Eplerenone-containing composition as well as pharmaceutical preparation, preparation method and application thereof

Abstract

The invention discloses a composition containing eplerenone as well as a pharmaceutical preparation, a preparation method and application thereof. The composition comprises 98.5 wt%-99.9 wt% of eplerenone and a compound shown in a formula A, and the content of the compound shown in the formula A does not exceed 0.1 wt%; wherein the clinical safety of the medicine can be influenced when the content of the compound shown in the formula A is higher than a certain content in eplerenone, and the research result shows that related clinical adverse reactions are obviously increased. The invention also discloses a preparation method and a pharmaceutical preparation of the eplerenone composition. The compound in the formula A is perfectly researched, the content of the compound in the formula A is controlled, and the quality and safety of eplerenone are improved. # imgabs0 # formula A is shown in the specification.

Description

Technical Field

[0001] The present invention belongs to, but is not limited to, the field of pharmaceutical technology. Specifically, it relates to a composition containing eplerenone, its pharmaceutical preparations, preparation methods, quality control methods and uses. Background Art

[0002] Eplerenone is a highly selective aldosterone receptor (MR) antagonist, which exerts its therapeutic effects on hypertension and heart failure after myocardial infarction by blocking the renin-angiotensin-aldosterone system; eplerenone highly selectively blocks the mineralocorticoid receptors (MR) inside and outside the kidney, and does not show the antagonistic effects on androgens and estrogens possessed by spironolactone (a non-selective aldosterone receptor blocker).

[0003] Eplerenone is a highly selective aldosterone receptor antagonist. The typical clinical side effects reported by Pfizer Inc. in the United States and Pfizer Inc. in Japan mainly include: hyperkalemia, gynecomastia, breast pain, abnormal vaginal bleeding, increased transaminase, upper respiratory tract infection, headache, dizziness, fatigue, palpitations, etc. There is currently no research and literature report on the causes of the above adverse reactions. Summary of the Invention

[0004] Chinese Patent Application with Publication No. CN1209136A discloses a method for preparing eplerenone. The raw material enoate is dissolved in dichloromethane, trichloroacetamide, dipotassium hydrogen phosphate, and 30% hydrogen peroxide are added for an oxidation reaction. After the reaction work-up and purification using methyl ethyl ketone, eplerenone with a purity of 99.6% is obtained.

[0005] However, through the research by the inventors, it is found that the eplerenone obtained by this preparation method inevitably accompanies a relatively large amount of Compound A. Due to the presence of an epoxy structure in the eplerenone structure, for other preparation methods of eplerenone in the existing process technology, the reaction conditions for forming the epoxy structure are basically the same, only the order of forming the epoxy structure in the preparation route is different. The Compound A will also be present in the raw drug; moreover, limited by the different ultraviolet absorption characteristics of Compound A (210 nm) and the ultraviolet absorption characteristics (240 nm) of the related substance detection method of this product in the European Pharmacopoeia, as well as the different composition and ratio of the eluent in the mobile phase, it is impossible to detect and effectively detect the accompanied Compound A. The related substance detection method of this product in the European Pharmacopoeia cannot detect Compound A and scientifically and effectively control it.

[0006] In the patent CN1433427A, 99% eplerenone was used in the examples for crystal form preparation, but no purity detection method was provided; in the examples of the patent CN113173968A, eplerenone was refined with different ratios of ethanol / water, and the purity was about 99.5%. The purity detection used the detection method in European Pharmacopoeia EP9.0, with a wavelength of 240 nm, and this detection wavelength could not detect the compound of formula A; in the patent CN104262450A, methyl ethyl ketone was used for the refinement of eplerenone, and the purity was 99.9%. This patent did not provide a detection method, but the attached drawing showed that the detection wavelength was 241 nm, and this wavelength also could not detect the compound of formula A; in the patent CN104844681B, the crude eplerenone was refined with 1,2-dimethoxyethane, and the purity was 99.97%. The detection method showed that the detection wavelength was selected as 245 nm, and it also could not effectively detect the compound of formula A.

[0007] In Example A of the patent CN1377365A, it was exemplified that "eplerenone with purity > 99%" and the total content of "dioxide" and "11,12-epoxide" (< 0.2%) were used to prepare "methyl ethyl ketone compound" with methyl ethyl ketone; in Example B, it was exemplified that "eplerenone with purity > 99.9%" was used to prepare crystal form L. Table 7A listed that eplerenone with 100% purity was recrystallized with methyl ethyl ketone, and as a result, 0.18% - 0.38% of "11,12-epoxide" and 0.36 - 0.80% of "dioxide" were detected in the product; this patent also disclosed that the solubility of "11,12-epoxide" in methyl ethyl ketone solvent was about 2 times that of "dioxide". After repeated research and verification by the inventor, it was confirmed that eplerenone recrystallized with methyl ethyl ketone solvent would not degrade to generate "dioxide" and "11,12-epoxide"; and at 0 °C and 25 °C, the solubility of "11,12-epoxide" in methyl ethyl ketone was more than 2 times that of "dioxide"; after repeated research and verification by the inventor, it was also confirmed that in the above Example A, the content of "dioxide" was between 2 and 3 times that of "11,12-epoxide". Therefore, obviously the actual content of "dioxide" in this example was more than 0.1%. At the same time, neither this patent nor the corresponding priority documents provided a detection method for "dioxide" and "11,12-epoxide", and the expressions of eplerenone purity such as 99.9%, 100%, and 100.80% listed were actually the values of the external standard method content, not the HPLC purity.

[0008] When a certain amount of the compound of formula A is accompanied in eplerenone, the characteristic diffraction peaks (2θ) of the compound of formula A cannot be observed by testing the XRPD pattern of eplerenone. Due to defects and problems such as detection sensitivity and the uniformity of the distribution of the two solid substances in the powder XRPD method, the powder XRPD method cannot accurately and effectively determine the content of the compound of formula A accompanied in eplerenone.

[0009] Further in - depth research of the present invention has found that the compound of formula A (CAV34 - IMP12) can bind to a variety of hormone receptors. When the compound of formula A co - exists in eplerenone, it will reduce the specificity and selectivity of the antagonism between eplerenone and the aldosterone receptor, resulting in binding to other hormone receptors in the human body, such as androgen receptors, estrogen receptors, etc., and ultimately showing a certain proportion and probability of adverse reactions related to hormones clinically. The inventor of the present invention controlled the content of the compound of formula A in eplerenone and carried out human bioequivalence studies and randomized controlled (RCT) phase III clinical studies with eplerenone containing a specific limit of the compound of formula A, achieving the effect of significantly reducing clinical adverse reactions related to hormone receptors.

[0010] The chemical structure of the compound of formula A involved in the present application is shown as follows: Compound of formula A.

[0011] In a first aspect, the present invention provides a composition containing eplerenone, the composition comprising eplerenone and the compound of formula A, wherein the content of eplerenone is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is not more than 0.1 wt% or 0.003 wt% to 0.1 wt%: Compound of formula A.

[0012] In some embodiments, the content of eplerenone in the composition is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.10 wt% or 0.003 wt% to 0.099 wt%.

[0013] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.099 wt% or 0.003 wt% to 0.098 wt%.

[0014] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.099 wt% or 0.005 wt% to 0.098 wt%.

[0015] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.098 wt% or 0.003 wt% to 0.097 wt%.

[0016] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.097 wt% or 0.003 wt% to 0.096 wt%.

[0017] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.096 wt% or 0.003 wt% to 0.095 wt%.

[0018] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.095 wt% or 0.003 wt% to 0.094 wt%. In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.094 wt% or 0.003 wt% to 0.093 wt%.

[0019] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.093 wt% or 0.003 wt% to 0.092 wt%.

[0020] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.092 wt% or 0.003 wt% to 0.091 wt%.

[0021] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.091 wt% or 0.003 wt% to 0.090 wt%. In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.090 wt% or 0.003 wt% to 0.089 wt%.

[0022] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.089 wt% or 0.003 wt% to 0.088 wt%.

[0023] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.088 wt% or 0.003 wt% to 0.087 wt%. In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.087 wt% or 0.003 wt% to 0.086 wt%.

[0024] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.086 wt% or 0.003 wt% to 0.085 wt%.

[0025] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.085 wt% or 0.003 wt% to 0.084 wt%.

[0026] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.084 wt% or 0.003 wt% to 0.083 wt%.

[0027] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.083 wt% or 0.003 wt% to 0.082 wt%.

[0028] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.082 wt% or 0.003 wt% to 0.081 wt%.

[0029] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.081 wt% or 0.003 wt% to 0.080 wt%; or, the content of eplerenone is 98.9 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.080 wt% or 0.003 wt% to 0.079 wt%.

[0030] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.079 wt% or 0.003 wt% to 0.078 wt%.

[0031] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.078 wt% or 0.003 wt% to 0.077 wt%.

[0032] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.077 wt% or 0.003 wt% to 0.076 wt%.

[0033] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.076 wt% or 0.003 wt% to 0.075 wt%.

[0034] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.075 wt% or 0.003 wt% to 0.074 wt%.

[0035] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.074 wt% or 0.003 wt% to 0.073 wt%.

[0036] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.073 wt% or 0.003 wt% to 0.072 wt%.

[0037] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.072 wt% or 0.003 wt% to 0.071 wt%.

[0038] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.071 wt% or 0.003 wt% to 0.070 wt%.

[0039] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.070 wt% or 0.003 wt% to 0.069 wt%.

[0040] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.069 wt% or 0.003 wt% to 0.068 wt%.

[0041] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.068 wt% or 0.003 wt% to 0.067 wt%.

[0042] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.067 wt% or 0.003 wt% to 0.066 wt%.

[0043] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.066 wt% or 0.003 wt% to 0.065 wt%.

