KR20010029723A - Low Substituted Hydroxypropylcellulose and Solid Drug - Google Patents

Abstract

PURPOSE: To improve the wettability and significantly shorten the disintegration time of a solid formulation even in the same amount added and formulating composition as those of a conventional formulation by using a specific hydroxypropyl cellulose having a low degree of substitition. CONSTITUTION: A hydroxypropyl cellulose having a low degree of substitution of 0.04-0.1 average number of substituted mol of hydroxypropoxyl groups based on the glucose unit (C6H10O5) is used. The object to which the objective hydroxypropyl cellulose is applied may be a solid formulation requiring the shortening of the disintegration time and, e.g. the hydroxylpropyl cellulose can be added at the time of granulating a tableting powder in the production of a tablet or mixed with the tableting powder after the granulation. Besides the abode hydroxypropyl cellulose, for example, a crude drug, a lubricant such as magnesium stearate, an excipient such as corn starch or lactose or other disintegrating agents or binders may be contained in the solid formulation. When the above hydroxypropyl cellulose is used as a binder for granulation, the amount thereof added is preferably 3-15 wt.% based on the solid formulation. after drying.

Description

Low Substituted Hydroxypropylcellulose and Solid Drug

The present invention relates to a low-substituted hydroxypropyl cellulose and a solid preparation containing the same, which can improve the wettability and can significantly reduce the disintegration time of the solid preparation even in the same amount and combination composition as before.

Low-substituted hydroxypropyl cellulose is one of the most commonly used disintegrants listed in most process documents as a pharmaceutical additive. These disintegrants are added for the purpose of shortening the disintegration time of solid preparations such as tablets, granules, capsules and the like.

Disintegration of tablets is one of the important factors that define the bioavailability of the drug. Absorption of the drug from the digestive tract is said to occur following the disintegration of the tablet and dissolution of the drug by the digestive tract fluid. In recent years, from the viewpoint of the effective use and equivalence evaluation of drugs, dissolution testing of solid preparations such as tablets has been reviewed, and the main idea is that fast-dissolving preparations guarantee efficacy or equivalence. Therefore, there is a demand for tablets that disintegrate faster.

Examples of disintegrating agents include synthetic polymers such as cellulose derivatives such as carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium and low-substituted hydroxypropyl cellulose, starch derivatives such as carboxymethyl starch sodium and partially α-starch, and cross-linked polyvinylpyrrolidone. Ga is widely used. The choice of these disintegrants is judged by the disintegration force (swelling force), moldability, hygroscopicity, coloring stability and compounding suitability of the respective disintegrating agents.

In particular, low-substituted hydroxypropyl cellulose has the advantages of nonionicity, low hygroscopicity, excellent coloring stability, and excellent formulation suitability for most drugs, but other additives depending on the type of drug and the prescription Compared with other cases, the decay time cannot be shortened to the target time, and the improvement has been desired.

The disintegration mechanism of the tablet composed of powder particles is caused by the effect of particles in which liquid (water), such as digestive tract fluid, enters into the tablet through the capillary, and then swells by dissolving a water-soluble substance or wetting of the disintegrating agent. This is achieved by dispersing the constituent particles. Thus, the entry of water into the tablet becomes the first stage of tablet collapse.

The rate of entry of water into the tablet is complicated by factors (R) related to purification, factors (γ and η) related to the test solution, and factors (θ) related to both, as shown by the following Washburn equation. (Design formulation method (1), acquaintances' library, P507, 1971).

L ² = {(Rγcosθ) / (2η)} t

Where L is the length of the wet capillary at time t, R is the radius of the capillary, γ is the surface tension of the solution, η is the viscosity of the solution, and θ is the contact angle of the solid-liquid interface.

