JPH07330606A - Granule for nicardipine prolonged-action preparation - Google Patents

Abstract

PURPOSE:To obtain granules for a nicardipine prolonged-action preparation useful as a treating agent for angina pectoris and cerebrovascular lesion by coating a nucleus of a small particle, e.g. sugar with layer consisting of crystals of nicardipine or its salt as it is together with an enteric material. CONSTITUTION:A layer consisting of crystals of nicardipine [chemical name: 2,6-dimethyl-4-(3'-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid 3-metyl 5-beta-(N-benzyl-N-methylamino)ethyl ester] or its salt and an enteric material is applied on nuclei of small particles to obtain granules. Subsequently, the obtained granules are further coated with a layer of an enteric material optionally further containing a water-swelling material to obtain the objective granules for a nicardipine prolonged-action preparation. An example of a nucleus of a small particle includes sucrose, crystalline cellulose, a sucrose-starch mixture, etc., and that of an enteric material includes hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to nicardipine (chemical name: 2,6-dimethyl-4- (3'-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-β- (N-benzyl-N-methylamino) ethyl ester] or a salt thereof, for a sustained-release granule.

[0002]

2. Description of the Related Art Nicardipine has coronary vasodilatory action and cerebral vasodilatory action, and is known as a therapeutic drug for angina and cerebral vascular disorders. It is preferable that a drug having this kind of action has a long-lasting effect. In order to make a sustained-release oral preparation, it is necessary to make the preparation enteric.However, since nicardipine and its salts in the crystalline state are poorly soluble in weakly acidic and neutral liquids, such acidity Very insoluble in some intestines. For this reason, the bioavailability of nicardipine from the intestinal tract is extremely low, and a sufficient effective blood concentration cannot be obtained. Therefore, it is difficult to produce a sustained-release preparation using crystals of nicardipine or a salt thereof.

For this reason, conventionally, in order to obtain a sustained-release nicardipine preparation, for example, (a) nicardipine was mixed with hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, etc., and, if desired, polyethylene glycol, a surfactant, etc., in water. Alternatively, a method such as once dissolving in an organic solvent, removing the solvent and then pulverizing the solid obtained, and adding polyethylene oxide thereto (JP-A-56-49314), (b) optionally a pulverizing aid Using nicardipine, which is amorphous by grinding and pulverizing crystals with a ball mill etc. (JP-A-56-133217), and (c) nicardipine or a salt thereof, an enteric base and / or stomach. A solution prepared by dissolving a soluble base and a surfactant in an organic solvent is spray-coated on the small particle nuclei. A method of using granules obtained by coating with amorphous nicardipine (JP-A-58-1164)
No. 14) was known.

[0004]

However, in the above method (a) or (c), a large amount of solvent is required and it takes a long time to remove the solvent, or a highly toxic solvent such as methylene chloride is used. Therefore, it took a long time to completely remove the solvent, and in addition, control was required to prevent environmental pollution due to the use of such a toxic solvent.

Further, in the above method (b), not only it takes time to pulverize nicardipine to make it amorphous, but it also takes a considerable time to reach an effective blood concentration after administration, but it is still effective. There was a drawback that the blood concentration was not maintained sufficiently.

[0006]

The present inventors have found that nicardipine or a salt thereof remains crystalline (that is, without being amorphous) and is placed on a core composed of small particles such as sugar and crystalline cellulose. It was found that when it is coated with an enteric base, it becomes very soluble in a weakly acidic or neutral liquid such as the acidity in the intestine, and based on that, the granules for sustained-release preparations of nicardipine of the present invention are prepared. completed.

That is, the present invention provides a granule for continuous preparation of nicardipine, which comprises a small particle core coated with a layer containing crystals of nicardipine (or a salt thereof) and an enteric base, and the granules. Is a granule for continuous preparation of nicardipine, which is further coated with a layer containing an enteric base or a water-soluble or water-swellable base.

Examples of suitable materials as small particles to form nuclei include, for example, small particles of carbohydrates, in particular:
Sucrose, crystalline cellulose [eg Avicel (trade name):
Asahi Kasei], sucrose-starch mixture, crystalline cellulose-
Examples include particles consisting of a lactose mixture. Among sucrose, for example, nonpareil (Nonpareil (trade name): Freund Sangyo) is particularly preferable. Regarding the solubility of nicardipine in the granules of the present invention, the particle size of the small particles is not particularly limited. For example, when it is filled in a capsule, it can be about 250 to 1500 μm, but it may exceed this range unless there is a problem in the manufacturing process.