[0044] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.065 wt% or 0.003 wt% to 0.064 wt%.

[0045] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.064 wt% or 0.003 wt% to 0.063 wt%.

[0046] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.063 wt% or 0.003 wt% to 0.062 wt%.

[0047] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.062 wt% or 0.003 wt% to 0.061 wt%.

[0048] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.061 wt% or 0.003 wt% to 0.060 wt%. Alternatively, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.060 wt% or 0.003 wt% to 0.059 wt%.

[0049] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.059 wt% or 0.003 wt% to 0.058 wt%.

[0050] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.058 wt% or 0.003 wt% to 0.057 wt%.

[0051] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.057 wt% or 0.003 wt% to 0.056 wt%.

[0052] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.056 wt% or 0.003 wt% to 0.055 wt%.

[0053] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.055 wt% or 0.003 wt% to 0.054 wt%.

[0054] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.054 wt% or 0.003 wt% to 0.053 wt%.

[0055] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.053 wt% or 0.003 wt% to 0.052 wt%.

[0056] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.052 wt% or 0.003 wt% to 0.051 wt%.

[0057] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.051 wt% or 0.003 wt% to 0.050 wt%. Alternatively, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.050 wt% or 0.003 wt% to 0.049 wt%.

[0058] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.049 wt% or 0.003 wt% to 0.048 wt%.

[0059] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.048 wt% or 0.003 wt% to 0.047 wt%.

[0060] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.047 wt% or 0.003 wt% to 0.046 wt%.

[0061] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.046 wt% or 0.003 wt% to 0.045 wt%.

[0062] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.045 wt% or 0.003 wt% to 0.044 wt%.

[0063] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.044 wt% or 0.003 wt% to 0.043 wt%.

[0064] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.043 wt% or 0.003 wt% to 0.042 wt%.

[0065] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.042 wt% or 0.003 wt% to 0.041 wt%.

[0066] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.041 wt% or 0.003 wt% to 0.040 wt%; Or, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.040 wt% or 0.003 wt% to 0.039 wt%.

[0067] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.039 wt% or 0.003 wt% to 0.038 wt%.

[0068] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.038 wt% or 0.003 wt% to 0.037 wt%.

[0069] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.037 wt% or 0.003 wt% to 0.036 wt%.

[0070] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.036 wt% or 0.003 wt% to 0.035 wt%.

[0071] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.035 wt% or 0.003 wt% to 0.034 wt%.

[0072] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.034 wt% or 0.003 wt% to 0.033 wt%.

[0073] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.033 wt% or 0.003 wt% to 0.032 wt%.

[0074] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.032 wt% or 0.003 wt% to 0.031 wt%.

[0075] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.031 wt% or 0.003 wt% to 0.030 wt%; Or, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.03 wt% or 0.003 wt% to 0.029 wt%; Or, the content of eplerenone is 99.1 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.030 wt% or 0.003 wt% to 0.029 wt%.

[0076] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.029 wt% or 0.003 wt% to 0.028 wt%.

[0077] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.028 wt% or 0.003 wt% to 0.027 wt%.

[0078] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.027 wt% or 0.003 wt% to 0.026 wt%.

[0079] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0080] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.025 wt% or 0.003 wt% to 0.024 wt%.

[0081] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.024 wt% or 0.003 wt% to 0.023 wt%.

[0082] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.023 wt% or 0.003 wt% to 0.022 wt%.

[0083] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.022 wt% or 0.003 wt% to 0.021 wt%.

[0084] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.021 wt or 0.003 wt% to 0.020 wt%; Or, the content of eplerenone is 99.2 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.020 wt% or 0.003 wt% to 0.019 wt%.

[0085] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.019 wt% or 0.003 wt% to 0.018 wt%.

[0086] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.018 wt% or 0.003 wt% to 0.017 wt%.

[0087] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.017 wt% or 0.003 wt% to 0.016 wt%.

[0088] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.016 wt% or 0.003 wt% to 0.015 wt%.

[0089] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.015 wt% or 0.003 wt% to 0.014 wt%.

[0090] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.014 wt% or 0.003 wt% to 0.013 wt%.

[0091] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.013 wt% or 0.003 wt% to 0.012 wt%.

[0092] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.012 wt% or 0.003 wt% to 0.011 wt%.

[0093] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.011 wt% or 0.003 wt% to 0.010 wt%.

[0094] In some embodiments, the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.010 wt% or 0.003 wt% to 0.009 wt%.

[0095] In some embodiments, the composition further comprises one or more of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H: Formula B Formula C Formula D Formula E Formula F Formula G Formula H.

[0096] In some embodiments, the content of the compound of Formula B in the composition is 0 wt% to 0.05 wt%, the content of the compound of Formula C is 0 wt% to 0.05 wt%, the content of the compound of Formula D is 0 wt% to 0.05 wt%, the content of the compound of Formula E is 0 wt% to 0.05 wt%, the content of the compound of Formula F is 0 wt% to 0.05 wt%, the content of the compound of Formula G is 0 wt% to 0.05 wt%, and the content of the compound of Formula H is 0 wt% to 0.05 wt%; moreover, the sum of the contents of the compound of Formula B, the compound of Formula C, the compound of Formula D, the compound of Formula E, the compound of Formula F, the compound of Formula G, and the compound of Formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0097] In some embodiments, for the composition, the content of the compound of Formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of Formula G is 0.003 to 0.09 wt%, and the compounds of Formula B, C, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt%); or, the content of the compound of Formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of Formula C is 0.003 to 0.09 wt%, and the compounds of Formula B, D, E, F, G, and H are not detected (the detection limits are all less than 0.003 wt%); or, the content of the compound of Formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of Formula C is 0.003 to 0.09 wt%, the content of the compound of Formula G is 0.003 to 0.09 wt%, and the compounds of Formula B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt%); moreover, the sum of the contents of the compound of Formula B, the compound of Formula C, the compound of Formula D, the compound of Formula E, the compound of Formula F, the compound of Formula G, and the compound of Formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0098] In some embodiments, the composition, wherein the content of the compound of formula A is 0.003 wt% to 0.09 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.003 wt% to 0.09 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula C is 0.003 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.003 wt% to 0.09 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula C is 0.003 to 0.09 wt%, the content of the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0099] In some embodiments, the composition, wherein the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0100] In some embodiments, the composition wherein the content of Compound A is 0.005 wt% to 0.088 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of Compound G is 0.005 to 0.09 wt%, and Compounds B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or the content of Compound A is 0.005 wt% to 0.088 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of Compound C is 0.005 to 0.09 wt%, and Compounds B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or the content of Compound A is 0.005 wt% to 0.09 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of Compound C is 0.005 to 0.09 wt%, the content of Compound G is 0.005 to 0.09 wt%, and Compounds B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of Compounds B, C, D, E, F, G, and H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0101] In some embodiments, the composition wherein the content of Compound A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9%, the content of Compound G is 0.005 to 0.09 wt%, and Compounds B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or the content of Compound A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of Compound C is 0.005 to 0.09 wt%, and Compounds B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or the content of Compound A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of Compound C is 0.005 to 0.09 wt%, the content of Compound G is 0.005 to 0.09 wt%, and Compounds B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of Compounds B, C, D, E, F, G, and H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0102] In some embodiments, the composition, wherein the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.85 wt% to 99.9 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.85 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.85 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0103] In some embodiments, the composition, wherein the compound of formula A: 0.005 to 0.085 wt%, the content of eplerenone is 99.85% to 99.91 wt%, the content of the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.085 wt%, the content of eplerenone is 99.85 wt% to 99.91 wt%, the content of the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.085 wt%, the content of eplerenone is 99.85 wt% to 99.91 wt%, the content of the compound of formula C is 0.005 to 0.07 wt%, the content of the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0104] In some embodiments, the composition, wherein the compound of formula A: 0.005 to 0.084 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0105] In some embodiments, the composition, wherein the compound of formula A: 0.005 to 0.083 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0106] In some embodiments, the composition, wherein the compound of formula A is from 0.005 to 0.082 wt%, eplerenone is from 99.85% to 99.91 wt%, the compound of formula G is from 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is from 0.005 wt% to 0.082 wt%, eplerenone is from 99.85 wt% to 99.91 wt%, the compound of formula C is from 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is from 0.005 wt% to 0.082 wt%, eplerenone is from 99.85 wt% to 99.91 wt%, the compound of formula C is from 0.005 to 0.07 wt%, the compound of formula G is from 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is from 0 wt% to 0.10 wt% and does not include 0 wt%.

[0107] In some embodiments, the composition, wherein the compound of formula A is from 0.005 to 0.081 wt%, eplerenone is from 99.85% to 99.91 wt%, the compound of formula G is from 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is from 0.005 wt% to 0.081 wt%, eplerenone is from 99.85 wt% to 99.91 wt%, the compound of formula C is from 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is from 0.005 wt% to 0.081 wt%, eplerenone is from 99.85 wt% to 99.91 wt%, the compound of formula C is from 0.005 to 0.07 wt%, the compound of formula G is from 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is from 0 wt% to 0.10 wt% and does not include 0 wt%.

