Stable eplerenone oral suspension and preparation method thereof

Abstract

The invention discloses a stable eplerenone oral suspension and a preparation method thereof. According to the oral suspension, a buffer pair pH regulator is adopted to regulate the pH value of the oral suspension of the system to 3.0-5.0, so that the stability of the product in the storage process is maintained. Meanwhile, compared with eplerenone tablets, the eplerenone oral suspension provided by the invention has the advantages that the absorption is faster, the in-vivo exposure of the medicine is larger, the bioavailability is obviously improved by about 50%, and a reliable high-stability and high-bioavailability eplerenone oral suspension preparation scheme is provided clinically.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a eplerenone oral suspension with stable quality and a preparation method thereof, which has high bioavailability. BACKGROUND

[0002] Eplerenone is a selective aldosterone receptor antagonist, which has important clinical value in the treatment of cardiovascular diseases such as hypertension and heart failure. At present, it is marketed in the form of tablets, which provides a basic medication option for clinical use.

[0003] Eplerenone is (7α, 11α, 17α)-9, 11-epoxy-17-hydroxy-3-oxopregn-4-ene-7, 21-dicarboxylic acid γ-lactone 7-methyl ester, and its chemical structural formula is shown as formula (A). The solubility of the compound is non-pH dependent, and in the aqueous solvent system with pH 1.2-7.4, the saturated solubility is maintained at a low level of about 0.4 mg / mL, which belongs to a poorly soluble drug.

[0004] SUMMARY

[0005] Although eplerenone tablets have been widely used in clinical practice, their dosage form limitations still lead to unmet clinical needs that need to be addressed. First, patients with sequelae of cerebral apoplexy, heart failure and dysphagia caused by Parkinson's disease and the like have difficulty in swallowing tablets, which not only reduces the medication compliance, but also may affect the treatment effect. Second, for patients with heart failure with reduced ejection fraction, precise dose titration according to blood potassium levels is required during treatment, and the fixed dose limitation of tablets cannot meet the demand for precise dose titration of individual treatment, which restricts the precise dose control of the treatment plan for patients. Eplerenone is prone to hydrolytic degradation when prepared into a solution, resulting in poor stability of the product.

[0006] The present application provides a eplerenone oral suspension with high stability and high bioavailability and a preparation method thereof, which solves the technical bottleneck problem of poor stability of the dosage form in the prior art and meets the application needs of eplerenone oral suspension in clinical practice.

[0007] Specifically, the present application provides a eplerenone oral suspension, which comprises a buffer pair pH regulator and a suspending agent, and the pH value of the oral suspension is controlled in the range of 3.0-5.0 (including both end values) by the buffer pair pH regulator.

[0008] In embodiments of the present application, the buffer pair pH adjuster is selected from one or more combinations of citric acid-citric acid sodium, tartaric acid-tartaric acid sodium, acetate buffer pair, lactic acid-lactic acid sodium, benzoic acid-benzoic acid sodium, phosphate buffer pair, which achieves precise control and stable maintenance of pH value through the synergistic effect of the buffer pair; here, the phosphate buffer pair can be monobasic phosphate (such as monobasic sodium phosphate or monobasic potassium phosphate) and dibasic phosphate (such as dibasic sodium phosphate or dibasic potassium phosphate). In one embodiment, the buffer pair pH adjuster is a combination of citric acid and sodium citrate. In one embodiment, the buffer pair pH adjuster is a combination of tartaric acid and sodium tartarate. In one embodiment, the buffer pair pH adjuster is a combination of monobasic sodium phosphate and dibasic sodium phosphate.

[0009] In embodiments of the present application, the mass fraction of the buffer pair pH adjuster in the oral suspension of eplerenone is 0.05wt% to 3wt%, more preferably 0.1wt% to 1.5wt%, or 0.1wt% to 1.0wt%.

[0010] In embodiments of the present application, the suspending agent is selected from one or more combinations of xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose (weight ratio (8-9.5):(2-0.5)) complex, gum arabic, gelatin, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, etc. In some embodiments, the suspending agent is one or more of xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose complex, and hydroxypropyl methyl cellulose.

[0011] In embodiments of the present application, the mass fraction of the suspending agent in the oral suspension of eplerenone is 0.1wt% to 10wt%, further preferably 0.2wt% to 3wt%, or 0.5wt% to 3wt%.

[0012] In embodiments of the present application, the oral suspension of eplerenone further comprises one or more of a bacteriostatic agent, an antifoaming agent, and a flavoring agent.

[0013] In embodiments of the present application, the bacteriostatic agent is selected from one or more combinations of organic acids and their salts (such as sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, etc.), p-hydroxybenzoic acid esters (such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.). In preferred embodiments, the bacteriostatic agent is one or more combinations of sorbic acid, potassium sorbate, and propyl p-hydroxybenzoate.

[0014] In embodiments of the present application, the total mass fraction of the bacteriostatic agent in the oral suspension of eplerenone is 0.05wt% to 0.3wt%, more preferably 0.1wt% to 0.2wt%.

