JP2686215B2 - Sustained-release tablets - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a matrix type sustained release tablet which releases a medicinal component at a constant rate.

[0002]

2. Description of the Related Art When a drug has side effects, it is necessary to increase the adaptability of the drug to patients. Sustained-release tablets are formulations that have been developed so that the concentration of the medicinal component dissolved in the blood can be controlled below a certain level or the number of doses can be reduced in order to increase the adaptability of the drug. . It must be possible to maintain the drug effect for a long time by suppressing the dissolution rate in the body and continuously releasing the drug component at a constant low concentration.

There are various types of sustained-release tablets.
For example, there are a matrix type in which a medicinal ingredient is mixed with a water-soluble polymer or a wax and compressed into a tablet, a capsule type in which enteric coated granules containing a medicinal ingredient and a medicinal ingredient are filled, and a compression-molded multiple unit type.

Matrix-type sustained-release tablets are also called diffusion-controlled tablets. The medicinal component is released to the outside of the system by using the concentration gradient of the medicinal component itself caused by the permeation of water as a driving force. The diffusion rate is adjusted by the sustained-release base component. As the sustained-release base component, for example, in the case of a gel matrix type among matrix types, a water-soluble polymer compound such as hydroxypropylmethylcellulose (hereinafter referred to as “HPM
C ") is used. When sustained release tablets are taken, HP
MC and the like form a gel layer on the tablet surface inside the body to suppress the elution of medicinal components. Many of the properties of a sustained release formulation depend on the properties of its sustained release base component. Particularly, the factors such as the molecular weight of the sustained-release base component and the hydration rate (dissolution rate) are factors.

In the case of sustained-release tablets containing a highly water-soluble active ingredient and sustained-release tablets having a high concentration of the active ingredient, the sustained-release base component used suppresses the dissolution rate of the active ingredient. In particular, it is required that the elution suppressing effect is large. Matrix type sustained release tablets are easier and cheaper to manufacture than multiple unit type tablets, and some improvements have already been seen. The sustained-release tablet disclosed in Japanese Examined Patent Publication No. 58-110531 has a viscosity of 800 cP or less in a 2% aqueous solution at 20 ° C. and has a hydroxypropoxyl group substitution degree of 9 to.
12 wt% HPMC is used. Japanese Patent Examination 4-1520
The sustained release tablet disclosed in Japanese Patent No. 8 contains 25.8% by weight or more as a sustained release base component of HPMC in which the viscosity of a 2% aqueous solution at 20 ° C. is 800 cP or more. In this case, the substitution degree of hydroxypropoxyl group of HPMC is 4 to
32 wt%, degree of substitution of methoxyl group is 16-24 wt%
It is.

In the case of these conventional sustained-release tablets, when the medicinal component begins to elute, the sustained-release base component begins to hydrate or dissolve in water and swell, eventually forming a gel layer. However, when the particle size of the sustained-release base is large, the hydration rate of the base is slow and the swelling amount during hydration is large,
There has been a problem that the tablet form collapses before the sustained-release base component sufficiently forms the gel layer, and as a result, the dissolution rate of the medicinal component is not effectively controlled. In addition, the desired hardness could not be obtained even by tableting, and the shape of the tablet was disintegrated at the initial stage of dissolution, so that sufficient sustained release properties were not exhibited in some cases.

[0007] Japanese Patent Publication No. 62-149632 discloses the same HP
Sustained release tablets are disclosed in which MC is used as a matrix base. In this case, HPMC has a viscosity of a 2% aqueous solution at 20 ° C. of 800 cps or more, a degree of substitution of hydroxypropoxyl groups of 7 to 12% by weight, and a degree of substitution of methoxyl groups of 28 to 30% by weight. Particle size is 10
It is adjusted so that 95% by weight or more passes through a 0 mesh sieve.

[0008]

The present invention has been made to solve the above-mentioned problems, and an object thereof is to provide a sustained-release tablet capable of effectively and continuously controlling the dissolution rate of a medicinal component. To do.

[0009]

Means for Solving the Problems In controlling the dissolution rate of a medicinal component in a sustained-release tablet, the inventor of the present invention uses the particle size of HPMC as a sustained-release base component, a methoxyl group and a hydroxypropoxyl group. It has been found that the so-called loose apparent density value has a great influence on the substitution degree, the viscosity when dissolved in water, and the like.

Based on this finding, the sustained-release tablet of the present invention comprises HPMC particles having a degree of substitution of methoxyl groups of 19 to 30% by weight and a degree of substitution of hydroxypropoxyl groups of 4 to 12% by weight. , 95% by weight or more can pass through a 100 mesh sieve, and the loose apparent density is 0.35 g
/ Milliliter or less sustained release base component. 20
The viscosity of a 2% aqueous solution of HPMC at 1000C is 1000 cP
As described above, the HPMC content is preferably 5 to 90% by weight. The loose apparent density is obtained by measuring the weight in a fixed volume without applying force using a powder property comprehensive measuring device.

