JPS6137247B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a solid dosage composition that provides an excellent dissolution rate and excellent stability over time. More specifically, at least both the β-cyclodextrin and the medicinal ingredient are dry mixed and crushed to such an extent that the presence of diffraction peaks characteristic of crystalline substances is no longer recognized by X-ray diffraction measurement, and the mixture is processed into tablets, capsules, powders, etc. The present invention relates to a solid pharmaceutical composition for application to fine granules, granules, etc. A method of mixing and pulverizing crystalline cellulose and medicinal ingredients has been disclosed, for example, in JP-A No. 51-32718 and 51-32719, but this technology has the effect of increasing the dissolution rate of solid preparations and ensuring rapid and complete absorption in the body. has been attracting attention in the pharmaceutical industry. Various studies have shown that solid preparations obtained from this pulverized mixture of crystalline cellulose and medicinal ingredients exhibit excellent stability over time, instantaneous dissolution, and excellent availability in vivo. It had defects such as: In other words, to maximize its effectiveness,
It is necessary to increase the mixing and pulverizing time, which is not only disadvantageous in terms of production efficiency of the preparation, but also undesirable because it may lead to deterioration and alteration of the medicinal ingredients in some cases. In order to solve this problem, a method using β-cyclodextrin instead of crystalline cellulose was proposed. According to our company, mixing and grinding with medicinal ingredients can be completed in a significantly shorter time than in the case of crystalline cellulose. However, there were major problems in formulating a pulverized mixture of β-cyclodextrin and medicinal ingredients. Compression molding of the pulverized mixture of β-cyclodextrin and medicinal ingredients to form tablets is as follows:
This was difficult due to poor moldability, fluidity, and smoothness.
Even if it were made into a tablet, the physical properties of the tablet, such as tablet hardness, changed over time, making it impractical. It has also been difficult to apply a pulverized mixture of β-cyclodextrin and medicinal ingredients to capsule formulations. That is, the mixed pulverized product had extremely poor fluidity and developed stickiness, making it difficult to fill into capsules. Furthermore, when dry molding is performed to impart fluidity, the moldability is poor as described above, and granulation is difficult. Applying a pulverized mixture of β-cyclodextrin and medicinal ingredients to granules or fine granules has a poor granulation yield, and the powdering rate of the resulting granules and fine granules is too high for practical use. It didn't make sense. Application of a pulverized mixture of β-cyclodextrin and medicinal ingredients to a powder has also had the problem of poor fluidity, which results in large variations in measurements during packaging, and furthermore makes it difficult to take. As mentioned above, the pulverized mixture of β-cyclodextrin and medicinal ingredients has contributed to shortening the mixing and pulverization time, but it is difficult to apply it to actual preparations.
Its performance was insufficient. The present invention provides a solid preparation composition that enables the production of solid preparations with excellent practical properties and productivity while maintaining the effect of rapid dissolution of a mixed pulverized mixture of β-cyclodextrin and medicinal ingredients, which has been problematic. It is about things. First, when a pulverized mixture containing at least β-cyclodextrin and a medicinal ingredient is applied as a tablet, excipients and other formulation additives are added to impart formability, smoothness, and stability over time. It is necessary to add. The excipients mentioned here are
It refers to calcium phosphate, calcium sulfate, lactose, sucrose, mannitrate, starch, and derivatives thereof, and these may be used alone or in combination. Other formulation additives include binders, lubricants,
It refers to flow agents, etc., but as a binder, β-1・
