KR20070073596A - Pharmaceutical formulation containing amlodipine and aspirin - Google Patents

Abstract

Provided are a kit and a pharmaceutical composition containing amlodipine maleate which shows improved stability of amlodipine and aspirin by containing the amlodipine and aspirin separately. The kit comprises a formulation including an amlodipine free base or a pharmaceutically acceptable salt thereof and a formulation including aspirin. The pharmaceutical composition containing amlodipine maleate comprises a stabilizer such as sodium citrate, butylated hydroxy toluene, succinic acid, fumaric acid, tartaric acid, and ascorbic acid.

Description

Pharmaceutical formulation containing amlodipine and aspirin

The present invention relates to pharmaceutical preparations or kits containing amlodipine and aspirin, and to pharmaceutical compositions containing amlodipine maleic acid.

Amlodipine is a dihydropyridine calcium channel blocker that inhibits calcium ion influx into the smooth and vascular calcium channels in the blood vessels, thereby relaxing the coronary smooth muscles and expanding the coronary arteries. It is a drug that increases.

Aspirin has been used to relieve fever and pain, but has recently been used to reduce the risk of nonfatal myocardial infarction and ischemic attack in patients with unstable angina due to platelet aggregation inhibitory action, and to prevent reinfarction after initial myocardial infarction.

In combination with amlodipine and aspirin, synergistic effects on the inhibition of platelet activity have been increasing.Inhibition of platelet activity in vivo by amlodipine alone and combined with aspirin, Int J Cardiol , 1997 62: S111-S117 and End Organ Protection by Calcium-Channel Blockers, Clin . Cardiol . , 2001; 24: 102-106).

However, there is no known combination formulation containing two drugs yet.

Therefore, the present invention is to provide a pharmaceutical formulation or kit containing both amlodipine and aspirin.

Another object of the present invention is to provide a maleic acid amlodipine-containing pharmaceutical composition with improved stability.

The present invention is based on the surprising fact that amlodipine and aspirin, when contacted or mixed, have a very bad effect on the stability of each other. The present invention is also based on another surprising fact that when a maleic acid amlodipine is used as the amlodipine component, the addition of certain stabilizers significantly improves the stability of the maleic acid amlodipine.

Therefore, in order to achieve the above technical problem of the present invention, the present invention (a) amlodipine free base or a pharmaceutically acceptable salt thereof; And (b) aspirin is isolated so as not to contact each other.

When amlodipine and aspirin were mixed and stored together, the stability of amlodipine was about 5 times worse and that of aspirin was about 10 times worse. This is thought to be due to the unique molecular structure of amlodipine and aspirin. Therefore, when developing pharmaceutical preparations containing them simultaneously, amlodipine and aspirin should be separated and included.

In general, when developing a combination formulation, it is common for two drugs to be mixed with each other, but in the case of amlodipine and aspirin, they should be contained separately from each other. Considering the manufacturing cost, it is much more economical to prepare a complex formulation containing a separated state, but the mixing stability of amlodipine and aspirin is an important problem so as to ignore this manufacturing cost problem.

The pharmaceutical formulation of the present invention is not limited to the content of amlodipine and aspirin, but preferably contains 10 to 500 mg of aspirin and 1 to 30 mg of amlodipine per pharmaceutical formulation, and 20 to 400 mg of aspirin and 2 to 20 mg of amlodipine per pharmaceutical formulation. More preferably, it is most preferably contained 30 to 300 mg of aspirin and 3 to 10 mg of amlodipine per pharmaceutical formulation.

As amlodipine of the present invention, amlodipine free base or a pharmaceutically acceptable salt of amlodipine can be used. Pharmaceutically acceptable salts of amlodipine may include, but are not limited to, maleic acid amlodipine (amlodipine maleate), amlodipine besylate, amlodipine camsylate, amlodipine adipate, amlodipine mesylate and amlodipine nicotinate.

More preferably, the present invention provides a pharmaceutical formulation in which the granules containing any one or any one of (a) amlodipine or its pharmaceutically acceptable salt and (b) aspirin are coated with a polymer. It provides a pharmaceutical formulation, characterized in that the contact with the other ingredient is prevented.

Any of the polymers described above may be used as long as it can form a coating film that physically blocks the other component by surrounding the outside of the granules containing any one or any of the components (a) and (b). For example, alkyl cellulose, hydroxyalkyl cellulose, carboxyalkyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylacetate, polyalkene oxide, polyalkeneglycol, polyethylene-polypropylene polymer, polyoxyethylene-poly Oxypropylene polymers, zein, shellac, diethylaminoacetate, aminoalkylmethacrylate copolymers, sodium alginate, chitosan, gelatin, gum, poly-L-lysine and the like can be used, but ease of preparation and used amlodipine In terms of the stability of hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, phthalate At least one selected from succinic acid hydroxypropylmethyl cellulose, methacrylic polymer Sanko, aminoalkyl methacrylate copolymer, and the group consisting of echil cellulose is preferred.

