KR20230094053A - Combined pharmaceutical composition for treating hypertension - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of angiotensin-2-receptor-related diseases, particularly hypertension, and more specifically, pimasartan or a pharmaceutically acceptable salt thereof as a first active ingredient, and pharmaceutically acceptable salts thereof. granules containing acceptable additives; and as a second active ingredient, a complex pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof, characterized in that it is in the form of a monolayer tablet. The present invention exhibits excellent dissolution properties while containing two active ingredients, fimasartan and escamlodipine, and can ultimately improve bioavailability, which is effective in preventing, alleviating or treating complications caused by hypertension and/or hyperlipidemia. . In particular, not only the dissolution characteristics of fimasartan with low solubility were greatly improved, but also the dissolution characteristics at low pH were also greatly improved, thereby increasing the effect of the drug.

Description

Composite pharmaceutical composition for treating hypertension {COMBINED PHARMACEUTICAL COMPOSITION FOR TREATING HYPERTENSION}

The present invention relates to a pharmaceutical composition for preventing or treating angiotensin-2-receptor-related diseases, particularly hypertension.

Since the approval of losartan, the first angiotensin II receptor blocker (ARB) in 1995, numerous ARBs have been developed and are widely used as antihypertensive drugs worldwide.

All ARBs are generally similar in that they have the same target of limiting the activity of angiotensin II, but differ in potency according to pharmacokinetic factors. Among these efficacy differences, it is known that there are additional effects such as improvement of serum lipid level and glucose metabolism and lowering of serum uric acid level.

Among these ARB drugs, Fimasartan is the first ARB drug developed in Korea. It shows a strong blood pressure lowering effect by maximizing the effect of selective blocking.

As a result of comparing AT1 binding affinity between actual ARB preparations, among the ARB preparations, pimasartan had the highest association rate, the lowest dissociation rate, and dissociation half-life (T1/2). has been reported to be the longest.

Currently, fimasartan is an angiotensin II receptor antagonist, an antihypertensive drug, and is marketed under the trade name Kanarb™ in three doses of 30 mg, 60 mg, and 120 mg in tablet form administered once a day.

However, although the fimasartan exhibits excellent pharmacological activity, it has a problem in that its solubility is low, and thus dissolution characteristics and bioavailability may be reduced.

In particular, fimasartan tends to cause gelation in acidic conditions, and because of this tendency, it exhibits a lower level of dissolution properties in acidic environments with relatively low pH.

In the prior art, to improve these problems, it is mainly used in the form of fimasartan potassium salt, and various drug delivery systems such as SEDDS (Self-Emulsifying Drug Delivery System) and SMEDDS (Self-microemulsifying drug delivery system) are also used.

However, these conventional techniques may have problems in that the size of the preparation increases, causing difficulty in swallowing, and side effects such as allergy may occur due to the use of a surfactant.

Due to these problems of existing pharmaceutical compositions, various methods have been attempted to increase the solubility and bioavailability of fimasartan, but pharmaceutical compositions showing satisfactory solubility and dissolution characteristics are still insufficient.

On the other hand, despite the excellent effects of ARB drugs, combination therapy with other antihypertensive agents is becoming essential to achieve target blood pressure in diseases such as poorly controlled hypertension.

Amlodipine is a representative drug used in combination with fimasartan, and the combination of fimasartan and amlodipine shows superior blood pressure control effects compared to each monotherapy and placebo. In particular, patients who failed to control systolic blood pressure less than 140 mmHg with 60 mg of fimasartan were randomly classified into the 60/10 mg group of fimasartan/amlodipine and the 60 mg group of fimasartan, and treated for 8 weeks. Diastolic blood pressure was lowered by about 8 mmHg. There are also clinical results that showed a difference in the treatment response rate, with 82% in the combination group and 49.2% in the single group.

In addition to this, in order to improve medication compliance, which is pointed out as a problem of combination therapy, it would be preferable to have one formulation containing two active ingredients rather than using two drugs in combination, which is actually pointed out as a problem of combination therapy. In order to improve medication compliance, European guidelines recommend a "single-pill combination" rather than a combination therapy of two drugs.