4-glucan and its derivatives, such as crystalline cellulose, cellulose powder, carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose, and polyvinylpyrrolidone and starch derivatives can also be used. Any of these may be used alone or in combination of two or more. Lubricants include stearyl alcohol, aluminum stearate, magnesium stearate, talc, etc. Glidants include magnesium oxide, particulate silicon oxide, talc, etc. β-1.4 glucan, starch, etc. Sometimes used for this purpose. In addition, disintegrants such as carboxymethylcellulose calcium salts and ion exchange resins, coloring agents, and flavoring agents can be used as necessary. There is no limit to the amount of these excipients and other pharmaceutical additives added in tabletting the mixed pulverized product containing at least β-cyclodextrin and a medicinal active ingredient. This is because the prescription is determined by conditions such as the amount of medicinal ingredients in one tablet, which is the final product, and the weight of one tablet. but,
In order to maintain practical strength and prevent deterioration of tablet quality over time, the amount of binder is preferably 10 to 50% by weight in the case of the direct compression method, and 1 to 30% by weight in the case of the wet compression method. Both the direct compression method and the wet compression method can be used to manufacture the tablets, and the tablets can be manufactured under the same conditions as normal tablet manufacturing. The tablets thus obtained have rapid dissolution properties, excellent practical strength and disintegration properties, and also have good stability over time. Next, when applying the pulverized mixture containing at least β-cyclodextrin and medicinal ingredients as a capsule, in order to impart fluidity and smoothness,
Addition of flow agents and/or lubricants is necessary. Further, part or all of the flow agent and/or lubricant may be replaced with a filler or binder having good fluidity such as lactose, starch, or crystalline cellulose. In addition, coloring agents and flavoring agents may also be added freely. Although there is no limit to the amount of pharmaceutical additives added in encapsulating the mixed pulverized product containing at least β-cyclodextrin and a medicinal ingredient, for example, the amount of a lubricant and/or flow agent may be from 0.2 to
3% by weight gives favorable results. In order to replace part or all of the fluidity and lubricant functions with excipients and binders such as lactose, starch, and crystalline cellulose that have good fluidity, an amount of 5% by weight or more is required. Furthermore, when preparing a capsule preparation in the form of granules rather than powder, the composition of the solid preparation may be made in accordance with that of tablets. However, in this case, the lubricant and/or
Alternatively, a flow agent may not necessarily be added. The capsules thus obtained have a uniform filling volume with rapid dissolution. When a pulverized mixture containing at least β-cyclodextrin and a medicinal ingredient is applied to granules or fine granules, whether the manufacturing method is a dry method or a wet method, excipients to be added and other preparations are required. The additives and their amounts are the same as for tabletting. However, the addition of lubricants and/or flow agents is not always necessary. The granules or fine granules thus obtained have rapid dissolution and adequate strength to prevent pulverization during handling, transportation, etc. Furthermore, it is economical because the granulation yield is good during the manufacturing process. When applying a pulverized mixture containing at least β-cyclodextrin and a medicinal ingredient as a powder, it is necessary to add a flow agent. Further, part or all of the fluidity may be replaced by an excipient or binder with good fluidity such as lactose, starch, or crystalline cellulose. Additionally, flavoring agents and the like can be added freely.
The reason why the amount of flow agent to be added cannot be limited is the same as in the case of tabletting, but in order to obtain the desired flowability, the amount of the additive for formulation is preferably 5% by weight or more. The powder thus obtained has rapid dissolution and good fluidity, so there is little variation in measurements during packaging and it is easy to take. When applying a pulverized mixture containing at least β-cyclodextrin and a medicinal ingredient to various solid preparations, it is extremely effective to use β-1,4 glucan as an additive for the preparation. β-1.4 glucan acts as a binder, increasing the strength of tablets, granules, fine granules, and capsules, and also has a fluidity function, so it is used during the production of tablets, capsules, and powders. also demonstrates its effectiveness. In other words, at least the problems when applying a pulverized mixture of β-cyclodextrin and medicinal ingredients to various solid preparations can be solved by using β-cyclodextrin as an additive for formulations.
