KR100839283B1 - A film-coated amlodipine preparation - Google Patents

Abstract

The present invention relates to film-coated granules containing amlodipine, its optical isomers or pharmaceutically acceptable salts thereof. The film-coated granules of the present invention prevent the degradation of amlodipine by blocking moisture and light to provide an amlodipine formulation having improved stability.

Amlodipine, S-Amlodipine, Film Coated Granule, Stability

Description

A film-coated amlodipine preparation containing amlodipine and salts thereof

1 is a graph showing the dissolution rate at pH = 1.2 of the amlodipine maleate film-coated granules of Examples 1 and 2 (Example 1 and ΔExample 2),

2 is an HPLC picture of amlodipine maleate,

Figure 3 is a HPLC picture at the time of manufacturing the film-coated granules,

Figure 4 is an HPLC picture after 3 months under accelerated storage conditions of film-coated granules.

The present invention relates to a film-coated granule with increased stability containing amlodipine, its optical isomers or pharmaceutically acceptable salts thereof, and more particularly, to amlodipine malate and S-amlodipine malate film-coated granules. . Amlodipine is a calcium antagonist of the dihydropyridine family and is used to treat hypertension. On the other hand, S-amlodipine, an optical isomer of amlodipine, substantially lowers blood pressure, and another isomer, R-amlodipine, is known to show side effects such as headache and drowsiness.

In Korean Patent Laid-Open Publication No. 2003-0070594, since impurities such as amlodipine aspartate and amlodipine pyridine analogues are produced when the 20% weight aqueous slurry of the amlodipine maleate composition is pH 7.0 or higher or 5.5 or lower, the pH is adjusted to 5.5 to Formulations with increased stability by controlling within 7 ranges are described.

Republic of Korea Patent Publication No. 10-2006-0084892 introduces the content of amlodipine maleate tablets with improved stability. The patent states that the use of small amounts of pharmaceutically acceptable additives produces less than 1% impurities.

In Korean Patent Laid-Open Publication No. 10-2006-0073830, it was pointed out that the development of coating amlodipine salt formulations was difficult to commercialize into new formulations of the same administration route, and the storage stability of the same formulation as that of the existing formulations was ensured by containing molten material. The formulation is described.

In Korean Patent Laid-Open Publication No. 10-2005-0075705 and the Korean Journal of Pharmaceutical Sciences (2004), Volume 34, No. 5, 407-411, the amplification of amlodipine was performed while securing a stable bioavailability with sufficient dissolution rate through the coating of amlodipine maleate itself. A pharmaceutical composition of amlodipine maleate formulations that can be prevented is described.

In addition, US Patent 2005 / 0170003A1 also describes a composition to which an appropriate acid is added to prevent the generation of impurities in the amlodipine maleate.

Republic of Korea Publication No. 10-2006-0073830 and Journal of the Korean Pharmaceutical Society (2004), Volume 34, No. 5, 407-411 introduce the dissolution patterns of the commercially available amlodipine salt formulations. Herein, most amlodipine formulations are tablets or primary granules with amlodipine salts and excipients, and granules of a certain size are selected and compressed into tablets. The dissolution rate is about 80-95% in 10 minutes. In particular, page 6 of the Republic of Korea Publication No. 10-2006-0073830 Table 4 describes the instability of the amlodipine salt formulation to a degree of 13.2% of the total amount of flexible substances in a high-density polyethylene (HDPE) packaging of commercially available products, resulting in 13.2% of the total soft substance Doing.

In the prior art, in the case of Korean Patent Application Publication No. 10-2005-0075705, in order to avoid contact with other excipients, a commercially available material under the trade names OPADRY and Eudragit is selected and coated with amlodipine malate itself, and then sieved through No. 35 sieve. The tablets are prepared by selecting the particles by size and then mixing the mixture with an appropriate excipient. In such a case, it is inevitable that the cumbersome process and the reduction in yield are inevitable because the size of the particles coated with amlodipine maleate itself and the uniformity of the coating must be maintained to maintain uniformity of the coating. In addition, it uses OPADRY series and Eudragit series which are expensive and imported as coating materials.

The composition of Korean Patent Laid-Open Publication No. 2003-0070594 has a disadvantage in that it cannot have stability even when the excipient is selected and prepared to have a pH of 5.5 to 7.0.