Accordingly, complex formulations containing two or more active ingredients are being developed, and Boryung Pharmaceutical's Ducarb™ tablets have been developed and marketed. There is a concern that this problem may occur, and ultimately, there is a concern that problems such as a decrease in bioavailability may occur, so that an additional process is required and the unit production cost is relatively high.

Therefore, it is necessary to develop a formulation that minimizes the dissolution characteristics of two or more active ingredients or the interaction between drugs while taking the form of a single-layer tablet so as to be one formulation for convenience of administration.

“Pharmacokinetic comparison between fixed-dose combination of fimasartan/amlodipine 60/10 mg and the corresponding loose combination through partially replicated crossover study in healthy subjects” Transl Clin Pharmacol (TCP), 2019;27(4):134-140

Therefore, the object of the present invention is to prevent, alleviate or treat complications caused by hypertension and/or hyperlipidemia by exhibiting excellent dissolution properties and ultimately improving bioavailability while containing two active ingredients of fimasartan and escamlodipine. It is to provide a pharmaceutical composition for effective blood pressure lowering.

The present invention has been made to solve the above-mentioned prior art,

A granular part containing fimasartan or a pharmaceutically acceptable salt thereof as a first active ingredient, and pharmaceutically acceptable additives; and

A complex pharmaceutical composition comprising escamlodipine or a pharmaceutically acceptable salt thereof as a second active ingredient,

It provides a combination pharmaceutical composition characterized in that it is in the form of a single-layer tablet.

In the present invention, the additive provides a complex pharmaceutical composition, characterized in that at least one selected from the group consisting of excipients, binders, disintegrants, lubricants, and solubilizers.

In the present invention, the solubilizing agent provides a combination pharmaceutical composition characterized in that it is included in 3 to 30% by weight relative to the weight of the first active ingredient.

In the present invention, the solubilizing agent provides a combination pharmaceutical composition, characterized in that the HLB value is a nonionic surfactant within the range of 20 to 30.

In the present invention, the nonionic surfactant provides a combination pharmaceutical composition, characterized in that poloxamer188, poloxamer407, or a combination thereof.

In the present invention, the first active ingredient provides a complex pharmaceutical composition comprising 30 to 60 mg of fimasartan potassium.

In the present invention, the first active ingredient is fimasartan potassium, which provides a combination pharmaceutical composition characterized in that the particle size distribution satisfies at least one of the following conditions.

1) The average particle size (D10) of the lower 10% of the particles is 1 to 20㎛

2) The average particle size (D50) of the lower 50% of the particles is 5 to 100㎛

3) The average particle size (D90) of the lower 90% of the particles is 25 to 150㎛

In the present invention, the second active ingredient is escamlodipine, which provides a combination pharmaceutical composition comprising 2.5 to 5 mg.

In the present invention, the combination pharmaceutical composition provides a combination pharmaceutical composition, characterized in that for preventing or treating angiotensin-2-receptor-related diseases.

In the present invention, the composite pharmaceutical composition provides a composite pharmaceutical composition, characterized in that in the form of a film-coated tablet provided with a coating layer.

The present invention exhibits excellent dissolution properties while containing two active ingredients, fimasartan and escamlodipine, and can ultimately improve bioavailability, which is effective in preventing, alleviating or treating complications caused by hypertension and/or hyperlipidemia. . In particular, not only the dissolution characteristics of fimasartan with low solubility were greatly improved, but also the dissolution characteristics at low pH were also greatly improved, thereby increasing the effect of the drug.

1 is a real photograph of a film-coated tablet prepared in Example 7.
Figure 2 shows the raw material particle size distribution of fimasartan potassium trihydrate used in Examples.
3 is a comparative dissolution graph comparing Example 7 and Comparative Example.

Hereinafter, the present invention will be described in detail.

The present invention, as a first active ingredient, a granular part containing fimasartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and

A complex pharmaceutical composition containing escamlodipine or a pharmaceutically acceptable salt thereof as a second active ingredient, characterized in that it is in the form of a monolayer tablet.

Although it is difficult to control the dissolution characteristics of the single-layer tablet compared to the multi-layer tablet, the process is simple, the production cost can be reduced, and the use of additives can be relatively reduced compared to the multi-layer tablet.

