JPS6344416B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates to spherical matrix granules obtained based on a submerged agitation granulation method.

"Industrial Application Field" According to the present invention, it is possible to use a binder, a coating agent, and a wax-like substance that have been used in conventional dry or wet granulation methods as a matrix material. A powder substance (drug powder) can be formed into spherical matrix granules by submerged stirring.

Further, according to the present invention, as a basic device, if there is a container equipped with a stirrer, it can be easily manufactured and the equipment is inexpensive. Therefore, it is easy to use in various fields, for example, powder substances with different solubility such as pharmaceuticals: In the formulation of drugs,
It has great advantages in terms of granulation.

"Prior Art" The basic means for granulating powdered substances and the like under submerged agitation is already known.

However, according to the conventional submerged stirring granulation method, in order to make the granules into uniform spherical granules,
During the process, various complicated treatments were required, and it was also necessary to combine other equipment (equipment).

That is, if the formed cross section of the granules (granules) obtained by the conventional submerged agitation granulation method is schematically shown, it will be as shown by B and C in Fig. 1, Powdered substances are often not coated with the matrix material, and in order to form granules that are uniform and close to perfect spheres, more complex processing is required, and the result is that equipment such as a sprayer is required. That's why I was there.

Therefore, the practical fields of use of granules obtained by known granulation methods using submerged stirring are limited, for example, fields where they can be used without requiring a matrix material, or It was often specified for use with granules that do not need to contain powdered substances. In addition, the typical form of granules is as shown by B in Figure 1, in which case most of them are made by applying the caking ability of powdered substances such as salts themselves. The particles were granulated, and were far from true spherical matrix granules.

Furthermore, recently, in the system under submerged stirring, the temperature inside the container is changed, heating and cooling operations are added, and the reaction of melting and solidifying the matrix material added to the system is applied. There are known methods for producing spheroidized granules for specific uses.
In this case, the matrix material was also specified, and the powder material as the main component was also unsuitable for granulation of something unstable to heat by heating or heat treatment.

``Problems to be Solved by the Invention'' A major problem with the granulation method using submerged stirring is how to easily obtain matrix granules that are close to perfect spheres for many powdered substances. Ta. The most ideal means would be to widely use known binders, coating agents, and wax-like substances as matrix materials, which are widely used in the processes of known wet and dry granulation methods. If so, granulation by submerged stirring could be used more widely.

That is, the greatest advantage of the granulation method using submerged stirring is that as long as the basic equipment includes a stirring device and a container (stirring tank), no other special equipment is required.

Therefore, the present inventors have conducted research and development on the theme of matrix granulation of many powdered substances by effectively utilizing this merit.

As a result, according to the method specifically shown below,
It has been found that many powdered substances can be easily formed into spherical matrix granules. That is, according to the present invention, as shown by A in FIG. 1, granules can be obtained that are almost perfectly spherical.

In other words, the technical means related to the present invention include heating,
This makes it possible to form spherical matrix granules at room temperature in a container equipped with a stirrer, without requiring any equipment such as heating or spraying.

"Structure of the Invention" The present invention uses a powder substance as a main component, and when the powder substance does not have hydrophobicity, the powder is subjected to a hydrophobic treatment in advance, and the powder is dispersed by placing it in water under stirring. Next, as a matrix material, any one of binders, coating agents, and wax-like substances used in known dry or wet granulation is dissolved in a water-immiscible solvent to form a solution, added, and stirred. The process consists of obtaining matrix granules and removing the water-immiscible solvent remaining in the matrix granules, and the resulting matrix granules are characterized by being spherical. It's in the law.

``Means for Solving the Problems'' The present invention involves dispersing an insoluble main component: a powder substance in distilled water at room temperature with a stirrer, and then adding an appropriate amount of a binder, coating agent, or wax-like substance to the water. and added as a solution in an immiscible solvent,
By continuing stirring, the main component is formed into spherical matrix granules.

That is, the method according to the present invention utilizes the hydrophobicity of the surface of the powder component to dissolve the binder,
This is a method in which particles are granulated by forming liquid bridges between particles using a solution of a coating agent or a wax-like substance.

The granules obtained by the present invention are formed in the state of spherical matrix granules, and the particle size is 60μ ~
It is in the range of 4.0mm.

In addition, during the process according to the present invention, the particle size of the spherical matrix granules is increased by processing the matrix material (binder, coating agent, wax-like substance) with a large liquid volume and a slow stirring speed. I can do it.

Furthermore, when the elution rate of the main component contained in the granules is measured based on the spherical matrix granules obtained by the present invention, the elution rate is significantly delayed and the matrix effect is significant.

More specific details will be given below using examples and the like. The sizes and shapes of the devices used in the examples: the stirring tank and the stirrer, and the main components used: powder substances are as follows.

(Production equipment) A cylindrical glass container with a diameter of 8 cm and a height of 18.5 cm was used as the stirring tank. On the other hand, the stirrer used was a four-blade stirrer with a blade diameter of 5 cm and a stirring speed that could be freely adjusted. Furthermore, the position of the stirrer blades is as follows:
The test was carried out by installing it 1 cm from the bottom of the glass container.