The problem can often be solved by using 1.4 glucan. For example, in direct compression tablet manufacturing, β-
Compared to the case of using tablet additives other than 1,4-glucan, the fluidity of the formulation mixture is significantly improved, and the hardness of the tablets can also be greatly increased. The content of β-1.4 glucan in the total composition varies depending on the dosage form, i.e., tablet, granule, fine granule, capsule, or powder, as well as the type and amount of medicinal ingredient. Although this cannot be said unconditionally, it is usually desirable that the content be 5 to 50% by weight. If the amount is less than 5% by weight, the effect will be weak, and if the amount is more than 50% by weight, the increase in the improvement effect will be small. In carrying out mixing and pulverization containing at least β-cyclodextrin and medicinal ingredients, it is difficult to limit the mixing ratio of β-cyclodextrin and medicinal ingredients. This is because the mixing ratio can be appropriately selected depending on the elution rate. However, if, for example, it is necessary to maximize the dissolution rate, it is desirable that the weight ratio of β-cyclodextrin/medicinal ingredient is 40/60 or more. Below this range, the elution rate tends to decrease, which may be undesirable. Mixing and pulverization may be carried out as long as the mixture consists of at least β-cyclodextrin and a medicinal ingredient. and,
The excipients and other pharmaceutical additives referred to in the present invention may be added together with β-cyclodextrin and the medicinal ingredient during mixing and pulverization, or they may be added after the β-cyclodextrin and medicinal ingredient have been mixed and pulverized in advance. It's okay. The former has the advantage of eliminating the need to add excipients and other pharmaceutical additives later, and the latter has the advantage of making mixing and grinding equipment more compact, but they can be used freely depending on the form of use. As excipients and other formulation additives, β
When using -1.4 glucan, this β-1.
An effective method is to add part or all of the 4-glucans together with β-cyclodextrin and the main drug ingredient during mixing and pulverization. The synergistic effect of β-cyclodextrin and β-1,4 glucan further increases the elution rate. Furthermore, it is possible to obtain a powder mixture that does not contain β-1,4 glucan, that is, a powder with lower hygroscopicity and better fluidity than, for example, a mixture pulverization product of β-cyclodextrin and a medicinal ingredient. At this time, it is possible to prevent adhesion and sticking to the grinding equipment and increase the yield of mixed powder. Although it is possible to use the pulverized mixture of β-cyclodextrin, β-1,4 glucan, and medicinal ingredients as it is in tablets, capsules, granules, fine granules, and powders, it is also possible to use excipients. It may be desirable to add other formulation additives.
For example, when making tablets using the direct compression method, the addition of a lubricant such as metal stearate further facilitates the tabletting process, and when making tablets using the wet compression method, the addition of methylcellulose, hydroxypropyl cellulose, etc. is recommended. It is valid. Also in encapsulation, the addition of flow agents and/or lubricants further reduces filling variations in capsules. In addition, excipients, flavoring agents, disintegrants,
Coloring agents can also be added freely. The crushing equipment used for mixed crushing is mechanically crushing,
It has the function of grinding into fine particles, such as a rotary ball mill, a vibrating ball mill, a hammer mill, etc., but the choice is free as long as it does not require the presence of water or a solvent. The time for mixed pulverization varies depending on the type of pulverizer, the amount of sample, the size of the pulverizing power, etc.
