JPH10120571A - Diltiazem hydrochloride sustained release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a diltiazem hydrochloride-containing sustained release preparation through an easy process and attain the same levels of elution rate and bioavailability as those of conventional preparation. SOLUTION: This diltiazem hydrochloride-containing sustained release preparation is prepared by filling a capsule with the sustained release component which is prepared by coating the core substance containing diltiazem hydrochloride with a sustained release coating layer and the prompt release component which is prepared by coating the core substance containing diltiazem hydrochloride with or without a prompt release coating layer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sustained release formulation of diltiazem hydrochloride.

[0002]

2. Description of the Related Art Diltiazem hydrochloride is a benzodiazepine derivative having a calcium antagonistic activity, and inhibits the influx of calcium ions into the heart muscle and exerts a strong cardiovascular effect. Therefore, it has been conventionally used as a therapeutic agent for angina pectoris, myocardial ischemia and hypertension. Diltiazem hydrochloride, when administered orally, shows a plasma peak at 2 to 3 hours after administration and a half-life in blood concentration of about 4.5 hours. Needed.

[0003] However, since such frequent drug administration reduces patient compliance, in order to maintain the blood concentration of diltiazem hydrochloride, diltiazem hydrochloride coated with a dense coating of a hydrophobic polymer or the like must be used. Sustained-release preparations have been developed. However, such a preparation is suitable for gradually dissolving the pharmaceutically active ingredient after administration, and as soon as an effective blood concentration is obtained, the effective blood concentration is controlled by controlling the dissolution rate over a long period of time. It is also known that it is difficult to hold.

[0004] On the other hand, there has been proposed a method of controlling the release of a pharmaceutically active ingredient by coating the pharmaceutically active ingredient by selecting a kind of a polymer substance and adjusting the film thickness or porosity. But reached the effective blood concentration immediately after administration,
Moreover, it has been difficult to produce a preparation that maintains its effective blood concentration for a long time at low cost and with an easy method.

[0005]

According to the present invention, a core material containing diltiazem hydrochloride is coated with a sustained-release component and a core material containing diltiazem hydrochloride is coated with a fast-dissolving film. There is provided a diltiazem hydrochloride sustained-release preparation comprising a capsule and a fast-dissolving ingredient which is not coated or coated.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The sustained-release preparation of diltiazem hydrochloride according to the present invention comprises a sustained-release component obtained by applying a sustained-release coating to a core substance containing diltiazem hydrochloride, and a fast-dissolving property in a core substance containing diltiazem hydrochloride. The capsules may be filled with a fast-dissolving component, coated or uncoated. The sustained-release component is obtained by applying a sustained-release coating to a core substance containing diltiazem hydrochloride. The core substance is prepared by mixing diltiazem hydrochloride and optionally additives such as excipients, lubricants, and binders in a manner known per se, for example, wet extrusion granulation, fluidized bed granulation, and tumbling granulation. It can be obtained by forming into granules, for example, granules by a method, a pan coating method or the like. The size of the core material is not particularly limited and may be, for example, about 3
About 00 to 2000 μm.

[0007] The sustained-release coating covering the core substance is a polymer substance which is insoluble or slightly soluble in water, for example, ethyl cellulose, cellulose acetate, benzylaminomethyl cellulose, carboxyethyl cellulose, carboxypropyl cellulose, carboxymethyl cellulose phthalate. , Polyvinyl acetoacetal phthalate,
1 such as methacrylic acid / methyl methacrylate copolymer
To the polymer substance of the species or a combination of two or more, optionally, additives such as higher fatty acids and inorganic substances, and dissolved and suspended in an organic solvent such as ethanol, methanol, isopropanol, acetone and toluene, preferably ethanol. It can be formed by using the same. Here, the organic solvent may be a single organic solvent or a combination of organic solvents, and further contains an acceptable amount of water (for example, about several% v / v). Is also good. That is, when the porosity is a problem in the sustained release coating, the mixing ratio of water and the organic solvent is important, but in the present invention, the porosity of the sustained release coating itself is not particularly problematic. Therefore, an organic solvent that can dissolve the polymer substance can be used alone.

The coating can be formed by a method known per se, for example, by spray coating a coating solution on the core substance by a fluidized bed coating method, a pan coating method or the like. The fast-dissolving component can be produced as granules containing diltiazem hydrochloride by the same method as the above-mentioned method for producing the core substance. When a fast-dissolving film is formed, a water-soluble polymer substance (polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, etc.) is dissolved in water, a mixed solution of water and an organic solvent, and a method known per se The coating liquid can be spray-coated on the core material. The fast-dissolving component does not necessarily need to be in the form of granules (fine granules, granules, etc.), and may be used as it is in a powder form.

