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. Formula A

Description

Technical Field

[0001] The present invention belongs to but is not limited to the field of medical technology, and specifically relates to a composition containing eplerenone and its pharmaceutical preparation, preparation method, quality control method and use. Background Art

[0002] Eplerenone (Epoxymexrenone, Eplerenone) is a highly selective aldosterone receptor (MR) antagonist that treats hypertension and heart failure after myocardial infarction by blocking the renin-angiotensin-aldosterone system. Eplerenone highly selectively blocks mineralocorticoid receptors (MR) inside and outside the kidney and does not have the androgen and estrogen antagonism effects of spironolactone (a non-selective aldosterone receptor blocker).

[0003] Eplerenone is a highly selective aldosterone receptor antagonist. Typical clinical side effects reported by Pfizer Inc. (USA) and Pfizer Japan include: hyperkalemia, gynecomastia, breast pain, abnormal vaginal bleeding, increased transaminases, upper respiratory tract infection, headache, dizziness, fatigue, and palpitations. The causes of these adverse reactions have not yet been studied or reported in the literature. Summary of the Invention

[0004] Chinese patent application publication number CN1209136A discloses a method for preparing eplerenone, wherein the raw material enester is dissolved in dichloromethane, trichloroacetamide, dipotassium hydrogen phosphate, and 30% hydrogen peroxide are added to carry out an oxidation reaction, and after post-reaction treatment and purification with butanone, eplerenone with a purity of 99.6% is obtained.

[0005] However, the inventors discovered that the eplerenone obtained under these preparation conditions inevitably produces a large amount of compound A. Because eplerenone contains an epoxy structure, other existing methods for preparing eplerenone share essentially the same reaction conditions for epoxy formation, differing only in the order in which the epoxy structures are formed during the preparation process. Consequently, compound A is also produced in the API. Furthermore, due to the difference in the ultraviolet absorption characteristics (210 nm) of compound A compared to the known ultraviolet absorption characteristics (240 nm) used in the European Pharmacopoeia method for the detection of related substances of this product, as well as the differences in the composition and ratio of the mobile phase eluent, this concomitant compound A cannot be discovered and effectively detected. Consequently, the European Pharmacopoeia method for the detection of related substances of this product is unable to detect compound A and effectively control its production.

[0006] Patent CN1433427A exemplifies the use of 99% eplerenone for crystalline preparation, but does not provide a purity detection method; Patent CN113173968A examples illustrate the purification of eplerenone using different ratios of ethanol / water, with a purity of approximately 99.5%. The purity detection method uses the detection method in European Pharmacopoeia EP9.0 at a wavelength of 240 nm, which is insufficient for detecting compound A; Patent CN104262450A uses butanone to purify eplerenone with a purity of 99.9%. The patent does not provide a detection method, but its accompanying drawings show a detection wavelength of 241 nm, which is also insufficient for detecting compound A; Patent CN104844681B discloses that crude eplerenone is purified using 1,2-dimethoxyethane with a purity of 99.97%. The detection method shows that the detection wavelength is selected at 245 nm, which is also insufficient for effectively detecting compound A.

[0007] Example A of patent CN1377365A exemplifies the use of "eplerenone with a purity greater than 99%, and a combined content of "diepoxide" and "11,12-epoxide" (less than 0.2%)" in butanone to prepare a "butanone compound." Example B exemplifies the use of "eplerenone with a purity greater than 99.9%" to prepare Form L. Table 7A illustrates the use of 100% pure eplerenone recrystallized with butanone, resulting in the product containing 0.18%-0.38% of "11,12-epoxide" and 0.36-0.80% of "diepoxide." The patent also discloses that the solubility of "11,12-epoxide" in butanone solvent is approximately twice that of "diepoxide." However, the inventors have repeatedly confirmed that recrystallization of eplerenone using butanone does not degrade to form "diepoxide" and "11,12-epoxide." Furthermore, the solubility of "11,12-epoxide" in butanone at both 0°C and 25°C is more than twice that of "diepoxide." Similarly, the inventors have repeatedly confirmed that the "diepoxide" content in Example A is between two and three times that of "11,12-epoxide." Therefore, it is clear that the actual "diepoxide" content in this example is greater than 0.1%. Furthermore, neither the patent nor the corresponding priority document provides methods for detecting "diepoxide" and "11,12-epoxide." The eplerenone purity values ​​listed, such as 99.9%, 100%, and 100.80%, are actually values ​​obtained by external standard analysis, not HPLC purity.

[0008] When a certain amount of the compound of formula A is present in eplerenone, no characteristic diffraction peak (2θ) containing the compound of formula A can be observed by testing the XRPD pattern of eplerenone. Due to defects and problems such as detection sensitivity and distribution uniformity of the two solid substances, the powder XRPD method cannot accurately and effectively determine the content of the compound of formula A in eplerenone.

[0009] Further research has revealed that the compound of Formula A (CAV34-IMP12) can bind to multiple hormone receptors. When present in eplerenone, the compound can reduce the specificity and selectivity of eplerenone's antagonism of the aldosterone receptor, leading to binding to other hormone receptors in the body, such as the androgen receptor and the estrogen receptor, ultimately causing a certain proportion and probability of hormone-related adverse reactions in clinical practice. The inventors controlled the content of the compound of Formula A in eplerenone and conducted human bioequivalence studies and randomized controlled phase III clinical trials using eplerenone containing a specific limit of the compound of Formula A, achieving a significant reduction in hormone receptor-related clinical adverse reactions.

[0010] The chemical structure of the compound of formula A involved in this application is shown below: Compound of formula A.

[0011] In a first aspect, the present invention provides an eplerenone-containing composition, comprising eplerenone and a compound of formula A, wherein the eplerenone content is 98.5 wt % to 99.9 wt %, and the content of the compound of formula A is no 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 %; 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 %.

[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 composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.043 wt% or 0.003 wt% to 0.042 wt%.

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

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

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

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

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

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

[0071] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of 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 %; Alternatively, the eplerenone content 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 %.

[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 composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0080] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0081] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0082] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0083] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0084] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%. In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0085] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

[0086] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of greater than 0 wt% and less than 0.026 wt% or 0.003 wt% to 0.025 wt%.

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

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

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

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

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

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

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

[0094] In some embodiments, the composition has an eplerenone content of 98.7 wt% to 99.9 wt%, and a content of the compound of Formula A of 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 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.

[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 %; and 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, the composition, wherein the content of the compound of formula A is 0.003 wt% to 0.1 wt%, eplerenone is 98.7 wt% to 99.9 wt%, the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 98.7 wt% to 99.9 wt%, the compound of formula C is 0.003 to 0.09 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). The detection limits are all less than 0.003wt%); alternatively, the content of the compound of formula A is 0.003wt% to 0.1wt%, eplerenone is 98.7wt% to 99.9wt%, the compound of formula C is 0.003 to 0.09wt%, the compound of formula G is 0.003 to 0.09wt%, and the compounds of formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003wt%); and 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 0wt% to 0.10wt% and does not include 0wt%.