Although the disintegration time of a tablet depends on the kind of chemical | medical agent, a compounding quantity, etc., there are not many formulations which are difficult to achieve the target disintegration time under the constraint of the target tablet size, a chemical compounding quantity, and the like. As a general technique for rapidly disintegrating tablets, an increase in the amount of disintegrant added, an increase in porosity inside the tablet, and the like can be considered. However, the method of increasing the amount of disintegrant has a limitation in improving effect because it increases the volume of the tablet, while the method of increasing the porosity may reduce the molding pressure when compacting the powder to form the tablet. There is a problem that the hardness is lowered.

When the tablet disintegration time is the same in the tablet composition, the compounding amount of the disintegrating agent, etc., that is, the voids (capillary radius) in the tablet are the same and the environment (test solution) is the same, the wettability (solid-liquid) is obtained by the above-described wash propagation. The contact angle of the interface).

Low-substituted hydroxypropyl cellulose has a lower wettability than other additives (high contact angle), as seen in Gissinger's report (Drug Dev. Ind. Pharm, 6 (5), 511-536, 1980). ). For example, while the low-substituted hydroxypropyl cellulose is 50 °, the microcrystalline cellulose added for the purpose of improving the formability of tablets is about 20 °, and the cross-linked carboxymethyl cellulose sodium is 0 ° and carboxymethyl starch sodium. Is 0 °, 0 ° and partially crosslinked polyvinylpyrrolidone is 34 °, which is inferior in wettability.

An object of the present invention is to provide a low-substituted hydroxypropyl cellulose and a solid preparation containing the same, which can improve the wettability and can significantly reduce the disintegration time of the solid preparation even in the same amount and blending composition as before.

The present inventors have diligently studied to solve these problems, and as a result, a low-substituted hydroxypropyl cellulose having a mean substitution mole number of hydroxypropoxyl group per glucose unit of 0.04 to 0.1 and a solid preparation containing the same may improve wettability. It was found that the disintegration time of the solid-forming agent can be significantly shortened even in the same amount of additives and compounding composition as before, and the present invention has been completed.

The low-substituted hydroxypropyl cellulose of the present invention can be synthesized by known methods such as those disclosed in Japanese Patent Application Laid-Open Nos. 48-38858 and 57-53100.

In general, hydroxypropyl cellulose means that the average number of moles of hydroxypropoxyl groups per glucose unit (C ₆ H ₁₀ O ₅ ) is 2.0 to 4.2, and the average number of moles of substitution of 0.11 to 0.39 is low-substituted hydroxy. It is called propyl cellulose.

On the other hand, the average substituted mole number of the hydroxypropoxyl group in the low-substituted hydroxypropyl cellulose of the present invention is preferably in the range of 0.04 to 0.1 per glucose unit. The hydroxypropoxyl group exhibits a hydrophobic effect on the wettability. The lower the substitution amount of the hydroxypropoxyl group is, the more hydrophilic the wettability is and the wettability as the disintegrating agent is lowered. Therefore, if the average substituted mole number of the hydroxypropoxyl group is less than 0.04 per glucose unit, the swelling force is greatly lowered, which is not preferable. If the average substitution mole number of the hydroxypropoxyl group is more than 0.1, wettability equivalent to that of the existing low-substituted hydroxypropyl cellulose becomes. Moreover, control of an average substitution mole number is easily achieved by adjusting the addition amount of hydroxypropylating agents, such as propylene oxide made to react with alkali cellulose.

The average number of substituted moles per unit of glucose can be obtained by calculating the% substitution of the hydroxypropoxyl group in accordance with the method of quantifying low-substituted hydroxypropyl cellulose of the Japanese pharmacy room, and converting this.

The object to which the low-substituted hydroxypropyl cellulose of the present invention is applied is applied to any solid preparation for which shortening of the disintegration time is required. For example, in manufacture of a tablet, it can add at the time of granulation of a tableting powder, or can mix with the tableting powder after granulation. In addition, it can add to granulation composition in manufacture of granules, and can mix and mix with a capsule filling powder in manufacture of a capsule.

In addition to the low-substituted hydroxypropyl cellulose of the present invention, the solid preparation may include, for example, a lubricant, a lubricant such as magnesium stearate, an excipient such as corn starch or lactose, other disintegrating agents or a binder, and the like. . That is, even if the low substitution hydroxypropyl cellulose of this invention is used, a conventional compounding composition can be used.