The above-mentioned sustained-release component and fast-dissolving component are filled in a capsule at a fixed ratio. The ratio at this time is appropriately adjusted so that the effective blood concentration can be quickly reached after administration by the action of the fast-dissolving component, and the effective blood concentration can be maintained for a long time by the sustained-release component. Preferably, the sustained-release component is 90 to 7
It is preferable to fill the capsules with a weight ratio of about 0:10 to 30. Optionally, an additive such as a lubricant is added to the sustained-release component and the fast-dissolving component in an amount of about 2 to 0.5% based on the total weight of the sustained-release component and the fast-dissolving component. You may.

As the capsule, a gelatin capsule or the like having an appropriate volume usually used for a pharmaceutical preparation can be used, and the capsule may be optionally coated with a gastric or enteric coating film.

[0011]

EXAMPLES The sustained-release formulation of diltiazem hydrochloride in the present invention will be described based on the following examples. Example 1: Formulation In this example, diltiazem hydrochloride sustained release formulation
It was manufactured based on the manufacturing flow shown in FIG.

First, examples of formulation of sustained-release granules and fast-dissolving granules contained in a sustained-release formulation of diltiazem hydrochloride are shown below. -Formulation example of fast-dissolving granules (1 capsule) Diltiazem hydrochloride 15.0 mg Excipient (lactose) 17.0 mg Total 32.0 mg Based on the above formula, 85 parts by weight of diltiazem hydrochloride (manufactured by Daito Co., Ltd.) , 46 parts by weight of crystalline cellulose and 51 parts by weight of lactose are mixed and granulated to obtain spherical granules to obtain a core substance. At this time, the average particle size of the core material was about 900 μm.

Next, the spherical core material was coated with a coating machine to obtain sustained release granules. The coating solution at this time was prepared by adding 1.75 parts by weight of stearic acid and 1.75 parts by weight of talc to 27 parts by weight of Eudragged RS-100 (aminoalkyl methacrylate copolymer, manufactured by Laem Pharma Co., Ltd.). What was dissolved and suspended in ethanol was used.

[0014] Stearic acid, due to its hydrophobic nature, delays the ingress of water from the coating into the core material of the drug, thereby delaying the release of the drug. On the other hand, talc is for preventing adhesion of grains. Also, based on the above prescription,
15.0 parts by weight of diltiazem hydrochloride and 17.0 mg of lactose were mixed and granulated to obtain fast-dissolving granules having an average particle size of about 800 μm. 212.5 mg of the sustained release granules obtained above
And 0.5 mg of talc to 32.0 mg of fast-dissolving granules,
By filling the capsules, diltiazem hydrochloride 10
A once-daily sustained-release capsule containing 0 mg was obtained.

Example 2: Dissolution rate The dissolution rate of the three sustained-release capsules containing diltiazem hydrochloride obtained in Example 1, water, a pH 6.8 aqueous solution, a pH 4.0 aqueous solution, and a pH 1.2 aqueous solution was determined. It was measured. The results are shown in FIGS. From the results of FIGS. 2 to 5, all of the sustained-release capsules containing diltiazem hydrochloride of the present invention,
It was confirmed that water and any aqueous solution gradually eluted over 15 to 24 hours.

Example 3 Bioequivalence test The sustained-release capsule containing diltiazem hydrochloride (containing 100 mg of diltiazem hydrochloride) obtained in Example 1 was orally administered to humans (n = 12) together with 150 ml of water. And examined bioequivalence. FIG. 6 shows the result. FIG. 6 shows the average blood concentration of twelve subjects at each time. As is clear from FIG. 6, the sustained-release capsule of diltiazem hydrochloride of the present invention shows a blood peak at about 15 hours after administration, and a blood peak of diltiazem hydrochloride that has not been treated at all (2 to 3 hours after administration). ) Was observed very late.

[0017]

According to the present invention, a sustained-release preparation containing diltiazem hydrochloride can be produced by an easy production method, and the rapid-dissolving component of diltiazem hydrochloride dissolves promptly after administration, thereby promptly dissolving it. A desired blood concentration can be achieved, and the sustained-release component of diltiazem hydrochloride is gradually released into the blood, whereby the desired blood concentration can be controlled, and the same level as that of a conventional formulation can be obtained. Dissolution rate and bioavailability can be obtained.

[Brief description of the drawings]

FIG. 1 is a view showing a production flow of a preparation of the present invention.

FIG. 2 is a graph showing the dissolution rate of the preparation of the present invention in water.

FIG. 3 is a graph showing the dissolution rate of the preparation of the present invention in an aqueous solution having a pH of 1.2.

FIG. 4 is a graph showing the dissolution rate of a formulation of the present invention in an aqueous solution of pH 4.0.

FIG. 5 is a graph showing the dissolution rate of a formulation of the present invention in an aqueous solution of pH 6.8.

FIG. 6 is a graph showing changes in plasma concentration after oral administration of the preparation of the present invention.

Claims (1)

[Claims] 1. A sustained-release component in which a core material containing diltiazem hydrochloride is provided with a sustained-release coating, and a fast-dissolving component in which a core material containing diltiazem hydrochloride is coated or not coated with a fast-dissolving film. A sustained release formulation of diltiazem hydrochloride, wherein is filled in a capsule.