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

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

[0100] In some embodiments, the composition, wherein the content of the compound of formula A is 0.005 wt% to 0.088 wt%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected. (The detection limits are all less than 0.003wt%); alternatively, the content of the compound of formula A is 0.005wt% to 0.09wt%, eplerenone is 99.83wt% to 99.9wt%, the compound of formula C is 0.005 to 0.09wt%, the compound of formula G is 0.005 to 0.09wt%, and the compounds of formulas B, D, E, F and H are not detected (the detection limits are all less than 0.003wt%); and 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 0wt% to 0.10wt% and does not include 0wt%.

[0101] In some embodiments, the composition, wherein the content of the compound of formula A is 0.005 wt% to 0.087 wt%, eplerenone is 99.83 wt% to 99.9%, the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected ( The detection limits are all less than 0.003wt%); alternatively, the content of the compound of formula A is 0.005wt% to 0.087wt%, eplerenone is 99.83wt% to 99.9wt%, the compound of formula C is 0.005 to 0.09wt%, the compound of formula G is 0.005 to 0.09wt%, and the compounds of formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003wt%); and 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 0wt% to 0.10wt% and does not include 0wt%.

[0102] In some embodiments, the composition wherein the compound of Formula A is present in an amount of 0.005 wt% to 0.086 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.9 wt%, the compound of Formula G is present in an amount of 0.005 to 0.09 wt%, and none of the compounds of Formulae B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); or the compound of Formula A is present in an amount of 0.005 wt% to 0.086 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.9 wt%, the compound of Formula C is present in an amount of 0.005 to 0.09 wt%, and none of the compounds of Formulae B, D, E, F, G, and H are detected (all with detection limits less than 0.003 wt%); or the compound of Formula A is present in an amount of 0.005 wt% to 0.086 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.9 wt%, the compound of Formula C is present in an amount of 0.005 to 0.09 wt%, and the compound of Formula G is present in an amount of 0.005 to 0.09 wt%, and none of the compounds of Formulae B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); and the combined amount of the compounds of Formulae B, C, D, E, F, G, and H is 0 wt% to 0.10 wt% and not including 0 wt%.

[0103] In some embodiments, the composition wherein the compound of Formula A is present in an amount of 0.005 wt% to 0.085 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.91 wt%, the compound of Formula G is present in an amount of 0.005 to 0.07 wt%, and none of the compounds of Formulae B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); or the compound of Formula A is present in an amount of 0.005 wt% to 0.085 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.91 wt%, the compound of Formula C is present in an amount of 0.005 to 0.07 wt%, and none of the compounds of Formulae B, D, E, F, G, and H are detected (all with detection limits less than 0.003 wt%); or the compound of Formula A is present in an amount of 0.005 wt% to 0.085 wt%, the eplerenone is present in an amount of 99.85 wt% to 99.91 wt%, the compound of Formula C is present in an amount of 0.005 to 0.07 wt%, and the compound of Formula G is present in an amount of 0.005 to 0.07 wt%, and none of the compounds of Formulae B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); and the combined amount of the compounds of Formulae B, C, D, E, F, G, and H is 0 wt% to 0.10 wt% and not including 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: 0.005 to 0.07 wt%, and none of the compounds of Formula B, C, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); or, the compound of Formula A: 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of Formula C: 0.005 to 0.07 wt%, and none of the compounds of Formula B, D, E, F, G, and H are detected (all with detection limits less than 0.003 wt%); or, the compound of Formula A: 0.005 wt% to 0.084 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of Formula C: 0.005 to 0.07 wt%, and the compound of Formula G: 0.005 to 0.07 wt%, and none of the compounds of Formula B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); and, the sum of the amounts 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 not including 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: 0.005 to 0.07 wt%, and none of the compounds of Formula B, C, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); or, the compound of Formula A: 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of Formula C: 0.005 to 0.07 wt%, and none of the compounds of Formula B, D, E, F, G, and H are detected (all with detection limits less than 0.003 wt%); or, the compound of Formula A: 0.005 wt% to 0.083 wt%, eplerenone 99.85 wt% to 99.91 wt%, the compound of Formula C: 0.005 to 0.07 wt%, and the compound of Formula G: 0.005 to 0.07 wt%, and none of the compounds of Formula B, D, E, F, and H are detected (all with detection limits less than 0.003 wt%); and, the sum of the amounts 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 not including 0 wt%.

[0106] In some embodiments, the composition, wherein the compound of formula A is 0.005 to 0.082 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 formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the compound of formula A is 0.005 wt% to 0.082 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 formulas B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). Alternatively, the content of the compound of formula A is 0.005 wt % to 0.082 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 formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

[0107] In some embodiments, the composition, wherein the compound of formula A is 0.005 to 0.081 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 formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the compound of formula A is 0.005 wt% to 0.081 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 formulas B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). Alternatively, the content of the compound of formula A is 0.005 wt % to 0.081 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 formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

[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 formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, 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 formulas B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). Alternatively, 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 formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

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

[0110] In some embodiments, the composition, wherein the compound of formula A is 0.01 to 0.08 wt%, eplerenone is 99.85 wt% to 99.92 wt%, the compound of formula G is 0.01 to 0.07 wt%, and the compounds of formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the compound of formula A is 0.01 wt% to 0.08 wt%, eplerenone is 99.85 wt% to 99.92 wt%, the compound of formula C is 0.01 to 0.07 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). Alternatively, the content of the compound of formula A is 0.01 wt% to 0.08 wt%, eplerenone is 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 formulae B, D, E, F, and H are not detected (the detection limits are all less than 0.003 wt%); and 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%.

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

[0112] In a second aspect, the present invention provides a method for preparing the above-mentioned composition, comprising: conducting an oxidation reaction of an enester (17α-hydroxy-3-oxopregnanol-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester, γ-lactone) with hydrogen peroxide to obtain an eplerenone product, and performing post-treatment to obtain a crude eplerenone product; and The crude eplerenone is refined with a refining solvent for more than two times to obtain the composition, wherein the refining solvent is a mixed solvent of dichloromethane and cyclohexane; and The post-treatment includes recrystallization, and the recrystallization solvent is butanone.

[0113] In some embodiments of the second aspect, the volume mass ratio of the recrystallization solvent butanone 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 2:1 to 1:3; preferably, such as 1:1 or 1:1.5.

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

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

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

[0118] In a third aspect, the present invention provides a pharmaceutical preparation comprising 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 a tablet, capsule, or granule, etc., preferably a tablet, more preferably a film-coated tablet.