In particular, in the case of aspirin gastrointestinal disorders, it is more preferable to prevent contact with amlodipine by coating with an enteric or sustained release polymer. In addition, when maleic acid amlodipine is used as the component (a), maleic acid amlodipine is coated with a polymer, thereby preventing contact with external moisture and the like, thereby improving stability of maleic acid amlodipine itself.

Coating of amlodipine, aspirin or granules containing the same may be used in any device capable of spraying the coating liquid after flowing the raw powder or granules, for example, a fluidized bed coater may be used.

More preferably, the present invention provides a tablet or granule wherein the aforementioned pharmaceutical formulation comprises any one of (a) component and (b) component; A first coating layer made of a film coating base surrounding the tablet or granules; And it provides a pharmaceutical formulation comprising a second coating layer containing another component further coated on the outside of the first coating layer.

In the case of a combination formulation containing two drugs, a form in which two drugs are contained in one tablet is preferable in terms of patient compliance. After preparing a tablet including one of amlodipine and aspirin, the polymer is separated into the aforementioned polymer. By forming a coating layer and coating another component with an additive used as a coating base, a tablet containing both drugs may be prepared without amlodipine and aspirin contacting each other. However, since the content of aspirin is higher than that of amlodipine, it is more preferable to prepare a tablet containing aspirin, to make a separation coating layer, and to further coat with a coating solution containing amlodipine to prepare a tablet containing two drugs.

The device used for coating of tablets may be any device used when preparing general film coated tablets.

Preferably, the present invention provides a pharmaceutical formulation, characterized in that the above-described pharmaceutical formulation is a multilayered tablet consisting of one layer comprising the component (a) and two layers comprising the component (b), Preferably, the present invention provides a pharmaceutical formulation, characterized in that there is a separator or a separation layer between the first layer and the second layer in the above-described multi-layer tablet.

Multi-layered tablets refer to tablets prepared by two or three layers by adding other granules to pre-made tablets or by further tableting or by supplying different types of granules sequentially into a tablet press punching cavity. Amlodipine and aspirin of the present invention may be included in different layers in a multilayer tablet to prevent contact. In addition, it is more preferable that there is a separator or separation layer between the amlodipine-containing layer and the aspirin-containing layer to block the minimum contact.

Preferably, the present invention comprises a core tablet wherein the pharmaceutical formulation described above comprises any one of (a) component and (b) component; And an outer layer comprising another component surrounding the core tablet. The present invention provides a pharmaceutical formulation comprising a press-coated tablet, more preferably, wherein the core tablet is coated with a polymer. It provides a pharmaceutical formulation, characterized in that.

Nucleated tablets are tablets made by placing a small tablet (nucleated tablet) made by using a special tableting machine in granules when tableting and recompressing them.The stability of the two drugs by containing amlodipine and aspirin separately in the outer layer surrounding the core tablet and core tablet Can be improved. In addition, it is more preferable to coat the core tablet with the above-described polymer to block the minimum contact.

The present invention also provides a formulation comprising (a) an amlodipine free base or a pharmaceutically acceptable salt thereof; And (b) a preparation comprising aspirin; in a separate fraction, preferably, the present invention provides a kit characterized in that the preparation is a capsule, microcapsules, tablets or granules. to provide.

Formulations of the present invention may further comprise excipients, binders, disintegrants, lubricants and the like, in addition to amlodipine and aspirin. Excipients, binders, disintegrants and glidants commonly used for the preparation of the formulations can be used so long as they do not impair the stability of amlodipine and aspirin, for example, the respective additives mentioned in the examples described below are preferred.

The present invention also provides a maleic acid amlodipine-containing pharmaceutical composition comprising a stabilizer. When maleic acid amlodipine is used as the amlodipine component, maleic acid amlodipine is unstable due to the formation of analog D, the Michael reaction, and the instability can be improved by adding a stabilizer.

As a result of evaluating the stability through various repeated experiments, it is preferable to use any one or more selected from the group consisting of sodium citrate, butylated hydroxytoluene, succinic acid, fumaric acid, tartaric acid and ascorbic acid. Most preferably, hydroxytoluene is added to the maleic acid amlopdine containing composition as a stabilizer.

Hereinafter, the following examples and the like will be described in order to describe the present invention in more detail. However, embodiments according to the present invention can be modified in many different forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided by way of example in order to facilitate a specific understanding of the present invention.