The granular part may be prepared according to any method for preparing wet coated tablets. That is, it can be prepared by obtaining granules according to the wet granulation method and tableting them. Specifically, according to an embodiment of the present invention, after mixing a drug with an excipient, etc., a binder solution containing a binder and a solubilizing agent is prepared. It can be prepared by granulating according to the wet granulation method using a wet granulation method, adding a pharmaceutically acceptable additive such as a second active ingredient, an excipient, and a lubricant to the tablet.

The wet granulation method may employ a conventional method, and may be obtained by, for example, wet granulation while mixing in a high shear mixer and drying in a fluidized bed dryer.

The first active ingredient contained in the granular part may be 30 to 60 mg of fimasartan potassium. Here, since it contains 30 to 60 mg of fimasartan potassium, it includes cases with various forms such as salts, hydrates, and solvates, and also includes cases in which the weight increases or decreases due to these form factors.

In addition, the first active ingredient of the granular part may be fimasartan potassium, which has a particle size distribution that satisfies one or more of the following conditions.

1) The average particle size (D10) of the lower 10% of the particles is 1 to 20㎛

2) The average particle size (D50) of the lower 50% of the particles is 5 to 100㎛

3) The average particle size (D90) of the lower 90% of the particles is 25 to 150㎛

The second active ingredient may include 2.5 to 5 mg of escamlodipine. Here, since it is contained in 2.5 to 5 mg as amlodipine, it includes cases with various forms such as salts, hydrates, and solvates, and also includes cases in which the weight increases or decreases due to these form factors.

The second active ingredient may be mixed with the granules and then compressed into tablets, and at this time may be mixed together with additives such as pharmaceutically acceptable excipients, disintegrants, solubilizers, and lubricants.

The additive is included in an amount of 30 to 85% by weight, preferably 50 to 70% by weight, based on the total composition. If it is out of the above range, the size and volume of the formulation may increase due to excessive addition of additives, which may cause a feeling of rejection.

Additives that can be used in the present invention generally include, but are not limited to, all pharmaceutically acceptable additives, and examples thereof are at least one selected from the group consisting of excipients, binders, disintegrants, lubricants, and solubilizers. can hear

The excipient may be included in an amount of 25 to 70% by weight based on the total composition.

The excipients may be pharmaceutically acceptable excipients, but examples thereof include lactose, sucrose, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose, cellulose derivatives, and dextrin. , calcium monohydrogen phosphate, calcium dihydrogen phosphate, calcium carbonate, potassium polyacrylic acid, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascor Binic acid, ascorbyl parmitate, etc. are mentioned.

The disintegrant may be included in an amount of 0.5 to 20% by weight, based on the total composition, and the binder in an amount of 0.1 to 20% by weight based on the total composition.

The disintegrant may use pharmaceutically acceptable excipients without limitation, examples thereof include low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose , crospovidone, sodium lauryl sulfate, and the like. The excipients and disintegrants may be used simultaneously or separately.

The binder may be a pharmaceutically acceptable excipient, but examples thereof include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and polyvinyl. Pyrrolidone, polyvinyl alcohol, gelatin, dextrin, etc. are mentioned.

The lubricant may be a pharmaceutically acceptable excipient, but examples thereof include magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silicon dioxide, colloidal silicon dioxide, and the like.

At least one lubricant selected from among the lubricants may be contained in an amount of 0.1 to 20% by weight based on the total composition. If it is less than 0.1% by weight, there is a concern that mass deviation or content non-uniformity may occur during charging, and if it exceeds 20% by weight, contact with moisture may be hindered and the dissolution rate may decrease.

The solubilizing agent is intended to improve the dissolution properties of the active ingredient, and in particular, can improve the dissolution properties of the first active ingredient among the active ingredients, and thus, 1 to 50% by weight based on the weight of the first active ingredient. It may be, preferably, it may be included in 3 to 30% by weight, more preferably, it may be included in 5 to 20% by weight. If the solubilizing agent is added too little, the dissolution property improvement is insufficient, and if it is added too excessively, the effect of improving the dissolution property per unit use of the solubilizing agent is reduced, while the dosage form such as a tablet becomes large, and the dissolution property is drastically increased. Dissolution may occur, or the possibility of variation between individuals may increase, and the possibility of causing problems such as allergic reactions to solubilizers or irritation of the gastrointestinal mucosa may increase.