[0015] In embodiments of the present application, the antifoaming agent is selected from one or more of silane-based antifoaming agents (such as dimethyl silicone oil, silicone, polysiloxane, etc.), polyether-based antifoaming agents (such as polyoxyethylene polyoxypropylene ether, polyether polyol, etc.). In preferred embodiments, the antifoaming agent is dimethyl silicone oil.

[0016] In embodiments of the present application, the antifoaming agent is present in the oral suspension of eplerenone in an amount of 0.01wt% to 0.3wt%, more preferably 0.02wt% to 0.2wt%.

[0017] In embodiments of the present application, the flavoring agent is selected from one or more of combinations of sucralose, fruit flavoring (such as strawberry flavoring, honey peach flavoring, orange flavoring, blueberry flavoring, etc.). In preferred embodiments, sucralose and fruit flavoring are included. In embodiments of the present application, the total amount of the flavoring agent in the oral suspension of eplerenone is 0.1wt% to 5wt%, more preferably 0.5wt% to 3wt%.

[0018] In embodiments of the present application, the oral suspension of eplerenone contains 0.1wt% to 1wt% of eplerenone, preferably 0.25wt% to 0.5wt% of eplerenone.

[0019] In embodiments of the present application, the oral suspension of eplerenone contains 75wt% to 98wt% of a solvent system, preferably, here, the solvent system is a combination of one or more of water, glycerol, propylene glycol.

[0020] In embodiments of the present application, the oral suspension of eplerenone contains 0.1wt% to 1wt% of eplerenone, 75wt% to 98wt% of a solvent system, 0.1wt% to 10wt% of a suspending agent, 0.05wt% to 2wt% of a buffer pH adjusting agent, 0.05wt% to 3wt% of a bacteriostatic agent, 0.01% to 1% of an antifoaming agent, and 0.1% to 5% of a flavoring agent.

[0021] In addition, the amount of each excipient in the pharmaceutical composition needs to be adjusted appropriately according to the actual production process, formulation specifications, and stability investigation results, and through the synergistic effect of multiple factors, the oral suspension of eplerenone is ensured to achieve the best performance in terms of chemical stability, physical stability, and microbial stability.

[0022] In preferred embodiments of the present application, after the pharmaceutical composition is exposed to 40°C / 75%RH for 6 months, the individual impurity content of related substances is ≤0.2%, and the total amount of impurities is ≤1.0%. The amount of related substances is determined by high performance liquid chromatography (HPLC).

[0023] The bioavailability comparison test of the embodiment of the present application and the reference preparation, the eplilzerone tablet, shows that the bioavailability of the eplilzerone oral suspension of the present application is significantly improved by about 50% compared with the eplilzerone tablet, indicating that the drug in the eplilzerone oral suspension is dispersed in the form of microparticles, has a larger contact area with the gastrointestinal mucosa, and avoids the drug dissolution step of the tablet, thereby significantly improving the drug absorption rate and bioavailability.

[0024] In another aspect, the present application provides a preparation method of the eplilzerone suspension, which comprises the following steps:

[0025] (1) Preparation of the suspending agent high molecular colloid solution

[0026] About 50% of the purified water of the prescription amount is heated to 40-70°C, the suspending agent of the prescription amount is slowly added under stirring (300-600 rpm), and the stirring (600-1600 rpm) is continued for 20-60 min until the complete swelling and the formation of the uniform high molecular colloid solution;

[0027] (2) Preparation of the aqueous phase solution

[0028] Another about 40% of the purified water of the prescription amount is heated to 40-70°C, the pH adjuster (such as citric acid-sodium citrate) of the buffer system, 50% of the polyol (glycerol / propylene glycol) of the prescription amount is sequentially added, and the bacteriostatic agent can be added as needed, and the complete dissolution is achieved by stirring at 300-600 rpm for 15-30 min;

[0029] (3) Pre-dispersion treatment of the defoaming agent (operation as needed)

[0030] If the defoaming agent needs to be added, it is uniformly mixed with the remaining 50% of the polyol (glycerol or propylene glycol) of the prescription amount by stirring (100-500 rpm) for 10-20 min;

[0031] (4) Preparation of the drug suspension

[0032] The aqueous phase solution of step (2) is slowly added to the suspending agent colloid of step (1), and stirred (500-1500 rpm) to mix, to obtain the blank suspending system, the eplilzerone raw material of the prescription amount is slowly added under stirring (500-1500 rpm), and the stirring is continued for 20-60 min to preliminarily disperse, if the defoaming agent dispersion has been prepared, the defoaming agent dispersion of step (3) is added, and a high-speed shearing machine is used to shear at 10000-15000 rpm for 10-30 min to form the uniform suspension system. The temperature is reduced to 25°C±5°C, the fruit essence and the sweetener can be added as needed, and the dissolution is mixed under stirring at 500-1500 rpm for 10-30 min, and finally the purified water is added to make up the weight / volume, and the stirring is mixed to obtain the eplilzerone oral suspension. Attached Figure Description

[0033] Figure 1 The figure shown is an HPLC chromatogram of related substances in the eplerenone oral suspension of the present invention (Example 1);

[0034] Figure 2 This represents a comparison of the bioavailability of the eplerenone oral suspension of the present invention (Example 1) and eplerenone tablets. Detailed Implementation

[0035] The present invention will be further described below through embodiments. For those skilled in the art, equivalent substitutions or improvements to the following embodiments using existing technology, based on the teachings of the present invention, will still fall within the scope of protection of the present invention.