Example 1 Aspirin and Maleic Acid Amlodipine Mutual Stability Test

A mixture of 10 g of aspirin, 0.642 g of maleic acid amlodipine and 0.642 g of aspirin and 0.642 g of maleic acid ammonium was placed in a high-density polyethylene (HDPE) plastic bottle, respectively, and subjected to stability experiments under accelerated conditions (40 ± 2 ° C., 75 ± 5% RH). After 90 and 180 days, the color change and the corresponding analog were analyzed under the following conditions using HPLC.

Maleic acid Amlodipine Leading substance HPLC  Measuring conditions

As amlodipine, 50 mg equivalent is precisely taken into a flask and 50 ml is added to the mobile phase.

Detector: Ultraviolet absorption photometer (detection wavelength: 237 nm)

Column: Capcellpak ™ C18 4.5 × 150mm, 5㎛

Mobile phase: pH3.0 buffer: acetonitrile: methanol = 60: 20: 20 (pH 3.0 buffer: triethylamine 7.0mL is added, 1L is used with water and pH is adjusted to 3.0 with phosphoric acid.)

Flow rate: 1.0 mL / min

Injection volume: 20uL

Calculation:% lead (= peak area of the corresponding lead x 100) / amlodipine peak area (However, lead D is multiplied by a correction factor of 3.03.)

Measurement Conditions of Free Salicylic Acid in Aspirin

100 mg of the equivalent of aspirin was precisely taken into a flask and tested according to the free salicylic acid test section of the US Pharmacopeia Aspirin Enteric Tablet.

The results are summarized in Table 1 below.

Ingredient Name  Maleic Acid Amlodipine Lead Aspirin Degradation Products Leading substance D Leading substances related to Michael reaction Unknown Leads (Max) Total lead Free salicylic acid 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Maleic acid amlodipine 0.12 0.16 N.D. N.D. N.D. N.D. 0.12 0.16 - - aspirin - - - - - - - - 0.08 0.12 A mixture of maleic acid amlodipine and aspirin 0.29 0.43 0.05 0.13 0.10 0.24 0.44 0.80 0.60 1.10

In Table 1 and the following tables, N.D. means that it was not detected at the measurement conditions.

As shown in Table 1, it has been shown that by admixing amlodipine, in particular, maleic acid amlodipine and aspirin, it promotes mutual decomposition to increase the formation of a flexible substance, which indicates that the two substances adversely affect the stability of each other. it means.

Example 2: Evaluation of Mixing Stability with Formulation Additives

Maleic acid amlodipine and additives frequently used in formulations were mixed in the ratios described in the following tables, and stability experiments were carried out under accelerated conditions (40 ± 2 ° C., 75 ± 5% RH) in the same manner as in Example 1. After 90 days and 180 days, the color change and the corresponding flexible material were analyzed under the same conditions as in Example 1.

The excipients and maleic acid amlodipine were mixed at a ratio of 9: 1 to evaluate the stability of each excipient on the maleic acid amlodipine, and the results are shown in Table 2.

Excipient additive name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Lactose 0.15 0.17 N.D. 0.11 N.D. 0.15 N.D. N.D. 0.15 0.43 Unchanged Light yellow Microcrystalline cellulose 0.16 0.17 0.29 0.48 N.D. N.D. N.D. N.D. 0.45 0.65 Unchanged Unchanged Mannitol 0.15 0.19 N.D. N.D. N.D. N.D. N.D. N.D. 0.15 0.19 Unchanged Unchanged Whole Gelatinized Starch 0.14 0.18 N.D. N.D. N.D. N.D. N.D. N.D. 0.14 0.18 Unchanged Unchanged Corn starch 0.17 0.19 N.D. 0.13 N.D. N.D. 0.10 0.11 0.27 0.43 Unchanged Light yellow Anhydrous calcium hydrogen phosphate 0.16 0.19 1.19 2.08 N.D. N.D. 0.10 0.11 1.45 2.38 Light yellow Brown Magnesium Aluminate 0.20 0.25 1.10 2.31 N.D. N.D. 0.11 0.11 1.41 2.67 yellow yellow

As shown in Table 2, lactose, mannitol and pregelatinized starch have been shown to be useful for the stability of maleic acid amlodipine.

The binder and maleic acid amlodipine were mixed at a ratio of 1: 1 to evaluate the stability of each binder on maleic acid amlodipine, and the results are shown in Table 3.