When used as a binder for granulation, the low-substituted hydroxypropyl cellulose of the present invention is preferably added in an amount of 3 to 15% by weight based on the solid formulation after drying, and when mixed with a tableting powder or capsule-filled powder after granulation, It is preferable to add 10 to 10 weight%, and when using as an excipient, it is preferable to add 30 weight% or more. That is, it can use in the range of the same compounding quantity conventionally.

The solid preparation prepared as described above may be subjected to a pharmaceutically acceptable method, for example, film coating or enteric coating.

In the following, the present invention will be described in more detail through examples and comparative examples, but the present invention is not limited to the description of these examples.

<Example 1>

(Measurement of Wetting Time)

500 mg of the sample was put into a 100 ml beaker containing 50 ml of distilled water, and the time until the sample was wet from the water was measured.

(Preparation of tableting powder)

A small fluidized bed granulation apparatus (400 g of acetoaminophen (pulverized powder, manufactured by Yamamoto Chemical Co., Ltd.) and an aqueous solution of 20 g of hydroxypropylmethylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 265 g of purified water as a binder. Granulated powder was prepared by spraying in accordance with a conventional method using Multiplex MP-01, manufactured by Faurex.

(Low substitution)

The propylene oxide used for reaction in the synthesis process of low-substituted hydroxypropyl cellulose was reduced, and it wash | cleaned, dried, and grind | pulverized on the following conditions normally. The average substituted mole number of the hydroxypropoxy group of the obtained powder was 0.1 per glucose unit. In addition, powder physical properties were equivalent to LH-11 used in Comparative Example 1 described later.

(Preparation of tablet)

285 g of the acetoaminophen granulated powder and 15 g of a low-substituted hydroxypropyl cellulose (the average substituted mole number of the hydroxypropoxy group is 0.1) are mixed well, and then magnesium stearate (SM-1000, Sakai Chemical) as a lubricant. 6 g of high school product) was mixed to obtain a tableting powder. The tableting was a rotary tableting machine (RT-S15K-T35, manufactured by Kikusui Seisakusho Co., Ltd.) using a ball of 9 mm in diameter and 12 mm R, and tableted to a tablet pressure of 157 MPa and one tablet of 306 mg.

(Evaluation of physical property)

The obtained tablets were subjected to the disintegration test method of the Japanese Pharmacy Chamber, using purified water as the test liquid, and the disintegration time was measured under the condition that no disk was used. Table 1 shows the wetting time and the disintegration time of the low-substituted hydroxypropyl cellulose.

<Comparative Example 1>

Example 1 using acetoaminophen granulated powder adjusted in Example 1 and low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu Chemical Co., Ltd., the average number of moles of hydroxypropoxyl group is 0.26) It was compressed in the same composition and conditions. Table 1 shows the wetting time and the disintegration time of the obtained low-substituted hydroxypropyl cellulose.

<Example 2>

(Low substitution)

The average substituted mole number of the hydroxypropoxyl group of the powder synthesize | combined similarly to Example 1 was 0.05 per glucose unit. In addition, powder physical properties were equivalent to LH-11 used in Comparative Example 1.

(Preparation of tablet)

Using the acetoaminophene granules prepared in Example 1, the same composition and tableting conditions as in Example 1 were tableted. Table 1 shows the wetting time and the disintegration time of the obtained low-substituted hydroxypropyl cellulose.

<Example 3>

(Low substitution)

The average substituted mole number of the hydroxypropoxyl group of the powder synthesize | combined similarly to Example 1 was 0.09 per glucose unit. In addition, powder physical properties were equivalent to LH-11 used in Comparative Example 1.

(Preparation of tablet)

Using the acetoaminophene granules prepared in Example 1, the same composition and tableting conditions as in Example 1 were tableted. Table 1 shows the wetting time and the disintegration time of the obtained low-substituted hydroxypropyl cellulose.