[0108] In some embodiments, the composition wherein the compound of formula A is 0.005 to 0.080 wt%, eplerenone is 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or the content of the compound of formula A is 0.005 wt% to 0.080 wt%, eplerenone is 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or the content of the compound of formula A is 0.005 wt% to 0.080 wt%, eplerenone is 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0109] In some embodiments, the composition wherein the compound of formula A is 0.005 to 0.08 wt%, eplerenone is 99.85 wt% to 99.91 wt%, the compound of formula G is 0.01 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or the content of the compound of formula A is 0.005 wt% to 0.08 wt%, eplerenone is 99.85 wt% to 99.91 wt%, the compound of formula C is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or the content of the compound of formula A is 0.005 wt% to 0.08 wt%, eplerenone is 99.85 wt% to 99.91 wt%, the compound of formula C is 0.01 to 0.07 wt%, the compound of formula G is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0110] In some embodiments, the composition is as follows: Compound of formula A: 0.01 to 0.08 wt%, eplerenone: 99.85 wt% to 99.92 wt%, Compound of formula G: 0.01 to 0.07 wt%, and Compounds of formula B, C, D, E, F, and H are not detected (detection limit is less than 0.003 wt%); or, Compound of formula A content is 0.01 wt% to 0.08 wt%, eplerenone: 99.85 wt% to 99.92 wt%, Compound of formula C: 0.01 to 0.07 wt%, and Compounds of formula B, D, E, F, G, and H are not detected (detection limit is less than 0.003 wt%); or, Compound of formula A content is 0.01 wt% to 0.08 wt%, eplerenone: 99.85 wt% to 99.92 wt%, Compound of formula C: 0.01 to 0.07 wt%, Compound of formula G: 0.01 to 0.07 wt%, and Compounds of formula B, D, E, F, and H are not detected (detection limit is less than 0.003 wt%); moreover, the sum of the contents of Compound of formula B, Compound of formula C, Compound of formula D, Compound of formula E, Compound of formula F, Compound of formula G, and Compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0111] In the above embodiments, the eplerenone composition is prepared by the following preparation method; the preparation method includes a step of selective oxidation using enoate (17α-hydroxy-3-oxopregn-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester, γ-lactone, CAS No.: 95716-70-4) or its analog, and at least two refining steps. In some embodiments, the eplerenone composition is prepared by the preparation method of the second aspect of the present invention.

[0112] Second aspect, the present invention provides a preparation method of the above composition, including: an oxidation reaction of enoate (17α-hydroxy-3-oxopregn-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester, γ-lactone) with hydrogen peroxide to obtain an eplerenone product, and after post-treatment, obtaining a crude eplerenone; and The crude eplerenone is refined more than 2 times with a refining solvent; to obtain the composition, here, the refining solvent is a mixed solvent of dichloromethane and cyclohexane; and The post-treatment includes recrystallization, and the recrystallization solvent is methyl ethyl ketone.

[0113] In some embodiments of the second aspect, the volume-mass ratio of the recrystallization solvent methyl ethyl ketone to the eplerenone product is 1:(10 - 30), ml / g, preferably 1:15.

[0114] In some embodiments of the second aspect, the volume ratio of dichloromethane to cyclohexane in the mixed solvent of dichloromethane and cyclohexane is from 2:1 to 1:3; preferably, such as 1:1 or 1:1.5.

[0115] In some embodiments of the second aspect, the temperature of the recrystallization is -10~40 °C; preferably, it is 0~5 °C.

[0116] In some embodiments of the second aspect, the concentration of the enoate (methyl 17α-hydroxy-3-oxopregn-4,9(11)-diene-7α,21-dicarboxylate, γ-lactone) dissolved in dichloromethane ranges from 2 wt% to 20 wt%.

[0117] In some embodiments of the second aspect, the mass ratios of the addition amounts of trichloroacetamide, dipotassium hydrogen phosphate, and hydrogen peroxide to the enoate are 1:0.876, 1:0.624, and 1:4.082, respectively.

[0118] In a third aspect, the present invention provides a pharmaceutical preparation, and the pharmaceutical preparation includes the above-mentioned composition and pharmaceutical excipients.

[0119] In some embodiments of the third aspect, the pharmaceutical preparation is an oral pharmaceutical preparation, optionally, an oral solid pharmaceutical preparation; the oral solid pharmaceutical preparation can be tablets, capsules, granules, etc., preferably tablets, and more preferably film-coated tablets.

[0120] In some embodiments of the third aspect, when the oral solid pharmaceutical preparation is a tablet, the pharmaceutical excipients include at least one of the following substances: fillers (or diluents), lubricants (which can also have the functions of glidants or anti-adhesives), disintegrants, wetting agents (which can have wetting assistance effects), and binders, etc.

[0121] In some embodiments of the third aspect, the pharmaceutical preparation is eplerenone tablets, and its components are calculated by weight percentage, including: eplerenone accounts for 10 wt% - 35 wt%; the filler (or diluent) accounts for 50 wt% - 80 wt%, and one or a combination of the following can be selected, such as lactose, dextrin, starch (such as corn starch, potato starch, tapioca starch or wheat starch) or its derivatives (soluble starch, pregelatinized starch or pregelatinized hydroxypropyl starch), cellulose or its derivatives (microcrystalline cellulose, powdered cellulose, methyl cellulose, hydroxypropyl cellulose, etc.), inorganic calcium salts, sorbitol, glycine, calcium sulfate, and mannitol, etc., preferably, a combination of lactose and microcrystalline cellulose, and more preferably, a combination of anhydrous lactose and microcrystalline cellulose; optionally, the weight ratio of anhydrous lactose to microcrystalline cellulose is 1:(0.5 - 3), preferably, the weight ratio is 1:1.8.

[0122] The lubricant (which can also function as a glidant or anti-adhesive) accounts for 0.1 wt% - 5 wt%, and one or more of, for example, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, and colloidal silica can be selected. Preferably, it is a combination of magnesium stearate and talc. Optionally, the weight ratio of magnesium stearate to talc in the combination is 1:(1 - 2), and preferably, the weight ratio is 1:1.6.

[0123] The disintegrant accounts for 3 wt% - 10 wt%, and can be selected from one or more of, for example, starch, crospovidone, sodium croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, and cross-linked polyvinylpyrrolidone, etc.; preferably, it is sodium croscarmellose.

[0124] The binder accounts for 0.5 wt% - 5 wt%, and can be selected from one or more of, for example, gelatin solution, starch paste, polyvinylpyrrolidone, syrup, gum arabic, and cellulose or its derivatives (such as hydroxypropyl methylcellulose), etc.; preferably, it is hydroxypropyl methylcellulose.

[0125] The wetting agent (with wetting assistance function) accounts for 0.5 wt% - 5 wt%, and, for example, sodium dodecyl sulfate can be selected to play the role of wetting assistance.

[0126] In addition, in the preparation process of the pharmaceutical preparation, an appropriate amount of water or alcohol can be added, and the water or alcohol will be removed in subsequent process steps.

[0127] In some embodiments of the third aspect, the eplerenone tablets provided by the present invention are film-coated tablets, that is, the eplerenone tablets further include a film coating agent. The proportion of the film coating agent is 1 wt% to 6 wt% (calculated based on the eplerenone tablets). The film coating agent can be selected from gastric-soluble film coating premixes, such as Opadry™ produced by Colorcon Coating Technology Co., Ltd., or gastric-soluble film coating premixes from other excipient manufacturers, or prepared by oneself; optionally, the formulation of the film coating agent is: 8 wt% - 30 wt% plasticizer (such as polyethylene glycol 400), 50 wt% - 85 wt% film-forming agent (such as hydroxypropyl methylcellulose), 5 wt% - 15 wt% opacifier (such as titanium dioxide), 0.5 wt% - 5 wt% colorant (such as iron oxide yellow / red / black), etc. When using the premix, purified water is used as the solvent for preparation, and the preparation concentration range is 10% - 20% (w / w).

[0128] In some embodiments of the third aspect, the eplerenone tablets provided by the present invention comprise 20 wt% - 35 wt% eplerenone, 30 wt% - 40 wt% anhydrous lactose, 0.5 wt% - 1 wt% magnesium stearate, 20 wt% - 25 wt% microcrystalline cellulose, 5 wt% - 7 wt% croscarmellose sodium, 2 wt% - 3 wt% hypromellose, 1 wt% - 2 wt% sodium lauryl sulfate, 0.5 wt% - 1 wt% talc, and 2 wt% - 5 wt% film coating agent (such as gastric-soluble film coating premix).

[0129] In some embodiments of the third aspect, the eplerenone tablets provided by the present invention comprise 26 wt% - 29 wt% eplerenone, 34 wt% - 38 wt% anhydrous lactose, 0.5 wt% - 0.8 wt% magnesium stearate, 20 wt% - 22 wt% microcrystalline cellulose, 5 wt% - 7 wt% croscarmellose sodium, 2 wt% - 3 wt% hypromellose, 1 wt% - 2 wt% sodium lauryl sulfate, 0.5 wt% - 1 wt% talc, and 2 wt% - 5 wt% film coating agent (such as gastric-soluble film coating premix).

[0130] In some embodiments of the third aspect, the eplerenone tablets provided by the present invention comprise 28.5 wt% eplerenone, 36.5 wt% anhydrous lactose, 0.6 wt% magnesium stearate, 20.5 wt% microcrystalline cellulose, 5.7 wt% croscarmellose sodium, 2.9 wt% hypromellose, 1.4 wt% sodium lauryl sulfate, 0.9 wt% talc, and 3.0 wt% film coating agent (such as gastric-soluble film coating premix).

[0131] In some embodiments of the third aspect, for the above-mentioned pharmaceutical preparation provided by the present invention, wherein the composition comprises eplerenone and a compound of formula A, wherein the content of eplerenone is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is not more than 0.1 wt% or 0.003 wt% to 0.1 wt%; the content of the compound of formula A is not more than 0.10 wt% or 0.003 wt% to 0.10 wt%; or, the content of eplerenone is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.10 wt% or 0.003 wt% to 0.099 wt%.

[0132] In some embodiments of the third aspect, for the above-mentioned pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.099 wt% or 0.003 wt% to 0.098 wt%.

[0133] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.099 wt% or 0.005 wt% to 0.098 wt%.