[0036] Methods for the detection of related substances in eplerenone

[0037] The method was determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512).

[0038] Test solution: Take 4 ml of this product and place it in a 10 ml volumetric flask. Add 4 ml of acetonitrile, sonicate to dissolve eplerenone, dilute to the mark with water-acetonitrile (50:50), shake well, filter, and collect the filtrate.

[0039] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (e.g., Waters XBridge Shield RP18, 4.6 mm × 150 mm, 3.5 μm or equivalent column); 0.1% phosphoric acid aqueous solution was used as mobile phase A, and acetonitrile was used as mobile phase B, with gradient elution according to Table 1; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; the detection wavelength was 220 nm; and the injection volume was 5 μL.

[0040] Table 1

[0041]

[0042] Determination method: Accurately measure the test solution and inject it into the liquid chromatograph, and record the chromatogram.

[0043] Formula for calculating impurity content:

[0044]

[0045] A 杂质 Indicates the area of ​​impurity peaks in the sample solution graph

[0046] A 总 This represents the sum of the peak areas of all components in the sample solution diagram, excluding the solvent and excipient peaks. Example 1

[0047] The formulation of eplerenone suspension is shown in Table 2.

[0048] Table 2

[0049]

[0050] Preparation process:

[0051] (1) Preparation of suspending agent high molecular colloidal solution

[0052] About 50% of the prescription amount of purified water was heated to 40°C, and the prescription amount of xanthan gum was slowly added under stirring (500 rpm) and stirring (1200 rpm) was continued for 20-60 min until complete swelling and formation of a uniform high molecular colloidal solution.

[0053] (2) Preparation of aqueous phase solution

[0054] Another about 40% of the prescription amount of purified water was heated to 40°C, and the prescription amount of citric acid, sodium citrate and glycerol was added in sequence, and stirred at 600 rpm for 15-30 min to completely dissolve.

[0055] (3) Preparation of drug suspension

[0056] The aqueous phase solution of step (2) was slowly added to the suspending agent colloidal solution of step (1), stirred (1000 rpm) to mix evenly, and a blank suspending agent was obtained. Under stirring (1000 rpm), the prescription amount of eplerenone raw material was slowly added, and stirring was continued for 20-60 min to preliminarily disperse. A high-speed shearing machine was used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature was lowered to 25°C±5°C, fruit flavor and sucralose were added, stirred at 1000 rpm for 10-30 min to dissolve and mix evenly, and finally purified water was added to make up the weight / volume, stirred and mixed evenly to obtain eplerenone oral suspension.

[0057] The pH value of eplerenone oral suspension was measured to be 4.5.

[0058] Example 2

[0059] The prescription of eplerenone oral suspension is shown in Table 3

[0060] Table 3

[0061]

[0062] Preparation process:

[0063] (1) Preparation of suspending agent high molecular colloidal solution

[0064] Take about 50% of the prescription amount of purified water heated to 50°C, the prescription amount of xanthan gum, slowly added under stirring (500 rpm) conditions, and continue stirring (1200 rpm) for 20-60 min to completely swell and form a uniform high molecular colloid solution.

[0065] (2) Water phase solution preparation

[0066] Another about 40% of the prescription amount of purified water heated to 50°C, sequentially added prescription amount of citric acid, sodium citrate and glycerol, stirring at 600 rpm for 15-30 min to completely dissolved.

[0067] (3) Preparation of drug suspension

[0068] The water phase solution of step (2) is slowly added to the suspending agent colloid of step (1), stirring (1000 rpm) mixed, to obtain a blank suspending agent, under stirring (1000 rpm) conditions, slowly add the prescription amount of eplerenone raw material, and continue stirring for 20-60 min to be initially dispersed, using a high-speed shear machine under the condition of 10000 rpm shear 10-30 min, forming a uniform suspension system. Cooling to 25°C ± 5°C, add fruit flavor and sodium saccharin 1000 rpm stirring for 10-30 min to dissolve and mix evenly, finally add purified water to make up the weight / volume, stirring and mixing to obtain eplerenone oral suspension.

[0069] The pH value of eplerenone oral suspension is 3.0.

[0070] Example 3

[0071] The prescription of eplerenone oral suspension is shown in Table 4

[0072] Table 4

[0073]

[0074] Preparation process:

[0075] (1) Preparation of suspending agent high molecular colloid solution

[0076] Take about 50% of the prescription amount of purified water heated to 50°C, the prescription amount of xanthan gum, slowly added under stirring (500 rpm) conditions, and continue stirring (1200 rpm) for 20-60 min to completely swell and form a uniform high molecular colloid solution.

[0077] (2) Water phase solution preparation

[0078] Another about 40% of the prescription amount of purified water heated to 50°C, sequentially added prescription amount of citric acid, sodium citrate and glycerol, stirring at 600 rpm for 15-30 min to completely dissolved.

