JP4675751B2 - Stabilized pharmaceutical composition containing amlodipine - Google Patents

Description

  The present invention relates to a pharmaceutical composition containing amlodipine.

  Amlodipine is a calcium antagonist having a dihydropyridine skeleton, and is a drug used for the treatment of hypertension and angina. Amlodipine has pharmacologically acceptable salt forms such as maleate, tartrate and fumarate. In Japan, benzenesulfonate (besylate salt, besylate) is approved and sold (hereinafter referred to as amlodipine).

  Calcium antagonists having a dihydropyridine skeleton, such as nifedipine and nicardipine, are liable to discolor and reduce the content of light. Therefore, in order to avoid direct exposure to light, film coating or sugar coating is often applied to shading packaging or naked tablets containing the main drug to prevent alteration.

  In the case of film coating, in order to further improve the stability of the drug to light, blending titanium oxide with the film coating agent skin is used as a conventional technique.

However, when a film coating containing titanium oxide was applied to a bare tablet containing amlodipine, the content of amlodipine was decreased and the decomposition product increased. In order to avoid this problem, it may be possible to reduce the influence by reducing the content of titanium oxide in the film coating film, but the film layer may be thickened to reduce the light shielding effect of titanium oxide. This is necessary, leading to a delay in elution and an increase in process time.

JP-A-2001-81033 discloses an epinastine hydrochloride film-coated tablet in which a polymer film layer not containing a titanium oxide pigment is provided between a naked tablet containing an active ingredient in an epinastine hydrochloride tablet and the colored film layer. Yes. JP 2004-210711 A discloses a naked tablet containing 5-[(1Z, 2E) -2-methyl-3-phenyl-2-propenylidene] -4-oxo-2-thioxo-3-thiazolidineacetic acid, A coating preparation provided with an inner film layer containing at least one layer of titanium oxide or substantially free of titanium oxide and an outer film layer containing titanium oxide, and a method for producing the same are disclosed. Here, it is said that there is a problem that a part of the tablet collapses in the coating machine and the powder adheres to the tablet surface. Thus, the example of the content fall by contact of a dihydropyridine type | system | group chemical | medical agent and titanium oxide is not known.

In addition, in the compounding test of the active ingredient and additives, it is suggested that when silicic acid compounds such as light anhydrous silicic acid, hydrous silicon dioxide and magnesium aluminate metasilicate, which are usually used as fluidizing agents, come into contact with amlodipine, the formation of decomposition products is promoted. discovered.

An object of the present invention is to provide a film-coated pharmaceutical composition containing amlodipine that is stable to light and has no discoloration.

In a film-coated tablet containing amlodipine or a salt thereof, an intermediate layer made of a water-soluble polymer containing no titanium oxide is provided between the outer tablet containing the active ingredient and the outer layer, and a film coat layer containing titanium oxide is applied to the outer layer. . Film-coated tablets that do not discolor due to exposure to light can be obtained without using light-shielding packaging.

That is, this invention provides the following coating formulation and its manufacturing method.

The amlodipine used in the present invention is in the form of a pharmacologically acceptable salt such as maleate, tartrate or fumarate, but besylate is particularly preferred.

Bare tablets containing amlodipine or a salt thereof used in the present invention are produced by granulation by a conventional method such as dry granulation, wet granulation, stirring granulation, fluidized bed granulation, and then tableting. Taking into consideration the influence of moisture on the active ingredient, direct tableting or tableting by dry granulation is preferred. In that case, excipients (for example, lactose, D-mannitol, glucose, crystalline cellulose, starch, anhydrous calcium hydrogen phosphate), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone), disintegrants (for example, , Low-substituted hydroxypropylcellulose, carmellose calcium), a lubricant (eg, magnesium stearate, hydrogenated oil), and one or more adjuvants selected from stabilizers can be contained.

When the active ingredient is sparingly water-soluble like amlodipine of the present invention, surface modification of the active ingredient with a fluidizing agent may be performed to improve dissolution and handling. However, the above-mentioned silicic acid oxide is not preferred as a fluidizing agent because of poor compounding properties. For example, talc, tricalcium phosphate, calcium stearate and the like can be used except for light anhydrous silicic acid, hydrous silicon dioxide and magnesium aluminate metasilicate.