Binder Additive Name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Povidone 0.17 0.20 0.43 1.03 N.D. N.D. 0.25 0.73 0.96 2.11 Light yellow yellow Low Substituted Hydroxypropyl Cellulose 0.24 0.36 N.D. 0.28 N.D. N.D. N.D. N.D. 0.24 0.64 Unchanged Light yellow Hydroxypropyl cellulose 0.26 0.39 N.D. 0.22 N.D. N.D. N.D. N.D. 0.26 0.61 Unchanged Light yellow Copovidone 0.15 0.18 0.21 0.59 N.D. N.D. N.D. 0.10 0.36 0.87 Light yellow yellow Polyvinyl Alcohol Polyethylene Glycol Copolymer 0.33 0.49 0.15 0.32 N.D. N.D. 0.16 0.25 0.64 1.19 Light yellow yellow Carboxymethyl Cellulose Sodium 0.20 0.22 0.28 0.63 N.D. N.D. 0.08 0.10 0.56 0.95 Light yellow Brown Poloxamer 0.21 0.26 1.86 3.20 N.D. N.D. 0.07 0.09 2.14 3.55 Unchanged Light yellow Carbopol 0.20 0.21 N.D. N.D. N.D. N.D. N.D. N.D. 0.20 0.21 Unchanged Unchanged

As shown in Table 3, hydroxypropyl cellulose and carbopol have been shown to be useful for the stability of maleic acid amlodipine.

Disintegrants and maleic acid amlodipine were mixed in a ratio of 1: 1 to evaluate the stability of each disintegrant to amlodipine maleic acid and the results are shown in Table 4.

Disintegrant Additive Name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Sodium starch glycolate 0.14 0.16 N.D. 0.13 N.D. N.D. N.D. N.D. 0.14 0.29 Unchanged Unchanged Crospovidone 0.16 0.18 0.10 0.22 N.D. N.D. N.D. N.D. 0.26 0.40 Unchanged Unchanged Croscarmellose Sodium 0.13 0.20 0.11 0.28 N.D. N.D. N.D. N.D. 0.24 0.48 Unchanged Unchanged Carboxymethyl Cellulose Calcium 0.19 0.21 0.24 0.49 N.D. N.D. 0.10 0.10 0.53 0.80 Unchanged Light brown

As shown in Table 4 above, sodium starch glycolate, crospovidone and croscarmellose sodium have been shown to be useful for the stability of maleic acid amlodipine.

Glidants and maleic acid amlodipine were mixed at a ratio of 0.5: 1 to evaluate the stability of each glidant to amlodipine maleic acid and the results are shown in Table 5.

Lubricant additive name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Magnesium stearate 0.16 0.21 0.12 0.32 N.D. N.D. N.D. N.D. 0.28 0.53 Unchanged Unchanged Sodium stearyl fumarate 0.15 0.19 0.13 0.29 N.D. N.D. N.D. N.D. 0.28 0.48 Unchanged Unchanged Stearic acid 0.18 0.23 0.10 0.19 N.D. N.D. N.D. N.D. 0.28 0.42 Unchanged Unchanged Colloidal Silicon Oxide 1.45 2.15 0.58 1.04 N.D. N.D. 0.14 0.16 2.17 3.35 Light yellow yellow Talc 0.39 0.61 0.34 0.61 N.D. N.D. 0.10 0.14 0.83 1.36 Unchanged Unchanged

As shown in Table 5, it was shown that colloidal silicon oxide and talc are not useful for the stability of maleic acid amlodipine.

Stabilizers and maleic acid amlodipine were mixed at a ratio of 0.05: 1 to evaluate the stability of each stabilizer on maleic acid amlodipine and the results are shown in Table 6.

Stabilizer Additive Name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Profile gallate 0.11 0.14 N.D. 0.10 N.D. N.D. 1.02 2.10 1.13 2.34 Unchanged Unchanged Citric acid 0.37 0.52 N.D. N.D. N.D. N.D. N.D. N.D. 0.37 0.52 Light yellow Brown Sodium citrate 0.18 0.23 N.D. N.D. N.D. N.D. N.D. N.D. 0.18 0.23 Unchanged Unchanged Butylated hydroxytoluene 0.12 0.13 N.D. N.D. N.D. N.D. N.D. N.D. 0.12 0.13 Unchanged Unchanged Butylated hydroxyanisole 0.17 0.26 N.D. N.D. N.D. N.D. N.D. N.D. 0.17 0.26 Unchanged Red Succinic acid 0.11 0.12 N.D. N.D. N.D. N.D. N.D. N.D. 0.11 0.12 Unchanged Unchanged Fumaric acid 0.10 0.11 N.D. N.D. N.D. N.D. N.D. N.D. 0.10 0.11 Unchanged Unchanged Glutamic acid 0.14 0.18 0.11 0.19 N.D. N.D. N.D. N.D. 0.25 0.37 Unchanged Unchanged EDTA 0.15 0.18 0.12 0.23 N.D. N.D. N.D. N.D. 0.27 0.41 Unchanged Unchanged Tartaric acid 0.11 0.13 N.D. N.D. N.D. N.D. N.D. N.D. 0.11 0.13 Light yellow Brown Malic acid 0.34 0.63 N.D. N.D. N.D. N.D. N.D. N.D. 0.34 0.63 Light yellow Brown Sodium Metabisulfite 0.51 0.79 N.D. N.D. N.D. N.D. N.D. N.D. 0.51 0.79 Unchanged Unchanged Ascorbic acid 0.12 0.15 N.D. N.D. N.D. N.D. N.D. N.D. 0.12 0.15 Light yellow yellow