In addition, Korean Patent Laid-Open Publication No. 10-2006-0084892 discloses amlodipine maleate and a minimum of excipients mixed with apples using No. 30 sieve to granule 1, and another excipient including microcrystalline cellulose is mixed with apples to granule 2 to double. The hassle of making double tablets by tableting and the compositions can be simply mixed with apples to produce granules, which may result in differences in composition particle size.

The present invention provides a composition comprising amlodipine salt and excipients in a drug support such as sugar granules (sugar spheres) having an appropriate size without producing primary granules or fine particles of a constant size, such as Korean Patent Publication No. 10-2005-0075705 Spray-dried to form a drug layer, and spray-dried a film solution composed of titanium oxide for the purpose of light shielding and cellulose derivatives used for water blocking and film-forming bases to form a film-coated granule to produce a film-coated granule do. On the other hand, the film coating layer can be prepared by spray-drying a film solution containing a disintegrating agent or surfactant in addition to the cellulose derivative and titanium oxide to promote the disintegration of the film coating layer.

In the present invention, the entire process of manufacturing the drug layer and the film coating layer has the advantage that it can be carried out uniformly in the fluidized bed spray coating machine can proceed without cross-contamination and loss of yield by the separation of the process.

In addition, when the outer layer is a film-coated granule as in the present invention, the drug is not released until the film layer disappears, and the drug is not released during the disintegration time of the capsule filled with the film-coated granules. This might be different. Thus, in the present invention, a disintegrating agent or a surfactant was added to the film coating layer in order to control the drug release rate, thereby achieving a dissolution rate similar to that of commercially available tablets, thereby completing a formulation that is stable to light and moisture.

In the present invention, the film-coated granules of amlodipine, its optical isomers or pharmaceutically acceptable salts thereof are similar to those of commercially available formulations, and the entire process of the formulations is carried out uniformly in a fluidized bed spray coater to achieve cross contamination and yield. It is to provide a hypertension treatment prepared by spray drying without loss. It is another object of the present invention to prepare a drug layer of a predetermined size by spray-drying a drug and an excipient onto a drug support such as sugar granules, without preparing the primary granules or fine particles, the hypertension therapeutic agent, and the drug layer of the water blocking and shading To provide a method for producing a film-coated granules by spray-drying a film solution composed of a cellulose derivative and titanium oxide for the purpose to form an outer layer, and further comprising a disintegrating agent or surfactant to promote disintegration of the film layer In providing a high blood pressure treatment excellent stability to form.

The composition of the present invention is the drug layer of amlodipine which is a therapeutic agent for hypertension, its optical isomers or pharmaceutically acceptable salts thereof, drug support such as sugar granules, binder such as hydroxypropylmethylcellulose 2910 (hereinafter HPMC2910), It contains a disintegrant such as sodium starch glycolate to promote disintegration of the drug layer, a plasticizer such as triethyl citrate, and the film coating layer includes a titanium oxide, a light shielding agent, and an HPMC 2910, which is a film forming agent and has a water blocking effect. . In addition, the film coating layer is composed of a film coating agent added with a disintegrating agent or a surfactant to promote disintegration of the film.

In addition, the present invention includes a method for producing a hypertension comprising the following steps.

1. Drug layer preparation process: amlodipine, its optical isomer or pharmaceutically acceptable salt thereof, binder such as HPMC2910, disintegrant such as sodium starch glycolate, plasticizer such as triethylcitrate, spray nozzle when sprayed Preparing a drug layer by spray-drying the sugar granules by dissolving or dispersing hard silicic anhydride in ethanol to prevent clogging and to prevent static electricity.

2. Film coating layer manufacturing process: preparing a film coating layer by dissolving or dispersing titanium oxide, a light shielding agent, and a water barrier agent and HPMC2910, a film coating layer forming agent, in ethanol on the outside of the drug layer.

3. In addition, the film coating layer may be prepared by spray-drying a film solution including a titanium oxide, HPMC2910, a surfactant such as Tween 80, or a polypyrrolidine-based disintegrant in addition to the film coating layer of the second step.

Hereinafter, a method for preparing a hypertension therapeutic agent according to the present invention will be described in detail.

In the present invention, amlodipine, its optical isomers or pharmaceutically acceptable salts thereof, preferably amlodipine malate, S-amlodipine malate, are added within a range of safe amounts that do not cause adverse effects on the human body.

The disintegrant used in the drug layer may be any disintegrant used in the pharmaceutical, but preferably the most widely used sodium starch glycolate is 0.01 to 20% by weight, preferably 0.1 to 5% by weight of the total drug layer. % May be added.

