JPS61212517A - Long-acting tablet - Google Patents

Abstract

PURPOSE:To obtain a long-acting tablet of a basic water-soluble medicine, enabling the proper and slow release of the medicine independent to the pH of the gastric or intestinal juice, by using ultrafine powder of an enteric polymer base as a polymeric matrix and using a hardened oil as an agent for controlling the release of the medicine. CONSTITUTION:Ultrafine powder of an enteric polymer base (e.g. hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, etc.) having a particle diameter of preferably <=20mu is used as a polymeric matrix and a hardened oil (e.g. hydrogenated rapeseed oil) is used as a release-controlling agent, in a long-acting tablet containing a basic water-soluble medicine (e.g. diltiazem hydrochloride, trimetazidine hydrochloride, dilazep hydrochloride, etc.). The amounts of the enteric polymer base and the release-controlling agent in the whole tablet are preferably 3.5-22W/W% and 7-33W/W%, respectively. The medicine is released from the tablet at a constant rate throughout the stomach and the intestines.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to depots containing basic water-soluble drugs.

Long-acting preparations reduce the number of drug administrations, reduce side effects,
It has many pharmaceutical advantages such as maintaining effective blood concentration. For this reason, various long-acting preparations have been developed in the past, including preparations containing large amounts of substances that are difficult to disintegrate in the stomach or intestines, preparations in which drug granules or tablets are coated with a water-repellent material, and semipermeable membranes. There have been proposed preparations coated with a drug, and preparations in which a poorly soluble or hydrophilic polymer compound is mixed with, adsorbed, or bound to the drug so as to gradually release the drug.

However, the solubility in the gastrointestinal tract, the site of absorption, etc. of the drugs contained in the preparations differ depending on their properties. Generally, basic drugs become more soluble when the pH is acidic, but
Conversely, on the alkaline side, the solubility is lower than on the acidic side. That is, in the gastrointestinal tract,
The acidic nature of the helmet allows for rapid drug release, while the neutral to slightly alkaline nature of the intestines slows down drug release.

Therefore, the present inventors attempted to develop a tablet that would release the drug at a constant rate and be absorbed at a constant rate in the stomach and intestines, and found that the pH of the gastrointestinal fluid
We have completed a long-acting tablet that achieves appropriate and slow dissolution regardless of the

The present invention applies to basic water-soluble drugs such as diltiazem hydrochloride, trimetazidine hydrochloride, and dilazeb hydrochloride. That is, the present invention uses an ultrafine powder enteric polymer base material as a polymer matrix material in matrix tablets designed to allow tablets containing these drugs to dissolve at a desired rate. It consists in using hydrogenated oil as a regulating agent.

The enteric polymer base material used in the present invention includes hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, or carboxymethyl ethyl cellulose, and the particle size thereof is suitably 50 μ or less and 20 μ or less. The enteric polymer base material is preferably in the range of 3.5 to 22 mm based on the total tablet weight.

In addition, it is possible to easily obtain an enteric polymer base material in the form of an ultrafine powder by using a pulverizer such as an atomizer or a jet mill.

The reason for using an ultrafine powder enteric polymer base material is to create a uniform matrix tablet. For example, for comparison with the present invention, particle diameters of 425μ to 180μ and 180μ to
When experiments were conducted using two types of 75μ, elution was completed in 2 hours in both comparative examples, and it was hoped that the effect would be longer lasting. Furthermore, it was found that the dispersion in elution at each time was very large, which caused problems as a formulation. (Table 29 Table 3) However, the one using the ultrafine powder of 20μ or less according to the present invention showed good special effects, and the dispersion in elution at each time was extremely small. (Table 1) On the other hand, in order to control the drug release rate to a desired level, hydrogenated oil is used as a dissolution modifier.

Suitable hydrogenated oils include hydrogenated vegetable oils, such as hydrogenated rapeseed oil, hydrogenated castor oil, and the like. The amount of the adjusting agent is preferably in the range of 7 to 33 cm based on the total tablet weight.

The blending ratio of enteric polymer base material and elution modifier is 1:0, 5
-5% to 1:1-3 is preferred.

In order to produce the preparation of the present invention, in addition to the drug, ultrafine powdered enteric-polymer base material, and hydrogenated oil, K, excipients, binders, and colorants may be optionally used in combination. The preparation of the present invention can be obtained by kneading the mixture with water or alcohol, granulating it, drying it, sizing it, adding a lubricant, and making it into tablets.