[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: a filler (or diluent), a lubricant (which may also function as a glidant or an anti-adhesive agent), a disintegrant, a wetting agent (which may have a wetting aid effect) and a binder, etc.

[0121] In some embodiments of the third aspect, the pharmaceutical preparation is an eplerenone tablet, comprising components by weight: eplerenone accounting for 10wt%-35wt%; the filler (or diluent) accounting for 50wt%-80wt%, and can be a combination of one or more of 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, methylcellulose, hydroxypropyl cellulose, etc.), inorganic calcium salts, sorbitol, glycine, calcium sulfate and mannitol, etc., preferably, a combination of lactose and microcrystalline cellulose, 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 may also serve as a glidant or anti-adhesive agent) accounts for 0.1wt%-5wt%, and can be selected from one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearate fumarate, talc and micro-powdered silica gel, etc. 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), preferably, the weight ratio is 1:1.6.

[0123] The disintegrant accounts for 3wt%-10wt% and can be selected from one or more of starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose and cross-linked polyvinyl pyrrolidone; preferably, cross-linked sodium carboxymethyl cellulose.

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

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

[0126] In addition, during the preparation process of the pharmaceutical preparation, an appropriate amount of water or alcohol may 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 herein are film-coated tablets, i.e., the eplerenone tablets further include a film-coating agent, the film-coating agent comprising 1 wt% to 6 wt% (based on the eplerenone tablet). The film-coating agent can be selected from a gastric-soluble film-coating premix, such as Opadry™, manufactured by Colorcon Coating Technology Co., Ltd., or a gastric-soluble film-coating premix from another excipient manufacturer, or can be prepared independently. Optionally, the film-coating agent comprises 8 wt% to 30 wt% of a plasticizer (e.g., polyethylene glycol 400), 50 wt% to 85 wt% of a film-forming agent (e.g., hypromellose), 5 wt% to 15 wt% of an opacifier (e.g., titanium dioxide), and 0.5 wt% to 5 wt% of a colorant (e.g., iron oxide yellow / red / black). When a premix is ​​used, purified water is used as the solvent for preparation, and the preparation concentration ranges from 10% to 20% (w / w).

[0128] In some embodiments of the third aspect, the present invention provides an eplerenone tablet comprising 20 wt % to 35 wt % of eplerenone, 30 wt % to 40 wt % of anhydrous lactose, 0.5 wt % to 1 wt % of magnesium stearate, 20 wt % to 25 wt % of microcrystalline cellulose, 5 wt % to 7 wt % of cross-linked sodium carboxymethyl cellulose, 2 wt % to 3 wt % of hypromellose, 1 wt % to 2 wt % of sodium lauryl sulfate, 0.5 wt % to 1 wt % of talc, and 2 wt % to 5 wt % of a film coating agent (e.g., a gastric-soluble film coating premix).

[0129] In some embodiments of the third aspect, the present invention provides an eplerenone tablet comprising 26 wt % to 29 wt % of eplerenone, 34 wt % to 38 wt % of anhydrous lactose, 0.5 wt % to 0.8 wt % of magnesium stearate, 20 wt % to 22 wt % of microcrystalline cellulose, 5 wt % to 7 wt % of cross-linked sodium carboxymethyl cellulose, 2 wt % to 3 wt % of hypromellose, 1 wt % to 2 wt % of sodium lauryl sulfate, 0.5 wt % to 1 wt % of talc, and 2 wt % to 5 wt % of a film coating agent (e.g., a gastric-soluble film coating premix).

[0130] In some embodiments of the third aspect, the present invention provides an eplerenone tablet comprising 28.5 wt % eplerenone, 36.5 wt % anhydrous lactose, 0.6 wt % magnesium stearate, 20.5 wt % microcrystalline cellulose, 5.7 wt % cross-linked carboxymethyl cellulose sodium, 2.9 wt % hypromellose, 1.4 wt % sodium lauryl sulfate, 0.9 wt % talc, and 3.0 wt % film coating agent (e.g., a gastric-soluble film coating premix).

[0131] In some embodiments of the third aspect, the present invention provides the above-mentioned pharmaceutical preparation, wherein the composition comprises eplerenone and a compound of formula A, wherein the eplerenone content is 98.5 wt% to 99.9 wt%, and the content of the compound of formula A is no more than 0.1 wt% or 0.003 wt% to 0.1 wt%; the content of the compound of formula A is no more than 0.10 wt% or 0.003 wt% to 0.10 wt%; or, the eplerenone content 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, the present invention provides the above-mentioned pharmaceutical preparation, wherein the content of eplerenone in the composition is 98.7wt% to 99.9wt%, and the content of the compound of formula A is greater than 0wt% and less than 0.099wt% or 0.003wt% to 0.098wt%.

[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 application provides an oral pharmaceutical formulation, 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%.

[0148] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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%.

[0150] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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%.

[0151] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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%. 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 application provides an oral pharmaceutical formulation, 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%.

[0153] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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%.

[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 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 0.063 wt% or 0.003 wt% to 0.062 wt%.

[0169] 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 0.062 wt% or 0.003 wt% to 0.061 wt%.

[0170] 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 0.061 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 %.

[0171] 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 0.059 wt% or 0.003 wt% to 0.058 wt%.

[0172] 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 0.058 wt% or 0.003 wt% to 0.057 wt%.

[0173] 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 0.057 wt% or 0.003 wt% to 0.056 wt%.

[0174] 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 0.056 wt% or 0.003 wt% to 0.055 wt%.

[0175] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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%. In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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 0.050 wt% or 0.003 wt% to 0.049 wt%.

[0180] In some embodiments of the third aspect, the present application provides an oral pharmaceutical formulation, 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 application provides an oral pharmaceutical formulation, 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 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 0.047 wt% or 0.003 wt% to 0.046 wt%.

[0183] 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 0.046 wt% or 0.003 wt% to 0.045 wt%.

[0184] 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 0.045 wt% or 0.003 wt% to 0.044 wt%.

[0185] 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 0.044 wt% or 0.003 wt% to 0.043 wt%.

[0186] 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 0.043 wt% or 0.003 wt% to 0.042 wt%.

[0187] 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 0.042 wt% or 0.003 wt% to 0.041 wt%.

[0188] 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 0.041 wt% or 0.003 wt% to 0.040 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 0.040 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 eplerenone content 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%; Alternatively, the eplerenone content is 99.2wt% to 99.9wt%. In the oral pharmaceutical preparation provided by the present invention, the content of the compound of formula A is greater than 0wt% and less than 0.020wt% or 0.003wt% to 0.019wt%.

[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 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 0.017 wt% or 0.003 wt% to 0.016 wt%.

[0210] 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 0.016 wt% or 0.003 wt% to 0.015 wt%.

[0211] 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 0.015 wt% or 0.003 wt% to 0.014 wt%.

