KR20240147572A - Pharmaceutical composition for treating hypertension comprising azilsartan - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating hypertension, which comprises azilsartan as an active ingredient, and more specifically, to a pharmaceutical composition for treating hypertension, which comprises azilsartan, an active metabolite of azilsartan medoxomil, and is administered at a novel dosage that ensures bioequivalence to an azilsartan medoxomil preparation.

Description

{Pharmaceutical composition for treating hypertension comprising azilsartan}

The present invention relates to a pharmaceutical composition for treating hypertension comprising azilsartan, and more specifically, to a pharmaceutical composition for treating hypertension comprising azilsartan, an active metabolite of azilsartan medoxomil, and administered at a novel dosage that ensures bioequivalence to an azilsartan medoxomil preparation.

Edarbi® is an antihypertensive drug belonging to the ARB (Angiotensin II Receptor Blocker) series containing the potassium salt of azilsartan medoxomil as its main ingredient. It has excellent blood pressure lowering effects and safety compared to other ARB series drugs.

Orally administered azilsartan medoxomil is hydrolyzed in the gastrointestinal tract during absorption to the active metabolite azilsartan, which selectively blocks the binding of AT1 receptors present in various tissues such as vascular smooth muscle and adrenal glands, thereby selectively inhibiting the effects of angiotensin II. Angiotensin II is the basic vasopressor in the renin-angiotensin system (RAS), causing vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal reabsorption of sodium.

However, azilsartan medoxomil has a unique unpleasant odor due to diacetyl, which is generated when medoxomil is broken down, and there is a need to resolve the problem caused by this.

To solve these problems, the inventors of the present invention attempted to develop a formulation containing only azilsartan, an active metabolite that does not contain medoxomil, as its main ingredient.

Meanwhile, Azilva®, a product containing azilsartan, is approved in Japan, and its approved dosages are 40 mg, 20 mg, and 10 mg.

However, as confirmed by the present inventors, the dosage of Azilba was not bioequivalent to Idalbi tablets (approved dosages of 80 mg, 40 mg, and 20 mg) as an approved Azilsartan medoxomil formulation, and the present invention was completed by confirming a new bioequivalent dosage.

Accordingly, the problem to be solved by the present invention is to provide a pharmaceutical composition for treating hypertension having a novel effective ingredient dosage comprising azilsartan medoxomil preparation and a biologically equivalent dosage of azilsartan.

The present inventors have conducted a comprehensive study to find a dosage range biologically equivalent to 80 mg of Idalbijeong, an approved azilsartan medoxomil formulation, and as a result, completed the present invention by producing a pharmaceutical composition for treating hypertension containing 50 to 54 mg of azilsartan as an active ingredient.

In the present invention, the active ingredient means a substance expected to cause the efficacy or effect of the pharmaceutical product, and the main ingredient means a substance including the active ingredient and a salt or isomer of the active ingredient.

A bioequivalence test is one of the in vivo tests conducted to prove bioequivalence. It refers to a test conducted to prove that two preparations containing the same active ingredient and administered via the same route are statistically equivalent in terms of bioavailability for a drug whose active ingredient is absorbed into the systemic circulation and exhibits its efficacy.

The evaluation of bioequivalence level can be conducted according to the standard guidelines of the Ministry of Food and Drug Safety. After log-transforming the AUC and Cmax values of azilsartan, the geometric mean is calculated, and if the 90% confidence interval for the ratio of the geometric means is 80 to 125%, the two preparations can be considered bioequivalent.

In one embodiment of the present invention, the pharmaceutical composition may have an area under the blood concentration-time curve (AUC) and a maximum blood concentration (Cmax) of 80 to 125% compared to when administered with a formulation comprising azilsartan medoxomil.

At this time, the preparation containing azilsartan medoxomil may contain 80 mg of azilsartan medoxomil, and the preparation may be Idalbi tablet 80 mg. For reference, the main ingredient of Idalbi tablet is azilsartan medoxomil potassium salt, the active ingredient is azilsartan medoxomil, and its active metabolite is azilsartan.

