JPS625915A - Diltiazem hydrochloride sustained release pharmaceutical and use thereof - Google Patents

Abstract

PURPOSE:To obtain the titled pharmaceutical useful as a remedy for angina pectoris, etc. industrially and advantageously, by adding an acrylic acid resin as a sustained releasing agent in a specific proportion in the form of a solution or dispersion to mixed powder of diltiazem hydrochloride and an excipient and granulating the resultant mixture. CONSTITUTION:An acrylic acid resin, e.g. a copolymer of methyl methacrylate and methacrylic acid, etc., as a sustained releasing agent in an amount of about 5-20% based on the weight of the aimed pharmaceutical is incorporated in diltiazem hydrochloride to afford the titled pharmaceutical. Specifically, diltiazem is incorporated with an excipient, preferably lactose, and an acrylic acid resin solution or dispersion is added to granulate the resultant mixture. The resultant granulated material can be dried, mixed with a lubricant and molded to afford industrially and advantageously the pharmaceutical. The addition of a small amount of the acrylic acid resin permits effective sustained release of the diltiazem hydrochloride and the effective concentration in blood can be maintained for a long period.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a sustained release preparation containing the known medicinal compound diltiazem hydrochloride and a method for producing the same.

Furthermore, the present invention provides a sustained-release preparation of diltiazem hydrochloride, characterized in that the preparation 1 containing diltiazem hydrochloride contains an acrylic acid resin in an amount of about 5 to about 20% based on the weight of the preparation. and its manufacturing method.

Diltiazem hydrochloride exhibits pharmacological activities such as increasing total coronary blood flow, dilating large coronary arteries, and dilating peripheral blood vessels. Diltiazem hydrochloride is an important known pharmaceutical compound used in the treatment of diseases such as improvement of heart disease and treatment of essential hypertension (Handbook of newly developed drugs, 3rd edition, p. 543, 1983). Because it is a pharmaceutical compound used in human body administration, in order for it to fully achieve its desired effect when administered into the human body, diltiazem hydrochloride must be rapidly eluted and absorbed from the administered preparation, and the blood concentration must be temporarily reduced. It is preferable that diltiazem hydrochloride is gradually eluted from the preparation and absorbed over a long period of time, rather than increasing the blood concentration, so that the effect is expressed over a prolonged period of time while maintaining an effective blood concentration.

Because diltiazem hydrochloride is a water-soluble compound, it does not disintegrate immediately in the gastrointestinal tract when administered orally to the human body using conventional formulation techniques, such as tabletting using hydroxypropyl cellulose as a binder. Diltiazem hydrochloride is eluted from the preparation and absorbed all at once, and the blood concentration increases only temporarily and the duration of action is short, so that the desired effect cannot be fully exerted.

Therefore, after a preparation of diltiazem hydrochloride is administered into the body,
It is desired to develop a preparation that is absorbed and maintains an effective blood concentration for a long period of time. Conventionally, as a proposal for a sustained release composition containing a water-soluble active ingredient including diltiazem hydrochloride, a sustained release composition containing diltiazem hydrochloride containing hydrogenated oil in the range of 10% to 80% of the total weight of the formulation has been proposed. A proposal for a sex composition is known (Japanese Patent Publication No. 59-59632). However, a drawback is that relatively large amounts of hydrogenated oil are required to achieve a satisfactory sustained release effect.

The present inventors have conducted research to develop a sustained-release preparation of diltiazem hydrochloride that can achieve a satisfactory sustained-release effect with a reduced amount of sustained-release agent and without any safety problems. .

As a result, the combination of acrylic resin and diltiazem hydrochloride, particularly the combination of acrylic resin and diltiazem hydrochloride in a reduced amount of about 5 to about 20% based on the weight of the formulation, effectively sustained release of diltiazem hydrochloride. It has been found useful to elute and thus achieve a satisfactory sustained release effect that maintains effective blood concentrations for an extended period of time.

Further, the sustained release preparation of diltiazem hydrochloride is prepared by mixing diltiazem hydrochloride and an excipient, and then adding an acrylic acid resin to a solution or dispersion so that the content is about 5 to about 20% based on the weight of the preparation. By adding it in the form of , granulating it, drying the resulting granules, mixing it with a lubricant and molding it,
I learned that it can be manufactured profitably.

Therefore, an object of the present invention is to provide an improved sustained-release preparation of diltiazem hydrochloride and an industrially advantageous method for producing the same.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

31 The sustained release preparation of diltiazem hydrochloride of the present invention is prepared by sieving diltiazem hydrochloride and an excipient, respectively, as desired, and then mixing them as uniformly as possible, and adding the sustained release agent to the resulting mixed powder. The acrylic acid resin is added in the form of a solution or dispersion and granulated, for example, the acrylic acid resin solution or dispersion dissolved or dispersed in water and/or an organic solvent is added and granulated. After drying the resulting granules, for example, by drying them with hot air, for example, after passing them through a sieve to make the particle size uniform,
It can be obtained in the form of tablets by mixing the lubricant as uniformly as possible and molding the mixture. For the above-mentioned granulation, any known granulation means can be used, such as stirring and kneading granulation and fluidized bed granulation.

