A pharmaceutical composition of ezetimibe simvastatin

Abstract

This invention obtains a stable ezetimibesimvastatin pharmaceutical composition by combining β-cyclodextrin and sulfite antioxidants. This pharmaceutical composition has better stability and satisfactory dissolution effect than the reference formulation. Furthermore, the preparation method of the ezetimibesimvastatin pharmaceutical composition of this invention is simple, the process does not require the use of organic solvents, and no special treatment is required, making it very suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an ezetimibesimvastatin pharmaceutical composition and its preparation method. Background Technology

[0002] Cardiovascular and cerebrovascular diseases are among the most common and serious health threats to middle-aged and elderly people. Hyperlipidemia leading to atherosclerosis, and further causing hypertension, coronary heart disease, and other cardiovascular and cerebrovascular diseases, is a major cause of death among this population. Lipid-lowering drugs can reduce the incidence and mortality of these diseases, playing a positive role in the prevention and treatment of cardiovascular diseases.

[0003] Ezetimibe is a selective cholesterol absorption inhibitor that primarily blocks the exogenous absorption of cholesterol. It attaches to the brush border of the small intestinal villi, inhibiting cholesterol absorption and thus reducing the transport of cholesterol from the small intestine to the liver. This mechanism of action increases the clearance of cholesterol from the blood by reducing cholesterol storage in the liver, and complements the effects of HMG-CoA reductase inhibitors. Simvastatin belongs to the class of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors. It inhibits cholesterol biosynthesis in the early stages, lowers very low-density lipoprotein (VLDL) and triglycerides (TG), and increases high-density lipoprotein (HDL). Simvastatin is highly effective and has few side effects, making it one of the most commonly used lipid-lowering drugs worldwide.

[0004] Ezetimibe and simvastatin tablets are a combination drug developed by Merck & Co., primarily used to treat primary hypercholesterolemia and homozygous familial hypercholesterolemia (HoFH). It belongs to the class of lipid-lowering drugs with complementary mechanisms of action of ezetimibe and simvastatin. It mainly works by inhibiting cholesterol absorption and synthesis, thereby reducing plasma levels of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and non-high-density lipoprotein cholesterol, while simultaneously increasing high-density lipoprotein cholesterol levels.

[0005] In the combination preparation of ezetimibe and simvastatin tablets, both active ingredients ezetimibe and simvastatin are low-soluble drugs, almost insoluble in water. Moreover, the active ingredient simvastatin is prone to oxidative degradation in high-temperature environments, producing many degradation impurities, which leads to instability of the active ingredient. Therefore, the combination preparation of ezetimibe and simvastatin has the problems of low dissolution and poor stability.

[0006] To address the aforementioned technical issues, existing technologies have disclosed the use of butylated hydroxyanisole (BHA) and propyl gallate as antioxidants for ezetimibe and simvastatin to solve their drug stability problems. However, BHA can accumulate in human organs through the skin, adversely affecting human health. Furthermore, both BHA and propyl gallate must be dissolved in ethanol before addition, and the introduction of organic solvents during the process poses difficulties in ensuring process safety and product quality. In addition, existing technologies have also disclosed the use of sodium citrate and sodium ascorbate to improve the stability of the ezetimibe-simvastatin drug composition, but this process still presents challenges related to process safety and product quality due to the introduction of high concentrations of organic solvents.

[0007] In addition to the above, existing technologies also include preparing ezetimibesimvastatin into special dosage forms or using hot melt extrusion and coating technologies, but these all suffer from complex processes, high energy consumption, and are unsuitable for industrial production. Therefore, it is urgent and necessary to explore a safe, effective, stable, reliable, and industrially suitable ezetimibesimvastatin pharmaceutical composition and its preparation method. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention, through extensive experimental screening of excipients, has yielded a stable pharmaceutical composition for ezetimibesimvastatin. This pharmaceutical composition does not require the use of antioxidants that may have adverse effects on human health, and the process does not involve high concentrations of organic solvents. The pharmaceutical composition obtained by this invention exhibits stable quality, rapid dissolution, and a simple preparation process, making it highly suitable for industrial production.

[0009] The technical solution of this invention is implemented as follows:

[0010] This invention provides a stable pharmaceutical composition of ezetimibe / simvastatin, comprising ezetimibe, simvastatin, β-cyclodextrin, a sulfite antioxidant, and pharmaceutically acceptable excipients. This invention significantly improves the stability of the ezetimibe / simvastatin pharmaceutical composition through the combined action of β-cyclodextrin and the sulfite antioxidant, achieving a stable ezetimibe / simvastatin pharmaceutical composition with satisfactory dissolution.