Idalbi tablet 80 mg contains 80 mg of azilsartan medoxomil, of which the weight of azilsartan excluding medoxomil group is approximately 64 mg. Idalbi tablet 40 mg contains 40 mg of azilsartan medoxomil, of which the weight of azilsartan excluding medoxomil group is approximately 32 mg.

In one embodiment of the present invention, the pharmaceutical composition may be a high-strength formulation corresponding to 80 mg of Idalbijeong, and may be a pharmaceutical composition containing 50 to 54 mg of azilsartan as an active ingredient.

In one embodiment of the present invention, the pharmaceutical composition may contain 50, 51, 52, 53 or 54 mg of azilsartan as an active ingredient, preferably 52 mg.

In one embodiment of the present invention, the pharmaceutical composition may be a low-dose formulation corresponding to 40 mg of Idalbijeong, and may be a pharmaceutical composition containing 25 to 27 mg of azilsartan as an active ingredient.

In one embodiment of the present invention, the pharmaceutical composition may contain 25, 25.5, 26, 26.5 or 27 mg of azilsartan as an active ingredient, preferably 26 mg.

In one embodiment of the present invention, the pharmaceutical composition may be a low-dose formulation corresponding to 20 mg of Idalbijeong, and may be a pharmaceutical composition containing 12.5 to 13.5 mg of azilsartan as an active ingredient.

In one embodiment of the present invention, the pharmaceutical composition may contain 12.5, 13 or 13.5 mg of azilsartan as an active ingredient, preferably 13 mg.

In one embodiment of the present invention, the daily dosage of the pharmaceutical composition may be about 12.5 to 54 mg of azilsartan as an active ingredient. The recommended initial dose is 25 to 27 mg, and the dosage may be appropriately adjusted depending on the age of the subject, underlying disease, and whether or not the blood pressure-lowering effect is present.

In one embodiment of the present invention, the pharmaceutical composition can be administered orally once daily.

In one embodiment of the present invention, the pharmaceutical composition may be orally administered in a single dose of 1 to 3 tablets.

In one embodiment of the present invention, the composition comprising azilsartan or a pharmaceutically acceptable salt thereof may be in the form of a tablet, capsule, granule, powder, liquid, suspension, etc., and is preferably a tablet.

In one embodiment of the present invention, the composition of the present invention may comprise a pharmaceutically acceptable salt of azilsartan.

In one embodiment of the present invention, the pharmaceutically acceptable salt of azilsartan is a salt that can be commonly used in the art, and examples thereof include, but are not limited to, hydrochloride, magnesium salt, strontium salt, lithium salt, sodium salt, potassium salt, calcium salt, and the like.

In one embodiment of the present invention, azilsartan or a pharmaceutically acceptable salt thereof may be present in an amount of 10 to 50 wt%, preferably 15 to 35 wt%, relative to the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may additionally contain additives such as pharmaceutically acceptable excipients, binders, disintegrants, stabilizers, lubricants, and coating agents.

In one embodiment of the present invention, the pharmaceutical composition may use at least one selected from the group consisting of lactose monohydrate, starch, sucrose, lactose, mannitol, sorbitol, powdered cellulose, microcrystalline cellulose, and dicalcium phosphate anhydrous as an excipient, and preferably lactose, starch, microcrystalline cellulose, and mannitol may be used.

In one embodiment of the present invention, the pharmaceutical composition may contain 5 to 50 wt% of lactose, preferably 10 to 30 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain 1 to 30 wt% of starch, preferably 3 to 15 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain 1 to 50 wt% of microcrystalline cellulose based on the total weight of the pharmaceutical composition, preferably 5 to 25 wt%.