[0134] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.098 wt% or 0.003 wt% to 0.097 wt%.

[0135] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.097 wt% or 0.003 wt% to 0.096 wt%.

[0136] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.096 wt% or 0.003 wt% to 0.095 wt%.

[0137] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.095 wt% or 0.003 wt% to 0.094 wt%.

[0138] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.094 wt% or 0.003 wt% to 0.093 wt%.

[0139] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.093 wt% or 0.003 wt% to 0.092 wt%.

[0140] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.092 wt% or 0.003 wt% to 0.091 wt%.

[0141] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.091 wt% or 0.003 wt% to 0.090 wt%.

[0142] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.090 wt% or 0.003 wt% to 0.089 wt%.

[0143] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.089 wt% or 0.003 wt% to 0.088 wt%.

[0144] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.088 wt% or 0.003 wt% to 0.087 wt%.

[0145] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.087 wt% or 0.003 wt% to 0.086 wt%.

[0146] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.086 wt% or 0.003 wt% to 0.085 wt%.

[0147] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.085 wt% or 0.003 wt% to 0.084 wt%.

[0148] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.084 wt% or 0.003 wt% to 0.083 wt%.

[0149] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.083 wt% or 0.003 wt% to 0.082 wt%.

[0150] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.082 wt% or 0.003 wt% to 0.081 wt%.

[0151] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.081 wt% or 0.003 wt% to 0.080 wt%; Alternatively, the content of eplerenone is 98.9 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.080 wt% or 0.003 wt% to 0.079 wt%.

[0152] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.079 wt% or 0.003 wt% to 0.078 wt%.

[0153] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.078 wt% or 0.003 wt% to 0.077 wt%.

[0154] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.077 wt% or 0.003 wt% to 0.076 wt%.

[0155] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.076 wt% or 0.003 wt% to 0.075 wt%.

[0156] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.075 wt% or 0.003 wt% to 0.074 wt%.

[0157] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.074 wt% or 0.003 wt% to 0.073 wt%.

[0158] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.073 wt% or 0.003 wt% to 0.072 wt%.

[0159] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.072 wt% or 0.003 wt% to 0.071 wt%.

[0160] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.071 wt% or 0.003 wt% to 0.070 wt%.

[0161] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.070 wt% or 0.003 wt% to 0.069 wt%.

[0162] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.069 wt% or 0.003 wt% to 0.068 wt%.

[0163] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.068 wt% or 0.003 wt% to 0.067 wt%.

[0164] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.067 wt% or 0.003 wt% to 0.066 wt%.

[0165] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.066 wt% or 0.003 wt% to 0.065 wt%.

[0166] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.065 wt% or 0.003 wt% to 0.064 wt%.

[0167] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.064 wt% or 0.003 wt% to 0.069 wt%.

[0168] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.063 wt% or 0.003 wt% to 0.062 wt%.

[0169] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.062 wt% or 0.003 wt% to 0.061 wt%.

[0170] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.061 wt% or 0.003 wt% to 0.060 wt%; Or, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.060 wt% or 0.003 wt% to 0.059 wt%.

[0171] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.059 wt% or 0.003 wt% to 0.058 wt%.

[0172] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.058 wt% or 0.003 wt% to 0.057 wt%.

[0173] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.057 wt% or 0.003 wt% to 0.056 wt%.

[0174] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.056 wt% or 0.003 wt% to 0.055 wt%.

[0175] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.055 wt% or 0.003 wt% to 0.054 wt%.

[0176] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.054 wt% or 0.003 wt% to 0.053 wt%.

[0177] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.053 wt% or 0.003 wt% to 0.052 wt%.

[0178] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.052 wt% or 0.003 wt% to 0.051 wt%.

[0179] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.051 wt% or 0.003 wt% to 0.050 wt%; Or, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.050 wt% or 0.003 wt% to 0.049 wt%.

[0180] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.049 wt% or 0.003 wt% to 0.048 wt%.

[0181] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.048 wt% or 0.003 wt% to 0.047 wt%.

[0182] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.047 wt% or 0.003 wt% to 0.046 wt%.

[0183] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.046 wt% or 0.003 wt% to 0.045 wt%.

[0184] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.045 wt% or 0.003 wt% to 0.044 wt%.

[0185] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.044 wt% or 0.003 wt% to 0.043 wt%.

[0186] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.043 wt% or 0.003 wt% to 0.042 wt%.

[0187] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.042 wt% or 0.003 wt% to 0.041 wt%.

[0188] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.041 wt% or 0.003 wt% to 0.040 wt%; Or, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.040 wt% or 0.003 wt% to 0.039 wt%.

[0189] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.039 wt% or 0.003 wt% to 0.038 wt%.

[0190] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.038 wt% or 0.003 wt% to 0.037 wt%.

[0191] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.037 wt% or 0.003 wt% to 0.036 wt%.

[0192] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.036 wt% or 0.003 wt% to 0.035 wt%.

[0193] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.035 wt% or 0.003 wt% to 0.034 wt%.

[0194] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.034 wt% or 0.003 wt% to 0.033 wt%.

[0195] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.033 wt% or 0.003 wt% to 0.032 wt%.

[0196] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.032 wt% or 0.003 wt% to 0.031 wt%.

[0197] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.031 wt% or 0.003 wt% to 0.030 wt%; Alternatively, the content of eplerenone is 99.0 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.03 wt% or 0.003 wt% to 0.029 wt%; Alternatively, the content of eplerenone is 99.1 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.030 wt% or 0.003 wt% to 0.029 wt%.

[0198] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.029 wt% or 0.003 wt% to 0.028 wt%.

[0199] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.028 wt% or 0.003 wt% to 0.027 wt%.

[0200] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.027 wt% or 0.003 wt% to 0.026 wt%.

[0201] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0202] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.025 wt% or 0.003 wt% to 0.024 wt%.

[0203] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.024 wt% or 0.003 wt% to 0.023 wt%.

[0204] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.023 wt% or 0.003 wt% to 0.022 wt%.

[0205] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.022 wt% or 0.003 wt% to 0.021 wt%.

[0206] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.021 wt% or 0.003 wt% to 0.020 wt%; Or, the content of eplerenone is 99.2 wt% to 99.9 wt%, and the present invention provides an oral pharmaceutical preparation, wherein the content of the compound of formula A is greater than 0 wt% and less than 0.020 wt% or 0.003 wt% to 0.019 wt%.

[0207] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.019 wt% or 0.003 wt% to 0.018 wt%.

[0208] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.018 wt% or 0.003 wt% to 0.017 wt%.

[0209] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.017 wt% or 0.003 wt% to 0.016 wt%.

[0210] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.016 wt% or 0.003 wt% to 0.015 wt%.

[0211] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.015 wt% or 0.003 wt% to 0.014 wt%.

[0212] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.014 wt% or 0.003 wt% to 0.013 wt%.

[0213] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.013 wt% or 0.003 wt% to 0.012 wt%.

[0214] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.012 wt% or 0.003 wt% to 0.011 wt%.

[0215] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.011 wt% or 0.003 wt% to 0.010 wt%.

[0216] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of eplerenone in the composition is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.010 wt% or 0.003 wt% to 0.009 wt%.

[0217] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the composition further comprises one or more of the compounds of formula B, formula C, formula D, formula E, formula F, formula G and formula H.

[0218] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein the content of the compound of formula B in the composition is 0 wt% to 0.05 wt%, the content of the compound of formula C is 0 wt% to 0.05 wt%, the content of the compound of formula D is 0 wt% to 0.05 wt%, the content of the compound of formula E is 0 wt% to 0.05 wt%, the content of the compound of formula F is 0 wt% to 0.05 wt%, the content of the compound of formula G is 0 wt% to 0.05 wt%, and the content of the compound of formula H is 0 wt% to 0.05 wt%; moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0219] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein in the composition, the content of the compound of formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.003 wt% to 0.10 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula C is 0.003 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.003 wt% to 0.1 wt%, the content of eplerenone is 98.7 wt% to 99.9 wt%, the content of the compound of formula C is 0.003 to 0.09 wt%, the content of the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0220] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein in the composition, the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.089 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0221] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein in the composition, the content of the compound of formula A is 0.005 wt% to 0.088 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.088 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.09 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0222] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, wherein in the composition, the content of the compound of formula A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.087 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0223] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.83 wt% to 99.9 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.85 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.086 wt%, the content of eplerenone is 99.85 wt% to 99.9 wt%, the content of the compound of formula C is 0.005 to 0.09 wt%, the content of the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0224] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.085 wt%, the content of eplerenone is 99.85% to 99.91 wt%, the content of the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.085 wt%, the content of eplerenone is 99.85 wt% to 99.91 wt%, the content of the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.085 wt%, the content of eplerenone is 99.85 wt% to 99.91 wt%, the content of the compound of formula C is 0.005 to 0.07 wt%, the content of the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0225] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.084 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0226] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.083 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0227] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.082 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.082 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.082 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0228] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.081 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.081 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.081 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0229] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.080 wt%, eplerenone 99.85% to 99.91 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.080 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.080 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, the compound of formula G is 0.005 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0230] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.005 to 0.080 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.08 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.005 wt% to 0.08 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of formula C is 0.01 to 0.07 wt%, the compound of formula G is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compounds of formula B, formula C, formula D, formula E, formula F, formula G, and formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0231] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.080 wt%, eplerenone 99.85 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.01 wt% to 0.08 wt%, eplerenone 99.85 wt% to 99.92 wt%, the compound of formula C is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%); or, the content of the compound of formula A is 0.01 wt% to 0.08 wt%, eplerenone 99.85 wt% to 99.92 wt%, the compound of formula C is 0.01 to 0.07 wt%, the compound of formula G is 0.01 to 0.07 wt%, and the compounds of formula B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt% and does not include 0 wt%.