[0011] In the ezetimibe / simvastatin pharmaceutical composition of the present invention, the weight ratio of simvastatin to β-cyclodextrin is 1:4 to 8, preferably 1:5 to 7; the weight ratio of simvastatin to sulfite antioxidant is 1:0.001 to 0.005, preferably 1:0.002 to 0.004.

[0012] In the ezetimibesimvastatin pharmaceutical composition of the present invention, the sulfite antioxidant is selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; preferably, the sulfite antioxidant is selected from sodium thiosulfate and sodium metabisulfite.

[0013] In the ezetimibesimvastatin pharmaceutical composition of the present invention, the pharmaceutically acceptable excipients include one or more of fillers, disintegrants, binders or lubricants.

[0014] In one specific embodiment of the present invention, the pharmaceutical composition comprises the following components in the indicated weight percentages: ezetimibe 1-12%, simvastatin 5-15%, β-cyclodextrin 40-80%, sulfite antioxidant 0.01-0.05%, filler 10-30%, disintegrant 1-5%, binder 1-3%, and lubricant 0.5-2%.

[0015] Preferably, the pharmaceutical composition comprises the following components in the indicated weight percentages: 5% ezetimibe, 10% simvastatin, 63.5% β-cyclodextrin, 0.025% sulfite antioxidant, 15% filler, 3% disintegrant, 2% binder, and 1.5% lubricant.

[0016] Furthermore, in the pharmaceutical composition, the sulfite antioxidant is selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; the filler is selected from one or more of sorbitol, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose; the binder is selected from one or more of povidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

[0017] The ezetimibesimvastatin pharmaceutical composition of the present invention is preferably prepared as a tablet.

[0018] This invention also discloses a method for preparing ezetimibesimvastatin tablets, the specific steps of which are as follows:

[0019] (1) Mixing: Mix simvastatin, β-cyclodextrin and sulfite antioxidants evenly and set aside;

[0020] (2) Wet granulation: The mixture from step (1) is placed in a high-efficiency wet granulator with ezetimibe, filler, disintegrant and binder, mixed, and then an appropriate amount of purified water is added to stir and shear to granulate. After drying, the granules are sized for later use.

[0021] (3) Mixing: Mix the granules after granulation in step (2) with the lubricant until homogeneous;

[0022] (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

[0023] The beneficial effects of this invention are:

[0024] This invention, through the combined use of β-cyclodextrin and sulfite antioxidants, significantly enhances the stability of the active ingredient simvastatin, resulting in a stable ezetimibe-simvastatin pharmaceutical composition. Furthermore, the combined use of β-cyclodextrin and sulfite antioxidants provides a superior stabilizing effect compared to using β-cyclodextrin or sulfate antioxidants alone, and also surpasses the stabilizing effect of other antioxidants in the prior art.

[0025] Furthermore, the ezetimibesimvastatin pharmaceutical composition obtained by combining β-cyclodextrin and sulfite antioxidants of the present invention has better stability and satisfactory dissolution effect than the reference formulation; and the preparation method of the ezetimibesimvastatin pharmaceutical composition of the present invention is simple, the process does not require the use of organic solvents and does not require special treatment, making it very suitable for industrial production. Detailed Implementation

[0026] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific implementation examples. However, those skilled in the art should recognize that the present invention is not limited to these embodiments.

[0027] Example 1

[0028]

[0029] Preparation method:

[0030] (1) Mixing: Mix simvastatin, β-cyclodextrin and sodium thiosulfate evenly and set aside;

[0031] (2) Wet granulation: The mixture from step (1) is placed in a high-efficiency wet granulator with ezetimibe, microcrystalline cellulose, croscarmellose sodium cellulose and hydroxypropyl methylcellulose. Then purified water is added, stirred and sheared to granulate. After drying, the granules are sized for later use.

[0032] (3) Mixing: Mix the granules after granulation in step (2) with magnesium stearate evenly;

[0033] (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

[0034] Example 2

[0035]

[0036]

[0037] Preparation method:

[0038] (1) Mixing: Mix simvastatin, β-cyclodextrin and sodium metabisulfite evenly and set aside;

[0039] (2) Wet granulation: The mixture from step (1) is placed in a high-efficiency wet granulator with ezetimibe, sorbitol, crospovidone and povidone and mixed; then purified water is added, stirred and sheared to granulate, dried and granulated for later use.