Examples of excipients used in the method for producing the above-mentioned preparations include lactose, sucrose, glucose, starch, crystalline cellulose, etc. In particular, water-soluble and non-swellable excipients such as lactose are used. is preferable. The amount used can be, for example, about 60% to about 80% of the total weight of the preparation.

In the method of the present invention, the acrylic acid resin used as a sustained release agent is a general term for polymer or copolymer resins derived from acrylic acid, methacrylic acid, and their functional derivatives, such as their alkyl esters. Examples of such acrylic acid resins include polymethylacrylic acid methyl ester, polymethylacrylic acid ethyl ester, polyacrylic acid methyl ester, polyacrylic acid ethyl ester (average molecular weight of about 80,000 or so); acrylic acid and methacrylic acid methyl ester,
Copolymer of acrylic acid and methacrylic acid ethyl ester (including some quaternary ammonium groups, average molecular weight of about 150,000); Copolymer of methacrylic acid and methacrylic acid methyl ester (anionic, average molecular weight of about 1
35,000); a copolymer of polymethacrylic acid and acrylic acid methyl ester; a copolymer of polymethacrylic acid and acrylic acid ethyl ester (anionic, average molecular weight of about 250,000); and the like. These resins can be used alone or in combination in any proportion. These acrylic acid resins are available on the market, and for example, the acrylic acid resin sold under the trade name Eudragit can be cited. The safety of such acrylic acid resins is high, for example, L
Low toxicity results have been obtained with a D5o value of 10 g or more 1/kg (rat, oral administration). The amount of these acrylic acid resins used is preferably about 5% to about 20% of the total weight of the formulation.

Examples of the solvent for dissolving or dispersing these acrylic acid resins include ethanol, inpropatol, methylene chloride, water, or a mixed solvent of these in arbitrary proportions. The amount to be used can be selected as appropriate, and for example, it can be used in an amount that provides a solution of about 5% to about 15% (w/1II) of acrylic acid resin. The dried granules are preferably passed through a sieve of about 24 mesh to make the particle size uniform.

Lubricants include hydrogenated vegetable oils such as hydrogenated castor oil, hydrogenated soybean oil, and hydrogenated cottonseed oil, hydrogenated fish oil, magnesium stearate, calcium stearate, aluminum stearate, stearic acid, magnesium silicate,
Examples include silicic acid, talc, and macrogol.

The amount to be used can be selected as appropriate, and may be, for example, about 1% to about 10% of the total weight of the preparation.

It can be seen that the sustained-release preparation of diltiazem hydrochloride of the present invention prepared in this manner exhibits extremely good sustained release as shown in the dissolution tests of Examples and Comparative Examples described later. A dissolution test was conducted using the diurnal dissolution test paddle method (100 r, p, m, , artificial gastric juice) on a formulation manufactured using the formulation of the comparative example using hydroxypropyl cellulose as a binder instead of the acrylic acid resin. As shown in the figure, dissolution was completed within a short time of about 30 minutes to about 60 minutes, but when the same dissolution test was conducted on the preparations prepared according to the formulations in Examples 1 to 5 of the present invention, As shown in the figure, it was found that the elution was gradual and required more than 180 minutes to complete the elution.

Examples 1 to 3 Formulation Diltiazem hydrochloride and lactose were each sieved through a 100 mesh sieve and then mixed uniformly. Next, a mixed solution of a copolymer of methyl methacrylate and methacrylic acid in ethanol and methylene chloride in equal weights (10%=/w) was added while stirring, kneading, and granulating. After drying the granules with hot air,
The particles were passed through a 24-mesh sieve to ensure uniform particle size. Then hydrogenated vegetable oil was added and mixed uniformly. This has a diameter of 8.0
Tablets each having a weight of 190 cm were obtained using a kinematic of m.m.

Examples 4-5 Prescription *Cocondensation polymer of ethyl methacrylate and trimethylmethacrylethylammonium chloride (average molecular weight approximately 135
000) The same manufacturing operations as those shown in Examples 1 to 3 were carried out to compression mold using a kineter having a diameter of 8.0 mm.

Comparative Examples 1-2 Formulation-10 = Compression molding was carried out using the same manufacturing operation as shown in Examples 1-3 using a kinematic machine with a diameter of 8.0 mm.

Dissolution Test The tablets manufactured in Examples 1 to 5 and Comparative Examples 1 to 2 were subjected to a diurnal dissolution test/J? Dollar method (100?', 7), a,
It was measured using artificial gastric juice, 11).

Elution rate -11=

[Brief explanation of the drawing]

FIG. 1 of the accompanying drawings is a graph showing the results of dissolution tests for the formulations of the present invention prepared in Examples 1 to 5, and FIG.
The figure is a graph showing the results of dissolution tests similar to those in FIG. 1 for comparative formulations prepared in Comparative Examples 1 and 2.

Claims (1)

[Scope of Claims] 1. A sustained-release preparation of diltiazem hydrochloride, which contains about 5 to about 20% of acrylic acid resin based on the weight of the preparation. 2. After mixing diltiazem hydrochloride and excipients, acrylic acid resin is added in the form of a solution or dispersion to a content of about 5 to about 20% based on the weight of the formulation and granulated. . A method for producing a sustained-release preparation of diltiazem hydrochloride, which comprises drying the obtained granules, mixing a lubricant, and then molding.