[0079] (3) Preparation of the drug suspension

[0080] Slowly add the aqueous solution of step (2) into the suspension aid colloid of step (1), mix well under stirring (1000 rpm), to obtain the blank suspension aid. Slowly add the prescribed amount of eplerenone raw material under stirring (1000 rpm), and continue stirring for 20-60 min to achieve initial dispersion. Use a high-speed shearing machine to shear at 10000 rpm for 10-30 min to form a uniform suspension system. Cool to 25°C±5°C, add fruit flavor and sucralose under stirring (1000 rpm) for 10-30 min to achieve dissolution and mixing. Finally, add purified water to make up the weight / volume, mix well under stirring to obtain the eplerenone oral suspension.

[0081] The pH value of the eplerenone oral suspension is 5.0.

[0082] Example 4

[0083] The prescription of the eplerenone oral suspension is shown in Table 5

[0084] Table 5

[0085]

[0086] Preparation process:

[0087] (1) Preparation of the suspension aid high molecular colloid solution

[0088] Take about 50% of the prescribed amount of purified water and heat to 50°C. Slowly add the prescribed amount of xanthan gum under stirring (500 rpm), and continue stirring (1200 rpm) for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0089] (2) Preparation of the aqueous solution

[0090] Take another about 40% of the prescribed amount of purified water and heat to 50°C. Add the prescribed amount of citric acid, sodium citrate and glycerol in sequence, and stir at 600 rpm for 15-30 min to achieve complete dissolution.

[0091] (3) Preparation of the drug suspension

[0092] The water phase solution of step (2) is slowly added into the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescription amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirring is continued for 20-60 min to achieve initial dispersion. A high-speed shearing machine is used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature is reduced to 25°C±5°C, fruit flavor and sucralose are added, stirred at 1000 rpm for 10-30 min to dissolve and mix, and finally purified water is added to make up the weight / volume, stirred and mixed to obtain an eplerenone oral suspension.

[0093] The pH value of the eplerenone oral suspension is 4.0.

[0094] Example 5

[0095] The prescription of the eplerenone oral suspension is shown in Table 6

[0096] Table 6

[0097]

[0098] Preparation process:

[0099] (1) Preparation of suspending agent high molecular colloid solution

[0100] About 50% of the prescription amount of purified water is heated to 50°C, and the prescription amount of microcrystalline cellulose-sodium carboxymethyl cellulose complex is slowly added under stirring (500 rpm), and stirring (1200 rpm) is continued for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0101] (2) Preparation of water phase solution

[0102] Another 40% of the prescription amount of purified water is heated to 50°C, and the prescription amount of sorbic acid, citric acid, sodium citrate and 50% of the prescription amount of glycerol is added in sequence, and stirred at 600 rpm for 15-30 min to completely dissolve.

[0103] (3) Pre-dispersion treatment of defoaming agent

[0104] Dimethicone is mixed uniformly with the remaining 50% of the prescription amount of glycerol by stirring (500 rpm) for 10-20 min.

[0105] (4) Preparation of drug suspension

[0106] The water phase solution of step (2) is slowly added into the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescription amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirring is continued for 20-60 min to achieve initial dispersion. The defoaming agent dispersion of step (3) is added, and a high-speed shearing machine is used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature is lowered to 25°C±5°C, fruit flavor and sucralose are added, and stirring is carried out at 1000 rpm for 10-30 min to dissolve and mix uniformly. Finally, purified water is added to make up the weight / volume, and stirring and mixing are carried out to obtain an eplerenone oral suspension.

[0107] The pH value of the eplerenone oral suspension is 4.0.

[0108] Example 6

[0109] The prescription of the eplerenone suspension is shown in Table 7

[0110] Table 7

[0111]

[0112]

[0113] Preparation process:

[0114] (1) Preparation of suspending agent high molecular colloid solution

[0115] About 50% of the prescription amount of purified water is heated to 40°C, and the prescription amount of xanthan gum is slowly added under stirring (500 rpm) and stirring (1200 rpm) is continued for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0116] (2) Preparation of water phase solution

[0117] Another about 40% of the prescription amount of purified water is heated to 40°C, and the prescription amount of sorbic acid, tartaric acid, sodium tartrate and 50% of the prescription amount of glycerol is added in sequence. Stirring is carried out at 600 rpm for 15-30 min to completely dissolve.

[0118] (3) Pre-dispersion treatment of defoaming agent

[0119] Dimethicone is mixed uniformly with the remaining 50% of the prescription amount of glycerol by stirring (500 rpm) for 10-20 min.

[0120] (4) Preparation of drug suspension

[0121] The water phase solution of step (2) is slowly added into the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescription amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirring is continued for 20-60 min to achieve initial dispersion. The defoaming agent dispersion of step (3) is added, and a high-speed shearing machine is used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature is lowered to 25°C±5°C, fruit flavor and sucralose are added, stirred at 1000 rpm for 10-30 min to dissolve and mix, and finally purified water is added to make up the weight / volume, stirred and mixed to obtain an eplerenone oral suspension.

[0122] The pH value of the eplerenone oral suspension is 4.0.