An example of the enteric polymer base is Eudragit L [(trade name): component; methacrylic acid / methyl methacrylate copolymer. Methacrylic acid / methyl methacrylate = 1/1: Rohm and Haas Company],
Eudragit S [(trade name): component; methacrylic acid
Methyl methacrylate copolymer. Methacrylic acid / methylmethacrylate = about 1/2], Eudragit LD
[(Trade name): component; methacrylic acid copolymer LD],
Eudragit L100 [(trade name): component; methacrylic acid copolymer L100], and Eudragit LD100
[(Trade name): component; methacrylic acid copolymer LD100
] Acrylic acid copolymer derivative, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and cellulose acetate phthalate. These can be used alone or in combination of two or more.

Examples of the water-soluble or water-swellable polymer base include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, Eudragit E [trade name:
Component: Aminoalkylmethacrylate copolymer E: Rohm and Haas Co., Eudragit RS [(trade name): Component: A copolymer of acrylic acid ester and methacrylic acid ester having a low content of quaternary ammonium group. The content ratio of the quaternary ammonium group to the neutral methacrylate unit and acrylate unit is about 1/4.
0], and polyethylene glycol (for example, polyethylene glycol 4000 or 6000). These may be used alone or in combination of two or more.

Further, each layer may further contain a surfactant and may further contain a glycerin fatty acid ester. If necessary, talc or the like may be further contained in order to prevent the formation of aggregates among the granules.

Examples of the above surfactant include sorbitan monofatty acid ester, polysorbate, polyoxyethylene hydrogenated castor oil, and sodium lauryl sulfate.

Examples of sorbitan monofatty acid esters include sorbitan monolaurate (trade name: Span 20),
Examples include sorbitan monopalmitate (trade name: Span 40), sorbitan monostearate (trade name: Span 60), and the like. Examples of polysorbates include polysorbates 40, 60 and 80 (trade names are Tween 40, 60 and
80). Examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oils 40, 50 and 60 (trade names are HCO-40, 50 and 60 (Nikko Chemicals), respectively).

The granules of the present invention can be manufactured as follows. That is, the enteric base is dissolved in a solvent,
This solution is sprayed onto small particle-shaped nuclei while adding a crystal of nicardipine (or a salt thereof), and coated / granulated by a centrifugal granulation coating method or a fluidized bed coating method. The nicardipine may be added by sprinkling the crystals as they are or by spraying a liquid in which the crystals are suspended. That is, in the present invention, the crystal of nicardipine (or its salt) is crushed or dissolved.
There is no need to make it amorphous by solidification.

When the granules thus produced are further coated with an enteric base material or a water-soluble or water-swellable base material, a conventional method may be used.

If desired, a surfactant may be added to each layer, and a glycerin fatty acid ester may be further added thereto. The amount of the polymer base used in the granules of the present invention is 1/2 with respect to the amount of nicardipine (or its salt).
It is preferably in the range of 0 to 20/1, particularly preferably in the range of 1/2 to 2/1.

[0017]

As shown in the following dissolution comparison test part, the granules of the present invention usually contain nicardipine hydrochloride in a crystalline state even though nicardipine hydrochloride is contained in the crystalline state under weak acidic or neutral conditions. In contrast to the extremely poor solubility observed,
The solubility of nicardipine has been improved to the extent that it has the same solubility as amorphous nicardipine. Therefore, the nicardipine granules of the present invention can sufficiently secure bioavailability from the intestine and can be used for enteric-coated sustained-release nicardipine preparations.

[Dissolution comparison test] Japanese Pharmacopoeia (12th revision)
According to the second dissolution test method, the concentration of dissolved nicardipine in the granules of Example 1 and Comparative Examples 1 and 2 below was measured over time, and the profiles of the dissolution rate of nicardipine were compared. The eluent used was pH 7.2 phosphate buffer, and the number of revolutions was 100 times per minute. The amount of dissolved nicardipine was determined by filtering the solution, diluting the filtrate, and measuring the absorbance.

FIG. 1 shows the results of the dissolution test. As is clear from the figure, the granules of Example 1 show the same excellent elution profile as the granules of Comparative Example 1 with prior art amorphous nicardipine. Also, like the granules of Comparative Example 1,
The dissolution profile of the granules of Example 1 is very good compared to the composition of Comparative Example 2, which is a simple mixture of nicardipine hydrochloride crystals and lactose, with substantially no elution.