[0232] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.070 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%).

[0233] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.060 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%).

[0234] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.050 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%).

[0235] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.040 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt% for all).

[0236] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.030 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt% for all).

[0237] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, in the composition, the compound of formula A: 0.010 to 0.020 wt%, eplerenone 99.83 wt% to 99.92 wt%, the compound of formula G is 0.010 to 0.07 wt%, and the compounds of formula B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt% for all).

[0238] In some embodiments of the third aspect, for the oral pharmaceutical preparation provided by the present invention, when detected by high performance liquid chromatography, when the detection wavelength is 195 - 220 nm, when calculating the content of the compound of formula A by the external standard method, the content of the compound of formula A is greater than 0 wt% and less than 0.1 wt%.

[0239] In the fourth aspect, the present invention provides a preparation method of the above-mentioned pharmaceutical preparation, and the preparation method includes mixing the above-mentioned composition with pharmaceutical excipients; in some embodiments of the fourth aspect, when the pharmaceutical preparation is a tablet, the preparation method includes the well-known tablet preparation methods in the art, and this preparation method includes mixing the composition with suitable excipients and directly tabletting, or tabletting after dry granulation or wet granulation or fluidized bed granulation, and the tabletting pressure ≤ 20 kN, and pressing into a round or irregular solid preparation.

[0240] In the fifth aspect, the present invention provides a detection method for the content of the compound of formula A, and the content of the compound of formula A is detected by ultraviolet detection or high performance liquid chromatography, and its detection wavelength: 195 - 220 nm, preferably 205 - 215 nm.

[0241] In some embodiments of the fifth aspect, the detection method further includes the detection of the contents of other Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, and Compound H listed in the present invention; for example, the detection method for related substances of this product included in the European Pharmacopoeia is used for detection.

[0242] In some embodiments of the fifth aspect, the detection method further includes the European Pharmacopoeia analysis method for related substances of eplerenone. Chromatographic conditions: Chromatographic column: octadecylsilyl silica gel chromatographic column, 4.6 mm × 150 mm, 3 μm; Detection wavelength: 240 nm; Flow rate: 1.0 ml / min; Column temperature: 30 °C; Injection volume: 20 μL; Mobile phase A: 0.1% phosphoric acid aqueous solution; Mobile phase B: phosphoric acid - acetonitrile - methanol (0.1:40:60); The gradient elution program is shown in Table 1: Table 1

[0243] In the sixth aspect, the present invention provides the use of the above composition or the above pharmaceutical preparation in the preparation of a drug for treating hypertension, improving left ventricular systolic dysfunction and / or congestive heart failure after acute myocardial infarction. For heart failure with reduced ejection fraction: The initial dose is 25 mg once a day; The dose is gradually increased to 50 mg once a day within 4 weeks; The dose can be adjusted according to the blood potassium level. Hypertension: 50 mg once a day, alone or in combination with other antihypertensive drugs. For patients with insufficient antihypertensive response, the dose is increased to 50 mg twice a day. Higher doses are not recommended.

[0244] In the seventh aspect, the present invention provides the application of a Compound A as a reference substance in the content analysis or quality control of a composition containing eplerenone or its pharmaceutical preparation. In the above application, it is preferred that the content of Compound A in the composition containing eplerenone is greater than 0 wt% and less than 0.1 wt%. The detection wavelength used in the content analysis or quality control is 205 - 220 nm.

[0245] In some embodiments of the seventh aspect, the content of Compound A in the pharmaceutical composition is greater than 0 wt% and less than 0.1 wt% when examined under (temperature 40 °C ± 2 °C, relative humidity 75% ± 5%) and under long-term test conditions (temperature 25 °C ± 2 °C, relative humidity 60% ± 5%).

[0246] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0247] The reagents and raw materials used in the present invention are all commercially available.

[0248] The positive and progressive effects of the present invention are as follows: The present invention provides a stable pharmaceutical composition of high-purity eplerenone and Compound A; at the same time, in combination with the synthetic route, the purification process is improved to control the content of Compound A. When the content of Compound A is lower than the set control limit, common related serious clinical adverse reactions can be reduced, ensuring the quality and safety of the drug. Description of the Drawings

[0249] Figure 1 It is the ultraviolet spectrum diagram of Compound A; Figure 2 It is the mass spectrum diagram of the LC-MS of Compound A; Figure 3 It is the single crystal diffraction diagram of Compound A; Figure 4 It is the powder XRPD diagram of Compound A.

[0250] Figure 5 It is the HPLC detection diagram of the related substances of Compound A in the crude eplerenone of Example 2. The CAV34-IMP12 marked in the figure is Compound A in the present invention.

[0251] Figure 6 It is the drug concentration-inhibition rate curve of spironolactone and different hormone receptors.

[0252] Figure 7 It is the drug concentration-inhibition rate curve of eplerenone and different hormone receptors.

[0253] Figure 8 It is the drug concentration-inhibition rate curve of Compound A and different hormone receptors.

[0254] Figure 9 It is the HPLC detection diagram of the related substances of Compound A in the first refined eplerenone of Example 3. The CAV34-IMP12 marked in the figure is Compound A in the present invention.

[0255] Figure 10 It is the HPLC detection diagram of the related substances of Compound A in the second refined eplerenone of Example 3. The CAV34-IMP12 marked in the figure is Compound A in the present invention.

[0256] Figure 11 It is the HPLC detection diagram of the related substances of Compound A in the second refined eplerenone of Example 4. The CAV34-IMP12 marked in the figure is Compound A in the present invention.

[0257] Figure 12HPLC detection chart of related substances of eplerenone and compound A in Example 7. CAV34-IMP12 marked in the chart is the compound A in the present invention.

[0258] Figure 13 HPLC detection chart of related substances of eplerenone and compound A in Example 8. CAV34-IMP12 marked in the chart is the compound A in the present invention.

[0259] Figure 14 HPLC detection chart of related substances of compound A in eplerenone reference preparation (batch number: N56748) in Example 12. CAV34-IMP12 marked in the chart is the compound A.

[0260] Figure 15 XRPD chart of crude eplerenone containing 0.82% compound A in Example 2.

[0261] Figure 16 HPLC (240nm) detection chart of refined eplerenone using EP pharmacopoeia method in Example 3. Detailed implementation mode

[0262] The present invention will be further described below through examples. For those skilled in the art, according to the teachings of the present invention, equivalent replacement and improvement of the following examples using existing technologies still fall within the protection scope of the present invention.

[0263] Abbreviations ESI Electrospray ionization TMS Tetramethylsilane LC-MS High performance liquid chromatography - mass spectrometry tandem instrument In the examples of the present invention: The high performance liquid chromatograph is: Agilent1200 type, 1260 type.

[0264] The mass spectrometer is: Agilent 6460 MS, ion source: ESI.

[0265] The nuclear magnetic resonance spectrometer is: German Bruker AVANCE-400MHz nuclear magnetic resonance spectrometer Solvent: DMSO-d6; Internal standard: TMS.

[0266] Single crystal X-ray diffractometer: Single crystal X-ray diffraction plane detector Nonius cad4; Temperature: 20°C; Detect sample characteristics, state: granules.

[0267] The X-ray powder diffractometer is: Bruker D8 Advance ECO X-ray diffractometer; using Cu Kα target; the wavelength λ is 1.5418 Å; the tube voltage and current are 40 kV and 25 mA respectively; the divergence slit is 1.0 mm; the pre-soller slit is 4.1°; the post-soller slit is 2.5°; the detector is LYNXEYE_XE_T (1D mode).

[0268] Example 1 Preparation and detection of Compound A used as a standard reference Add 120 ml of methanol, 15 g of eplerenone, 60 ml of dichloromethane, 12 g of 30% hydrogen peroxide, and 1.2 g of sodium hydroxide to the reaction flask, and react at room temperature for more than 32 hours. After the reaction is completed, let it stand for phase separation, wash with 40 ml of water, and concentrate the organic phase at 45 °C. Load 300 g of silica gel in the chromatography column with ethyl acetate / cyclohexane (1 / 3). After loading the concentrate, elute with ethyl acetate / cyclohexane (1 / 3). Collect the target product, concentrate it, and dry it to obtain 1.4 g of Compound A. The ultraviolet spectrum of Compound A is shown in Figure 1 .

[0269] ESI: [M+Na]+ 453.10 ( Figure 2 ) 1 1H-NMR (400 MHz, DMSO-d6): δ3.528(s,3H),3.246~3.233(d,1H), 3.191 (s,1H), 2.876~1.383(m,22H),0.891(s,3H) 13 13C-NMR (400MHz, DMSO-d6): δ206.987,176.529,173.136,94.455,67.198,66.117,65.374,52.162,51.548,44.046,37.759,37.578,37.311,34.639,34.188,32.410,30.771,30.454,28.936,27.639,22.505,21.656,16.665

[0270] Dissolve 100 mg of Compound A in 5 ml of dichloromethane and 5 ml of methyl ethyl ketone solvents, and filter. Transfer the filtrate to a beaker and cultivate single crystals by the evaporation method. The single crystal XRD diffraction is shown in Figure 3 . The XRPD powder diffraction is shown in Figure 4 .

[0271] Single crystal XRD: The crystal of this product belongs to the orthorhombic system, space group P212121, with unit cell parameters a = 8.151 Å, b = 15.2029(1) Å, c = 33.5571(1) Å, unit cell volume V = 4158.10(3) Å3, Dx = 1.375 mg / m 3 , and each unit cell contains 8 molecules (Z = 8), F(000) = 1840. In the molecular structure, atoms C4, C10, C11, C12, C13, C15, C16, and C20 are in the R configuration, and C7 and C8 are in the S configuration.