[0040] (3) Mixing: Mix the granules after granulation in step (2) with stearic acid until homogeneous;

[0041] (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

[0042] Example 3

[0043]

[0044] Preparation method:

[0045] (1) Mixing: Mix simvastatin, β-cyclodextrin and sodium sulfite evenly and set aside;

[0046] (2) Wet granulation: The mixture from step (1) is placed in a high-efficiency wet granulator with ezetimibe, pregelatinized starch, sodium carboxymethyl starch and hydroxypropyl cellulose and mixed; then purified water is added, stirred and sheared to granulate, dried and granulated for later use.

[0047] (3) Mixing: Mix the granules after granulation in step (2) with talc powder evenly;

[0048] (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

[0049] Example 4

[0050]

[0051]

[0052] Preparation method:

[0053] (1) Mixing: Mix simvastatin, β-cyclodextrin and sodium bisulfite evenly and set aside;

[0054] (2) Wet granulation: The mixture from step (1) is mixed with ezetimibe, lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in a high-efficiency wet granulation machine; then purified water is added, stirred and sheared to granulate, and dried and granulated for later use.

[0055] (3) Mixing: Mix the granules after granulation in step (2) with sodium stearoyl fumarate until homogeneous;

[0056] (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

[0057] Examples 5-9

[0058]

[0059] The preparation methods of Examples 5-9 are the same as those of Example 1, except that the weight ratio of simvastatin to β-cyclodextrin and the weight ratio of simvastatin to sodium thiosulfate in the prepared ezetimibesimvastatin tablets are different.

[0060] Comparative Example

[0061]

[0062]

[0063] Comparative Example 1 only added sulfite antioxidants, without β-cyclodextrin, and used lactose instead; Comparative Example 2 only added β-cyclodextrin, without any antioxidants; Comparative Example 3 added β-cyclodextrin, along with propylparaben and butylated hydroxyanisole antioxidants; and Comparative Example 4 added β-cyclodextrin, along with sodium ascorbate and sodium citrate antioxidants. The reference formulation did not add β-cyclodextrin, but used lactose, and added propylparaben and butylated hydroxyanisole antioxidants, as well as citric acid as an antioxidant synergist.

[0064] The preparation methods of Comparative Examples 1-4 can be referred to Example 1. Those skilled in the art can make slight adjustments to the preparation process of the ezetimibesimvastatin drug composition in Comparative Examples 1-4 according to the properties of different antioxidants, including the selection of ethanol solvent.

[0065] Stability test

[0066] The ezetimibe / simvastatin drug formulations of Examples 1-9 and Comparative Examples 1-5 were used to investigate their product quality stability at room temperature for 0 days, at a high temperature of 60°C for 30 days, and at 40°C / RH 75% for 60 days. The main indicator of simvastatin quality stability was related substances, and the detection method was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix VD). The results are shown in Tables 1-3. RRT0.25, RRT0.47, RRT0.48, and RRT0.62 represent other oxidative degradation impurities of simvastatin, and are marked by their peak positions in the chromatogram.

[0067] Table 1. Results of related substances investigation (0 days, simvastatin oxidative degradation products)

[0068]

[0069]

[0070] Table 2. Results of related substance investigation (Simvastatin oxidative degradation products at high temperature (60℃, 30 days)

[0071]

[0072] Table 3. Results of related substances investigation (40℃ / RH 75%, 6 months, simvastatin oxidative degradation products)

[0073]

[0074]

[0075] From the results of the stability tests in Tables 1-3 above, we can see that:

[0076] (1) The ezetimibe-simvastatin drug preparations prepared in Examples 1-9 were placed at 0 days and 60°C for 30 days, and at 40°C and RH 75% for 6 months. The growth levels of related substances in simvastatin were comparable and showed no significant difference. All were far below the impurity limit requirements, indicating that the combined use of β-cyclodextrin and sulfite antioxidants can effectively improve the stability of the product, especially the stability of simvastatin in the compound preparation. Among them, the growth levels of related substances in simvastatin in Examples 1, 2 and 5-9 were slower than those in Examples 3 and 4, indicating that the drug preparations with a weight ratio of simvastatin to β-cyclodextrin of 1:5 to 7 and a weight ratio of simvastatin to sulfite antioxidant of 1:0.002 to 0.004 have better stability.

[0077] (2) In Comparative Example 1, only sulfite antioxidants were added, but no β-cyclodextrin was added, and lactose was used instead; in Comparative Example 2, only β-cyclodextrin was added, but no antioxidants were added. The growth level of simvastatin-related substances in the ezetimibesimvastatin drug formulation obtained in Comparative Example 2 was the fastest among all samples, indicating that only when β-cyclodextrin and sulfite antioxidants are used in combination can the ezetimibesimvastatin drug formulation achieve better product stability.