[0212] 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 0.014 wt% or 0.003 wt% to 0.013 wt%.

[0213] 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 0.013 wt% or 0.003 wt% to 0.012 wt%.

[0214] 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 0.012 wt% or 0.003 wt% to 0.011 wt%.

[0215] 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 0.011 wt% or 0.003 wt% to 0.010 wt%.

[0216] 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 0.010 wt% or 0.003 wt% to 0.009 wt%.

[0217] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the 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.

[0218] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, 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 %; and 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 %.

[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%, eplerenone is 98.7 wt% to 99.9 wt%, the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formulas 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 0.10 wt%, eplerenone is 98.7 wt% to 99.9 wt%, the compound of formula G is 0.003 to 0.09 wt%, and the compounds of formulas 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%. , eplerenone is 98.7wt% to 99.9wt%, the compound of formula C is 0.003 to 0.09wt%, and the compounds of formulas B, D, E, F, G and H are not detected (the detection limits are all less than 0.003wt%); alternatively, the content of the compound of formula A is 0.003wt% to 0.1wt%, eplerenone is 98.7wt% to 99.9wt%, the compound of formula C is 0.003 to 0.09wt%, the compound of formula G is 0.003 to 0.09wt%, and the compounds of formulas B, D, E, F and H are not detected (the detection limits are all less than 0.003wt%); and 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 0wt% to 0.10wt% and does not include 0wt%.

[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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%). and H compounds were not detected (the detection limits were all less than 0.003wt%); alternatively, the content of the compound of formula A was 0.005wt% to 0.089wt%, eplerenone was 99.83wt% to 99.9wt%, the compound of formula C was 0.005 to 0.09wt%, the compound of formula G was 0.005 to 0.09wt%, and the compounds of formulas B, D, E, F and H were not detected (the detection limits were all less than 0.003wt%); and 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 was 0wt% to 0.10wt% and did not include 0wt%.

[0221] 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 0.088 wt%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%). Neither G nor H compounds were detected (both detection limits were less than 0.003wt%); alternatively, the content of the compound of formula A was 0.005wt% to 0.09wt%, eplerenone was 99.83wt% to 99.9wt%, the compound of formula C was 0.005 to 0.09wt%, the compound of formula G was 0.005 to 0.09wt%, and the compounds of formulae B, D, E, F, and H were not detected (both detection limits were less than 0.003wt%); and 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 was 0wt% to 0.10wt% and did not include 0wt%.

[0222] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the content of the compound of formula A is 0.005 wt% to 0.087 wt%, eplerenone is 99.83 wt% to 99.9%, the compound of formula G is 0.005 to 0.09 wt%, and the compounds of formulas 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%, eplerenone is 99.83 wt% to 99.9 wt%, the compound of formula C is 0.005 to 0.09 wt%, and the compounds of formulas B, C, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). None of the compounds were detected (the detection limits were all less than 0.003wt%); alternatively, the content of the compound of formula A was 0.005wt% to 0.087wt%, eplerenone was 99.83wt% to 99.9wt%, the compound of formula C was 0.005 to 0.09wt%, the compound of formula G was 0.005 to 0.09wt%, and the compounds of formulas B, D, E, F and H were not detected (the detection limits were all less than 0.003wt%); and 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 was 0wt% to 0.10wt% and did not include 0wt%.

[0223] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.005 to 0.086 wt% of the compound of Formula A, 99.83 to 99.9 wt% of eplerenone, 0.005 to 0.09 wt% of the compound of Formula G, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.086 wt% of the compound of Formula A, 99.85 to 99.9 wt% of eplerenone, 0.005 to 0.09 wt% of the compound of Formula C, and none of the compounds of Formulae B, D, E, F, G, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.086 wt% of the compound of Formula A, 99.85 to 99.9 wt% of eplerenone, 0.005 to 0.09 wt% of the compound of Formula C, and 0.005 to 0.09 wt% of the compound of Formula G, and none of the compounds of Formulae B, D, E, F, and H (the detection limit of each is less than 0.003 wt%); and, the total content of the compounds of Formulae B, C, D, E, F, G, and H is 0 to 0.10 wt% and not including 0 wt%.

[0224] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.005 to 0.085 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.085 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and none of the compounds of Formulae B, D, E, F, G, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.085 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, D, E, F, and H (the detection limit of each is less than 0.003 wt%); and, the total content of the compounds of Formulae B, C, D, E, F, G, and H is 0 to 0.10 wt% and not including 0 wt%.

[0225] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.005 to 0.084 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.084 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and none of the compounds of Formulae B, D, E, F, G, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.084 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, D, E, F, and H (the detection limit of each is less than 0.003 wt%); and, the total content of the compounds of Formulae B, C, D, E, F, G, and H is 0 to 0.10 wt% and not including 0 wt%.

[0226] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.005 to 0.083 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.083 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and none of the compounds of Formulae B, D, E, F, G, and H (the detection limit of each is less than 0.003 wt%); or, the composition contains 0.005 to 0.083 wt% of the compound of Formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of Formula C, and 0.005 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, D, E, F, and H (the detection limit of each is less than 0.003 wt%); and, the total content of the compounds of Formulae B, C, D, E, F, G, and H is 0 to 0.10 wt% and not including 0 wt%.

[0227] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the compound of formula A is 0.005 to 0.082 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 formulas 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 is 99.85 wt% to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formulas B, D, E, F, G and H are not detected. Alternatively, the content of the compound of formula A is 0.005 wt % to 0.082 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 formulae B, D, E, F and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

[0228] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the composition comprises 0.005 to 0.081 wt% of the compound of formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of formula G, and no detection of the compounds of formulas B, C, D, E, F, and H (all detection limits are less than 0.003 wt%); or, the content of the compound of formula A is 0.005 to 0.081 wt%, eplerenone is 99.85 to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected. Alternatively, the content of the compound of formula A is 0.005 wt % to 0.081 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 formulae B, D, E, F and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

[0229] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, wherein the composition comprises 0.005 to 0.080 wt% of the compound of formula A, 99.85 to 99.91 wt% of eplerenone, 0.005 to 0.07 wt% of the compound of formula G, and no detection of the compounds of formulas B, C, D, E, F, and H (all detection limits are less than 0.003 wt%); or, the content of the compound of formula A is 0.005 to 0.080 wt%, eplerenone is 99.85 to 99.91 wt%, the compound of formula C is 0.005 to 0.07 wt%, and the compounds of formulas B, D, E, F, G, and H are not detected. Alternatively, 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 formulae B, D, E, F and H are not detected (the detection limits are all less than 0.003 wt %); and 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 %.