[0272] Method for detecting the content of Compound A in the composition (or bulk drug) of eplerenone: Compound A is determined by high performance liquid chromatography (General Principles 0512, Section IV, Chinese Pharmacopoeia 2020 Edition).

[0273] Test solution: Take this product, weigh accurately, dissolve it with water - acetonitrile (50:50) and quantitatively dilute to make a solution containing about 1 mg per 1 ml.

[0274] Reference solution: Take an appropriate amount of the reference substance of Compound A, weigh accurately, dissolve it with water - acetonitrile (50:50) and quantitatively dilute to make a solution containing about 1.5 μg per 1 ml.

[0275] Chromatographic conditions: Use an octadecylsilane chemically bonded silica gel as the filler, 4.6 mm × 150 mm, 3.5 μm or a chromatographic column with equivalent efficiency; use a mobile phase consisting of 10 mmol / L potassium dihydrogen phosphate solution (pH 7.0) - acetonitrile - methanol (58:36:6); the flow rate is 0.9 ml per minute; the column temperature is 35 °C; the detection wavelength is 210 nm; the injection volume is 20 μl.

[0276] Determination method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively.

[0277] Result calculation: In the chromatogram of the test solution, if there is a chromatographic peak with the same retention time as the peak of Compound A in the chromatogram of the reference solution, calculate according to the external standard method with the peak area.

[0278] The calculation formula is as follows: Content of Compound A (%) = (A 样 × C 对 ) / (A 对 × C 样 ) × 100% Where: A 样 is the peak area of Compound A in the chromatogram of the test solution A 对 is the peak area of Compound A in the chromatogram of the reference solution C 对The concentration of Compound A in the reference solution (mg / ml) C 样 The concentration of the test sample (mg / ml)

[0279] Example 2

[0280] Enol ester eplerenone Add 170 g of enol ester and 1500 ml of dichloromethane to a reaction flask and stir to dissolve. While stirring, add 149 g of trichloroacetamide and an aqueous solution of 106 g of dipotassium hydrogen phosphate (106 g). After addition, add 694 g of 30% hydrogen peroxide solution and react at room temperature for 18.5 hours. Add 695 ml of water for washing, separate the phases, and back-extract the aqueous phase with 700 ml of dichloromethane. After combining the organic phases, wash with 1220 ml of 3% aqueous sodium sulfite solution and 610 ml of 0.5 N aqueous sodium hydroxide solution respectively. Dry the organic phase over sodium sulfate, filter, concentrate the filtrate, add 1890 ml of methyl ethyl ketone for recrystallization, stir at 0 - 5°C for 2 hours, filter by suction, and dry to obtain 127 g of crude (unsolvated) eplerenone. Yield: 72%. Compound A: 0.82%, Compound C: 0.57%, Eplerenone: 97.2%. The XRPD powder diffraction of the crude eplerenone is shown in Figure 15 , and the XRPD test results show that the XRPD of the crude eplerenone containing 0.82% of Compound A cannot be detected.

[0281] Purify according to the method of Example 47A of WO98 / 25948 Add 50 g of the obtained crude eplerenone to 525 ml of methyl ethyl ketone, heat to dissolve, and distill off 262 ml of methyl ethyl ketone. Cool to 50°C and stir for 1 hour, then cool to 20 - 25°C and stir for 2 hours, filter by suction, and dry the filter cake. Obtain 44 g of the first refined (unsolvated) eplerenone. Yield: 88%. Compound A: 0.42%, Compound C: 0.19%, Eplerenone: 99.32%.

[0282] Add 40 g of the first refined eplerenone obtained above to 420 ml of methyl ethyl ketone, heat to dissolve, filter, and distill off 210 ml of methyl ethyl ketone from the filtrate. Cool to 50°C and stir for 1 hour, then cool to 20 - 25°C and stir for 2 hours, filter by suction, and dry the filter cake. Obtain 36.8 g of the second refined (unsolvated) eplerenone. Yield: 92%. Compound A: 0.22%, Compound C: 0.07%, Eplerenone: 99.63%. Compounds B, D, E, F, G, and H are not detected.

[0283] Comparative Example 1 Using the method taught in Example 3 of CN113173968A, 5 g of crude eplerenone (the content of Compound A is 0.82%) was added to a reaction flask, 60 mL of absolute ethanol, 10 mL of purified water, heated at 75 °C for 20 minutes, cooled to 30 °C, stirred while maintaining the temperature for 4 hours, filtered by suction, the filter cake was rinsed with absolute ethanol, and dried in vacuo at 55 °C for 12 hours to obtain 4.5 g of eplerenone, yield: 90%. Using the HPLC method of the present invention, the content of Compound A was detected to be 0.72%. This method has basically no ability to remove Compound A.

[0284] Comparative Example 2 Using the method taught in Example 2 of CN104844681B, 5 g of crude eplerenone (the content of Compound A is 0.82%) was added to a reaction flask, 120 mL of 1,2-dimethoxyethane, refluxed for dissolution, cooled to -5 - 0 °C, stirred while maintaining the temperature for 10 hours, filtered by suction, and the filter cake was dried in vacuo at 60 °C for 6 hours to obtain 3.35 g of refined eplerenone, yield: 67%. Using the HPLC method of the present invention, the content of Compound A was detected to be 0.59%. This method has poor ability to remove Compound A.

[0285] Comparative Example 3 Using the method taught in Example 3 of CN104262450A, 5 g of crude eplerenone (the content of Compound A is 0.82%) was added to a reaction flask, 47.5 mL of butanone, refluxed for dissolution, cooled to room temperature, stirred while maintaining the temperature for 6 hours, filtered by suction, and dried to obtain 4.3 g of refined eplerenone, yield: 86%. Using the HPLC method of the present invention, the content of Compound A was detected to be 0.44%. The residue of Compound A is still relatively large.

[0286] Comparative Example 4 Determination results of the solubility of Compound A and Compound C in butanone under the conditions of 0 °C and 25 °C.

[0287] Determination chromatographic conditions: Chromatographic column: Waters XBridge Shield RP18, 4.6×150 mm, 3.5 μm Mobile phase: 0.1% phosphoric acid aqueous solution - acetonitrile (60:40) Flow rate: 1.0 mL / min Column temperature: 30 °C Detection wavelength: 210 nm Injection volume: 2 μL Determination process: Appropriate amounts of samples were taken, an appropriate amount of butanone solvent was added, and their saturated solubilities were detected under the conditions of 0 °C and 25 °C respectively.

[0288] Table 2

[0289] Example 3 12.7 Kg of the crude eplerenone obtained by the same method as in Example 2 was added to 50 L of dichloromethane for dissolution, 50 L of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and the filter cake was dried. The dried filter cake was added to 50 L of dichloromethane for dissolution, 50 L of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and after drying the filter cake, 9.4 Kg of the first refined product of eplerenone (non-solvated) was obtained. Yield: 74%. Compound of formula A: 0.18%.

[0290] 9.21 Kg of the first refined product of eplerenone obtained above was added to 65 L of dichloromethane for dissolution, 97 L of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and after drying the filter cake, 8.41 Kg of the second refined product of eplerenone (non-solvated) was obtained. Yield: 91.3%. Compound of formula A: 0.09%, eplerenone: 99.85%, compound of formula C: 0.03%, compound of formula G: 0.01%, and compounds of formulas B, D, E, F, and H were not detected. The refined products in the examples were compared using the EP pharmacopoeia and the detection method of the present invention, as shown in Table 3 below.

[0291] Table 3

[0292] Example 4 8.75 Kg of the first refined product of eplerenone obtained by the same method as in Example 3 was added to 61 L of dichloromethane for dissolution, 92 L of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and after drying the filter cake, 7.59 Kg of the second refined product of eplerenone (non-solvated) was obtained. Yield: 86.7%. Compound of formula A: 0.08%, eplerenone: 99.87%, compound of formula C: 0.03%, compound of formula G: 0.01%, and compounds of formulas B, D, E, F, and H were not detected.

[0293] 20 g of the above second refined product was added to 140 ml of dichloromethane for dissolution, 210 ml of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and after drying the filter cake, 18 g of the third refined product of eplerenone (non-solvated) was obtained. Yield: 90%. Compound of formula A: 0.01%, eplerenone: 99.90%, and compounds of formulas B, C, D, E, F, G, and H were not detected.

[0294] 18 g of the above third refined product was added to 126 ml of dichloromethane for dissolution, 189 ml of cyclohexane was added, stirred at room temperature for 1 hour, filtered by suction, and after drying the filter cake, 16.4 g of the fourth refined product of eplerenone (non-solvated) was obtained. Yield: 91%. Compound of formula A: 0.003%, eplerenone: 99.99%, and compounds of formulas B, C, D, E, F, G, and H were not detected.

[0295] Example 5: Stability investigation The results of investigating the eplerenone product prepared in Example 3 under the accelerated test conditions (temperature 40°C ± 2°C, relative humidity 75% ± 5%) and long-term test conditions (temperature 25°C ± 2°C, relative humidity 60% ± 5%) in accordance with the guiding principles of "9001 Raw Drugs and Preparations Stability" in the Chinese Pharmacopoeia showed that the content of the compound of formula A remained stable and there was no obvious change.

[0296] Example 6 The inventors studied the content of the compound of formula A in multiple batches of "INSPRA™" tablets sold on the market in the United States and Japan.

[0297] Method for detecting the content of the compound of formula A in tablets: The compound of formula A was determined by high performance liquid chromatography (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0298] Test solution: Take 20 eplerenone tablets, accurately weigh, grind them finely, accurately weigh an appropriate amount (about equivalent to 25 mg of eplerenone), place it in a 25 ml volumetric flask, add an appropriate amount of water - acetonitrile (50:50), ultrasonicate for about 1 minute to dissolve eplerenone, cool to room temperature, dilute to the mark with water - acetonitrile (50:50), shake well, centrifuge, and take the supernatant.