In one embodiment of the present invention, the pharmaceutical composition may contain 5 to 17 wt% of mannitol, preferably 10 to 16.5 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain 50 to 90 wt% of lactose relative to the weight of azilsartan or its salt, preferably 65 to 80 wt%.

In one embodiment of the present invention, the pharmaceutical composition may contain 10 to 50 wt% of starch relative to the weight of azilsartan or its salt, preferably 25 to 40 wt%.

In one embodiment of the present invention, the pharmaceutical composition may contain microcrystalline cellulose in an amount of 60 to 110 wt%, preferably 80 to 100 wt%, relative to the weight of azilsartan or its salt.

In one embodiment of the present invention, the pharmaceutical composition may contain 40 to 69 wt% of mannitol relative to the weight of azilsartan or a salt thereof, preferably 50 to 65 wt%.

In one embodiment of the present invention, the pharmaceutical composition may use at least one selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, lactose, starch, gum arabic, gelatin, and povidone as a binder, and preferably, hydroxypropyl cellulose may be used.

In one embodiment of the present invention, the pharmaceutical composition may contain hydroxypropyl cellulose in an amount of 0.1 to 15 wt%, preferably 1 to 10 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain hydroxypropylcellulose in an amount of 1 to 30 wt%, preferably 5 to 20 wt%, relative to the weight of azilsartan or a salt thereof.

In one embodiment of the present invention, the pharmaceutical composition may use, as a disintegrant, at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, alginic acid, carboxymethylcellulose calcium salt or sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, and sodium alginate.

In one embodiment of the present invention, the pharmaceutical composition may not contain a disintegrant.

In one embodiment of the present invention, the pharmaceutical composition may use at least one selected from the group consisting of polyethylene glycol, sodium bisulfite, ascorbic acid, and ethylenediamine as a stabilizer, and preferably polyethylene glycol 6000 may be used.

In one embodiment of the present invention, the pharmaceutical composition may contain 0.1 to 20 wt% of polyethylene glycol 6000, preferably 1 to 10 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain 1 to 30 wt% of polyethylene glycol 6000, preferably 5 to 20 wt%, based on the weight of azilsartan or its salt.

In one embodiment of the present invention, the pharmaceutical composition may use at least one selected from the group consisting of fatty acid ester, stearic acid, magnesium stearate, glyceryl behenate, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, talc, hydrogenated oil, and carnauba wax as a lubricant, and preferably magnesium stearate and talc may be used.

In one embodiment of the present invention, the pharmaceutical composition may contain 0.1 to 10 wt% of magnesium stearate based on the total weight of the pharmaceutical composition, preferably 0.5 to 5 wt%.

In one embodiment of the present invention, the pharmaceutical composition may contain talc in an amount of 0.1 to 10 wt%, preferably 0.5 to 5 wt%, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition may contain 0.1 to 10 wt% of magnesium stearate relative to the weight of azilsartan or its salt, preferably 1 to 5 wt%.

In one embodiment of the present invention, the pharmaceutical composition may contain talc in an amount of 0.1 to 10 wt%, preferably 1 to 5 wt%, relative to the weight of azilsartan or its salt.

In one embodiment of the present invention, the pharmaceutical composition may be additionally coated.

In one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable coating agent, examples of which include polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, ethyl methacrylate-ethyl methacrylate chlorotrimethylammonium ethyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methyl cellulose acetate succinate, and hydroxypropyl methyl cellulose phthalate, or mixtures thereof.

The pharmaceutical composition according to the present invention is biologically equivalent to the previously approved azilsartan medoxomil preparation and thus has an excellent blood pressure lowering effect, and thus can be easily used for the treatment of hypertension.

The pharmaceutical composition according to the present invention can have the effect of reducing the unpleasant odor generated when medoxomil is decomposed by including azilsartan, an active metabolite of azilsartan medoxomil.

The pharmaceutical composition according to the present invention can have the effect of increasing the convenience of taking the medicine by reducing the tablet size by administering a dose of the active ingredient that is reduced compared to the dose of the existing azilsartan medoxomil preparation.