[0230] In some embodiments of the third aspect, the present invention provides an oral pharmaceutical preparation, 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 0.010 to 0.07 wt%, and the compounds of formulas B, C, D, E, F, and H are not detected (the detection limit is less than 0.003 wt%); or, the compound of formula A is 0.005 to 0.08 wt%, eplerenone is 99.85 to 99.91 wt%, the compound of formula C is 0.01 to 0.07 wt%, and the compounds of formulas B, C, D, E, F, G, and H are not detected (the detection limit is less than 0.003 wt%). None of the compounds were detected (the detection limits were all less than 0.003wt%); alternatively, the content of the compound of formula A was 0.005wt% to 0.08wt%, eplerenone was 99.85wt% to 99.91wt%, the compound of formula C was 0.01 to 0.07wt%, the compound of formula G was 0.01 to 0.07wt%, and the compounds of formulas B, D, E, F and H were not detected (the detection limits were all less than 0.003wt%); and 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 was 0wt% to 0.10wt% and did not include 0wt%.

[0231] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.010 to 0.080 wt% of the compound of Formula A, 99.85 wt% to 99.92 wt% of eplerenone, 0.010 to 0.07 wt% of the compound of Formula G, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%); or, the compound of Formula A is 0.01 wt% to 0.08 wt%, eplerenone is 99.85 wt% to 99.92 wt%, the compound of Formula C is 0.01 to 0.07 wt%, and none of the compounds of Formulae B, D, E, F, G, and H (the detection limit of each is less than 0.003 wt%); or, the compound of Formula A is 0.01 wt% to 0.08 wt%, eplerenone is 99.85 wt% to 99.92 wt%, the compound of Formula C is 0.01 to 0.07 wt%, and the compound of Formula G is 0.01 to 0.07 wt%, and none of the compounds of Formulae B, D, E, F, and H (the detection limit of each is less than 0.003 wt%); and, the total content of the compounds of Formulae B, C, D, E, F, G, and H is 0 wt% to 0.10 wt% and not including 0 wt%.

[0232] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.010 to 0.070 wt% of the compound of Formula A, 99.83 wt% to 99.92 wt% of eplerenone, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%).

[0233] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.010 to 0.060 wt% of the compound of Formula A, 99.83 wt% to 99.92 wt% of eplerenone, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%).

[0234] In some embodiments of the third aspect, the present application provides an oral pharmaceutical preparation, wherein the composition contains 0.010 to 0.050 wt% of the compound of Formula A, 99.83 wt% to 99.92 wt% of eplerenone, and none of the compounds of Formulae B, C, D, E, F, and H (the detection limit of each is less than 0.003 wt%).

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

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

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

[0238] In some embodiments of the third aspect, the oral pharmaceutical preparation provided by the present invention, when detected by high performance liquid chromatography at a detection wavelength of 195-220 nm, when the content of the compound of formula A is calculated using 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 a fourth aspect, the present invention provides a method for preparing the above-mentioned pharmaceutical preparation, which comprises 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 comprises a tablet preparation method well known in the art, which comprises mixing the composition with suitable excipients and directly tableting, or tableting after dry, wet or fluidized bed granulation, with a tableting pressure ≤20kN, and pressing into a round tablet or irregularly shaped solid preparation.

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

[0241] In some embodiments of the fifth aspect, the detection method further comprises detection of the content of other compounds of Formula B, Formula C, Formula D, Formula E, Formula F, Formula G and Formula H listed in the present application; for example, the detection method for related substances of the product recorded in the European Pharmacopoeia.

[0242] In some embodiments of the fifth aspect, the detection method further comprises the European Pharmacopoeia analysis method for related substances of eplerenone, chromatographic conditions: chromatographic column: octadecylsilane-bonded silica gel chromatographic column, 4.6 mm x 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); gradient elution program as shown in Table 1: Table 1

[0243] In the sixth aspect, the present application provides use of the above-mentioned composition or the above-mentioned pharmaceutical preparation in the preparation of a medicament 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. For 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 application provides use of a compound of Formula A as a control in the content analysis or quality control of a composition containing eplerenone or a pharmaceutical preparation thereof. In the above-mentioned use, the content of the compound of Formula A in the composition containing eplerenone is preferably greater than 0 wt% and less than 0.1 wt%. In the content analysis or quality control, the detection wavelength used in the detection method is 205-220 nm.

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

[0246] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, thereby obtaining various preferred examples of the present application.

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

[0248] The positive progress of the present invention is that: the present invention provides a stable pharmaceutical composition of high-purity eplerenone and a compound of formula A; at the same time, the present invention combines the synthesis route to improve the refining process, thereby controlling the content of the compound of formula A. When the content of the compound of formula A is below the set control limit, common related clinical serious adverse reactions can be reduced, thereby ensuring the quality and safety of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0249] Figure 1 Is the ultraviolet spectrum of the compound of formula A; Figure 2 is the LC-MS mass spectrum of the compound of formula A; Figure 3 is the single crystal diffraction pattern of the compound of formula A; Figure 4 This is the powder XRPD pattern of the compound of formula A.

[0250] Figure 5 This is a graph showing the related substances of the compound of formula A in the crude eplerenone product of Example 2 by HPLC. The CAV34-IMP12 marked in the figure is the compound of formula A in the present invention.

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

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

[0253] Figure 8 The graph shows the drug concentration-inhibition rate curve of the compound of formula A and different hormone receptors.

[0254] Figure 9 This is a HPLC detection chart of related substances of the compound of formula A in the primary refined product of eplerenone in Example 3. The CAV34-IMP12 marked in the figure is the compound of formula A in the present invention.

[0255] Figure 10 This is a HPLC detection chart of related substances of the compound of formula A in the secondary refined product of eplerenone in Example 3. The CAV34-IMP12 marked in the figure is the compound of formula A in the present invention.

[0256] Figure 11 This is a HPLC detection chart of related substances of the compound of formula A in the secondary refined product of eplerenone in Example 4. The CAV34-IMP12 marked in the figure is the compound of formula A in the present invention.

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

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

[0259] Figure 14 This is a graph showing the related substances detected by HPLC of the compound of formula A in the eplerenone reference preparation (batch number: N56748) in Example 12. The CAV34-IMP12 marked in the figure is the compound of formula A.

[0260] Figure 15 This is the XRPD pattern of the crude eplerenone product of Example 2 containing 0.82% of the compound of formula A.

[0261] Figure 16 This is the detection chart of the refined eplerenone product of Example 3 using the EP Pharmacopoeia method HPLC (240 nm). DETAILED DESCRIPTION

[0262] The present invention is further described below by way of examples. For those skilled in the art, based on the teachings of the present invention, equivalent replacement improvements made to the following examples using existing technologies still fall within the scope of protection of the present invention.

[0263] abbreviation ESI electrospray TMS Tetramethylsilane LC-MS high pressure liquid chromatography-mass spectrometry In an embodiment of the present invention: The high pressure liquid chromatograph is Agilent 1200 or 1260.

