A pharmaceutical composition for treating cardiovascular diseases and its preparation and use

Abstract

The application discloses a pharmaceutical composition for treating cardiovascular diseases and a preparation method and application thereof. The composition comprises perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and amino-modified silicon dioxide. The amino-modified silicon dioxide is prepared by modifying the surface of silicon dioxide by using 3-aminopropyl triethoxysilane as a coupling agent. The composition of the application can be stored stably without adding an antioxidant, and especially, can avoid or reduce impurities generated by oxidative degradation of perindopril and amlodipine, and improves the safety of the medicine.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a perindopril-amlodipine composition for treating cardiovascular diseases, its preparation method, and its application. Background Technology

[0002] Hypertension is the most common chronic non-communicable disease, causing damage to target organs such as the heart, brain, kidneys, and peripheral blood vessels, seriously affecting human health and quality of life. Studies have shown that most patients require combination therapy with at least two antihypertensive drugs to effectively control their blood pressure. Perindopril is an angiotensin-converting enzyme inhibitor, clinically used for the treatment of cardiovascular diseases, especially showing good efficacy in hypertension and heart failure. Amlodipine is a calcium channel blocker, primarily used to lower blood pressure, and is a first-line drug for the clinical treatment of hypertension. Perindopril-amlodipine tablets have been approved as a fixed-dose combination therapy (SPC), offering comparable safety and significant advantages in efficacy compared to monotherapy. However, because these drugs are for long-term use, requiring larger doses and longer durations of action, the quality requirements for these drugs are becoming increasingly stringent.

[0003] N-nitrosamines are products of the reaction between nitrites and secondary or tertiary amines. They are genotoxic impurities, classified as possible human carcinogens, and are a concern for the pharmaceutical industry and global regulatory agencies. Nitrites are present in many common excipients and water at concentrations of several parts per million (ppm). For example, lactose, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch, polyvinylpyrrolidone (PVP), and crospovidone (PVP) may all carry trace amounts of nitrite impurities. Perindopril and amlodipine both contain secondary amines in their molecular structures. If their combined formulation comes into contact with nitrites in excipients, there is a risk of forming N-nitrosamines; therefore, strict control during the production process is necessary.

[0004] In existing technologies, researchers control the formation of N-nitrosamines in formulations through various means. For example, patent application WO2024165666A1 involves mixing antioxidants with excipients for a period of time before mixing them with the active ingredient, thereby reducing the content of nitrosating agents in the excipients and thus reducing the probability of the active ingredient in the formulation being oxidized into N-nitrosamines. Another example is US patent application US20250127900A1, which directly adds antioxidants to the formulation to prevent the formation of N-nitrosamines. However, adding antioxidants to formulations also presents many problems and risks, such as the risk of sensitization from sulfite antioxidants, the mismatch between the antioxidant mechanism of vitamins and nitrosation reactions, or the need for large amounts of antioxidants due to insufficient antioxidant capacity. Therefore, there is an urgent need to develop a compound formulation that does not require the addition of antioxidants but produces virtually no N-nitrosamines during storage.

[0005] The information in the background section is merely intended to illustrate the general background of the invention and should not be construed as an admission or implication in any way that such information constitutes prior art known to those skilled in the art. Summary of the Invention

[0006] To address at least some of the technical problems in the prior art, the present invention provides a pharmaceutical composition for treating cardiovascular diseases, its preparation method, and its application. Specifically, the present invention includes the following.

[0007] In a first aspect, the present invention provides a pharmaceutical composition for treating cardiovascular diseases, the composition comprising perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and amino-modified silica, wherein the amino-modified silica is prepared by modifying the surface of silica with 3-aminopropyltriethoxysilane as a coupling agent.

[0008] In some embodiments, the composition further comprises at least one or more pharmaceutically acceptable excipients.

[0009] In some embodiments, the weight ratio of the amino-modified silica to the excipient is 0.2-6:100.

[0010] In some embodiments, the weight ratio of the perindopril or a pharmaceutically acceptable salt thereof to the amlodipine or a pharmaceutically acceptable salt thereof to the excipient is 1:7-9.