[0299] Reference solution: Take an appropriate amount of the reference substance of the compound of formula A, accurately weigh, dissolve and dilute with water - acetonitrile (50:50) to prepare a solution containing about 2 μg per 1 ml.

[0300] Chromatographic conditions: Use an octadecylsilane chemically bonded silica gel as the filler, 4.6 mm × 150 mm, 3.5 μm or a chromatographic column with equivalent efficiency; use 10 mmol / L potassium dihydrogen phosphate (pH 7.0) - acetonitrile - methanol (58:36:6) as the mobile phase; the flow rate is 0.9 ml per minute; the column temperature is 35°C; the detection wavelength is 210 nm; the injection volume is 20 μL.

[0301] Determination method: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively.

[0302] Result calculation: In the chromatogram of the test solution, if there is a chromatographic peak with the same retention time as the chromatographic peak of the compound of formula A in the chromatogram of the reference solution, calculate by the external standard method with the peak area.

[0303] The calculation formula is as follows: Content of formula A (%) = (A 样 × C 对 ) / (A 对 × C 样 ) × 100% Where: A 样 is the peak area of the peak of formula A in the chromatogram of the test solution A 对 is the peak area of peak A in the chromatogram of the reference solution C 对 is the concentration of A in the reference solution (mg / ml) C 样 is the concentration of eplerenone in the test solution (mg / ml) The determination results show that the content of compound A in multiple batches of "INSPRA™" tablets is between 0.17% and 0.21%. Specifically as shown in Table 4 below: Table 4 Detection results of compound A in INSPRA™ tablets

[0304] From the perspectives of drug safety and effectiveness, it is necessary to carefully evaluate the impact of related substances that inherently coexist in eplerenone and are difficult to remove by conventional means, other than those already reported in the European Pharmacopoeia, on the drug quality, safety, and effectiveness.

[0305] Example 7 Preparation of the eplerenone tablets of the present invention Active ingredient: Eplerenone 2500 g Inactive ingredients: Anhydrous lactose 3200 g Magnesium stearate 50 g Microcrystalline cellulose 1800 g Croscarmellose sodium 500 g Hydroxypropyl methylcellulose 250 g Sodium lauryl sulfate 120 g Talc powder 80 g Film coating premix (Colorcon gastric-soluble Opadry 15B130004) 260 g The prescription is designed based on a batch of 100,000 tablets.

[0306] Preparation process: Mix the eplerenone raw material obtained in Example 3 in the prescribed amount with anhydrous lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl sulfate, croscarmellose sodium, and talc powder in a three-dimensional mixer until evenly mixed. Set the dry granulation parameters to obtain dry granules, then add magnesium stearate and mix thoroughly, and then press tablets. Prepare the coating solution according to the solid content of the coating solution being 10% - 20%, and the coating weight gain ranges from 2% - 6% to obtain the eplerenone tablets. In the eplerenone tablets, compound A: 0.09 wt%, eplerenone: 99.85 wt%, compound C: 0.03 wt%, compound G: 0.02 wt%, and compounds B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt%).

[0307] Example 8 Preparation of Eplerenone Coated Tablets of the Invention Active ingredient: Eplerenone 2500 g Inactive ingredients: Anhydrous lactose 3200 g Magnesium stearate 50 g Microcrystalline cellulose 1800 g Croscarmellose sodium 500 g Hydroxypropyl methylcellulose 250 g Sodium lauryl sulfate 120 g Talcum powder 80 g Film coating premix (Opadry 15B130004, gastro-resistant type of Colorcon) 260 g The prescription is designed according to a batch of 100000 tablets.

[0308] Preparation process: Mix the eplerenone raw material drug obtained from Example 4 (secondary refined product) in the prescription amount with anhydrous lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl sulfate, croscarmellose sodium, and talcum powder evenly in a three-dimensional mixer. Set the parameters for dry granulation to obtain dry granules, then add magnesium stearate and mix thoroughly. After mixing evenly, press tablets. Prepare a coating suspension by adding purified water according to the solid content of the coating solution being 10% - 20%, and when the coating weight gain reaches the range of 2% - 6%, the eplerenone tablets are obtained. In the eplerenone tablets, Compound A: 0.08 wt%, Eplerenone: 99.87 wt%, Compound C: 0.03 wt%, Compound G: 0.02 wt%, and Compounds B, D, E, F, and H are not detected (the detection limit is less than 0.003 wt% for all).

[0309] Example 9: Stability Study Stability study of Compound A in the tablets of Example 8: According to the guiding principle of "9001 Raw Drugs and Preparations Stability" in the Chinese Pharmacopoeia, under the accelerated test conditions (temperature 40°C ± 2°C, relative humidity 75% ± 5%) and long-term test conditions (temperature 25°C ± 2°C, relative humidity 60% ± 5%), the results show that the content of Compound A in the composition remains stable without obvious changes.

[0310] Example 10: Determination of in vitro Hormone Receptor Binding Capacity A total of three test substances are selected: Eplerenone, Compound A, and Spironolactone, and their binding capacities with different hormone receptors are tested respectively. The hormone receptors include: Mineralocorticoid Receptors (MR), Androgen Receptors (AR), and Estrogen Receptors (ER).

[0311] Determination process: 1. Stable cell lines (MR, AR, ER) Day 1: Compound treatment and cell seeding a) Antagonist detection: Gradiently dilute the three test substances, transfer 5 mL of the compound to the detection plate, and then transfer 5 mL of the agonist (final concentration of the agonist = EC 80 ) to all detection wells.

[0312] b) Prepare cell culture medium: 89% phenol red-free DMEM medium, 10% charcoal-treated fetal bovine serum, and 1% glutamine.

[0313] c) Remove the medium from the culture flask.

[0314] d) Add 6 mL of phosphate-buffered saline (DPBS) to the culture flask, shake the culture flask back and forth several times, and then remove the liquid.

[0315] e) Add 3 mL of pre-warmed trypsin to the culture flask, shake the culture flask back and forth several times, and then remove the liquid.

[0316] f) Place the culture flask in a 37°C incubator for approximately 2 minutes.

[0317] g) Tap the culture flask, observe the cells under a microscope. When ≥90% of the cells have detached from the flask wall, resuspend the cells with 10 mL of pre-warmed medium and transfer the cell suspension to a 50 mL centrifuge tube.

[0318] h) Disperse the cells by pipetting up and down several times, and aspirate 0.6 m of the cell suspension for counting.

[0319] i) Dilute the cell suspension with medium to a concentration of 1.33×10 6 cells per milliliter. Add 25 mL of phosphate-buffered saline (PBS) to the edge wells of a 384-well plate, and add 15 mL of the cell suspension to the detection wells. Place the culture plate at room temperature for 15 minutes, and then transfer the culture plate to an incubator with humidity control, at 37°C and containing 5% carbon dioxide, and culture for 24 hours.

[0320] Day 2: Detection a) Add 25 mL of luciferase detection reagent to the detection plate and shake at room temperature for 20 minutes.

[0321] b) Read the data of the culture plate on an Envison instrument.

[0322] c) Add 25 mL of Stop&Glo detection reagent to the detection plate and shake at room temperature for 20 minutes.

[0323] d) Read the culture plate data on the Envison instrument again.

[0324] Test results: (1) Eplerenone has a strong binding affinity to the mineralocorticoid receptor (IC 50 = 2593 nM), while within the tested concentration range, eplerenone does not show binding affinity to the androgen receptor and estrogen receptor (IC 50 > 10000 nM).

[0325] (2) Spironolactone shows strong binding affinity to the mineralocorticoid receptor, estrogen receptor, and androgen receptor, with IC 50 values of 264.2, 344, and 116.6 nM respectively, but has poor selectivity in binding to these three hormone receptors simultaneously.

[0326] (3) Compound A shows certain binding affinity to the mineralocorticoid receptor, estrogen receptor, and androgen receptor, with the strongest binding ability to the estrogen receptor (IC 50 = 615.6 nM), followed by the androgen (IC 50 = 1889 nM) and mineralocorticoid (IC 50 = 4892 nM).

[0327] The above research results indicate that eplerenone shows high selectivity for binding to the mineralocorticoid receptor, while Compound A has poor selectivity and stronger binding ability to estrogen and androgen compared to the mineralocorticoid.

[0328] Table 5 Half - inhibitory concentration IC 50 (nM) of three test substances for different hormone receptors

[0329] Example 11: Clinical study of eplerenone tablets of the present invention The eplerenone tablets of the present invention are the test drug, prepared according to the method of Example 8, containing 0.08 wt% of Compound A. The inventors conducted a multi - center, randomized, double - blind, placebo - controlled, positive - drug parallel - controlled study in China (Clinical Trial Registration Number: CTR20191434) to evaluate the efficacy and safety of the eplerenone tablets of the present invention in the treatment of mild to moderate essential hypertension (Clinical Study Number TG1902EPL). A total of 331 patients with essential hypertension were randomly enrolled to complete this clinical study. The clinical trial information is shown in Table 6 below.

[0330] Table 6

[0331]

[0332]

[0333] Clinical research results show that: in the research group of the eplerenone tablets of the present invention, no adverse reactions of increased blood potassium occurred; no adverse reactions related to hormones occurred, such as gynecomastia, impotence, vaginal bleeding in women, abnormal menstruation and other adverse reactions.

[0334] The public review reports of INSPRA™ approved for marketing in the United States and Japan show that the most common typical adverse reactions in clinical research are adverse reactions and events characterized by increased blood potassium, increased liver enzymes, gynecomastia, impotence in men, breast pain in women, etc., as shown in Table 7.