(Main Component: Powder Material) In carrying out the present invention, it is necessary that the powder material that is the main component is hydrophobic. If it is not hydrophobic, it is necessary to perform a treatment to make it hydrophobic in advance. In the steps disclosed in the following examples, examples in which hydrophobic treatment was performed will mainly be shown.

Example 1 An example in which a drug (sulfur drug): sulfamethoxazole is used as a powder substance is shown here.

When granulating sulfamethoxazole,
First, those whose average particle diameter is 380μ, and
It was pulverized to 6 μm or less and was previously subjected to hydrophobization treatment.

For hydrophobization treatment, 100g of sulfamethoxazole
By dispersing it in 200 ml of an alcoholic solution (approximately 3%) of higher fatty acids such as oleic acid and palmitic acid and leaving it for 48 hours, the higher fatty acids are adsorbed onto the surface of sulfamethoxazole, making the surface hydrophobic. This hydrophobic sulfamethoxazole is filtered and then washed with alcohol.
The material was dried at 30 to 40°C for 24 hours.

Add 10 g of sulfamethoxazole, made hydrophobic in the above step, to a stirring tank along with 300 ml of distilled water, and stir (stirring speed: 241, 382, 620, 1100 rpm).
and disperse in distilled water.

Next, as a matrix material, a 7% benzene solution of ethyl cellulose (addition amount: 0.5, 1.3, 3.0
ml) and stirring, spherical matrix granules are formed. Therefore, 2-3
The remaining benzene was removed by evaporation from the spherical matrix granules produced by the continuous stirring for several hours.
Do time drying. By this, spherical matrix granules can be easily obtained (in Fig. 2,
(denoted by A).

On the other hand, in the above process, the surface of sulfamethoxazole was previously subjected to hydrophobization treatment to obtain spherical matrix granules. Considering this, and for comparison of the data, we attempted to perform granulation directly without adding hydrophobization treatment.
In other words, heating (warming) is required during the process.
Based on known means, the present inventors made improvements,
For this purpose, we adopted a method of heating the entire stirring vessel with a mantle heater, took 10g of sulfamethoxazole with an average particle size of 380μ, and 10g of sulfamethoxazole that had been finely pulverized to 6μ or less, and distilled each of these. The bead wax was introduced into a stirring tank together with 300 ml of water, and the temperature inside the stirring tank was raised to 90°C using the speed of the stirrer: 241, 382, 620, and 1100 rpm. (mp60-70℃), in this case, add 1.5 g of finely ground material and 1.25 g of non-ground material, continue stirring for 10 minutes, then remove the mantle heater and continue stirring. It was left to cool until it reached room temperature. This forms spherical matrix granules. So next, we filtered this out and
After drying at 40°C for 24 hours, spherical matrix granules were obtained and used for data comparison (indicated by B in Figure 2).

Example 2 An example using the drug sulfanilamide as a powder substance is shown here.

The solubility of sulfanilamide in water is
It is higher than that of sulfamethoxazole shown in Example 1. Therefore, the same hydrophobization treatment as in Example 1 is performed using 10 g of sulfanilamide. At this time, bead wax was used here, and 4 ml or 8 ml of a solution (9.0%) of benzene dissolved therein was added, and the stirring speed was 620 rpm. The subsequent operations are carried out in accordance with Example 1 to obtain annular matrix granules.

In addition, according to the method of the present invention shown in Examples 1 and 2, which does not involve heating (heating) treatment during the process, sulfur drugs such as sulfisomidine and sulfamethizole, calcium carbonate, magnesium carbonate, Matrix formation of inorganic powders such as synthetic aluminum silicate can also be carried out.

Further, as the matrix material, other wax-like substances such as sugar ester, stearyl alcohol, glyceryl monostearate, and cetanol can be used.

Furthermore, when the powder substance is water-soluble and insoluble in an organic solvent, the matrix can be formed by dispersing the powder substance in an organic solvent and using a water-soluble binder or coating agent. It is possible to perform conversion.

"Confirmation of physical properties or effects" The matrix granules obtained in Examples 1 and 2 were
As shown by A in FIG. 1, it is formed into a substantially spherical body.

In addition, during the manufacturing process of the granules, an operation for hydrophobizing the powder material particles that are the main component,
Regarding the relationship between the stirring speed and the effect on the particle size distribution of the finally obtained spherical matrix granules, the results are as shown in FIG.

In other words, Fig. 2 shows the particle size of the spherical matrix granules of sulfamethoxazole obtained in Example 1. The faster the stirring speed, the smaller the particle size. All will be ready.

It was also confirmed that by employing hydrophobization treatment during the process, although the particle size increased, the particle size distribution became non-uniform.

Next, regarding the relationship between the amount of matrix material used and the stirring speed used during the manufacturing process of the spherical matrix granules obtained in the examples,
When calculated from the average particle diameter of matrix granules, the relationship is as shown in Figures 3 and 4.
The larger the amount of matrix material used and the lower the stirring speed, the larger the average particle diameter will be.