[0264] The mass spectrometer was Agilent 6460 MS, and the ion source was ESI.

[0265] The NMR instrument is a German Bruker AVANCE-400MHz NMR instrument. Solvent: DMSO-d6; Internal standard: TMS.

[0266] Single crystal X-ray diffractometer: Single crystal X-ray diffraction surface detector Nonius cad4; temperature: 20℃; Detection sample characteristics and state: particles.

[0267] The X-ray powder diffractometer was a Bruker D8 Advance ECO X-ray diffractometer using a Cu Kα target, a wavelength of 1.5418 Å, a tube voltage of 40 kV and a current of 25 mA, a divergence slit of 1.0 mm, a front Soller slit of 4.1°, and a rear Soller slit of 2.5°. The detector was a LYNXEYE_XE_T (1D mode).

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

[0269] ESI: [M+Na]+ 453.10 ( Figure 2 ) 1 H-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 C- 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] 100 mg of compound A was dissolved in 5 ml of dichloromethane and 5 ml of butanone, and filtered. The filtrate was transferred to a beaker and a single crystal was grown by evaporation. The XRD diffraction of the single crystal is shown in FIG. Figure 3 . XRPD powder diffraction see Figure 4 .

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

[0272] Method for detecting the content of the compound of formula A in the composition (or raw material drug) of eplerenone: The compound of formula A is determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512).

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

[0274] Control solution: Take the compound of formula A control product, accurately weigh, dissolve and quantitatively dilute with water-acetonitrile (50:50) to prepare a solution containing about 1.5 μg per 1 ml.

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

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

[0277] Results calculation: in the chromatogram of the test solution, if there is a chromatographic peak with the same retention time as the peak of the compound of formula A in the chromatogram of the control solution, calculate by the external standard method with peak area.

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

[0279] Example 2

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

[0281] Purified according to the method of Example 47A of WO98 / 25948 To 50g of the crude eplerenone, add 525ml of butanone, heat and dissolve, then distill off 262ml of butanone. Cool to 50°C and stir for 1 hour, then cool to 20-25°C and stir for 2 hours. Filter with suction and dry the filter cake. This yields 44g of (unsolvated) purified eplerenone. Yield: 88%. Formula A: 0.42%, Formula C: 0.19%, eplerenone: 99.32%.

[0282] To 40g of the primary refined eplerenone obtained above, 420ml of butanone was added, the mixture was heated to dissolve, filtered, and 210ml of butanone was distilled off the filtrate. The mixture was cooled to 50°C and stirred for 1 hour, then cooled to 20-25°C and stirred for 2 hours. The mixture was filtered with suction and the filter cake dried. 36.8g of the (unsolvated) secondary refined eplerenone was obtained. Yield: 92%. Compound A: 0.22%, Compound C: 0.07%, eplerenone: 99.63%. Compounds B, D, E, F, G, and H were not detected.

[0283] Comparative Example 1 Using the method described in Example 3 of CN113173968A, 5g of crude eplerenone (containing 0.82% of Compound A), 60mL of anhydrous ethanol, and 10ml of purified water were added to a reaction flask. The mixture was heated at 75°C for 20 minutes, cooled to 30°C, and stirred for 4 hours. The mixture was then filtered, and the filter cake was rinsed with anhydrous ethanol and dried under vacuum at 55°C for 12 hours. This yielded 4.5g of eplerenone, a 90% yield. The HPLC method of the present invention was used to detect 0.72% of Compound A. This method has little ability to remove Compound A.

[0284] Comparative Example 2 Using the method described in Example 2 of CN104844681B, 5g of crude eplerenone (containing 0.82% of Compound A) and 120ml of 1,2-dimethoxyethane were added to a reaction flask. The mixture was refluxed to dissolve, cooled to -5-0°C, and stirred for 10 hours. The mixture was filtered, and the filter cake was vacuum-dried at 60°C for 6 hours to obtain 3.35g of refined eplerenone, with a yield of 67%. The HPLC method of the present invention was used to detect 0.59% of Compound A. This method has poor scavenging ability for Compound A.

[0285] Comparative Example 3 Using the method described in Example 3 of CN104262450A, 5g of crude eplerenone (containing 0.82% of Compound A) and 47.5ml of butanone were added to a reaction flask. The mixture was refluxed to dissolve, cooled to room temperature, stirred for 6 hours, filtered, and dried to obtain 4.3g of refined eplerenone (yield: 86%). The HPLC method of the present invention was used to detect 0.44% of Compound A. However, the residual amount of Compound A was still relatively high.

[0286] Comparative Example 4 Solubility test results of the compound of formula A and the compound of formula C in butanone at 0°C and 25°C.

[0287] Chromatographic conditions: 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: 210nm Injection volume: 2 μL Determination process: Take appropriate amount of each sample, add appropriate amount of butanone solvent, and test its saturated solubility at 0℃ and 25℃ respectively.

[0288] Table 2

[0289] Example 3 The crude eplerenone of 12.7 Kg from Example 2 was dissolved in dichloromethane 50 L and cyclohexane 50 L was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried. The dried filter cake was dissolved in dichloromethane 50 L and cyclohexane 50 L was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried to obtain the first purified eplerenone (non-solvated) 9.4 Kg. Yield: 74%. Compound of Formula A: 0.18%.

[0290] The first purified eplerenone of 9.21 Kg from above was dissolved in dichloromethane 65 L and cyclohexane 97 L was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried to obtain the second purified eplerenone (non-solvated) 8.41 Kg. Yield: 91.3%. Compound of Formula A: 0.09%, eplerenone 99.85%, Compound of Formula C: 0.03%, Compound of Formula G: 0.01%, Compounds of Formulae B, D, E, F and H were not detected. The purified eplerenone from Example was compared using the EP Pharmacopoeia and the test method of the present application, respectively, and the results are shown in Table 3 below.

[0291] Table 3

[0292] Example 4 The first purified eplerenone of 8.75 Kg from Example 3 was dissolved in dichloromethane 61 L and cyclohexane 92 L was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried to obtain the second purified eplerenone (non-solvated) 7.59 Kg. Yield: 86.7%. Compound of Formula A: 0.08%, eplerenone 99.87%, Compound of Formula C: 0.03%, Compound of Formula G: 0.01%, Compounds of Formulae B, D, E, F and H were not detected.

[0293] The second purified eplerenone of 20 g from above was dissolved in dichloromethane 140 ml and cyclohexane 210 ml was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried to obtain the third purified eplerenone (non-solvated) 18 g. Yield: 90%. Compound of Formula A: 0.01%, eplerenone 99.90%, Compounds of Formulae B, C, D, E, F, G and H were not detected.