The pharmaceutical composition according to the present invention can have a superior effect compared to the 40 mg dose of Azilva, which was expected to have an equivalent effect to the azilsartan medoxomil preparation, by having a dose that has an equivalent effect to the azilsartan medoxomil preparation.

The pharmaceutical composition according to the present invention can exhibit biological activity equivalent to that of azilsartan medoxomil without the unpleasant odor of azilsartan medoxomil.

Figures 1 and 2 are graphs comparing the observed mean plasma concentrations of azilsartan predicted by the constructed pharmacokinetic model with the concentrations measured in Test Examples 1 and 2.
Figure 3 is a graph comparing the dissolution patterns of 52 mg and 26 mg formulations of azilsartan.

Hereinafter, the present invention will be described in detail based on the following examples and experimental examples. However, the following manufacturing examples and test examples are only intended to illustrate the present invention and the scope of the present invention is not limited thereto.

Reference Example: Preparation of Azilsartan preparation

According to the formulation in Table 1 below, azilsartan, lactose, corn starch, and microcrystalline cellulose were mixed, and an aqueous solution of hydroxypropyl cellulose (viscosity 6 to 10 mPa s) in which polyethylene glycol 6000 was dissolved was sprayed as a binder, and granulated, dried, and sieved. Mannitol and microcrystalline cellulose were added and mixed, and magnesium stearate was additionally mixed, followed by tableting to manufacture tablets.

Composition Reference Example 1 Reference example 2 In the granules Azilsartan 40 44 Lactose 29.3 32.2 Corn starch 13 14.3 Microcrystalline Cellulose 13 14.3 Polyethylene glycol 6000 4 4.4 Hydroxypropyl cellulose 4 4.4 Outside of granules Mannitol 27.9 39 Microcrystalline Cellulose 27.9 6.4 Magnesium stearate 0.9 1 Grand total 160 160

Test Example 1: Pharmacokinetic analysis of azilsartan 40 mg formulation

A phase 1 clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of azilsartan formulation (test drug) and azilsartan medoxomil formulation (reference drug) in healthy adult volunteers.

The azilsartan medoxomil preparation used in the test was commercially available Idalbi tablet 80 mg (Company name: Celltrion Pharmaceutical Co., Ltd.), and the azilsartan preparation used was azilsartan 40 mg preparation manufactured by the method described in Reference Example 1.

Healthy adults were divided into two groups as described in Table 2 and orally administered the test drug and the control drug. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 34, and 48 hours after each administration to measure the blood drug concentration profile.

Dosage group 1st dose Rest period 2nd dose 1st Army
(n=25) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg) 7 days Reference Example 1 Preparation 1 tablet
(Azilsartan 40 mg) 2nd Army
(n=25) Reference Example 1 Preparation 1 tablet
(Azilsartan 40 mg) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg)

The bioequivalence assessment was conducted according to the standard guidelines of the Ministry of Food and Drug Safety. That is, the pharmacokinetic parameters such as AUCt and Cmax for each administration group were log-transformed to obtain the geometric least squares means (GSMs) of the reference drug and the test drug, and the geometric least squares mean ratio (GSMs) of the test drug to the reference drug. The two-sided 90% confidence intervals were calculated to evaluate whether they were within the range of log 0.80 to log 1.25.

The results of the bioequivalence evaluation performed as above are shown in Table 3 below.

Variable geometric least squares mean Geometric mean ratio 90% confidence interval Contrast medicine Test drug Cmax (ng/mL) 5419.490 4634.643 0.8552 0.8091 ; 0.9039 AUCt (hr*ng/mL) 46205.681 33327.015 0.7213 0.6952 ; 0.7483

As a result of the test, it was confirmed that the 40 mg azilsartan preparation of Reference Example 1 did not satisfy the bioequivalence level with the 80 mg azilsartan medoxomil preparation (Idalbi tablets).