On the other hand, the data shown in FIGS.
This shows the results of an elution test of the main component powder substance: sulfur agent on the spherical matrix granules obtained based on 2, but it was found that hydrophobization treatment was applied during the process. It was confirmed that the elution rate decreased.

It has also been found that when the particle size of the starting material (powder material) used is small, the dissolution rate is increased compared to a powder material with a large particle size.

The outline of the dissolution test method is as follows.

(Elution test method: Annotations to Figures 5 and 6) Sift the matrix granules and -16+32
Mesh: For particles with an average particle size of 750 μm, the amount of the main component (sulfur drug) eluted from the matrix granules was determined in accordance with the elution test method specified by the US Pharmacopoeia.

As the eluate, 900 ml of distilled water was placed in a dissolution tester, 90 mg of the sample was added thereto, and the particles (matrix granules) were dispersed at a stirring speed of 150 rpm, and the dissolution test was conducted at a temperature of 37°C. For measurement, sample the eluate at appropriate time intervals, pass the solution through a 0.2μ Millipore filter, and measure the absorbance at absorption wavelengths of 257 and 250 nm using a dual-wavelength spectrophotometer. The amount of sulfur drug used was calculated using the method.

Figures 5 and 6 are plots of elution rate versus elution time.

"Effects of the Invention" In the known granulation method using submerged stirring, in order to obtain spherical matrix granules, a specific powder substance, which is the main component, is dispersed in wax that melts under heating, and then solidified by cooling. Further, the powdered material is dispersed under heating in the wax melted in the above-mentioned process, by grinding the powdered material after it has been made into a solid material, and It has been known to obtain matrix granules by spraying a dispersion into cold air.

In contrast, the present invention uses only a stirrer and a container (stirring tank), and does not require a crusher or a sprayer, as shown in the Examples. Furthermore, the granulation method using submerged stirring according to the present invention is characterized in that operations such as heating and melting of the matrix material by heating are not required. In other words, in the conventional granulation method using submerged stirring, in order to obtain spherical granules, operations such as heating and cooling were required in a stirring tank or in a spray device. There is no need to operate the temperature.

Furthermore, according to the conventional method, it was necessary to mainly select a wax-like substance that melts at the lowest possible temperature as the matrix material, but according to the present invention, the selection is limited to wax-like substances. There is no need to use binders or coatings, as have been employed in wet or dry granulation processes, and therefore a wide range of different powder materials can be used, depending on the application of the powder material. can be formed into spherical matrix granules.

Furthermore, the submerged agitation granulation method according to the present invention is inexpensive because the equipment is simple;
The manufacturing process is also simple, and the diameter of the granules can be arbitrarily adjusted from several tens of microns to several mm.

[Brief explanation of drawings]

FIG. 1 shows the state of granulation by submerged stirring. A
are spherical matrix granules according to the invention, B and C
is a granulated material produced by conventional submerged stirring. A is a powder substance, B is a matrix material. FIG. 2 shows the relationship between the particle size of matrix granules granulated using sulfamethoxazole as a powder substance and the stirring speed (stirring speed and particle size). A is a powder material whose surface has been hydrophobized in advance. B is a powder material whose surface was not hydrophobized. FIG. 3 shows the relationship between the particle size of matrix granules granulated using sulfamethoxazole as a powder substance and the amount of crosslinking agent (ethyl cellulose solution) added. FIG. 4 shows a powder material granulated using sulfamethoxazole.
This figure shows the relationship between the stirring speed and the particle size of matrix granules. Beads wax is used as a crosslinking agent. FIG. 5 shows that from matrix granules of powder material (sulfamethoxazole) according to the invention:
This paper examines the elution behavior of the powder substance over time. a is the powder raw material (sulfamethoxazole) itself. Below, b to f are all granulated by the method according to the present invention, but as a pretreatment for granulation, b is a powder material that has been further pulverized (crushed), and a crosslinking agent is added. In this case, an ethyl cellulose solution was used. c performs both micronization and surface treatment,
As the crosslinking agent, an ethyl cellulose solution was used. d is a finely powdered product using bees wax as a crosslinking agent. e is surface treated and uses bead wax as a crosslinking agent.
f is untreated and uses beeswax as a crosslinking agent. FIG. 6 shows the elution behavior of a powder material (sulfamine) granulated according to the invention from matrix granules.

Claims (1)

[Claims] 1. When the main component is a powder substance and the powder substance does not have hydrophobicity, the powder that has been previously treated with hydrophobicity is used, and the process of dispersing it by putting it in water under stirring, and then mixing it with water. It is formed by adding a solution of a binder, a coating agent, or a wax-like substance used in known dry or wet granulation as a matrix material into a solvent that does not contain granules, and stirring the mixture. A simple method for producing spherical matrix granules of powdered material, comprising the step of removing residual water-immiscible solvent from the granules.