As shown in Table 6 above, propyl gallate and sodium metabisulfite were not useful for the stability of maleic acid amlodipine.

The film coating base and maleic acid amlodipine were mixed at a ratio of 3: 1 to evaluate the stability of each stabilizer on maleic acid amlodipine, and the results are shown in Table 7.

Film Coating Base Additive Name Lead material D Michael reaction Mylard reaction Unknown Leads (Max) Total lead Color change 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days 90 days 180 days Hydroxypropylmethylcellulose2910 0.14 0.15 N.D. 0.14 N.D. N.D. N.D. N.D. 0.14 0.29 Unchanged Unchanged Polyvinyl alcohol 0.77 1.04 0.11 0.20 N.D. N.D. N.D. N.D. 0.88 1.24 Unchanged Light yellow Phthalate Hydroxypropyl Methyl Cellulose 0.25 0.38 N.D. 0.10 N.D. N.D. N.D. N.D. 0.25 0.48 Unchanged Unchanged Acetic acid hydroxypropyl methyl cellulose 0.13 0.15 N.D. 0.10 N.D. N.D. N.D. N.D. 0.13 0.25 Unchanged Unchanged Methacrylic acid polymer 0.16 0.30 0.10 0.24 N.D. N.D. 0.12 0.15 0.38 0.69 Unchanged Light yellow Aminoalkyl methacrylate copolymer 0.18 0.28 0.18 0.27 N.D. N.D. N.D. 0.10 0.36 0.65 Unchanged Light yellow Ethyl Cellulose 0.14 0.23 N.D. N.D. N.D. N.D. N.D. N.D. 0.14 0.23 Unchanged Light yellow Propylene glycol 0.15 0.18 N.D. 0.10 N.D. N.D. N.D. N.D. 0.15 0.18 Unchanged Unchanged Polyethylene Glycol 6000 0.20 0.31 0.21 0.47 N.D. N.D. N.D. N.D. 0.41 0.78 Light yellow Brown Triethyl Citrate 0.19 0.29 N.D. 0.09 N.D. N.D. N.D. N.D. 0.19 0.38 Unchanged Light yellow Titanium oxide 0.20 0.28 0.10 0.31 N.D. N.D. N.D. N.D. 0.30 0.59 Unchanged Unchanged Fatty acid glycerin ester 0.16 0.21 0.14 0.25 N.D. N.D. N.D. N.D. 0.30 0.46 Unchanged Unchanged

As shown in Table 7, polyvinyl alcohol was the worst among the film coating bases for the stability of amlodipine maleic acid.

<Stability Test by Formulation>

Based on the results of the stability test of Example 2, capsules and tablets were prepared according to the following composition and preparation method.

end. aspirin/ Maleic acid Amlodipine Capsule

Example 3 Preparation of Maleic Acid Amlodipine Granules

Granules were prepared as shown in Table 8 based on the results of the stability test according to the maleic acid amlodipine and the additive combination. First, butylated hydroxytoluene and hydroxypropyl cellulose were dissolved in ethanol to prepare a binding solution, and maleic acid amlodipine, pregelatinized starch and mannitol were added to a mixer and mixed for about 10 minutes. Wet granules were prepared from the prepared binder and mixture.

number Ingredient Name Example 3  One Maleic acid amlodipine  6.42 mg (5.0 mg with amlodipine)  2 Whole Gelatinized Starch  30mg  3 Mannitol  15 mg  4 Butylated hydroxytoluene  0.35mg  5 Hydroxypropyl cellulose  0.60mg  6 ethanol  0.009 mL  7           Total weight  52.37mg

Example 4-6 Preparation of Aspirin Enteric Granules

Aspirin enteric granules were prepared as shown in Table 9 below.