Further, the tablets obtained in this manner may be used as products as they are, or may be coated with a film or sugar coating.

Next, the present invention will be specifically explained with reference to the following examples.

Example 1 A composition obtained according to the following formulation was compressed into tablets using an 8Φ, AR punch, and the dissolution was measured.

Prescription (in 1 tablet) Diltiazem hydrochloride 30 rIq Hydroxypropyl methylcellulose 9.3 Tephthalate hydrogenated oil 18.5119 Lactose 125.2η Magnesium stearate 2WI dissolution is Japanese Pharmacopoeia dissolution test method 2 (paddle method), 110
0rp, p) tested with IL2. 3 of 6 tablets
The elution rate over time is shown in Table 1. This result shows good specific effect and also shows that the variation in elution at each time is extremely small.

Table 1 Also, for comparison, the particle size range of hydroxypropyl methylcellulose phthalate in the above formulation is 425 μ to 1
80μ (40~8o mesh) and 180μ~75μ (
A similar experiment was conducted using two types of so~200 metsushun. These results are shown in Table 29 and Table 3.

Table 2 Table 3 Particle size 425
μ to 180 μ Particle size: 180 μ to 75 μ In all comparative examples, elution was completed in 2 hours, and a sustained effect could not be achieved. Furthermore, the dispersion in elution at each time was also very large.

Example 2 The composition obtained in the following formulation (a) t (b) j (C) was compressed into 8Φ, AR tablets, and the dissolution was measured. For comparison, similar experiments were also conducted for formulations (1) and (2).

The results of the elution test are shown in Figure 1 (eluate: pH 1, 2) and Figure 2.
(Eluate: paas). Prescription (a) t
(b), t, and (e) all showed good sustained effects.

Moreover, the eluate pH 1, 2 and a8 showed similar elution properties.

Example 3 In the formulation (a) t (b) t (e) of Example 2, cellulose acetate phthalate was used as the enteric polymer base material.

The results of the elution test are shown in Figure 3 (eluent: pH 12).

Example 4 Prescription (a) of Example 2? (b) In (e), please be sure to use male carboxymethylethyl cellulose as the enteric polymer base material. The results of the elution test are shown in Figure 4 (eluent: pH 1,
2).

Example 5 A composition obtained with the following formulation was compressed into tablets using a 7.5Φ, AR punch, and a dissolution test was conducted.

Prescription (in 1 tablet) Trimetazidine hydrochloride 611F hydrogenated oil
215 kg Lactose 105 m
9 Magnesium stearate 1.5 q
The results of the elution test are shown in Figure 5 (eluate: pH 1, 2)! /
c showed.

Example 6 A composition obtained using the following formulation was compressed into tablets using an 8Φ, AR punch,
A dissolution test was conducted.

Prescription (in 1 tablet) Dilazeb hydrochloride 5011q
Human axypropyl methylcellulose phthalate 9.519 Hydrogenated oil 15,2 Misaki Milk Sugar 11λ3
ηMagnesium stearate 21
The results of the 9 elution tests are shown in Figure 6 (eluent: pH 1, 2).

[Brief explanation of drawings]

Figures 1 and 2 show the formulation of Example 2 (a) t (b) t (
Formulation (1) of the long-acting tablet of the present invention obtained from e) and the comparative example of Example 2? FIG. 3 is a diagram showing the dissolution test results for the tablets obtained from (2) when the pH' of the eluate was 1.2 and 6.8, respectively. Figures 3.4.5 and 6 are diagrams showing the dissolution test results (eluent: pH 1, 2) of the long-acting tablets of the present invention obtained from the formulations of Examples 3, 4.5 and 6, respectively. Oil 14%

Claims (5)

[Claims] (1) A long-acting tablet containing a basic water-soluble drug is characterized by using an ultrafine powder enteric polymer base material as a polymer matrix material and using hydrogenated oil as a dissolution modifier. Long-acting tablets. (2) The long-acting tablet according to claim 1, wherein the enteric polymer base material is hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, or carboxymethyl ethyl cellulose. (3) The enteric polymer base material is 3.5 to 3.5% of the total tablet weight.
The long-acting tablet according to claim 1 or 2, which contains 22 w/w%. (4) Hydrogenated oil is 7 to 33 w/w% based on the total tablet weight
A long-acting tablet according to any one of claims 1 to 3. (5) The long-acting tablet according to any one of claims 1 to 4, wherein the drug is diltiazem hydrochloride, trimetazidine hydrochloride, or dilazeb hydrochloride.