[0123] Example 7

[0124] The eplerenone suspension prescription is shown in Table 8

[0125] Table 8

[0126]

[0127]

[0128] Preparation process:

[0129] (1) Preparation of suspending agent high molecular colloid solution

[0130] About 50% of the prescription amount of purified water is heated to 40°C, and the prescription amount of hydroxypropyl methyl cellulose is slowly added under stirring (500 rpm), and stirring (1200 rpm) is continued for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0131] (2) Preparation of water phase solution

[0132] Another about 40% of the prescription amount of purified water is heated to 40°C, and the prescription amount of hydroxypropyl methyl cellulose, citric acid, sodium citrate and 50% of the prescription amount of glycerol are sequentially added, and stirred at 600 rpm for 15-30 min to completely dissolve.

[0133] (3) Pre-dispersion treatment of defoaming agent

[0134] Dimethicone is mixed uniformly with the remaining 50% of the prescription amount of glycerol by stirring (500 rpm) for 10-20 min.

[0135] (4) Preparation of drug suspension

[0136] The water phase solution of step (2) is slowly added to the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescribed amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirring is continued for 20-60 min to achieve initial dispersion. The defoaming agent dispersion of step (3) is added, and a high-speed shearing machine is used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature is lowered to 25°C±5°C, and fruit essence and sucralose are added, stirred at 1000 rpm for 10-30 min to achieve dissolution and mixing, and finally purified water is added to make up the weight / volume, stirred and mixed to obtain an eplerenone oral suspension.

[0137] The pH value of the eplerenone oral suspension is 4.0.

[0138] Example 8

[0139] The eplerenone suspension prescription is shown in Table 9

[0140] Table 9

[0141]

[0142] Preparation process:

[0143] (1) Preparation of suspending agent high molecular colloid solution

[0144] About 50% of the prescribed amount of purified water is heated to 40°C, and the prescribed amount of xanthan gum is slowly added under stirring (500 rpm) and stirring (1200 rpm) is continued for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0145] (2) Preparation of water phase solution

[0146] Another about 40% of the prescribed amount of purified water is heated to 40°C, and the prescribed amount of sorbic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate and glycerol is added in sequence, and stirred at 600 rpm for 15-30 min to achieve complete dissolution.

[0147] (3) Preparation of drug suspension

[0148] The water phase solution of step (2) is slowly added to the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescribed amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirred continuously for 20-60 min to obtain a preliminary dispersion. A high-speed shearing machine is used to shear at 10000 rpm for 10-30 min, to form a uniform suspension system. The temperature is lowered to 25°C±5°C, and the fruit essence and sucralose are added under stirring at 1000 rpm for 10-30 min to dissolve and mix uniformly. Finally, purified water is added to make up the weight / volume, and stirred and mixed to obtain the eplerenone oral suspension.

[0149] The pH value of the eplerenone oral suspension is 5.0.

[0150] Comparative Example 1

[0151] The prescription of the eplerenone oral suspension is shown in Table 10

[0152] Table 10

[0153]

[0154] (1) Preparation of the suspending agent high molecular colloid solution

[0155] About 50% of the prescribed amount of purified water is heated to 50°C, and the prescribed amount of xanthan gum is slowly added under stirring (500 rpm), and stirred continuously (1200 rpm) for 20-60 min until completely swelled and a uniform high molecular colloid solution is formed.

[0156] (2) Preparation of the water phase solution

[0157] Another about 40% of the prescribed amount of purified water is heated to 50°C, and the prescribed amount of citric acid, sodium citrate and glycerol is added in sequence, and stirred at 600 rpm for 15-30 min until completely dissolved.

[0158] (3) Preparation of the drug suspension

[0159] The water phase solution of step (2) is slowly added to the suspending agent colloid of step (1), stirred (1000 rpm) and mixed, to obtain a blank suspending agent. The prescribed amount of eplerenone raw material is slowly added under stirring (1000 rpm), and stirred continuously for 20-60 min to obtain a preliminary dispersion. A high-speed shearing machine is used to shear at 10000 rpm for 10-30 min, to form a uniform suspension system. The temperature is lowered to 25°C±5°C, and the fruit essence and sucralose are added under stirring at 1000 rpm for 10-30 min to dissolve and mix uniformly. Finally, purified water is added to make up the weight / volume, and stirred and mixed to obtain the eplerenone oral suspension.

[0160] The pH of the oral suspension of eplerenone was about 5.5.

[0161] Comparative Example 2

[0162] The prescription of the oral suspension of eplerenone is shown in Table 11

[0163] Table 11

[0164]

[0165] (1) Preparation of the suspension aid high molecular colloid solution

[0166] About 50% of the prescription amount of purified water was heated to 50°C, and the prescription amount of xanthan gum was slowly added under stirring (500 rpm) and stirring (1200 rpm) was continued for 20-60 min until complete swelling and formation of a uniform high molecular colloid solution.

[0167] (2) Preparation of the aqueous phase solution

[0168] Another about 40% of the prescription amount of purified water was heated to 50°C, and the prescription amount of sorbic acid, citric acid and 50% of the prescription amount of glycerol were sequentially added, and stirring was continued at 600 rpm for 15-30 min until complete dissolution.

[0169] (3) Pre-dispersion treatment of the defoaming agent

[0170] The dimethicone was mixed uniformly with the remaining 50% of the prescription amount of glycerol by stirring (500 rpm) for 10-20 min.