[0335] Table 7

[0336] Note *: Using the trade name of eplerenone "INSPRA" as the keyword, search in the FDA-approved drug database (Drugs@FDA: FDA-Approved Drugs). Website link: https: / / www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=BasicSearch.process. Obtain the review report documents related to the clinical research of this product, including: (1) Medical Review(s), which is divided into eight parts (Part1~Part8); (2) INSPRA product label.

[0337] Eplerenone is a highly selective mineralocorticoid receptor antagonist, which exerts clinical efficacy by specifically binding to the aldosterone receptor. However, in multiple RCT clinical studies conducted by the original Pfizer company worldwide, this product has reported typical adverse reactions, as shown in the above table. The common adverse reactions in men are mainly manifested as gynecomastia, swelling, impotence; while the common adverse reactions in women are mainly manifested as abnormal menstruation, vaginal bleeding. The above adverse reactions indicate that Pfizer's eplerenone binds to other hormone receptors (such as androgen receptor, progesterone receptor, etc.) besides the mineralocorticoid receptor, leading to corresponding adverse reactions.

[0338] Conclusion: Clinical research results confirm that the preparation product of the present invention that controls the concomitant type A compound in this product has more excellent clinical safety compared with the safety reported by Pfizer's eplerenone tablets.

[0339] Example 12 Human bioequivalence study of the eplerenone preparation obtained in Example 7 of the present invention and the reference preparation Inspra™ (batch number: N56748 containing 0.21 wt% of type A compound) The beneficial effects of the present invention are further illustrated by human bioequivalence studies. A large amount of valid and reliable experimental data have been obtained, and the research content is as follows: A bioequivalence trial (Clinical Research Registration Number: CTR20180312) with a randomized, open-label, two-sequence, two-period, double-cross design was conducted on healthy Chinese volunteers who orally administered a single dose of 50 mg tablets of the eplerenone tablets of the present invention and 50 mg tablets of "INSPRA®" from G.D. Searle Division of Pfizer Inc.

[0340] The "test preparation" used in the study was the eplerenone preparation of the present invention, prepared by the method of Example 7, containing 0.09 wt% of the compound of formula A; the reference preparation was "INSPRA™", containing 0.21 wt% of the compound of formula A.

[0341] Table 8

[0342] Table 9 Results of human bioequivalence study under fasting administration conditions

[0343] Results of equivalence study: The bioavailability of the test preparation and the reference preparation is equivalent.

[0344] Table 10 Summary of adverse events

[0345] Drug-related adverse events: Adverse events for which the causal relationship between the drug and the adverse event is judged to be definite, very likely, or possible.

[0346] An adverse event whose onset or exacerbation occurs from the start of the current treatment cycle to before the next treatment cycle is defined as an adverse event related to the medication in the current cycle.

[0347] Table 11 Summary table of adverse events

[0348] Note 1 : Various examinations include laboratory examinations such as blood routine, blood biochemistry, and urine routine, vital signs, physical examinations, 12-lead electrocardiograms, etc.

[0349] Table 12 Severity of adverse events

[0350] An adverse event whose onset or exacerbation occurs from the start of the current treatment cycle to before the next treatment cycle is defined as an adverse event related to the medication in the current cycle.

[0351] Severity: Grade 1 - Mild; Grade 2 - Moderate; Grade 3 - Severe or of major medical significance but not immediately life-threatening; Grade 4 - Life-threatening; Grade 5 - Death.

[0352] Summary: According to the adverse reaction manifestations of the results of human bioequivalence studies, the adverse reactions of the formulation containing 0.21 wt% of Compound A are significantly more than those of the eplerenone preparation containing 0.09 wt%. According to the specific situation of adverse events, it shows that there may be an objective situation where the drug toxicity reaction of the reference preparation is greater than that of the test preparation.

Claims

1. An eplerenone composition, characterized in that, The composition comprises eplerenone and a compound of formula A, wherein the content of eplerenone is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is not more than 0.1 wt%: Compound of formula A.

2. The composition according to claim 1, wherein The content of the compound of formula A is 0.003 wt% to 0.1 wt%.

3. The composition according to claim 1, wherein The content of eplerenone is 98.7 wt% to 99.9 wt%.

4. The composition according to claim 1, wherein The content of eplerenone is 98.7 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.09 wt%.

5. The composition according to claim 1, wherein The content of eplerenone is 98.9 wt% to 99.9 wt%, and the content of the compound of formula A is greater than 0 wt% and less than 0.08 wt%.

6. The composition according to any one of claims 1 to 5, characterized in that, The described composition further comprises one or more of a compound of formula B, a compound of formula C, a compound of formula D, a compound of formula E, a compound of formula F, a compound of formula G, and a compound of formula H: Formula B Formula C Formula D Formula E Formula F Formula G Formula H Wherein, the content of the compound of formula B is 0 wt% to 0.05 wt%, the content of the compound of formula C is 0 wt% to 0.05 wt%, the content of the compound of formula D is 0 wt% to 0.05 wt%, the content of the compound of formula E is 0 wt% to 0.05 wt%, the content of the compound of formula F is 0 wt% to 0.05 wt%, the content of the compound of formula G is 0 wt% to 0.05 wt%, and the content of the compound of formula H is 0 wt% to 0.05 wt%; moreover, the sum of the contents of the compound of formula B, the compound of formula C, the compound of formula D, the compound of formula E, the compound of formula F, the compound of formula G, and the compound of formula H is 0 wt% to 0.10 wt%.

7. An eplerenone composition, characterized in that, The composition comprises eplerenone and a compound of formula A, wherein the content of eplerenone is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is not more than 0.1 wt%; Compound of formula A The preparation method of the composition comprises a step of selective oxidation using an enoate, and at least two refining steps; the enoate is methyl 17α-hydroxy-3-oxopregn-4,9(11)-diene-7α,21-dicarboxylate, γ-lactone; The refining solvent is a mixed solvent of dichloromethane and cyclohexane.

8. A method for preparing the composition according to any one of claims 1 to 7, characterized in that, Including: The enoate is dissolved in dichloromethane, trichloroacetamide, dipotassium hydrogen phosphate, and 30% hydrogen peroxide are added for an oxidation reaction to obtain an eplerenone product, and after post-treatment, a non-solvated eplerenone crude product is obtained; The enoate is methyl 17α-hydroxy-3-oxopregn-4,9(11)-diene-7α,21-dicarboxylate, γ-lactone; and The eplerenone crude product is refined more than 2 times with the refining solvent; the described composition is obtained, and the refining solvent is a mixed solvent of dichloromethane and cyclohexane.

9. The preparation method according to claim 8, characterized in that, The volume ratio of dichloromethane to cyclohexane in the refining solvent is 2:1 to 1:

3.

10. The preparation method according to claim 8, characterized in that, The volume ratio of dichloromethane to cyclohexane in the refining solvent is 1:1 or 1:1.

5.

11. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises the composition according to any one of claims 1 to 7 and pharmaceutical excipients.

12. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises eplerenone and pharmaceutical excipients, wherein the content of eplerenone is 20 wt% - 35 wt%, and the content of the compound of formula A in the pharmaceutical preparation is greater than 0 wt% and less than 0.1 wt%, Compound of formula A.

13. The pharmaceutical preparation according to claim 12, characterized in that, The pharmaceutical preparation is an oral pharmaceutical preparation, optionally an oral solid pharmaceutical preparation, and the oral solid pharmaceutical preparation includes one or more of tablets, capsules, and granules.

14. The pharmaceutical preparation according to claim 12, characterized in that, The pharmaceutical preparation is a film-coated tablet.

15. The pharmaceutical preparation according to claim 12, characterized in that, The pharmaceutical excipients include at least one of the following substances: fillers, lubricants, disintegrants, wetting agents, binders, film coating materials; The components of the pharmaceutical preparation are calculated by weight percentage and include: eplerenone accounting for 10%-35%; fillers accounting for 50%-80%, and one or more combinations of lactose, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts, sorbitol, glycine, calcium sulfate, and mannitol, etc. can be selected; lubricants accounting for 0.1%-5%, and one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc powder, and microcrystalline silica gel, etc. can be selected; disintegrants accounting for 3%-10%, and one or more of starch, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose, and crosslinked polyvinylpyrrolidone, etc. can be selected; binders accounting for 0.5%-5%, and one or more of gelatin slurry, starch slurry, polyvinylpyrrolidone, syrup, gum arabic, and cellulose and its derivatives can be selected; wetting agents accounting for 0.5%-5%, and sodium lauryl sulfate can be selected.

16. The pharmaceutical preparation according to claim 15, characterized in that, The pharmaceutical excipients are calculated by weight percentage and include 30%-40% anhydrous lactose, 0.5%-1% magnesium stearate, 20%-25% microcrystalline cellulose, 5%-7% croscarmellose sodium, 2%-3% hydroxypropyl methylcellulose, 1%-2% sodium lauryl sulfate, 0.5%-1% talc powder, and 2%-5% film coating materials.

17. A method for preparing a pharmaceutical preparation according to any one of claims 12 to 16, characterized in that, It includes mixing the eplerenone with the pharmaceutical excipients.

18. A method for detecting a compound of formula A, characterized in that, The detection method is to use ultraviolet spectroscopy or high performance liquid chromatography for detection; the detection wavelength is 195-220nm, Compound of formula A.

19. Use of a compound of formula A in the content detection or quality control of a composition containing eplerenone or its pharmaceutical preparation; Compound of formula A.

20. Use of the composition according to any one of claims 1 to 7 or the pharmaceutical preparation according to any one of claims 11 to 16 in the preparation of a drug for treating hypertension, improving left ventricular systolic dysfunction after acute myocardial infarction, and / or treating congestive heart failure.

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