Test Example 2: Pharmacokinetic analysis of azilsartan 44 mg formulation

A phase 1 clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of azilsartan formulation (test drug) and azilsartan medoxomil formulation (reference drug) in healthy adult volunteers.

Except for using the 44 mg azilsartan preparation of Reference Example 2 as the test drug, the test method was the same as that of Test Example 1 (Table 4).

Dosage group 1st dose Rest period 2nd dose 1st Army
(n=25) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg) 7 days Reference Example 2 Preparation 1 tablet
(Azilsartan 44 mg) 2nd Army
(n=25) Reference Example 2 Preparation 1 tablet
(Azilsartan 44 mg) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg)

The results of the bioequivalence evaluation performed as above are shown in Table 5 below.

Variable geometric least squares mean Geometric mean ratio 90% confidence interval Contrast medicine Test drug Cmax (ng/mL) 5115.317 4650.779 0.9092 0.8514 ; 0.9709 AUCt (hr*ng/mL) 44769.505 35199.779 0.7862 0.7487 ; 0.8256

As a result of the test, it was confirmed that the 44 mg azilsartan preparation of Reference Example 2 did not satisfy the bioequivalence level with the 80 mg azilsartan medoxomil preparation (Idalbi tablets).

Test Example 3: Pharmacokinetic Modeling and Simulation

Based on the clinical trial data of the 40 mg and 44 mg azilsartan formulations performed in Test Examples 1 and 2, the optimal dose that can satisfy bioequivalence with the reference drug (azilsartan medoxomil 80 mg) was predicted using a pharmacokinetic modeling approach.

In this study, data processing and analysis, including calculation of pharmacodynamic parameters, pharmacodynamic modeling and simulation, and bioequivalence evaluation, were performed using Phoenix Winnonin ver. 8.3.

In this study, the pharmacokinetic behavior of azilsartan after oral administration was set to a two-compartment model with a first-order absorption rate, and the model parameters derived at this time are as shown in Tables 6 and 7.

Parameter Units Estimate tvKa 1/hr 1.0084728 tvV mL 5995.1067 tvV2 mL 3996.1247 tvC1 mL/hr 1158.8074 tvC12 mL/hr 388.54504

tvKa, first-order absorption rate constant; tvV, volume of distribution (volume of central compartment); tvV2, volume of distribution (volume of peripheral compartment); tvCL, total elimination clearance for central compartment; tvCL2, distribution clearance between central and peripheral compartment

Parameter Units Estimate tvKa 1/hr 0.76 tvV mL 5999.1978 tvV2 mL 4005.8089 tvC1 mL/hr 1200 tvC12 mL/hr 400

tvKa, first-order absorption rate constant; tvV, volume of distribution (volume of central compartment); tvV2, volume of distribution (volume of peripheral compartment); tvCL, total elimination clearance for central compartment; tvCL2, distribution clearance between central and peripheral compartment

At this time, it was confirmed that the average plasma concentration of azilsartan observed in Test Examples 1 and 2 was very consistent with the concentration predicted by the constructed model (Figures 1 and 2).

Using the constructed pharmacokinetic model, the concentration according to time for each administered dose was predicted, and 45 random subjects were generated to predict the bioequivalence evaluation in the same population as the reference drug. Considering that the variability (CV) of the exposure level (AUC and Cmax) in the previously performed clinical trials (Test Examples 1 and 2) was observed to be less than 20%, a normally distributed random number with an arbitrary variability of 20% was generated for the model parameter first-order absorption rate constant ka to implement the variability.

Using the model proposed in this study, the drug concentration over time for each subject was predicted according to dose, and the main pharmacokinetic parameters were calculated. In addition, the main pharmacokinetic parameters of the reference drug azilsartan medoxomil preparation in Test Examples 1 and 2 were also calculated. Finally, a bioequivalence evaluation was performed using the predicted exposure level of the test drug azilsartan and the observed exposure level of the reference drug.