[0171] (4) Preparation of the drug suspension

[0172] The aqueous phase solution of step (2) was slowly added to the suspension aid colloid of step (1), and stirring (1000 rpm) was used to mix uniformly, and the prescription amount of eplerenone raw material was slowly added under stirring (1000 rpm), and stirring was continued for 20-60 min until initial dispersion, and the dispersion solution of the defoaming agent of step (3) was added, and a high-speed shearing machine was used to shear at 10000 rpm for 10-30 min to form a uniform suspension system. The temperature was lowered to 25°C±5°C, and fruit flavor and sucralose were added, and stirring was continued at 1000 rpm for 10-30 min until dissolution and mixing, and finally purified water was added to make up the weight / volume, and stirring was used to mix uniformly to obtain the oral suspension of eplerenone.

[0173] The pH of the oral suspension of eplerenone was about 2.5.

[0174] Comparative Example 3

[0175] The prescription of the oral suspension of eplerenone is shown in Table 12

[0176] Table 12

[0177]

[0178] (1) Suspending agent high molecular colloid solution preparation

[0179] Take about 50% of the prescription amount of purified water heated to 50°C, the prescription amount of xanthan gum, slowly added under stirring (500 rpm) conditions, and continue stirring (1200 rpm) for 20-60 min to completely swell and form a uniform high molecular colloid solution.

[0180] (2) Preparation of aqueous solution

[0181] Take another about 40% of the prescription amount of purified water heated to 50°C, add the prescription amount of sorbic acid, citric acid and 50% of the prescription amount of glycerol in turn, and stir at 600 rpm for 15-30 min to completely dissolve.

[0182] (3) Pre-dispersion treatment of defoaming agent

[0183] Mix the dimethicone with the remaining 50% of the prescription amount of glycerol by stirring (500 rpm) for 10-20 min.

[0184] (4) Preparation of drug suspension

[0185] Slowly add the aqueous solution of step (2) to the suspending agent colloid of step (1), mix well by stirring (1000 rpm), and obtain a blank suspending agent. Slowly add the prescription amount of eplerenone raw material under stirring (1000 rpm) conditions, and continue stirring for 20-60 min to preliminarily disperse. Add the defoaming agent dispersion of step (3), and shear at 10000 rpm for 10-30 min using a high-speed shear machine to form a uniform suspension system. Cool to 25°C±5°C, add fruit flavor and sucralose, and stir at 1000 rpm for 10-30 min to dissolve and mix well. Finally, add purified water to make up the weight / volume, mix well, and obtain the eplerenone oral suspension.

[0186] The pH value of the eplerenone oral suspension is about 4.0.

[0187] Experimental example

[0188] Place the above examples, comparative example samples in the accelerated (40°C±2°C, RH 75%±5%) condition for 6 months, take samples at different time points, and detect the sedimentation volume ratio and related substances.

[0189] Eplerenone related substance detection method:

[0190] The method is determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0191] Test solution: Take the product 4 ml, add acetonitrile 4 ml in a 10 ml volumetric flask, ultrasonic to dissolve the eplerenone, dilute to the mark with water-acetonitrile (50:50), shake well, filter, take the filtrate.

[0192] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (such as: Waters XBridge Shield RP18, 4.6 mm x 150 mm, 3.5 μm or a chromatographic column with equivalent performance); 0.1% phosphoric acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to Table 13; flow rate of 1.0 ml per minute; column temperature of 30 °C; detection wavelength of 220 nm; injection volume of 5 μl.

[0193] Table 13

[0194]

[0195] Determination method: accurately measure the sample solution injection liquid chromatograph, record the chromatogram.

[0196] Impurity content calculation formula:

[0197]

[0198] A 杂质 Impurity peak area in sample solution graph

[0199] A 总 The sum of the peak areas of each component in the sample solution graph except the solvent peak and the excipient peak

[0200] Under the accelerated (40 °C ± 2 °C, RH 75% ± 5%) test conditions, the sedimentation volume ratio and the related substance test results are shown in Table 14:

[0201] Table 14

[0202]

[0203]

[0204] Note: in the above table and the attached Figure 1 , the chemical structure of the IMP10 impurity is shown below:

[0205]

[0206] From Table 14, it can be seen that under the accelerated test conditions (40 °C ± 2 °C, RH 75% ± 5%) for 6 months, from the sedimentation volume ratio and the related substances, combined with different pH conditions, the stability of the examples and the comparative examples is analyzed as follows:

[0207] 1. Evaluation of the meaning of stability indicators:

[0208] (1) Sedimentation volume ratio: reflects the physical stability of the suspension (uniformity of the dispersion system, sedimentation tendency of the suspended particles), the closer the sedimentation volume ratio is to 1, the more stable the suspension system is, the suspended particles are less likely to settle, and the better the uniformity of the system is.

[0209] (2) Related substance evaluation: reflects the chemical stability of the suspension, the lower the related substance value is, and the slower the growth is with the extension of time, the better the chemical stability is.