Example 4 was prepared as follows. First, (S1) propylene glycol and hydroxypropyl methyl cellulose 2910 were sequentially stirred and dissolved in a mixture of methylene chloride and ethanol to prepare a sub-coating solution. Subsequently, aspirin was added to the fluidized bed coater (S2), and the coating solution of (S1) was used at a rate of 20-30 mL per minute under conditions of inlet temperature of 55-65 ° C, outlet temperature of 30-40 ° C, and injection pressure of 1.5-2.0 bar. Aspirin subcoated pellets were prepared by spraying and drying. (S3) Propylene glycol was added to purified water, stirred and dissolved, and then talc was added and dispersed. (S4) A methacrylic acid copolymer was added to the dispersion of (S3) and dispersed to prepare a coating solution. (S5) Aspirin was added to the fluidized bed coater, and the coating solution of (S4) was sprayed at a rate of 15-25 mL per minute under conditions of Inlet temperature 60-70 ° C, Outlet temperature 35-45 ° C and injection pressure 1.5-2.0 bar. Aspirin enteric pellets were prepared.

Example 5 was prepared as follows. First (S1) according to the coating composition and coating conditions of Example 4 to prepare aspirin sub-coated pellets. (S2) To the mixture of purified water and ethanol, fatty acid glycerine ester was added, stirred and dissolved, and then talc was added and dispersed. Phosphate hydroxypropyl methyl cellulose was added to the dispersion of (S3) and (S2), followed by stirring and dissolution to prepare a coating solution. (S4) Aspirin was added to the fluidized bed coater, and the coating solution of (S3) was sprayed at a rate of 20-30 mL per minute under conditions of inlet temperature of 55-65 ° C, outlet temperature of 30-40 ° C, and injection pressure of 1.5-2.0 bar. Aspirin enteric pellets were prepared.

Example 6 was prepared as follows. First (S1) according to the coating composition and coating conditions of Example 4 to prepare aspirin sub-coated pellets. (S2) Fatty acid glycerin ester was added to purified water and a mixture of ethanol, stirred and dissolved, and then talc was added and dispersed. (S3) A hydroxypropyl methyl cellulose acetate was added to the dispersion of (S2), stirred, and dissolved to prepare a coating solution. (S4) Put aspirin in the fluidized bed coater and dry with spraying at the rate of 20-30 mL per minute under the condition of Inlet temperature 55-65 ℃, Outlet temperature 30-40 ℃, injection pressure 1.5-2.0 bar Aspirin enteric pellets were prepared.

number Ingredient Name Example 4 Example 5 Example 6  One aspirin 100mg 100mg 100mg  2 Hydroxypropylmethylcellulose2910 3.5mg 3.5mg 3.5mg  3 Propylene glycol 0.35mg 0.35mg 0.35mg  4 Methylene chloride 35mg 35mg 35mg  5 ethanol 35mg 35mg 35mg  6 Methacrylic acid copolymer 66.7mg (20mg as a solid) - -  7 Phthalate Hydroxypropyl Methyl Cellulose - 20mg -  8 Acetic acid hydroxypropyl methyl cellulose - - 20mg  9 Propylene glycol 3.0mg - - 10 Fatty acid glycerin ester - 3.0mg 3.0mg 11 Talc 5.3mg 5.3mg 5.3mg 12 ethanol - 200 mg 200 mg 13 Purified water  60mg 200 mg 200 mg 14 Total weight (mg) 132.15mg 132.15mg 132.15mg

Comparative Example 1 Maleic Acid Amlodipine / Aspirin Complex Capsule

Maleic acid amlodipine and the aspirin enteric pellets of Example 4 were mixed and then filled into hard capsules.

Comparative Example 2 : Maleic Acid Amlodipine / Aspirin Complex Capsule

The maleic acid amlodipine granules of Example 3 were mixed with aspirin and then filled into hard capsules.

Formulation Example 1 : Maleic Acid Amlodipine / Aspirin Complex Capsule

The maleic acid amlodipine granules of Example 3, the aspirin enteric pellets of Example 4 and magnesium stearate were mixed for 10 minutes and then filled into hard capsules containing 185 mg per capsule.

Formulation Example 2 Maleic Acid Amlodipine / Aspirin Complex Capsule

The maleic acid amlodipine granules of Example 3, the aspirin enteric pellets of Example 5 and magnesium stearate were mixed for 10 minutes and then filled into hard capsules containing 185 mg per capsule.

Formulation Example 3 Maleic Acid Amlodipine / Aspirin Complex Capsule

The maleic acid amlodipine granules of Example 3, the aspirin enteric pellets of Example 6, and magnesium stearate were mixed for 10 minutes and then filled into hard capsules containing 185 mg per capsule.