The HPMC2910 as the film forming layer base may be added at 0.01 to 40% by weight, preferably 0.01 to 20% by weight of the total weight of the drug layer.

The disintegrant or surfactant used in the disintegration of the film coating layer used in the present invention may be added at 0.01 to 30% by weight, preferably 0.1 to 10% by weight of the HPMC2910 weight of the film forming layer base.

The plasticizer may be added an appropriate amount of polyethylene glycol, propylene glycol, glycerol, triethyl citrate and the like widely used in the pharmaceutical.

In addition, in the present invention, in order to prevent the amlodipine from generating impurities by light, titanium oxide may be added as 0.1 to 50% by weight, preferably 1 to 40% by weight of the weight of HPMC2910, which is a film forming layer base, as a light shielding agent.

In the production of the film-coated granules of the present invention, the fluidized bed granulator GPCG 3.1 (machine name: GLAT) was used, and the inlet temp. Was 45-55 ° C. under the spray drying conditions of the drug layer and the film-coated layer, and the product temperature ( Product Temp.) Is mainly manufactured within the range of 40-50 ℃ and Exhaust Temp. 40 ~ 50 ℃, but it is possible if the granules of the drug layer or the film coating layer do not aggregate together.

The present invention will be described in more detail in the following examples, but the present invention is not limited to the following examples.

Example 1

Drug layer

Sugar granules (25 mesh) 310 g

HPMC2910 10.85g

Triethyl citrate 1.55 g

4.65 g sodium starch glycolate

Light anhydrous silicic acid 1.55g

Amlodipine Maleate 9.95g

Ethanol anhydrous 496 g

Film coating layer

HPMC2910 3.1 g

Titanium oxide 0.9g

Ethanol Anhydrous 46.5g

First, 310 g of sugar granules (25 mesh) are put into a granulator chamber, and separately, 496 g of anhydrous ethanol, 10.85 g of HPMC2910, 1.55 g of triethyl citrate, 4.65 g of sodium starch glycolate, 1.55 g of hard silicic anhydride and 9.95 g of amlodipine malate Suspended liquid was spray-dried according to the conditions of Table 1 below to prepare a drug layer. The drug layer was spray-dried in accordance with the film coating conditions of Table 1 below to disperse the HPMC2910 3.1g and 0.9g titanium oxide in 46.5g of anhydrous ethanol to prepare a film-coated granules. At this time, the gross income rate was 99.1%.

[Table 1] Process conditions of drug layer and film coating layer

Example 2

Drug layer

Sugar granules (25 mesh) 310 g

HPMC2910 10.85g

Triethyl citrate 1.55 g

4.65 g sodium starch glycolate

Light anhydrous silicic acid 1.55g

Amlodipine Maleate 9.95g

Ethanol anhydrous 496 g

Film coating layer

HPMC2910 3.1 g

Titanium oxide 0.9g

Twin 80 0.08 g

Ethanol Anhydrous 46.5g

Performed according to the manufacturing conditions of Example 1, but the film coating granules were prepared by adding a twin 80 in the film coating. At this time, the total yield was 99.0%.

Example 3

Drug layer

Sugar granules (25 mesh) 310 g

HPMC2910 10.85g

Triethyl citrate 1.55 g

4.65 g sodium starch glycolate

Light anhydrous silicic acid 1.55g

Amlodipine Maleate 9.95g

Ethanol anhydrous 496 g

Film coating layer

HPMC2910 3.1 g

Titanium oxide 0.9g

Polyvinylpyrrolidine 0.08g

Ethanol Anhydrous 46.5g

Performed according to the preparation conditions of Example 1, but was prepared by adding polyvinylpyrrolidin to the film coating layer, the total yield was 98.9%.

Example 4

Drug layer

Sugar granules (25 mesh) 310 g

HPMC2910 0.85g

Triethyl citrate 1.55 g

4.65 g sodium starch glycolate

Light anhydrous silicic acid 1.55g

S-Amlodipine Maleate 4.98g

Ethanol anhydrous 496 g

Film coating layer

HPMC2910 3.1 g

Titanium oxide 0.9g

Ethanol Anhydrous 46.5g

A film-coated granule was prepared according to the preparation conditions of Example 1 but using S-amlodipine maleate as the main component instead of amlodipine maleate. At this time, the total yield was 99.1%.