Linear diffraction measurements are carried out to such an extent that the presence of diffraction peaks characteristic of crystalline substances is no longer recognized. Even if the mixture is mixed and pulverized more appropriately, it is disadvantageous in terms of energy efficiency and may cause deterioration of the medicinal ingredients. The medicinal ingredients applied to the present invention can be either water-soluble or poorly water-soluble, but the present technology is particularly effective in the case of sparingly water-soluble medicinal ingredients. Here, poorly water-soluble refers to medicinal ingredients that require 30 ml or more of solvent (water in this case) to dissolve 1 g of solute in the table shown in JP General Rules 21, such as caffeine, camphor, dimercaprol, phenoparbital, pyravital,
These include diquitoxin, sulfisoxazole, ampicillin, erythromycin, xatamycin, chloramphenicol, methyltestosterone, phenacetin, and theophylline. Cyclodextrin as used in the present invention is a cyclic oligosaccharide homolog also called Shardinger dextrin or cycloamylose, which is described in detail in, for example, "Food and Science" April issue (1977), p. 97-102, and is 6 to 8 α-
It is a compound with 1 and 4 bonds, and is classified into α, β, and γ-cyclodextrins depending on the number of constituent glucose molecules. The most effective in the present invention is β-
It is a cyclodextrin. In the present invention, β-1,4 glucan is obtained by subjecting vegetable cellulose raw materials such as pulp, linter, and recycled walnuts to acid hydrolysis, chemical treatment such as alkali oxidation, and/or mechanical crushing treatment. Refers to what you can get. Hereinafter, the effects of the present invention will be explained in detail along with Examples. Example 1 Porcelain ball mill with internal volume of 5 (ball diameter 20 to 30
mmφ, number of balls: 20, rotation speed: 90 rpm), add 30 g of pharmacopoeial standard phenacetin and 270 g of β-cyclodextrin [manufactured by Ando Kasei Co., Ltd.], and add 60 g of
Mixed and ground for minutes (sample A). 1.5 g of magnesium stearate was added to Sample A, thoroughly mixed in a plastic bag, and then placed in a cylindrical mold with a cross-sectional area of 1 cm ² to form tablets each weighing 500 mg (molding pressure 2 ton/cm ² ). The tablet hardness of this tablet measured using a Kiya hardness tester was 2 kg or less, indicating that it was brittle and easily broken, making it impractical (Tablet A-1). Crystalline lactose (DMV150 mesh) to 100g of sample A
40g, crystalline cellulose (Asahi Kasei Avicel PH
-301) 60g, magnesium stearate 1
After mixing thoroughly in a plastic bag, compression molding was performed in the above-mentioned cylindrical mold (molding pressure 1 ton/mold).
^cm2 ). The hardness of this tablet was 5 to 6 kg, and the degree of disintegration measured by JP (pure water, 37±1°C, no disk) was as fast as within 1 minute (tablet A-2). When tablets A-1 and A-2 were left for two weeks under the temperature and humidity conditions of 40℃ and 75%RH, A-1 was brittle and could no longer withstand the touch, but A-2 had a hardness of 4. The weight was ~5Kg, and almost no change over time was observed. Example 2 Sample A described in Example 1 was prepared in large quantities. Using sample A, direct compression tablets and wet compression tablets were prepared according to the formulations shown in Tables 1 and 2. For direct compression tablets, mix the powder with a 5-volume V-type blender to make 30 tablets.
1 minute (prepared amount: 500 g), add magnesium stearate in an amount equivalent to 0.5%, and then add 100 g of magnesium stearate.
After mixing for a minute, use a Kikusui Seisakusho RT-S9 tablet machine (8 mmφ, 12R punch, tablet weight 200 mg, tableting speed).
Tablets were prepared at 18 rpm). Wet tablets are made by mixing the raw materials except magnesium stearate in a V-type blender for 30 minutes.
500g), transferred to a kneader 5, mixed for 20 minutes while adding an appropriate amount of 3% methylcellulose paste (add until the wet kneaded material becomes dry), and then using a flat mill (manufactured by Fuji Powdal, screen pore size 3 mmφ). Wet granulate, dry in a hot air dryer at 60℃ for 8 to 10 hours, and pass through a 12-mesh sieve.
Magnesium stearate was added in an amount of 0.5% and mixed, and molded under the same conditions as direct compression tablets. Table 3 shows the results of measuring the tablet weight variation (CV value), tablet hardness, tablet disintegration degree, and tablet hardness after abuse test of the directly compressed tablets and wet compressed tablets obtained in this way.
It was shown to.