<Comparative Example 2>

(Low substitution)

The average substituted mole number of the hydroxypropoxyl group of the powder synthesize | combined similarly to Example 1 was 0.03 per glucose unit. In addition, powder physical properties were equivalent to LH-11 used in Comparative Example 1.

(Preparation of tablet)

The acetoaminophene granulated powder prepared in Example 1 was used, and the same composition and conditions as in Example 1 were compressed. Table 1 shows the wetting time and the disintegration time of the obtained low-substituted hydroxypropyl cellulose.

Hydroxypropyl cellulose refine Average Substitution Moles of Hydroxypropoxyl Groups / Glucose Units Wetting time Decay time Example 1 0.1 4.9 seconds 1 minute 44 seconds Example 2 0.05 2.3 seconds 2 minutes 4 seconds Example 3 0.09 3.3 sec 1 minute 47 seconds Comparative Example 1 0.26 11.2 sec 5 minutes 30 seconds Comparative Example 2 0.03 0.8 sec 4 minutes 21 seconds

<Example 4>

(Preparation of tablet)

90 g of the low-substituted hydroxypropyl cellulose of Example 1 and 210 g of chacontang extract powder (cacontang dry extract powder F, Alps Yakuching High School Co., Ltd.) were mixed well, and then magnesium stearate (SM-) was used as a lubricant. 1000 g of Sakai Kagaku Kogyo Co., Ltd.) was mixed to obtain a tableting powder. The tableting was a rotary tableting machine (RT-S15K-T35, manufactured by Kikusui Seisakusho Co., Ltd.) and tableted to a tablet pressure of 142 MPa and one tablet of 303 mg using a ball of 9 mm diameter and 12 mmR. Table 2 shows the wetting time and the disintegration time of the low-substituted hydroxypropyl cellulose.

<Example 5>

The tablet was prepared like Example 4 using the low substitution hydroxypropyl cellulose of Example 2, and the disintegration time was measured. The results are shown in Table 2.

<Example 6>

Tablets were prepared in the same manner as in Example 4 using the low-substituted hydroxypropyl cellulose of Example 3, and the disintegration time was measured. The results are shown in Table 2.

<Comparative Example 3>

Using LH-11 used in Comparative Example 1, tablets were prepared in the same manner as in Example 4, and the disintegration time was measured. The results are shown in Table 2.

<Comparative Example 4>

Using the low-substituted hydroxypropyl cellulose used in Comparative Example 2, tablets were prepared in the same manner as in Example 4, and the disintegration time was measured. The results are shown in Table 2.

Hydroxypropyl cellulose refine Average Substitution Moles of Hydroxypropoxyl Groups / Glucose Units Wetting time Decay time Example 4 0.1 4.9 seconds 27.5 minutes Example 5 0.05 2.3 seconds 33.2 minutes Example 6 0.09 3.3 sec 29.7 minutes Comparative Example 3 0.26 11.2 sec 47.5 minutes Comparative Example 4 0.03 0.8 sec 66.6 minutes

As can be seen from the examples, the low-substituted hydroxypropyl cellulose of the present invention has significantly improved wettability compared to the conventional product (Comparative Example 1), and the collapse time when made into tablets is also significantly shortened.

Extremely low average substitution moles of hydroxypropoxyl groups (Comparative Examples 2 and 4) improve the wettability, but the shortening effect of the disintegration time when made into tablets is greatly reduced or vice versa. This is because the average number of molar substitutions is extremely low, and it is considered that the swelling force is also a result of drastically decreasing.

The low-substituted hydroxypropyl cellulose of the present invention and the solid preparation including the same can improve the wettability, and can significantly shorten the collapse time of the solid preparation even in the same amount and blending composition as before.

Claims (2)

Low-substituted hydroxypropyl cellulose, characterized in that the average number of moles of hydroxypropoxyl groups per glucose unit is 0.04 to 0.1. A solid preparation comprising a low-substituted hydroxypropyl cellulose of claim 1.