[0020]

【Example】

[Example 1] Nonpareils (Nonp) having a particle size of 500 to 750 μm
areil (trade name): Ingredients; crystalline white sugar: Freund Industries)
Put 200 g in a centrifugal fluidized granulator (CF-360 EX type, Freund Sangyo) and roll it. Add 1 Eudragit LD100 to it.
While spraying 1170 mL of an ethanol solution containing a solution of 0% concentration, 117 g of crystalline nicardipine hydrochloride was added as a powder to form a coating around the nonpareil.
Granules were obtained by coating the small granular nuclei with a layer of enteric coated base containing crystalline nicardipine hydrochloride. Then, the obtained granules are coated with a fluidized bed coating device (flow coater mini,
20 g of Eudragit R.
S, 4 g of Macrogol 6000, and 16 g of talc were dissolved and mixed in 400 mL of water / ethanol mixture (1: 4), sprayed onto the granules, dried to give continuous granules containing nicardipine hydrochloride crystals. The present invention granules are obtained.

[Embodiment 2] Eudragit L of Embodiment 1
Example 1 was repeated except that 117 g of Eudragit LD100, 29 g of polysorbate 60, 29 g of glycerin fatty acid ester, and 15 g of talc dissolved in 1170 mL of ethanol were used in place of the 10% ethanol solution of D100. Similarly, the granules of the present invention were obtained.

[Example 3] 200 g of nonpareil having a particle size of 500 to 750 was placed in a fluidized bed coating apparatus (Flow Coater Mini: Freund), and Eudragit LD was added thereto.
Ethanol solution containing 100 dissolved in 20% concentration 585 m
L and crystalline nicardipine hydrochloride 117 g ethanol 500 m
Liquids suspended in L were alternately sprayed to obtain granules in which the small particulate nuclei were coated with a layer made of an enteric base containing crystalline nicardipine hydrochloride. Then, the obtained granules are put into a fluidized bed coating device (Floater Mini), and
20g Eudragit RS, 4g Macrogol 6000,
And 16 g of talc 40 in a water / ethanol mixture (1: 4)
The liquid dissolved and mixed in 0 mL was sprayed and dried to obtain the granules of the present invention.

Example 4 Instead of the ethanol solution containing the Eudragit LD100 dissolved in 20% concentration shown in Example 3, 117 g of Eudragit LD100, 29 g of polysorbate 60, 29 g of glycerin fatty acid ester and
A solution of 15 g of talc dissolved and dispersed in ethanol 585 m
The granules of the present invention were obtained in the same manner as in Example 3 except that L was used.

[Comparative Example 1] 2.6 kg of a methanol / methylene chloride solution (weight ratio 1/1) in which 117 g of nicardipine hydrochloride, 117 g of Eudragit L100 and 29 g of polysorbate 80 (Tween 80) were dissolved in 200 g of nonpareil was sprayed, Obtaining prior art granules based on amorphous nicardipine,
It was set as Comparative Example 1.

Comparative Example 2 To 200 g of powdered lactose, 117 g of crystalline nicardipine hydrochloride was added and mixed to give Comparative Example 2.

[0026]

EFFECTS OF THE INVENTION According to the present invention, unlike the prior art granules for nicardipine sustained-release preparations, nicardipine crystals can be used as they are without the need of making them amorphous by crushing or dissolution, and therefore, the preparation of sustained-release preparations of nicardipine is possible. Not only can the process be simplified, but the use of harmful solvents such as methylene chloride used to dissolve nicardipine can be avoided.

[Brief description of drawings]

FIG. 1 is a graph showing the elution profile of nicardipine from three nicardipine compositions at pH 7.2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/32 C D 47/36 B 47/38 B C D

Claims (7)

[Claims] 1. Granules for a sustained-release nicardipine preparation, comprising a small particle core coated with a layer comprising crystals of nicardipine or a salt thereof and an enteric base. 2. The granule for sustained-release nicardipine preparation according to claim 1, wherein the layer is further coated with an outer layer containing an enteric base or a water-soluble or water-swellable base. 3. The granule for sustained-release nicardipine preparation according to claim 1 or 2, wherein the small particle-shaped core is a particle composed of sucrose, crystalline cellulose, sucrose-starch mixture, crystalline cellulose-lactose mixture. 4. The one or more bases selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, and methacrylate polymer enteric bases. The granules for continuous preparation of nicardipine according to claims 1 to 3, wherein 5. The water-soluble or water-swellable base of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose, aminoalkylmethacrylate-based polymer and polyethylene. The granules for sustained-release nicardipine preparations according to claims 2 to 4, which are one or more polymer bases selected from the group consisting of glycols. 6. The granule for sustained-release nicardipine preparation according to claim 1, wherein any one of the layers further contains a surfactant or a surfactant and a glycerin fatty acid ester. 7. The nicardipine lasting agent according to claim 6, wherein the surfactant is one or more compounds selected from the group consisting of sorbitan monofatty acid ester, polysorbate, polyoxyethylene hydrogenated castor oil, and sodium lauryl sulfate. Granules for sex preparations.