[0210] 2. Stability data analysis of the examples:

[0211] (1) Examples (1-8): the sedimentation volume ratio at 0 month is 0.95-0.99, and can be maintained at 0.95-0.98 at 3 months and 6 months of acceleration, and the change with time is small, indicating that under the formulation of the suspending agent in example (1-7), the physical stability of the suspension system of the suspension of the example is good within 6 months under the accelerated condition in the pH range of 3.0-5.0.

[0212] (2) Examples (1-8): total impurities at 0 month are 0.18%-0.22%, and slightly slowly increase at 3 months and 6 months of acceleration (such as the total impurities of example 1 slightly increase from 0.18% to 0.20%), and the IMP10 impurity (tR10.3min) is always ≤0.12%, indicating that the chemical stability of the example is good in the suspension within the pH range of 3.0-5.0, and the formulation can effectively inhibit the degradation of the drug.

[0213] (3) The results of the examples show that the buffer salt system (pH range of 3.0-5.0) and the formulation of the suspending agent designed in the application exhibit excellent synergistic effects of physical stability and chemical stability during storage.

[0214] 3. Analysis of the stability data of the comparative examples:

[0215] (1) Comparative example (1-2): under the appropriate formulation ratio of the suspending agent, the physical stability (sedimentation volume ratio) of comparative example 1-3 is relatively stable, but due to the pH value exceeding the appropriate range, the chemical stability is seriously insufficient: ① comparative example 1 (pH 5.5), the maximum single impurity increases to 1.16% at 6 months of accelerated stability, and the total impurities reach 2.01%, far exceeding the examples; ② comparative example 2 (pH 2.5), the total impurities reach 1.36% at 6 months of accelerated stability, far exceeding the examples. It is shown that when the pH of the suspension is too high or too low, the chemical stability of the product will decrease sharply.

[0216] (2) Comparative Example 3: The pH value was adjusted using hydrochloric acid and sodium hydroxide, which was consistent with that of Examples (4-7), but the impurity level in the initial value and stability was still significantly higher than that of the examples, indicating that the pH value control of the buffer pair can inhibit the degradation reaction of the product more than the pH value control of strong acid and strong base.

[0217] In summary, the examples achieve excellent synergy in the chemical stability and physical stability of the eplerenone suspension by controlling the pH value in the range of 3.0-5.0 (preferably pH 4.0-4.5) using a buffer pair, and optimizing the dosage of the key excipient (suspending agent). The comparative examples may result in a significant decrease in stability due to the deviation of the pH value from the stable interval and the improper pH adjuster. It is shown that the present application can effectively solve the stability bottleneck of eplerenone oral suspension by precisely regulating the pH value with a buffer pair pH adjuster and the synergy of the key excipient (suspending agent), and provide a product with reliable stability guarantee for clinical use.

[0218] Bioavailability comparison test:

[0219] The beneficial effects of the present application are further illustrated by the bioavailability comparison test in beagle dogs. Effective and reliable experimental data are obtained, and the research content is as follows:

[0220] The test preparation used in this test is eplerenone oral suspension (Example 1), and the control preparation used is the domestic approved eplerenone tablet (trade name: Specification 25mg, batch number 240410).

[0221] 6 beagle dogs, half male and half female, weighed 1 day before the test, stratified according to body weight and randomly divided into 2 groups, 3 dogs / group, double cycle crossover, washout period 7 days, orally administered eplerenone tablets and suspension respectively. The dosing information is shown in Table 15. Oral gavage, during the administration process of the tablet group, 20ml of animal drinking water was given; during the administration process of the suspension, 10ml of animal drinking water was given; at least 12h but not more than 16h of fasting before administration, free drinking water, and food intake was resumed 4h after administration.

[0222] Table 15 List of beagle dog dosing information

[0223]

[0224] Sample collection and analysis: Whole blood about 1mL was collected from the forelimb vein of beagle dogs into EDTA-K2 anticoagulant tubes at the corresponding sampling time points, and 0.4mL of plasma was separated. The concentration of eplerenone in beagle dog plasma samples was quantitatively detected by LC-MS / MS method.

[0225] Sample collection time points: before administration (0h) and 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and 24h after administration.

[0226] Results of bioavailability comparison test (n=6):

[0227]

[0228] Note: T max The median (minimum, maximum) is given, and the other parameters are the mean ± SD.

[0229] The results of the bioavailability comparison study show that:

[0230] 1. C of eplerenone suspension (Drug T) max The T / R ratio (5432.50±296.44 ng / ml) was significantly higher than that of eplerenone tablets (R drug) (2668.33±231.12 ng / mL), with a T / R ratio of approximately 203.6%, indicating that the suspension formulation resulted in more complete drug absorption and a higher peak plasma concentration.

[0231] 2. T in drug T max The median duration was 0.5 h (range 0.5–0.5 h), significantly shorter than the T of drug R. max The median duration was 1.0 h (range 1.0–2.0 h), indicating that the oral suspension is absorbed more quickly, reaches peak blood concentration more rapidly, and exerts its effect more quickly.

[0232] 3. AUC of drug T 0-t The T / R ratio was 15654.09±1627.48 ng*h / ml, significantly higher than that of drug R (10281.03±1191.00 ng*hr / mL), with a T / R ratio of approximately 152.3%. AUC results showed that the T-drug eplerenone suspension had a higher exposure and significantly better bioavailability than drug R.