Example 7 : Preparation of maleic acid amlodipine-containing coating layer

(S1) Butylated hydroxytoluene, propylene glycol, and hydroxypropylmethylcellulose 2910 were added and dissolved in a mixture of ethanol and methylene chloride. (S2) Amlodipine maleic acid was added to ethanol and dissolved, followed by mixing with the solution of (S1). (S3) The maleic acid amlodipine-containing film coating solution was coated in the same manner as in Example 6 using the aspirin enteric granules of Example 4 as a core.

Example 8 : Preparation of maleic acid amlodipine-containing coating layer

Coating was carried out in the same manner as in Example 7, except that the aspirin enteric pellet of Example 5 was used as the core instead of the aspirin enteric pellet of Example 4.

Example 9 : Preparation of maleic acid amlodipine-containing coating layer

Coating was carried out in the same manner as in Example 7, except that the aspirin enteric pellet of Example 6 was used as the core instead of the aspirin enteric pellet of Example 4.

Table 10 summarizes the components and contents of Example 7-9.

number Ingredient Name Example 7 Example 8 Example 9  One Aspirin enteric pellets 132.15 mg (Example 4) 132.15 mg (Example 5) 132.15 mg (Example 6)  2 Maleic Acid Amlodipine 6.42mg (5.0mg with amlodipine)  3 Butylated hydroxytoluene 0.35mg 0.35mg 0.35mg  4 Hydroxypropylmethylcellulose 2910 10mg 10mg 10mg  5 Propylene glycol 1.08mg 1.08mg 1.08mg  6 Methylene chloride 100mg 100mg 100mg  7 ethanol 100mg 100mg 100mg  8             Total weight 150.0 mg 150.0 mg 150.1mg

Formulation Example 4 Maleic Acid Amlodipine / Aspirin Complex Capsule

The granules of Example 7 were filled in hard capsules.

Formulation Example 5 Maleic Acid Amlodipine / Aspirin Complex Capsule

The granules of Example 8 were filled into hard capsules.

Formulation Example 6 Maleic Acid Amlodipine / Aspirin Complex Capsule

The granules of Example 9 were filled in hard capsules.

Example 10

As shown in Table 11, to the granules of Example 3, microcrystalline cellulose, sodium crosamelose, fumaric acid, and low-substituted hydroxypropyl cellulose were added thereto, mixed for 10 minutes, and lubricated with magnesium stearate for 5 minutes to prepare a tablet. .

number Ingredient Name Example 10   One Maleic acid amlodipine wet granules (Example 3) 52.37mg (5.0mg with amlodipine)   2 Microcrystalline cellulose 20.08mg   3 Croscarmellose Sodium 3.0mg   4 Fumaric acid 0.15mg   5 Low Substituted Hydroxypropyl Cellulose 4.0mg   6 Magnesium stearate 0.4mg   7 Tablet weight 80 mg

Formulation example  7

The maleic acid amlodipine tablets of Example 10 and the aspirin enteric pellets of Example 4 were filled in hard capsules.

Formulation example  8

The maleic acid amlodipine tablets of Example 10 and the aspirin enteric pellets of Example 5 were filled in hard capsules.

Formulation example  9

The maleic acid amlodipine tablets of Example 10 and the aspirin enteric pellets of Example 6 were filled in hard capsules.

I. aspirin/ Maleic acid Amlodipine  Complex Tablet

Comparative example  3

Aspirin and maleic acid amlodipine granules of Example 3, microcrystalline cellulose, pregelatinized starch, and stearic acid were added to a mixer, mixed for 15 minutes, and then compressed.

Comparative example  4

(S1) Aspirin, microcrystalline cellulose, pregelatinized starch and stearic acid were placed in a mixer, mixed for 15 minutes, and then compressed. (S2) Aspirin enteric tablets are prepared from the uncoated tablet of (S1) using the methacrylic acid copolymer coating solution of Example 4.

Formulation example  10

The aspirin enteric tablet of Comparative Example 4 was coated with the maleic acid amlodipine-containing coating solution of Example 9.

Formulation example  11

(S1) Aspirin enteric tablets were prepared by coating the aspirin tablets of Formulation Example 10 with the phthalic acid hydroxypropylmethylcellulose coating solution of Example 5. (S2) The aspirin enteric tablet of (S1) was coated with the maleic acid amlodipine-containing coating solution of Example 9.

Formulation example  12

(S1) Aspirin enteric tablets were prepared by coating the aspirin tablets of Formulation Example 10 with the hydroxyacetic acid hydroxypropylmethylcellulose coating solution of Example 6. (S2) The aspirin enteric tablet of (S1) was coated with the maleic acid amlodipine-containing coating solution of Example 9.