Experimental Example 1 Filling of Film Coated Granules

The granules of Examples 1 and 2 were filled into hard capsules with a film-coated granule corresponding to 6.42 mg as amlodipine maleate.

Experimental Example 2: For Testing Stability of Packaging Containers

Hard capsules of Example 1 were placed in HDPE containers, respectively, and tested for stability of packaging containers under accelerated storage conditions of 40 ± 0.5 ° C. and 75% RH.

Experimental Example 3 Dissolution Test

Using a hard capsule filled with the film-coated granules of Example 1 according to the dissolution test method No. 2 of the 8 general test method of the Korean Pharmacopoeia, 500 mL of 0.01M hydrochloric acid at a stirring speed of 75rpm, 37 ± 5 ℃ conditions as elution medium The elution rate for 30 minutes was measured by the following HPLC operating conditions and shown in FIG. 1.

HPLC operating conditions

  HPLC: Agilent 1100

  Column: Octadecylsilylated silica gel, particle size 5μm, inner diameter 4.6mm * length 250mm

  Mobile phase: Acetonitrile. Methanol. Solution A * 1) = 15: 35: 50

  Flow rate: 1.5 mL / min

  Wavelength: 237 nm

  Main volume: 10 uL

  Column temperature: 30 ℃

※ 1) Solution A: 7.0 mL of triethylamine is dissolved in 1L of water, and then adjusted to pH 3.0 ± 0.1 with phosphate solution.

Experimental Example 4: Changes in moisture through packaging container stability tests

Table 2 shows the moisture changes of the film-coated granules, which were carried out at the time of manufacture and after 3 months in accelerated storage at 40 ± 0.5 ° C. and 75% RH with the hard capsules of Examples 1 and 2.

Table 2 Changes in moisture after 3 months according to accelerated storage conditions of Examples 1 and 2

Experimental Example 5: Change of Impurities through Stability Test of Packaging Containers

The HPLC picture of the film-coated granules carried out after 3 months in accelerated storage at 40 ± 0.5 ° C. and 75% RH with the hard capsule of Example 1 is shown in FIG. 4, and the amlodipine maleate itself used in the film-coated granules for comparison thereto. The HPLC picture at the time of manufacture is shown in FIGS. 2 and 3, respectively. In addition, the amount of each impurity and the total impurity shown in the HPLC figure are shown in Table 3.

[Table 3] The amount of impurities according to the accelerated storage conditions of the film-coated granules of Example 1 (%)

As can be seen from the above experimental results, the film-coated granules produced in the present invention had little change in moisture in the accelerated storage condition test after 3 months, and the generation of impurities was increased slightly by about 0.25% compared to the time of manufacture, improving stability. It was found. In addition, when the dissolution rate in the pH = 1.2 (gastric juice) of Figure 1, it was found that the dissolution rate of 80 ~ 90% at 10 minutes of dissolution start.

The film-coated granules containing amlodipine, the optical isomers thereof or salts thereof of the present invention secured stability by minimizing the contact of light with moisture, and showed similar dissolution patterns as commercially available tablets. In addition, it was possible to provide a high blood pressure therapeutic agent which is manufactured by spray drying without the production of primary granules or fine particles, and the entire manufacturing process is uniformly performed in a fluidized bed spray coating machine without cross contamination and loss of yield.

Claims (9)

Spraying and drying a composition containing amlodipine, its optical isomer, or a pharmaceutically acceptable salt and excipient thereof on the surface of the drug support to form a drug layer, the film layer consisting of a cellulose derivative and a light blocking agent for blocking water Film coating formulation prepared by spraying and drying to form a film coating layer. The film coating formulation of claim 1, wherein the salt is maleate, acetate, fumarate, lactate, besylate, nicotinate, camsylate, malonate gentisate, gluconate, mesylate, orotate The film coating agent according to claim 1, wherein the film coating layer forming base is hydroxypropylmethylcellulose. The formulation of claim 1, wherein the film coating layer comprises at least one selected from disintegrants and surfactants. The film coating formulation of claim 4 wherein the disintegrant of the film coating layer is polyvinylpyrrolidine. The film coating formulation of claim 4 wherein the surfactant of the film coating layer is Tween 80. The film coating formulation of Claim 1 whose light-shielding agent is a titanium oxide in a film coating layer. The film coating formulation of claim 1, wherein the optical isomer is S-Amlodipine. The film coating agent according to claim 1, wherein the drug support is a sugar granule.

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