The solubilizing agent is a surfactant, and examples of commonly used surfactants include monooleic acid esters, monolaurylic acid esters, monopalmitic acid esters, monostearic acid esters, other esters of polyoxyethylene sorbitan, dioctylsulfo sodium succinate, lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene lysine oil, polyoxyethylene fatty acid glyceride, poloxamer, and cremaphor, etc. ) It is preferable to use a nonionic surfactant within the range of 20 to 30.

In particular, the inventors of the present invention made a surprising discovery that the dissolution characteristics of the active ingredient can be significantly improved compared to cases where the Hydrophilic-Lipophilic Balance Value (HLB) value is lower or higher outside this range.

That is, an experiment was conducted to identify a solubilizer capable of increasing the solubility of fimasartan potassium trihydrate, and a nonionic surfactant having an HLB value (Hydrophilic-Lipophilic Balance Value) within the range of 20 to 30 had the best solubility. showed up A more detailed understanding of this can be made through experimental examples to be described later.

As an example of a nonionic surfactant having the HLB value (Hydrophilic-Lipophilic Balance Value) within the range of 20 to 30, poloxamer188 (HLB≒29), poloxamer407 (HLB≒20 to 23), or a combination thereof (HLB≒20 to 29) can be cited.

The composition according to the present invention may be formulated into solid preparations for oral administration such as tablets, capsules, granules, powders, pills, dry syrups, etc., preferably in the form of tablets or capsules, and more preferably in the form of tablets. It is an oral administration.

In particular, the composite pharmaceutical composition is preferably in the form of a film-coated tablet provided with a coating layer by a coating agent.

As the coating agent, a pharmaceutically acceptable coating agent may be used without limitation, but one containing hydroxypropylmethylcellulose (HPMC) may be preferably used.

The coating layer, but is not necessarily limited thereto, is preferably used within the range of 1 to 10% by weight, more preferably within the range of 3 to 5% by weight relative to the total weight of the composition. If the amount is less than the above range, problems such as lack of masking effect for improving the properties of uncoated tablets, lack of effect to improve storage stability, and increased wear may occur, and if the amount exceeds the above range, disintegration or dissolution delay, logo brit There may be a possibility of a jing phenomenon or the like.

The pharmaceutical composition according to the present invention has excellent physicochemical properties required pharmaceutically, such as processability as a dosage form. That is, when formulated in the form of tablets or capsules, tablets or capsules with uniform pharmacological effects can be produced, and the problem of deterioration of pharmacological effects does not occur during the formulation process, as well as excellent pharmacological effects and uniform pharmacological effects. A formulation having an effect can be economically produced.

The combined pharmaceutical composition of the present invention may be used for preventing or treating angiotensin-2-receptor related diseases.

The angiotensin-2-receptor-related diseases include previously known diseases as well as diseases to be revealed in the future, and non-limiting examples thereof include stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, Diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation, and the like.

Hereinafter, examples of the present invention will be described in more detail. However, it is made clear that the following examples are only for detailed description of the invention and are not intended to limit the scope of rights thereby.

Example

Each example was prepared with the ingredient content prescribed in Table 1 below.

combination
purpose ingredient name Amount (mg/tablet) Example One 2 3 4 5 6 7 chief ingredient Fimasartan Potassium Trihydrate 66.01 66.01 66.01 66.01 66.01 66.01 66.01 chief ingredient Amlodipine Besylate 7.38 7.38 7.38 7.38 7.38 7.38 7.38 excipient microcrystalline cellulose 50.00 65.00 50.00 - 60.00 60.00 62.75 excipient D-mannitol - - - 50.00 58.61 58.61 50.86 excipient pregelatinized starch - - - - - - - excipient corn starch 21.61 26.61 21.61 21.61 - - - binder Hydroxypropyl Cellulose - - - - - - 1.50 binder povidone 20.00 10.00 10.00 10.00 5.0 5.0 - disintegrant Croscarmellose Sodium 20.00 20.00 25.00 25.00 8.00 8.00 7.50 disintegrant sodium lauryl sulfate 5.00 10.00 15.00 15.00 - - 10.00 disintegrant crospovidone - - - - - - 10.00 solubilizing agent meglumine 10.00 - - 10.00 5.00 5.00 - solubilizing agent polysorbate 80 5.00 - - - - 10.0 - solubilizing agent Poloxamer 188 - 5.00 10.00 10.00 5.00 5.00 5.00 glidant colloidal silicon dioxide 3.00 3.00 3.00 3.00 3.00 3.00 2.00 glidant Magnesium Stearate 2.00 2.00 2.00 2.00 2.00 2.00 3.00 coating agent Opadry (03B530094) 10.00 10.00 10.00 10.00 10.00 10.00 10.00