Formulation example  13

Maleic acid amlodipine granules of Example 3 and aspirin enteric pellets of Example 4, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose and stearic acid were mixed for 10 minutes and then compressed.

All. Stability Test of Each Formulation

Example 11 Stability Test of Each Formulation

Formulation Examples and the prepared formulations were packed in HDPE bottles, 100 capsules or 100 tablets, respectively, and left for 90 days under accelerated conditions (40 ± 2 ° C, 75 ± 5% RH). Analysis conditions were tested according to the same analysis conditions as in Example 1.

1) Capsule stability test

The results are shown in Table 12 below.

Prescription name Maleic Acid Amlodipine Lead Aspirin Degradation Products Color variations Lead material D Michael reaction Unknown flexible material (maximum) Total Flexible Material Free salicylic acid Comparative Example 1 0.45 0.12 0.11 0.68 0.18 Unchanged Comparative Example 2 0.32 0.10 1.21 1.96 2.45 Light yellow Example 3 0.14 0.20 N.D. 0.34 - Unchanged Example 4 - - - - 0.18 Unchanged Formulation Example 1 0.15 0.36 0.09 0.60 0.19 Unchanged Formulation Example 2 0.14 0.37 0.10 0.61 0.26 Unchanged Formulation Example 3 0.16 0.33 N.D. 0.49 0.20 Unchanged Formulation Example 4 0.19 0.34 0.05 0.58 0.28 Unchanged Formulation Example 5 0.20 0.33 0.07 0.60 0.26 Unchanged Formulation Example 6 0.19 0.35 0.08 0.62 0.21 Unchanged Formulation Example 7 0.14 0.33 N.D. 0.47 0.22 Unchanged Formulation Example 8 0.13 0.32 N.D. 0.45 0.29 Unchanged Formulation Example 9 0.13 0.35 N.D. 0.48 0.23 Unchanged

As shown in Comparative Example 2 of Table 12, when aspirin and maleic acid amlodipine were in direct contact, the stability of both amlodipine and aspirin was significantly reduced. On the other hand, Comparative Examples 1 and Preparation Examples which prevented direct contact between aspirin and amlodipine were very superior in stability of both amlodipine and aspirin compared to Comparative Example 2.

2) tablet stability test

The results are shown in Table 13 below.

Prescription name Maleic acid amlodipine flexible Aspirin Degradation Products Color variations Lead material D Michael reaction Unknown flexible material (maximum) Total lead Free salicylic acid Comparative Example 3 3.80 44.39 57.21 117.40 13.23 Dark yellow Comparative Example 4 - - - - 0.16 Unchanged Example 10 0.15 0.21 N.D. 0.36 - Unchanged Formulation Example 10 0.31 0.29 0.16 0.60 0.21 Unchanged Formulation Example 11 0.27 0.22 0.11 0.60 0.19 Unchanged Formulation Example 12 0.18 0.28 0.10 0.56 0.22 Unchanged Formulation Example 13 2.10 24.0 33.50 65.75 8.82 Dark yellow

As can be seen in Comparative Example 3 of Table 13, when aspirin and maleic acid amlodipine are in direct contact, the stability of both amlodipine and aspirin was significantly reduced. On the other hand, the formulations that prevented direct contact between aspirin and amlodipine were significantly more stable in amlodipine and aspirin than in Comparative Example 3.

In addition, comparing Comparative Example 2 and Comparative Example 3, it can be seen that the stability of Comparative Example 3 is much worse, which is due to the difference in the formulation (capsules versus tablets), and the tablet formulation of Comparative Example 3 is amlodipine and aspirin There is a lot more contact with and it is believed that the stability is much worse.

Formulation Example 13 is thought to be poor in stability as the aspirin coating film was broken due to tableting, whereby aspirin and amlodipine contacted.

The present invention provides pharmaceutical formulations or kits with improved stability of both amlodipine and aspirin. The present invention also provides a maleic acid amlodipine-containing pharmaceutical composition with improved stability.

Claims (5)

(a) a formulation comprising amlodipine free base or a pharmaceutically acceptable salt thereof; And (b) an agent comprising aspirin; in a separate fraction. The kit of claim 1, wherein the formulation is a capsule, microcapsules, tablets or granules. Maleic acid amlodipine-containing pharmaceutical composition comprising a stabilizer. The pharmaceutical composition of claim 3, wherein the stabilizing agent is at least one selected from the group consisting of sodium citrate, butylated hydroxytoluene, succinic acid, fumaric acid, tartaric acid, and ascorbic acid. The pharmaceutical composition according to claim 4, wherein the stabilizer is butylated hydroxytoluene.