The results of the bioequivalence evaluation between the exposure level of the azilsartan preparation according to the administered dose predicted using the above model and the exposure level of the corresponding azilsartan medoxomil preparation are as shown in Tables 8 and 9 below. (Table 8 is a simulated bioequivalence test between the reference drug and the test drug generated by Test Example 1, and Table 9 is a simulated bioequivalence test between the reference drug and the test drug generated by Test Example 2)

Dose PK Ratio CI_90_Lower CI_90_Upper 44mg Cmax 80.99 74.68 87.85 AUClast 82.26 73.32 92.30 45mg Cmax 80.97 74.44 88.08 AUClast 85.41 75.53 96.59 46mg Cmax 82.77 76.09 90.04 AUClast 87.31 77.21 98.73 47mg Cmax 84.57 77.75 91.99 AUClast 89.21 78.89 100.88 48mg Cmax 86.37 79.40 93.95 AUClast 91.11 80.57 103.03 49mg Cmax 88.17 81.05 95.91 AUClast 93.00 82.25 105.17 50mg Cmax 89.97 82.71 97.87 AUClast 94.90 83.92 107.32 51mg Cmax 91.77 84.36 99.82 AUClast 96.80 85.60 109.47 52mg Cmax 93.57 86.02 101.78 AUClast 98.70 87.28 111.61 53mg Cmax 95.37 87.67 103.74 AUClast 100.60 88.96 113.76 54mg Cmax 97.17 89.33 105.69 AUClast 102.50 90.64 115.90 55mg Cmax 98.97 90.98 107.65 AUClast 104.39 92.32 118.05 56mg Cmax 100.76 92.63 109.61 AUClast 106.29 93.99 120.20 57mg Cmax 102.56 94.29 111.57 AUClast 108.19 95.67 122.34 58mg Cmax 104.36 95.94 113.52 AUClast 110.09 97.35 124.49 59mg Cmax 106.16 97.60 115.48 AUClast 111.99 99.03 126.64 60mg Cmax 107.96 99.25 117.44 AUClast 113.88 100.71 128.78

Dose PK Ratio CI_90_Lower CI_90_Upper 44mg Cmax 79.92 71.45 89.38 AUClast 84.32 71.08 100.04 45mg Cmax 81.73 73.08 91.41 AUClast 86.24 72.70 102.31 46mg Cmax 83.55 74.70 93.44 AUClast 88.16 74.31 104.58 47mg Cmax 85.36 76.33 95.47 AUClast 90.07 75.93 106.86 48mg Cmax 87.18 77.95 97.50 AUClast 91.99 77.54 109.13 49mg Cmax 89.00 79.57 99.54 AUClast 93.91 79.16 111.40 50mg Cmax 90.81 81.20 101.57 AUClast 95.82 80.77 113.68 51mg Cmax 92.63 82.82 103.60 AUClast 97.74 82.39 115.95 52mg Cmax 94.45 84.45 105.63 AUClast 99.66 84.01 118.22 53mg Cmax 96.26 86.07 107.66 AUClast 101.57 85.62 120.50 54mg Cmax 98.08 87.69 109.69 AUClast 103.49 87.24 122.77 55mg Cmax 99.89 89.32 111.72 AUClast 105.41 88.85 125.04 56mg Cmax 101.71 90.94 113.75 AUClast 107.32 90.47 127.32 57mg Cmax 103.53 92.57 115.79 AUClast 109.24 92.08 129.59 58mg Cmax 105.34 94.19 117.82 AUClast 111.16 93.70 131.87 59mg Cmax 107.16 95.81 119.85 AUClast 113.07 95.31 134.14 60mg Cmax 108.98 97.44 121.88 AUClast 114.99 96.93 136.41

In this study, based on the clinical trial results of Test Examples 1 and 2 previously conducted, the exposure level according to the dose of the test drug, azilsartan, was predicted using a pharmacokinetic modeling and simulation approach, and a bioequivalence evaluation was performed to predict the exposure level of the reference drug, azilsartan medoxomil, observed in each clinical trial.