Example 1 to 3

A binder solution was prepared by dissolving a solubilizing agent and a binder in a mixed solution of purified water and ethanol, combining fimasartan potassium trihydrate, microcrystalline cellulose, and croscarmellose sodium with the binder solution, drying and sizing it, and then Amlodipine besylate, corn starch, sodium lauryl sulfate, and a lubricant were then mixed and tableted to prepare uncoated tablets.

Thereafter, the uncoated tablet was coated with a coating base to finally prepare a film-coated tablet.

Example 4

A binder solution was prepared by dissolving a solubilizing agent and a binder in a mixed solution of purified water and ethanol, combining fimasartan potassium trihydrate, D-mannitol, and croscarmellose sodium with the binder solution, drying and sizing it, and then the sized product Amlodipine besylate, corn starch, sodium lauryl sulfate, and a lubricant were then mixed and tableted to prepare uncoated tablets.

Thereafter, the uncoated tablet was coated with a coating base to finally prepare a film-coated tablet.

Example 5 to 6

A solubilizing agent and a binder are dissolved in a mixture of purified water and ethanol to prepare a binder solution, and pimasartan potassium trihydrate, microcrystalline cellulose, and croscarmellose sodium are combined, dried and sized, , D-mannitol and a lubricant were mixed and tableted to prepare uncoated tablets.

Thereafter, the uncoated tablet was coated with a coating base to finally prepare a film-coated tablet.

Example 7

A solubilizing agent and a binder are dissolved in purified water to prepare a binder solution, and with the binder solution, fimasartan potassium trihydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate are combined, dried and sized, and then the sized product Amlodipine besylate, D-mannitol, and a lubricant were then mixed and tableted to prepare uncoated tablets.

Thereafter, the uncoated tablet was coated with a coating base to finally prepare a film-coated tablet.

comparative example

Ducarb™ Tablets 60/10mg (Manufacturer: Boryung Pharmaceutical)

Experimental Example

Evaluation of tablet physical properties

The physical parameters of the tablets prepared in the above examples were evaluated, and the results are shown in Table 2 below.

evaluation item Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 disintegration 5-7 minutes 7-9 minutes 3-4 minutes 14-16 minutes 5-6 minutes 14-16 minutes within 5 minutes Hardness 7~8kp 8~10kp 3kp 8~10kp 5-8kp 8~10kp 5-8kp Masondo 0.3% 0.3% 0.3% 0.4% 0.1% 0.2% 0.1% or less sleep disorder Sticking - Capping Sticking Sticking doesn't exist doesn't exist Review Poor wear and tear
(color, surface) disintegration delay
Poor wear and tear Poor wear and tear disintegration delay
Poor wear and tear
bad appearance
(color, surface) bad appearance
(color, surface) disintegration delay
bad appearance
(color, surface) Good

For reference, among the examples, examples using polysorbate 80 and meglumine had poor properties, such as a rough surface and a yellowish color.

Evaluation of purification dissolution characteristics

The dissolution characteristics of the tablets prepared in the above examples were evaluated, and the results are shown in Table 3 and FIG. 3 below.