[0294] The third purified eplerenone of 18 g from above was dissolved in dichloromethane 126 ml and cyclohexane 189 ml was added. The mixture was stirred at room temperature for 1 hour, filtered and the filter cake was dried to obtain the fourth purified eplerenone (non-solvated) 16.4 g. Yield: 91%. Compound of Formula A: 0.003%, eplerenone 99.99%, Compounds of Formulae B, C, D, E, F, G and H were not detected.

[0295] Example 5: Stability Study The eplerenone product prepared in Example 3 was subjected to 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 guidelines of the Chinese Pharmacopoeia "9001 Stability of Drug Substances and Preparations". The results showed that the content of the compound of formula A remained stable without significant changes.

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

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

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

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

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

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

[0302] Calculation of results: If there is a chromatographic peak in the chromatogram of the test solution with the same retention time as the peak of compound A in the chromatogram of the reference solution, calculate the peak area according to the external standard method.

[0303] The calculation formula is as follows: Formula A content (%) = (A 样 ×C 对 ) / (A 对 ×C 样 ) × 100% Where: A 样 is the peak area of ​​formula A in the chromatogram of the test solution A 对 Area of Formula A peak in the chromatogram of the test solution C 对 Concentration of Formula A in the test solution (mg / ml) C 样 Concentration of eplerenone in the test solution (mg / ml) The results of the determination showed that the content of Formula A compound in the batches of "INSPRA™" tablets was between 0.17% and 0.21%. The details are shown in Table 4 below: Table 4 Results of detection of Formula A compound in INSPRA™ tablets

[0304] From the perspectives of drug safety and effectiveness, it is necessary to carefully evaluate the influence of other related substances inherent in eplerenone, in addition to those reported in the European Pharmacopoeia, on the quality of the drug and the safety and effectiveness of the drug.

[0305] Example 7 Preparation of eplerenone tablets of the present application Active ingredient: eplerenone 2500g Inactive ingredient: anhydrous lactose 3200g Magnesium stearate 50g Microcrystalline cellulose 1800g Croscarmellose sodium 500g Hydroxypropyl methylcellulose 250g Sodium lauryl sulfate 120g Talc 80g Film coating premix (Klcom Ora-Tab 15B 130004) 260g The prescription was designed according to the batch size of 100000 tablets.

[0306] Preparation process: the prescription amount of eplerenone drug substance obtained in Example 3 was mixed with anhydrous lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl sulfate, croscarmellose sodium, and talc in a three-dimensional mixer to obtain uniform mixture. Dry granulation parameters were set to prepare dry granules, and magnesium stearate was added to the mixture to obtain tablets. The coating liquid was prepared according to the solid content of 10%~20%, and the coating weight was increased to 2%~6% to obtain eplerenone tablets. The content of Formula A compound in the eplerenone tablets was 0.09wt%, the content of eplerenone was 99.85wt%, the content of Formula C compound was 0.03wt%, the content of Formula G compound was 0.02wt%, and the contents of Formula B, D, E, F, and H compounds were not detected (the detection limit was less than 0.003wt%).

[0307] Example 8 Preparation of eplerenone coated tablets of the present invention Active ingredient: Eplerenone 2500g Inactive ingredients: Anhydrous lactose 3200g Magnesium stearate 50g 1800g microcrystalline cellulose Croscarmellose sodium 500g Hydroxypropyl methylcellulose 250g Sodium lauryl sulfate 120g 80g talcum powder Film coating premix (Colorcon gastric soluble Opadry 15B130004) 260g The prescription is designed based on a batch size of 100,000 tablets.

[0308] Preparation process: The eplerenone API obtained in Example 4 (secondary refined product) was mixed with anhydrous lactose, microcrystalline cellulose, hypromellose, sodium lauryl sulfate, croscarmellose sodium, and talc in a three-dimensional mixer. Dry granulation parameters were set to produce dry granules, which were then added with magnesium stearate. After mixing thoroughly, tablets were compressed. Purified water was added to a coating suspension with a solids content of 10% to 20%, and the coating weight gain reached 2% to 6%. Eplerenone tablets were obtained. The eplerenone tablets contained 0.08 wt% of the compound of formula A, 99.87 wt% of eplerenone, 0.03 wt% of the compound of formula C, and 0.02 wt% of the compound of formula G. Compounds of formulas B, D, E, F, and H were not detected (detection limits were all less than 0.003 wt%).

[0309] Example 9: Stability Study Stability of the compound of formula A in the tablets of Example 8: The stability of the compound of formula A in the tablets was investigated in accordance with the guidelines of the Chinese Pharmacopoeia "9001 Stability of APIs and Preparations". Under 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 showed that the content of the compound of formula A in the composition remained stable without significant changes.

[0310] Example 10: In vitro hormone receptor binding assay Three test substances were selected: eplerenone, compound of formula A, and spironolactone, and their binding abilities to different hormone receptors were tested. These included mineralocoticoid receptors (MR), androgen receptors (AR), and estrogen receptors (ER).

[0311] Measurement process: 1. Stability cell line (MR, AR, ER) Day 1: Compound treatment and cell seeding a) Antagonist assay, 5 mL of compound was transferred to the assay plate followed by 5 mL of agonist (final agonist concentration = EC 80 ).

[0312] b) Prepare cell culture media: 89% DMEM media without phenol red, 10% charcoal-stripped fetal bovine serum, and 1% glutamine.

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

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

[0315] e) Add 3 mL of pre-warmed trypsin to the culture flask, shake the flask several times before and after, 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 and observe the cells under a microscope. When >90% of the cells have detached from the flask walls, resuspend the cells with 10 mL of pre-warmed media and transfer the cell suspension to a 50 mL centrifuge tube.

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

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

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

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

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

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

[0324] Test results: (1) Eplerenone has a strong binding affinity with mineralocorticoid receptors (IC 50 =2593nM), while within the tested concentration range, eplerenone showed no binding affinity to either androgen receptors or estrogen receptors (IC 50 >10000nM).

[0325] (2) Spironolactone showed strong binding affinity to mineralocorticoid receptors, estrogen receptors and androgen receptors, IC 50 The concentrations of 264.2, 344, and 116.6 nM, respectively, but its selectivity for binding to these three hormone receptors is poor.

[0326] (3) The compound of formula A showed a certain binding affinity to the mineralocorticoid receptor, estrogen receptor and androgen receptor, and had the strongest binding affinity to the estrogen receptor (IC 50 =615.6nM), followed by androgen (IC 50 =1889nM) and mineralocorticoids (IC 50 =4892nM).

[0327] The above research results show that eplerenone exhibits highly selective mineralocorticoid receptor binding, while the selectivity of the formula A compound is poor, and it has a stronger ability to bind to estrogen and androgen than to mineralocorticoids.