When the molecular weight of HPMC increases, the elastic strength of the gel upon hydration increases, and HPMC acts to slow down the dissolution rate of the medicinal component. HPMC may be contained in a sustained release tablet in a minimum amount that exhibits such sustained release performance.
It is usually 5 to 90% by weight, preferably 10 to 50% by weight. If it is 5% by weight or less, sufficient sustained release performance may not be obtained, which is not preferable. When it is 90% by weight or more, when the medicinal component is released from the drug and the remaining amount decreases, the dissolution rate may decrease, which is not preferable.

[0012] To obtain HPMC, pulp may be reacted with a predetermined etherifying agent in the presence of an alkali catalyst such as sodium hydroxide. The above-mentioned HPMC used as a sustained-release base component is, for example, HPMC2906, HPMC2208, HPMC2910 of Japanese Pharmacopoeia 12 as a ready-made product.
There is. Such HPMC is manufactured, for example, by Shin-Etsu Chemical Co., Ltd. METOLOSE 60SH-4000, 60SH-.
10,000, 90SH-4000, 90SH-1500
It is also commercially available under the trade names of 0, 90SH-30000, 90SH-100000 and the like. The viscosities of these 2% aqueous solutions at 20 ° C. are 4000 cP and 1 respectively.
0000cP, 4000cP, 15000cP, 300
00cP and 100000cP.

Sustained-release tablets generally contain one or more active ingredients and other necessary pharmaceutical excipients. Examples of the medicinal component include theophylline, aspirin, acetaminophen, etenzamid, ibuprofen, naproxen, propranol, methyldopa, furosemide, nifedipine, pindol, captopril, erythromycin, procainamide hydrochloride, quinic acid gluconate, quinidine sulfate, isosorbite nitrate, Vitamin C, B ₁ , B ₂ , B ₆ , vitamin agents such as folic acid, iron agents such as ferrous sulfate, potassium chloride and the like. It can be effectively contained even when a hydrophilic drug component is used or when the concentration of the drug component must be increased. The amount of medicinal component added is 10 depending on its characteristics.
It is good to set it within the range of up to 95% by weight.

Examples of the medicinal agent additives which are optionally contained together with such medicinal components include excipients, lubricants, stabilizers and surfactants. Among them, examples of the excipient include corn starch, lactose, sucrose and mannose. Examples of the lubricant include magnesium stearate and the like. The lubricant is added to the tablet in the range of, for example, 0.5 to 3.0% by weight.

In addition to the above, a binder is included as a medicinal agent additive in the case of a wet method matrix type sustained release tablet formed by a wet method. The above HPMC serving as the sustained-release base component can also function as a binder in that case, but in addition thereto, any HPMC, hydroxypropyl cellulose, polyvinylpyrrolidone, etc. may be contained. Generally, such binders are used in a proportion of 2-5% by weight of the total weight.

As a method for producing a sustained release tablet, there are a dry method and a wet method. In the case of the dry method, the powdered medicinal component, the sustained-release base component HPMC and the excipient are uniformly mixed in a dry state, and a lubricant is further added and mixed, and the resulting mixture is rotated. Compress using a tablet press. As the HPMC, the above-mentioned HPMC having sufficiently fine and low apparent density is used. In the case of the wet method, the medicinally active ingredient, sufficiently fine HPMC and the excipient are kneaded with a high-speed stirrer or the like using water or an organic solvent or a mixed solvent thereof, and after drying, the dried product is sieved to form granules. Create. The granules thus obtained and other lubricants are mixed and compression molded using a rotary tableting machine.

[0017]

When such a sustained release tablet is taken into the body, the HPMC contained therein rapidly hydrates and swells,
A gel layer is formed on the tablet surface. HPM forming gel layer
The molecular weight of C, the hydration rate, etc. affect the dissolution rate of the medicinal component.

When 95% by weight or more of HPMC particles having a particle size capable of passing through a 100-mesh sieve, they are densely agglomerated with each other when compression-molded to suppress the disintegration of tablets at the initial stage of dissolution and release the excessive drug. Suppress. However, this action also differs depending on the particle size, and if the particle size is large, the density will be slightly rough even if they are aggregated. Loose apparent density affects the compression moldability of such coarsely agglomerated particles. If the loose apparent density is 0.35 g / ml or less, 20
It cannot pass through a 0 mesh sieve, but 95% or more is 1
For particles with a particle size that can pass through a 00 mesh sieve,
The hardness during compression molding is increased and the hydration rate is increased. It is considered that when the loosening apparent density is small, the surface area is increased by that amount, and thereby the compression moldability is improved.