【table】

【table】

【table】

[Table] Example 3 According to the method of Example 1, β-cyclodextrin, sulfisoxazole (manufactured by Yamanouchi Pharmaceutical Co., Ltd.)
A 6:4 mixture of was mixed and ground. Lactose (DMV100 mesh) was added to the obtained mixed pulverized product (sample B).
0, 5, 10, 20%, add 1% of magnesium stearate, V
After mixing in a mold blender for 20 minutes, the mixture was filled into No. 3 capsules using a Zanasi capsule filling machine model LZ-64, and variations in filling weight were investigated. The results are shown in Table 4 (the empty capsule weight was subtracted).

[Table] In addition, the C-1 formulation adhered to the spindle of the capsule filling machine when operated for a long time, hindering smooth operation. Example 4 Sulfisoxazole, β-cyclodextrin, crystalline cellulose (Asahi Kasei Avicel PH-
101) were mixed and ground in a ball mill according to Example 1 (the blending recipe is shown in Table 5). However, G-16 to G-18 do not contain crystalline cellulose. In addition, the observation results of the appearance of the powder after mixing and pulverization are shown in the remarks column of Table 5. Lactose (DMV 150 mesh), crystalline cellulose, and carboxymethylcellulose/calcium were added to the obtained pulverized material as shown in Table 6, and blended in a 5-volume V-type blender for 20 min.
Mix for 8 minutes and add calcium stearate.
After mixing for a minute, it was directly pounded according to the method of Example 2.

【table】

[Table] The dissolution rate of the tablets obtained in Table 6 was measured by the rotating basket method according to USP standards (dissolution medium:
water). Adjust the liquid temperature to 37±1°C, and take 2 ml of the test liquid (1 ml for G-1, G-2, and G-16) at regular intervals and transfer it to a 100 ml volumetric flask. 0.1N−
After adding 0.5 ml of NaOH, the volume was made up to 100 ml with pure water, and after being left for 20 minutes, the ultraviolet absorption was measured at a wavelength of 253 nm.
The elution amount was determined from the absorbance according to the calibration curve method. The results are shown in Table 7.

[Table] Example 5 Antibiotic chloramphenicol (Japanese Pharmacopoeia prescribed product) 100mg and β-cyclodextrin 900mg
A stainless steel sheaker mill (Yanagimoto Seisakusho)
It was sealed and crushed. The grinding conditions are: internal volume 80c.c.
There are 17 balls and a ball diameter of 11 mm. The grinding time was 6 hours. Based on the results of the preliminary experiment, the time until the X-ray diffraction diagram showed no crystalline peaks for both chloramphenicol and β-cyclodextrin was measured. An example of measurement conditions for the X-ray diffraction method is as follows. Measurement condition:

[Table] Equipment: The X-ray diffraction equipment is a self-recording X-ray diffraction equipment manufactured by Rigaku Denki.
Mode D-3F type was used. 50 parts by weight of crystalline lactose was added to 50 parts by weight of the obtained mixed pulverized product to prepare a powder. The dissolution rate of this powder is
It was 70% after 10 minutes and 100% after 60 minutes, indicating good fluidity and little variation during packaging, but the lactose-free system had large variations during packaging. Example 6 Mixing and pulverization were carried out with the formulation shown in Table 8, and Example 8
The formulation was carried out according to the following. In order to make a strict comparison, the tablet forming pressure was controlled and
Tablets that disintegrated in 20 minutes were prepared and the dissolution rate was measured. The measurement results are shown in Table 9.

[Table] was added and mixed.