[0078] (3) In Comparative Example 3, β-cyclodextrin was added, along with propylparaben and butylated hydroxyanisole antioxidants. In Comparative Example 4, β-cyclodextrin was added, along with sodium ascorbate and sodium citrate antioxidants. The growth level of simvastatin-related substances in the resulting ezetimibe-simvastatin drug formulation was significantly lower than that without antioxidants (Example 2). However, the control level of simvastatin-related substances in the compound formulation was comparable to or slightly worse than that of the reference formulation. It was significantly worse than the control level of related substances in Examples 1-9 of this application, especially Examples 1, 2 and 5-9 of this application.

[0079] (4) Compared with the reference formulation, the ezetimibesimvastatin drug formulations of Examples 1-9 have better control over the growth of simvastatin-related substances, indicating that the ezetimibesimvastatin drug formulations obtained by using β-cyclodextrin and sulfite antioxidants in combination have better product stability.

[0080] Dissolution test

[0081] Table 4 shows the dissolution results of ezetimibesimvastatin tablets in Examples 1-9 and Comparative Examples 1-5 of this invention. Dissolution test conditions: pH 7.0 + 0.5% SDS solution as the dissolution medium, slurry method; 20 min; the amount of ezetimibesimvastatin tablets dissolved was determined by high performance liquid chromatography.

[0082]

[0083] As shown in Table 3, the ezetimibesimvastatin tablets of Examples 1-9 of this invention have the same dissolution as the reference formulation, with a dissolution rate of more than 85% at 20 minutes. This indicates that the ezetimibesimvastatin drug formulation obtained by combining β-cyclodextrin and sulfite antioxidants of this invention has a dissolution rate that meets the requirements.

[0084] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. An ezetimibesimvastatin pharmaceutical composition, characterized in that, The pharmaceutical composition comprises ezetimibe, simvastatin, β-cyclodextrin, sulfite antioxidants, and pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of simvastatin to β-cyclodextrin in the pharmaceutical composition is 1:4 to 8; preferably 1:5 to 7.

3. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of simvastatin to sulfite antioxidant in the pharmaceutical composition is 1:0.001 to 0.005; preferably 1:0.002 to 0.

004.

4. The pharmaceutical composition according to claim 1, characterized in that, The sulfite antioxidant is selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; preferably, the sulfite antioxidant is selected from sodium thiosulfate and sodium metabisulfite.

5. The pharmaceutical composition according to claim 1, characterized in that, Pharmaceutically acceptable excipients include one or more of fillers, disintegrants, binders, or lubricants.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition comprises the following components in the indicated weight percentages: ezetimibe 1-12%, simvastatin 5-15%, β-cyclodextrin 40-80%, sulfite antioxidant 0.01-0.05%, filler 10-30%, disintegrant 1-5%, binder 1-3%, and lubricant 0.5-2%.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition comprises the following components in the indicated weight percentages: ezetimibe 5%, simvastatin 10%, β-cyclodextrin 63.5%, sulfite antioxidant 0.025%, filler 15%, disintegrant 3%, binder 2%, and lubricant 1.5%.

8. The pharmaceutical composition according to claim 6 or 7, characterized in that, The sulfite antioxidant is selected from one or more of sodium thiosulfate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, and sodium bisulfite; preferably, the sulfite antioxidant is selected from sodium thiosulfate and sodium metabisulfite.

9. The pharmaceutical composition according to claim 6 or 7, characterized in that, The filler is selected from one or more of sorbitol, microcrystalline cellulose, lactose, mannitol, and pregelatinized starch; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose; the binder is selected from one or more of povidone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, talc, and sodium stearoyl fumarate.

10. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition is prepared into tablets.

11. A method for preparing the pharmaceutical composition according to claim 10, characterized in that, The specific steps are as follows: (1) Mixing: Mix simvastatin, β-cyclodextrin and sulfite antioxidants evenly and set aside; (2) Wet granulation: The mixture from step (1) is placed in a high-efficiency wet granulator with ezetimibe, filler, disintegrant and binder, mixed, and then an appropriate amount of purified water is added to stir and shear to granulate. After drying, the granules are sized for later use. (3) Mixing: Mix the granules after granulation in step (2) with the lubricant until homogeneous; (4) Tableting: The mixture from step (3) is tableted using a tablet press to obtain the final product.

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