It is preferable to contain 20-60 mass% titanium oxide with respect to a film base in the outer layer provided with respect to the naked tablet containing the amlodipine of this invention or its salt. More preferably, it is 30-40 mass%.

In the present invention, the intermediate layer and the outer layer provided for the uncoated tablet containing amlodipine or a salt thereof contain a water-soluble polymer film base. The water-soluble polymer is a polymer component that is soluble in water, and particularly preferably has a low hygroscopic property and a low swelling property. Examples of the film base include polymer substances used in water-soluble coatings, enteric coatings, sustained-release coatings, and the like. Preferred water-soluble polymers in the present invention include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyvinyl alcohol. They can be used alone or in admixture of two or more.

The coating layer of the preparation of the present invention may contain additives other than the above, such as plasticizers and pigments. Plasticizers include Macrogol 6000, triethyl citrate, and triacetin. Examples of the pigment include titanium oxide (rutile type, anatase type) and yellow ferric oxide. The amount of the plasticizer is preferably less than 65% by mass with respect to titanium oxide in the coating layer. A more preferable content is 50% by mass or less, and particularly preferably 40% by mass or less.

In a film-coated tablet containing amlodipine or a salt thereof, an intermediate layer made of a water-soluble polymer containing no titanium oxide is provided between the outer tablet containing the active ingredient and the outer layer, and a film coat layer containing titanium oxide is applied to the outer layer. . By this method, a film-coated pharmaceutical composition containing amlodipine that is stable to light and has no discoloration can be produced. Film-coated tablets that do not discolor due to exposure to light can be obtained without using light-shielding packaging.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples.
(Composition change test)
Experimental Example Amlodipine besylate and each additive were mixed in a ratio of 1: 1 and mixed uniformly, and then stored openly at 50 ° C. and 75% RH. After 2 weeks, the main drug contained in the tablet 2-[(2-aminoethoxy) methyl] -4- (O-chlorophenyl) -6-methyl-3,5-pyridinecarboxylic acid 3-ethyl ester The ratio of 5-methyl ester to the main drug was determined by high performance liquid chromatography. Measured graphically.

From the results of the blending change test, it was shown that amlodipine promotes the formation of decomposition products when coexisting with titanium oxide and silicate compounds, and among them, hydrous silicon dioxide has a significant adverse effect.

(Stability with and without silicic acid compound)
As an example, light silicic acid anhydride is used as the silicic acid compound.
Example 1
Amlodipine besylate 6.94mg
Crystalline cellulose 97.06mg
Anhydrous calcium hydrogen phosphate 80mg
Carboxymethyl starch sodium 4mg
Hydroxypropylcellulose 10mg
Magnesium stearate 2mg

After the main ingredients and additives other than magnesium stearate are uniformly mixed, magnesium stearate is added and mixed. This mixture is directly compressed by a rotary tableting machine (杵 diameter: 8.0 mm) to obtain 200 mg of uncoated tablets per tablet.

Comparative Example 1
Amlodipine besylate 6.94mg
Crystalline cellulose 96.06mg
Anhydrous calcium hydrogen phosphate 80mg
Carboxymethyl starch sodium 4mg
Hydroxypropylcellulose 10mg
Light anhydrous silicic acid 1mg
Magnesium stearate 2mg

Same as Example 1 except that light anhydrous silicic acid was added.

The obtained preparation was stored openly under the conditions of 50 ° C. and 75% RH, and the ratio of the degradation product of amlodipine contained in the tablet (same as in the experimental example) to the main drug at each time point was measured by high performance liquid chromatography.

Thus, since light anhydrous silicic acid promotes the decomposition of amlodipine besylate, it was shown that a more stable preparation can be derived when amlodipine and light anhydrous silicic acid do not coexist.