[0328] Table 5 IC50 of the three test substances on different hormone receptors 50 (nM)

[0329] Example 11: Clinical study of eplerenone tablets of the present invention The eplerenone tablets of the present invention are an investigational drug, prepared according to the method of Example 8, and contain 0.08 wt % of the compound of Formula A. The present inventors conducted a multicenter, randomized, double-blind, sham, positive-controlled study in China (Clinical 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 in this clinical study. Clinical trial information is shown in Table 6 below.

[0330] Table 6

[0331]

[0332]

[0333] Clinical study results show that the eplerenone tablet study group of the present invention did not experience adverse reactions such as increased blood potassium; and did not experience hormone-related adverse reactions such as male breast development, impotence, female vaginal bleeding, menstrual abnormalities, and the like.

[0334] The public review reports for INSPRA™'s marketing approval in the United States and Japan show that the most common typical adverse reactions in clinical studies are adverse reactions and events characterized by increased blood potassium, increased liver enzymes, male breast development, male impotence, and female breast pain, as shown in Table 7.

[0335] Table 7

[0336] Note*: Search the FDA-approved drug database (Drugs@FDA: FDA-Approved Drugs) using the trade name "INSPRA" of eplerenone as the keyword. URL: https: / / www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=BasicSearch.process. This search retrieves the review reports related to the clinical studies of this product, including: (1) Medical Review(s), which is divided into eight parts (Part 1 to Part 8); and (2) INSPRA product insert.

[0337] Eplerenone is a highly selective mineralocorticoid receptor antagonist that exerts its clinical efficacy by specifically binding to the aldosterone receptor. However, in multiple international RCTs conducted by the original developer, Pfizer, typical adverse reactions have been reported for this product, as shown in the table above. Common adverse reactions in men include breast development, swelling, and impotence; while common adverse reactions in women include menstrual abnormalities and vaginal bleeding. These adverse reactions suggest that Pfizer's eplerenone binds to hormone receptors other than the mineralocorticoid receptor (such as the androgen receptor and progesterone receptor), triggering corresponding adverse reactions.

[0338] Conclusion: The clinical study results confirm that the preparation product of the present invention, which controls the compound of formula A associated with this product, has better clinical safety than the safety reported for 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 No.: N56748 containing 0.21 wt% of the compound of formula A) The beneficial effects of the present invention were further demonstrated through human bioequivalence studies. A large amount of valid and reliable experimental data was obtained, and the research contents are as follows: A randomized, open-label, two-sequence, two-period, double-crossover bioequivalence study was conducted in healthy Chinese volunteers after a single oral administration of 50 mg / tablet of the eplerenone tablets of the present invention and 50 mg / tablet of GD Earle Division of Pfizer Inc. "INSPRA®" (clinical study registration number: CTR20180312).

[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 "INSPRA™" contained 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 the equivalence study: The bioavailability of the test preparation was equivalent to that of the reference preparation.

[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 determined to be certain, probable, or possible.

[0346] The onset or worsening time of an adverse event is from the beginning of the current treatment cycle to the next treatment cycle, which is defined as an adverse event of the medication in this cycle.

[0347] Table 11 Summary of adverse events

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

[0349] Table 12 Severity of adverse events

[0350] The onset or worsening time of an adverse event is from the beginning of the current treatment cycle to the next treatment cycle, which is defined as an adverse event of the medication in this cycle.

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

[0352] Summary: Based on the adverse reactions observed in the human bioequivalence study, the adverse reactions were significantly greater in the formulation containing 0.21wt% of the compound of Formula A compared to the formulation containing 0.09wt% of eplerenone. The specific adverse events suggest that the reference formulation may have had greater toxicity than the test formulation.

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 no more than 0.1 wt %: Compound of formula A.

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

3. The composition according to claim 1, characterized in that The eplerenone content is 98.7 wt % to 99.9 wt %.

4. The composition according to claim 1, characterized in that 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, characterized in that 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 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 Among them, the content of the compound of formula B is 0wt% to 0.05wt%, the content of the compound of formula C is 0wt% to 0.05wt%, the content of the compound of formula D is 0wt% to 0.05wt%, the content of the compound of formula E is 0wt% to 0.05wt%, the content of the compound of formula F is 0wt% to 0.05wt%, the content of the compound of formula G is 0wt% to 0.05wt% and the content of the compound of formula H is 0wt% to 0.05wt%; and 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 0wt% to 0.10wt%.

7. An eplerenone composition, characterized in that The composition comprises eplerenone and a compound of formula A, wherein the content of eplerenone is 98.5wt% to 99.9wt%, and the content of the compound of formula A is no more than 0.1wt%; Compound of formula A The preparation method of the composition comprises a step of selective oxidation using an ene ester, and at least two purification steps; the ene ester is 17α-hydroxy-3-oxopregnano-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester, γ-lactone; The refined solvent is a mixed solvent of dichloromethane and cyclohexane.

8. The method for preparing the composition according to any one of claims 1 to 7, characterized in that: include: The enester is dissolved in dichloromethane, and trichloroacetamide, dipotassium hydrogen phosphate, and 30% hydrogen peroxide are added to carry out oxidation reaction to obtain eplerenone product, which is then post-treated to obtain non-solvated crude eplerenone; The enester is 17α-hydroxy-3-oxopregna-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester, γ-lactone; and The crude eplerenone is refined with a refining solvent for more than two times to obtain the composition, wherein 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 refined 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 refined 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 20wt%-35wt%, and the content of the compound of formula A in the pharmaceutical preparation is greater than 0wt% and less than 0.1wt%. 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, and film coating materials; The components of the pharmaceutical preparation are calculated by weight percentage and include: eplerenone accounting for 10%-35%; filler accounting for 50%-80%, which can be selected from a combination of one or more of lactose, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts, sorbitol, glycine, calcium sulfate and mannitol; lubricant accounting for 0.1%-5%, which can be selected from one or more of magnesium stearate, calcium stearate, stearic acid, sodium fumarate stearate, talc and micro-powdered silica gel; disintegrant accounting for 3%-10%, which can be selected from one or more of starch, cross-linked polyvinylpolypyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose and cross-linked polyvinylpyrrolidone; binder accounting for 0.5%-5%, which can be selected from one or more of gelatin slurry, starch slurry, polyvinylpyrrolidone, syrup, gum arabic and cellulose and its derivatives; wetting agent accounting for 0.5%-5%, which can be selected from sodium lauryl sulfate.

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

17. The method for preparing the pharmaceutical preparation according to any one of claims 12 to 16, characterized in that: The method comprises mixing the eplerenone with 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; wherein the detection wavelength is 195-220nm, Compound of formula A.

19. Use of a compound of formula A in content detection or quality control in a composition containing eplerenone or a pharmaceutical preparation thereof; 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 medicament for treating hypertension, improving left ventricular systolic dysfunction after acute myocardial infarction, and / or treating congestive heart failure.

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