As a result, it was confirmed that both AUC and Camx of azilsartan satisfied bioequivalence with the control drug when 49 to 58 mg of the test drug was administered based on the criteria of the clinical trial in Test Example 1, and it was confirmed that bioequivalence was satisfied when 50 to 54 mg of the test drug was administered based on the criteria of the clinical trial in Test Example 2.

Therefore, the range of 50–54 mg, which includes the optimal predicted dose derived from both clinical trials as a conservative approach, is considered to be the most appropriate dose that can satisfy the bioequivalence assessment approached based on existing clinical trials.

Test Example 4: Evaluation of safety, tolerability, and pharmacokinetic properties of azilsartan 52 mg formulation

In the above Test Example 3, a preparation having a median dose of 52 mg was manufactured from the optimal expected dose range of 50 to 54 mg derived from the two clinical trials, and its bioequivalence with the reference drug was evaluated.

The test method was the same as in Test Example 1, except that the 52 mg azilsartan preparation of Manufacturing Example 1 was used as the test drug (Table 10).

Dosage group 1st dose Rest period 2nd dose 1st Army
(n=25) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg) 7 days Manufacturing Example 1 Preparation 1 tablet
(Azilsartan 52 mg) 2nd Army
(n=25) Manufacturing Example 1 Preparation 1 tablet
(Azilsartan 52 mg) Idalbijeong 80 mg 1 tablet
(Azilsartan medoxomil 80 mg)

Fifty subjects were administered the clinical trial drug, but four subjects dropped out (three withdrew consent, one had an adverse event), so a final total of 46 subjects completed the clinical trial. Pharmacokinetic characteristics were evaluated for the 46 subjects who completed the clinical trial, and safety was evaluated for the 50 subjects who were administered the clinical trial drug at least once.

The pharmacodynamic characteristics between the administration groups for the primary pharmacodynamic endpoints ( _AUClast and _Cmax of azilsartan) were compared after administration of the test drug and the reference drug. As a result of statistical analysis of the pharmacodynamic endpoints, the geometric mean ratio of _Cmax for azilsartan was 1.1081, and the 90% confidence interval was 1.0243 to 1.1987, and the geometric mean ratio of _AUCt was 0.9697, and the 90% confidence interval was 0.9160 to 1.0264 (Table 11). In conclusion, when the 90% confidence intervals of the primary pharmacodynamic endpoints were confirmed, all primary pharmacodynamic endpoints satisfied the equivalence range (0.8 to 1.25).

Variable geometric least squares mean Geometric mean ratio 90% confidence interval Contrast medicine Test drug C _max (ng/mL) 5622.992 6230.679 1.1081 1.0243 ; 1.1987 AUC _last (hr*ng/mL) 48610.380 47135.843 0.9697 0.9160 ; 1.0264 AUC _inf (hr*ng/mL) 50343.945 48782.453 0.9690 0.9158 ; 1.0253 t _1/2 (hr) 11.509 11.479 0.9974 0.9762 ; 1.0190 AUC _t /AUC _∞ 0.966 0.966 1.0007 0.9988 ; 1.0026 K _el 0.060 0.060 1.0002 0.9789 ; 1.0221

Among the 50 subjects who took the clinical trial drug at least once, 9 adverse events occurred in 6 subjects, and there were no serious adverse events or deaths during the clinical trial.

Among the 9 adverse events, 2 adverse events that occurred after administration of the test drug were confirmed to be adverse drug reactions related to the clinical trial drug, and all adverse events recovered/resolved.

In summary of the above results, the test drug did not exhibit any adverse events that could be evaluated as having a difference in safety compared to the control drug, and the 90% confidence interval of the primary endpoint of this clinical trial met the standards for drug equivalence tests, confirming that the pharmacokinetic characteristics of 1 tablet of azilsartan medoxomil potassium 85.36 mg (80 mg as azilsartan medoxomil) and 1 tablet of azilsartan 52.00 mg are equivalent.