(Stability with or without intermediate layer)
Example 2
Uncoated tablet part amlodipine besylate 3.47mg
Crystalline cellulose 48.53mg
Anhydrous calcium hydrogen phosphate 40mg
Sodium carboxymethyl starch 2mg
Hydroxypropylcellulose 5mg
Magnesium stearate 1mg
Intermediate layer hydroxypropylmethylcellulose 3.4mg
Outer layer hydroxypropylmethylcellulose 1.84mg
Polyethylene glycol 6000 0.31mg
Talc 0.26mg
Titanium oxide 0.79mg

After the main ingredients and additives other than magnesium stearate are uniformly mixed, magnesium stearate is added and mixed. This mixture is directly tableted with a rotary tableting machine (杵 diameter 6.0 mm, tableting pressure 400 kg) to obtain 100 mg of uncoated tablets per tablet.

Hydroxypropyl methylcellulose is dissolved in purified water to prepare an intermediate layer coating solution. The tablet was placed in a ventilation drying type coating apparatus and sprayed with an intermediate layer coating solution to obtain a tablet with an intermediate layer.

Hydroxypropyl methylcellulose, polyethylene glycol 6000, talc and titanium oxide are dissolved or dispersed in purified water to prepare a coating solution for the outer layer.
The tablet on which the intermediate layer was applied was placed in a ventilation drying type coating apparatus and sprayed with an outer layer coating solution to obtain a tablet on which an outer layer was further applied.

Comparative Example 2
Uncoated tablet part amlodipine besylate 3.47mg
Crystalline cellulose 48.53mg
Anhydrous calcium hydrogen phosphate 40mg
Sodium carboxymethyl starch 2mg
Hydroxypropylcellulose 5mg
Magnesium stearate 1mg
Non-intermediate outer layer part hydroxypropylmethylcellulose 3.28mg
Polyethylene glycol 6000 0.55mg
Talc 0.46mg
Titanium oxide 0.91mg

In Example 2, the same as Example 2 except that the intermediate layer was not applied and the amount of the outer layer part was changed.

Comparative Example 3
Uncoated tablet part amlodipine besylate 3.47mg
Crystalline cellulose 48.53mg
Anhydrous calcium hydrogen phosphate 40mg
Sodium carboxymethyl starch 2mg
Hydroxypropylcellulose 5mg
Magnesium stearate 1mg
No intermediate layer No outer layer

In Example 2, the same as Example 2 except that the intermediate layer and the outer layer were not applied.

Humidity and temperature stability test The obtained preparation was stored under the same conditions as in Example 1, and the ratio of the degradation product contained in the tablet (same as in the experimental example) to the main drug was measured by high performance liquid chromatography at each elapsed point. did. The stability of amlodipine in each formulation was determined by comparing the ratio of amlodipine degradation products before and after storage.

In Table 3, the preparation having the intermediate layer and the outer layer was almost the same as the preparation not having the intermediate layer and the outer layer, while the preparation having no intermediate layer but containing titanium oxide in the outer layer resulted in inferior results. This indicates that it is more stable that amlodipine and titanium oxide do not contact with each other in an environment of high temperature and high humidity.

Stability test against light The obtained preparation was exposed at a temperature of 25 ° C. under a white fluorescent lamp in a light stability test apparatus (manufactured by Nippon Medical Chemical Co., Ltd.). The preparation was collected at a total illuminance of 600,000 lux · hr, and the ratio of the decomposed product contained in the tablet (same as in the experimental example) to the main drug was measured by high performance liquid chromatography. The stability of amlodipine in each formulation was determined by comparing the ratio of amlodipine degradation products before and after storage.

In Table 4, the coated preparation is more stable to light than the uncoated preparation, but the preparation that does not come into direct contact with the outer layer containing titanium oxide by providing an intermediate layer is more stable. Show.

Claims (3)

In a film-coated tablet containing amlodipine or a salt thereof, an intermediate layer made of a water-soluble polymer not containing titanium oxide is provided between a bare tablet containing the active ingredient and an outer layer, and the outer layer is a film-coated layer containing titanium oxide. A film-coated tablet containing amlodipine or a salt thereof, wherein The film-coated tablet according to claim 1, wherein the bare tablet does not contain a silicate compound. In a film-coated tablet containing amlodipine or a salt thereof, an intermediate layer made of a water-soluble polymer not containing titanium oxide is provided between a bare tablet containing the active ingredient and an outer layer, and the outer layer is a film-coated layer containing titanium oxide. A method for producing a film-coated tablet containing amlodipine or a salt thereof, wherein