particle size and a larger surface area than conventional products, it has superior pharmacokinetic properties in terms of formulation design such as downsizing and rapid dissolution of the formulation, and can be expected to improve the absorption rate in vivo. It has a great contribution to the development of outstanding formulations that never existed before.

Claims (6)

[Claims] 1. A pulverizing method characterized by pulverizing an adherent / cohesive drug at about −10 ° C. or lower. 2. The pulverization method according to claim 1, wherein the adhesive / cohesive drug is a substance having a tensile strength of about 2 to 5 MPa. 3. An adhesive / cohesive drug is diethyl 4-[(2R,
4S) -1,2,4,5-tetrahydro-4-methyl-7,
The grinding method according to claim 1, which is 8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamido] benzyl phosphate. 4. The pulverization method according to claim 1, wherein the adhesive / aggregating drug is N- (1-naphthalenesulfonyl)-(3S) -L-isoleucine-L-tryptophanal. 5. Diethyl 4 having an average particle size of about 2 to 20 μm
-[(2R, 4S) -1,2,4,5-Tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide] benzyl phosphate powder. 6. N- (1-naphthalenesulfonyl)-(3S) -L-isoleucine-L-tryptophanal powder having an average particle size of about 1 to 5 μm.