Manufacturing Example 1: Manufacturing of Azilsartan 52 mg formulation

In the same manner as disclosed in the reference example, it was manufactured according to the formulation in Table 12 below.

Composition Manufacturing example 1 In the granules Azilsartan 52 Lactose 38.06 Corn starch 16.9 Microcrystalline Cellulose 16.9 Polyethylene glycol 6000 5.2 Hydroxypropyl cellulose 5.2 Outside of granules Mannitol 30.87 Microcrystalline Cellulose 30.87 Magnesium stearate 2 Talk 2 Grand total 200

Manufacturing Example 2: Manufacturing of Azilsartan 26 mg formulation

As a low-dose formulation corresponding to the 40 mg azilsartan medoxomil formulation (Idalbi tablet 40 mg), the 26 mg azilsartan formulation was manufactured in the same manner as disclosed in the reference example, according to the formulation in Table 13 below.

Composition Manufacturing example 2 In the granules Azilsartan 26 Lactose 19.03 Corn starch 8.45 Microcrystalline Cellulose 8.45 Polyethylene glycol 6000 2.6 Hydroxypropyl cellulose 2.6 Outside of granules Mannitol 15.435 Microcrystalline Cellulose 15.435 Magnesium stearate 1 Talk 1 Grand total 100

Test Example 5: Comparison of dissolution rates of azilsartan preparations

The preparation according to Manufacturing Example 2 is a preparation having the same dosage form, type of active ingredient, and manufacturing method as the azilsartan 52 mg preparation (Manufacturing Example 1) that satisfies bioequivalence with the azilsartan medoxomil 80 mg preparation (Test Example 4), and has a different active ingredient content with similar excipients in a similar ratio, and bioequivalence can be proven by the same dissolution profile.

A dissolution test was performed on the tablets obtained in Manufacturing Example 2 under the following conditions according to the dissolution test method 2 of the Korean Pharmacopoeia. A dissolution test was performed under the same conditions using Manufacturing Example 1 as a control drug.

Elution conditions

Dissolution solution: pH 1.2 test solution (disintegration test method 1 of the Korean Pharmacopoeia), 900 mL

Device: USP method II (paddle method), 50 rpm

Temperature: 37 ± 0.5℃

As can be seen from the results in FIG. 3, it can be seen that the azilsartan 26 mg formulation of Manufacturing Example 2 exhibits a dissolution profile equivalent to that of the azilsartan 52 mg formulation, and therefore, the azilsartan medoxomil 40 mg formulation and the azilsartan 26 mg formulation, which are the same integer multiples of the azilsartan medoxomil 80 mg formulation and the azilsartan 52 mg formulation, respectively, can be viewed as mutually equivalent pharmaceutical products.

Claims (10)

A pharmaceutical composition for treating hypertension, comprising 50 to 54 mg of azilsartan as an active ingredient. A pharmaceutical composition comprising 50, 51, 52, 53 or 54 mg of azilsartan according to claim 1. A pharmaceutical composition comprising 52 mg of azilsartan according to claim 1. A pharmaceutical composition comprising 25 to 27 mg of azilsartan as an active ingredient. A pharmaceutical composition comprising 25, 25.5, 26, 26.5 or 27 mg of azilsartan according to claim 4. A pharmaceutical composition comprising 26 mg of azilsartan according to claim 4. A pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is administered orally once a day. A pharmaceutical composition according to any one of claims 1 to 6, wherein the composition comprises mannitol as an excipient. A pharmaceutical composition according to claim 8, wherein the composition comprises 40 to 69 wt% of mannitol relative to the weight of azilsartan. A pharmaceutical composition according to claim 8, wherein the composition comprises 50 to 65 wt% of mannitol relative to the weight of azilsartan.