test solution minute Average dissolution rate (%) Comparative Example (F)
(Fimasartan Potassium) Example 7 (F)
(Fimasartan Potassium) Comparative Example (A)
(amlodipine) Example 7 (SA)
(esamlodipine) pH 1.2 liquid 5 18.6 24.9 84.8 64.0 10 25.5 38.6 86.3 80.9 15 27.7 41.4 85.2 86.2 30 28.6 41.3 86.8 90.7 45 29.3 41.0 86.2 93.8 60 29.9 40.8 87.0 92.4 pH 4.0 liquid 5 15.3 10.7 88.4 54.8 10 10.9 14.0 93.0 70.6 15 8.4 14.1 89.8 82.8 30 13.6 12.6 96.6 90.4 45 22.3 10.4 96.9 95.1 60 19.9 9.7 97.0 98.0 pH 6.8 liquid 5 27.5 50.3 40.0 19.2 10 60.7 87.3 66.9 43.5 15 79.9 94.0 78.5 59.5 30 93.5 97.9 85.1 69.9 45 96.7 99.3 87.5 75.8 60 96.7 100.1 89.9 80.6 liquid 5 37.4 63.5 29.8 15.1 10 75.2 95.5 37.9 24.5 15 92.0 100.0 39.0 35.3 30 96.8 101.9 32.4 36.4 45 97.5 102.5 26.5 38.9 60 98.1 102.8 26.3 41.0

Overall, it was confirmed that the drug was not well released in the pH 1.2 solution and the dissolution rate was lowered in the pH 4.0 solution.

In addition, Example 7 confirmed that Fimasartan has the advantage of rapidly releasing the drug compared to Comparative Example.

according to solubilizing agent Fimasartan calcium trihydrate solubility measurement

Fimasartan potassium trihydrate and various types of solubilizing agents were mixed at a weight ratio of 1:0.5, and then stirred at room temperature at 500 rpm for 24 hours using pH 1.2 liquid and pH 4.0 liquid as medium, and then the solubility was measured. evaluated. The results were shown in Table 4 and Table 5 below.

pH1.2 control group
(Fimasartan
potassium trihydrate) poloxamer
188 poloxamer
407 SLS
(sodium lauryl sulfate) CTAB
(Cetrimonium bromide)
solubility
(mgml) 0.23 0.94 1.21 0.22 0.69 HLB Value - 29 22 40 10

pH4.0 control group
(Fimasartan
potassium trihydrate) poloxamer
188 poloxamer
407 solubility
(mgml) 16.36 88.81 24.94 HLB Value - 29 22

As confirmed in Tables 4 and 5, nonionic surfactants poloxamer188 and poloxamer407 having HLB values in the range of 20 to 30 were evaluated to exhibit significantly higher solubility performance than other solubilizers.

Claims (10)

A granular part containing fimasartan or a pharmaceutically acceptable salt thereof as a first active ingredient, and pharmaceutically acceptable additives; and
A complex pharmaceutical composition comprising escamlodipine or a pharmaceutically acceptable salt thereof as a second active ingredient,
A combination pharmaceutical composition, characterized in that it is in the form of a single-layer tablet. The complex pharmaceutical composition according to claim 1, wherein the additive is at least one selected from the group consisting of excipients, binders, disintegrants, lubricants, and solubilizers. The combination pharmaceutical composition of claim 2, wherein the solubilizing agent is included in an amount of 3 to 30% by weight based on the weight of the first active ingredient. The combination pharmaceutical composition according to claim 2, wherein the solubilizing agent is a nonionic surfactant having an HLB value in the range of 20 to 30. The combination pharmaceutical composition according to claim 3, wherein the nonionic surfactant is poloxamer188, poloxamer407, or a combination thereof. The combination pharmaceutical composition according to claim 1, wherein the first active ingredient is fimasartan potassium in an amount of 30 to 60 mg. The combination pharmaceutical composition according to claim 1, wherein the first active ingredient is fimasartan potassium and its particle size distribution satisfies at least one of the following conditions.
1) The average particle size (D10) of the lower 10% of the particles is 1 to 20㎛
2) The average particle size (D50) of the lower 50% of the particles is 5 to 100㎛
3) The average particle size (D90) of the lower 90% of the particles is 25 to 150㎛ The combination pharmaceutical composition according to claim 1, wherein the second active ingredient is escamlodipine in an amount of 2.5 to 5 mg. The combination pharmaceutical composition according to claim 1, wherein the combination pharmaceutical composition is for preventing or treating angiotensin-2-receptor related diseases. The combination pharmaceutical composition according to claim 1, wherein the combination pharmaceutical composition is in the form of a film-coated tablet having a coating layer.

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