【table】

[Table]
Note that No. 7 and No. 8 had poor moldability and could only yield brittle tablets, but No. 1 to No. 6 gave highly hard tablets. To make firm tablets with No. 7 and No. 8, it is necessary to add appropriate amounts of excipients and binders, such as crystalline cellulose if using the direct compression method, or appropriate amounts of excipients and binders when using the wet compression method. Example 7 Magnetic ball mill with internal volume 5 (ball diameter 20-30
mmφ, 20 balls, rotation speed 80 rpm), put 30 g of pharmacopoeial standard phenacetin, and add 270 g of β-cyclodextrin or β-1,4 glucan [“Avicel” PH-101 manufactured by Asahi Kasei Corporation]. Sample M and Sample N were mixed and ground for 3 hours.
I got it. When an X-ray diffraction diagram was drawn under the X-ray diffraction measurement conditions shown in Example 5, the disappearance of the diffraction peak unique to crystalline substances was observed in Sample M, but in Sample N,
Crystalline diffraction peaks, especially those of crystalline cellulose, remained strong. A mixture of 80% by weight of sample M or sample N, 0.5% by weight of magnesium stearate, and 19.5% by weight of β-1,4 glucan (Avicel PH-302) was thoroughly mixed in a plastic bag and then cut. Tablets each weighing 500 mg were prepared using a cylindrical mold with an area of 1 cm ² (molding pressure of 1.5 ton/cm ² ). The evaluation results of tablet physical properties are shown in Table 10, and the evaluation results of dissolution rate are shown in Table 11.

【table】

[Table] Implemented.
As is clear from the above results, the desired inventive effect can be obtained in a shorter time than the conventional β-1,4-glucan system when β-cyclodextrin is added at the time of mixing and pulverization. Tablets prepared by adding β-1,4 glucan as a formulation additive gave sufficient strength for practical use, had a high dissolution rate from the initial stage, and showed little change in the physical properties of the tablets after the abuse test. Example 8 1 g of each powder with the formulation shown in Table 12 was placed in a stainless steel sheaker mill (Yanagimoto Seisakusho) and pulverized. The grinding conditions are: internal volume 80 c.c., number of balls.
There were 17 balls with a diameter of 11 mm, and the grinding times were 1 hour, 3 hours, 6 hours, and 12 hours. After crushing,
Each sample was subjected to X-ray diffraction under the X-ray diffraction measurement conditions shown in Example 5. The length of mixing and grinding time was evaluated.

[Table] Compared to the sulfisoxazole single system and the sulfisoxazole/β-1,4 glucan mixed system, it takes a long time to lose the X-ray diffraction peak.
The system formulated with β-cyclodextrin clearly showed a rapid mixing and grinding effect. Add 1 part of lactose, 1 part of crystalline cellulose, and 0.03 part of magnesium stearate to 1 part of the 6-hour pulverized sample, and after thorough mixing, form tablets by the method of Example 7, and then apply the dissolution rate measurement conditions shown in Example 4. (However, the paddle method is used instead of a rotating basket)
The elution rate was evaluated.

[Table] The formulations containing β-cyclodextrin No. 2 and No. 3 had a high dissolution rate.

Claims (1)

[Scope of Claims] 1 Consists of β-cyclodextrin, a poorly water-soluble medicinal ingredient, and a pharmaceutical additive;
- A solid pharmaceutical composition characterized in that both cyclodextrin and a sparingly water-soluble medicinal ingredient are dry mixed and pulverized to such an extent that the presence of diffraction peaks characteristic of crystalline substances is no longer observed by X-ray diffraction measurements. 2. The solid pharmaceutical composition according to claim 1, wherein the pharmaceutical additive is β-1,4 glucan. 3. The composition for solid preparation according to claim 2, wherein the content of β-1.4 glucan is 5 to 50% by weight based on the total composition. 4. The solid pharmaceutical composition according to claim 2, wherein β-1.4 glucan is mixed and ground together with β-cyclodextrin and a medicinal ingredient. 5 The pharmaceutical additive consists of β-1,4 glucan and other pharmaceutical additives, and β-1,4 glucan consists of β-1,4 glucan.
The solid pharmaceutical composition according to claim 1, which is mixed and ground together with cyclodextrin and a medicinal ingredient.