[0233] In summary, the eplerenone oral suspension of the present invention, by using a buffered salt system and controlling the pH value within a specific range, solves the problem of the product being difficult to prepare as a solution, and the resulting suspension exhibits excellent quality stability. Compared with tablets, the eplerenone oral suspension of the present invention has the characteristics of faster absorption, higher peak concentration, faster onset of action, and greater drug exposure, with bioavailability increased by approximately 50%, superior pharmacokinetic performance, and good data extrapolation reliability.

[0234] When the oral suspension of the present invention achieves the same clinical efficacy as the tablet, it can effectively reduce the dosage and meet the clinical treatment needs of special patients.

Claims

1. An eplerenone oral suspension, characterized in that, The oral suspension contains a buffer-pair pH adjuster and a suspending agent, wherein the buffer-pair pH adjuster regulates the pH value of the oral suspension within the range of 3.0 to 5.

0.

2. The eplerenone oral suspension according to claim 1, characterized in that, The buffer pair pH adjuster is selected from one or more of the following: citrate-sodium citrate, acetate buffer pair, phosphate buffer pair, lactate-sodium lactate, and benzoate-sodium benzoate.

3. The eplerenone oral suspension according to claim 1 or 2, characterized in that, The suspending agent is selected from one or more combinations of xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose (weight ratio (8-9.5):(2-0.5)) complex, gum arabic, gelatin, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; or, the suspending agent is one or more of xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose complex, and hydroxypropyl methylcellulose.

4. The eplerenone oral suspension according to any one of claims 1 to 3, characterized in that, The suspending agent has a mass percentage of 0.1 wt% to 10 wt% in the eplerenone oral suspension, more preferably 0.2 wt% to 3 wt%, or 0.5 wt% to 3 wt%.

5. The eplerenone oral suspension according to any one of claims 1 to 4, characterized in that, The eplerenone oral suspension also includes one or more of the following: antibacterial agents, antifoaming agents, and flavoring agents; Optionally, the antibacterial agent is selected from one or more combinations of organic acids and their salts (such as sorbic acid, potassium sorbate, benzoic acid, sodium benzoate, etc.) and parabens (such as methylparaben, ethylparaben, propylparaben, etc.); or, the antibacterial agent is one or more combinations of sorbic acid, potassium sorbate, and propylparaben; and / or The defoamer is selected from one or more of silane defoamers (such as dimethyl silicone oil, silicone, polysiloxane, etc.) and polyether defoamers (such as polyoxyethylene polyoxypropylene ether, polyether polyol, etc.); or, the defoamer is dimethyl silicone oil; and / or The flavoring agent is selected from one or more combinations of sucralose and fruit flavorings (such as strawberry flavoring, peach flavoring, orange flavoring, blueberry flavoring, etc.), or the flavoring agent is sucralose and fruit flavorings.

6. The eplerenone oral suspension according to any one of claims 1 to 5, characterized in that, The eplerenone oral suspension comprises a solution system, wherein the solvent system is composed of one or more of water, glycerol, and propylene glycol.

7. The eplerenone oral suspension according to any one of claims 1 to 6, characterized in that, The eplerenone oral suspension contains 0.1 wt% to 1 wt% eplerenone, or 0.25 wt% to 0.5 wt% eplerenone.

8. The eplerenone oral suspension according to any one of claims 1 to 7, characterized in that, The eplerenone oral suspension comprises 0.1wt% to 1wt% eplerenone, 75wt% to 98wt% of a solvent system, 0.1wt% to 10wt% of a suspending agent, 0.05wt% to 2wt% of a buffer-pair pH adjuster, 0.05wt% to 3wt% of an antibacterial agent, 0.01% to 1% of an antifoaming agent, and 0.1% to 5% of a flavoring agent.

9. The eplerenone oral suspension according to any one of claims 1 to 8, characterized in that, The eplerenone oral suspension, after being stored at 40℃ / 75%RH for 6 months, simultaneously meets the requirements of physical stability (sedimentation volume ratio ≥0.9) and chemical stability, i.e., the content of individual related substances ≤0.2% and the total amount of impurities ≤1.0%.

10. A method for preparing the eplerenone oral suspension as described in any one of claims 7 to 9, characterized in that, Includes the following steps: (1) Heat approximately 50% of the prescribed amount of purified water to 40-70°C, add suspending agent and stir until fully swollen to form a high molecular colloidal solution; (2) Heat about 40% of the prescribed amount of purified water to 40-70°C, add antibacterial agent, buffer pH adjuster and 50% of the prescribed amount of polyol (e.g., one or both of glycerol and propylene glycol), stir to dissolve, and obtain an aqueous solution; (3) Mix the defoamer with the remaining 50% of the prescribed amount of polyol (e.g., one or both of glycerol and propylene glycol); (4) Add the aqueous solution from step (2) to the colloidal solution from step (1), stir, add eplerenone raw material, disperse initially, add the defoamer mixture from step (3), perform high-speed shearing, cool down, add flavoring agent, add purified water to the total volume, mix well to obtain the final product.

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