From the above, in the case of the present invention, the disintegration of the tablet, which tends to occur at the initial stage of the elution of the medicinal component, is effectively suppressed, and the release of the excessive medicinal component is also prevented.

[0020]

EFFECTS OF THE INVENTION Since the sustained-release tablet of the present invention has the above-mentioned constitution, the dissolution rate of the medicinal component can be easily controlled to a constant low value, and the medicinal component is continuously released at a constant concentration for a long time. Can be made.

[0021]

Embodiments of the present invention will be described below.

Example 1 Salicylamide and HPMC were uniformly mixed with the composition shown below, and then 3 at 100 kg / cm ² using an IR tableting machine.
Pressurized for 0 seconds to obtain a sustained release tablet. H for HPMC
PMC2910 (60SH-4000 manufactured by Shin-Etsu Chemical Co., Ltd.) was used with a 100-mesh sieve passing rate of 95% by weight or more and a loose apparent density of 0.25 g / ml.

[0023] salicylamide: 200mg HPMC: 50mg (total weight 250 mg) was prepared in the same manner as in Example 1, loose apparent density of 0.3 0
g / milliliter.

[0024] was prepared in the same manner as in Comparative Example 1 Example 1, loose apparent 0.4 density 5
g / ml, or 0.55 g / ml.

Example 3 Theophylline, HPMC, and magnesium stearate were mixed uniformly in a V-type mixer in the proportions shown below, and then tableted according to a conventional method to give sustained-release tablets. As HPMC, HPMC2910 was used in the same manner as in Example 1, a 100-mesh sieve passage rate was 98% by weight or more, and a loose apparent density was 0.3 2 g.
/ Ml was used.

Theophylline: 240 mg HPMC: 60 mg Magnesium stearate: 3 mg (total weight 303 mg) Comparative Example 3 The same procedure as in Example 3 was carried out, except that the 100 mesh sieve passage rate was 80% by weight or more, and the loose apparent density was 0.33 g / It was milliliters.

Example 4 Ethenzamide, HPMC and magnesium stearate were mixed uniformly in a V-type mixer in the proportions shown below, and then tableted according to a conventional method to give sustained release tablets. HPMC2208 (Metroze 90SH-100000 manufactured by Shin-Etsu Chemical Co., Ltd.) was used as the HPMC, and the 100 mesh sieve passage rate was 9
It was used in an amount of 5% by weight or more and a loose apparent density of 0.23 g / ml.

Ethenzamide: 220 mg HPMC: 80 mg Magnesium stearate: 3 mg (total weight 303 mg) Performance experiment Each sustained release tablet obtained in Examples 1 to 4 and Comparative Examples 1 to 3 was subjected to the paddle method of Japanese Pharmacopoeia 12. Therefore, it was dissolved, the elution rate was obtained for each elapsed time, and the dissolution rate was examined from there.
As the test solution, 900 ml of water at 37 ° C was used. The paddle rotation speed was 100 rotations per minute.

The results of Examples 1 to 4 and Comparative Examples 1 to 3 are shown in Table 1.
Shown in In Table 1, the unit of the elapsed time column is time, and the dissolution rate is% by weight.

[0030]

[Table 1]

Loosening than in Examples 1 and 2 and Comparative Examples 1 and 2, when the apparent density was more than 0.35 g / ml, the tablets began to disintegrate at the initial stage of dissolution and temporarily released a large amount of the medicinal component. It was found that the sustained release property of

From Example 3 and Comparative Example 3, it was found that the elution rate of particles having a 100-mesh passage rate of 95% by weight or more exhibits zero-order release behavior. It was found that when the 100-mesh passing rate was less than 95% by weight, the tablet disintegrated in the initial stage of dissolution and a large amount of the medicinal component was temporarily released.

Claims (3)

(57) [Claims] 1. Hydroxypropylmethylcellulose particles having a degree of substitution of methoxyl groups of 19 to 30% by weight and a degree of substitution of hydroxypropoxyl groups of 4 to 12% by weight, 95% by weight or more of which pass through a 100-mesh sieve. A sustained-release tablet characterized by comprising a sustained-release base component having a loose apparent density of 0.35 g / ml or less. 2. The sustained-release tablet according to claim 1, wherein the viscosity of the 2% aqueous solution of hydroxypropylmethyl cellulose at 20 ° C. is 1000 cP or more. 3. The sustained-release tablet according to claim 1, wherein the content of the hydroxypropylmethyl cellulose is 5 to 90% by weight.