[0011] In some embodiments, the weight ratio of perindopril or a pharmaceutically acceptable salt thereof to amlodipine or a pharmaceutically acceptable salt thereof is 1:2 to 2:1.

[0012] In some embodiments, the composition is selected from tablets, capsules, granules, and dry suspensions, preferably tablets.

[0013] A second aspect of the present invention provides a method for preparing the composition of the present invention, the method comprising:

[0014] (a) mixing perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, and optionally one or more pharmaceutically acceptable excipients to obtain a mixture, or further forming the mixture into granules; and optionally (b) compressing the mixture or granules into tablets or filling the granules into capsules.

[0015] In some embodiments, the granules are prepared by direct compression, wet granulation, or dry granulation.

[0016] A third aspect of the invention provides the use of the composition of the invention in the preparation of a medicament for the prevention, delay of progression or treatment of hypertension and related diseases in patients.

[0017] The compositions of this invention can maintain storage stability without the addition of antioxidants, and in particular, can avoid or reduce the formation of N-nitrosamines by perindopril and amlodipine, thereby improving drug safety. Detailed Implementation

[0018] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0019] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that the upper and lower limits of the range and each intermediate value between them are specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0020] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0021] The term "excipient" or "pharmaceutically acceptable excipient" refers to a component of the inactive ingredient in a pharmaceutical product, including but not limited to fillers, diluents, disintegrants, glidants, lubricants, surfactants, buffers, isotonic agents, thickeners, pH adjusters, carriers, fillers, and lyophilization protectants and / or combinations thereof. Excipients may also include those used to provide rapid release, immediate release, sustained release, delayed release, pulsatile release, orally disintegrating, etc. Excipients used in the preparation of pharmaceutical compositions are generally safe, non-toxic, and free from biological or other adverse effects, and are suitable for both veterinary and human use.

[0022] The term “hypertension and related diseases” is selected from, but not limited to, the following diseases or conditions: primary hypertension, secondary hypertension, atherosclerosis, arteriosclerosis, coronary artery disease, angina pectoris, myocardial infarction, congestive heart failure, diabetes, diabetic complications, stroke, cirrhosis with ascites, renal impairment or nephrotic syndrome.

[0023] The first aspect of the present invention provides a pharmaceutical composition for treating cardiovascular diseases, the composition comprising perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and amino-modified silica, wherein the amino-modified silica is prepared by modifying the surface of silica with 3-aminopropyltriethoxysilane as a coupling agent.

[0024] In this invention, the pharmaceutically acceptable salt of perindopril is selected from perindopril tert-butylamine salt, perindopril arginine salt, perindopril maleate, perindopril methanesulfonate, perindopril citrate, perindopril tartrate, perindopril malate, or perindopril citrate; preferably perindopril tert-butylamine salt or perindopril arginine salt; more preferably perindopril arginine salt.

[0025] In this invention, the amlodipine or its pharmaceutically acceptable salt is selected from amlodipine maleate, amlodipine mesylate, amlodipine besylate, L-aspartate, amlodipine camphor sulfonate, dextrorotatory camphor sulfonate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentianate, or amlodipine thioctic acid; preferably amlodipine maleate, amlodipine mesylate, or amlodipine besylate; more preferably amlodipine besylate.

[0026] In this invention, the amino-modified silica is prepared by modifying the surface of silica using 3-aminopropyltriethoxysilane as a coupling agent. Silica surfaces typically contain only a single functional group (-Si-OH), thus exhibiting a weakly acidic surface. Amino-modified silica, on the other hand, converts the (-Si-OH) functional group to -Si(CH2)3NH2, resulting in a weakly alkaline surface.

[0027] In a preferred embodiment, the amino-modified silica is prepared as follows: 100g of colloidal silica is activated under vacuum at 150°C for 5h and then cooled to room temperature. 50mL of toluene and 2mL of 3-aminopropyltriethoxysilane are added, and the mixture is refluxed at 80°C for 10h with stirring. The mixture is then filtered, and the filter cake is repeatedly washed with a large amount of anhydrous ethanol, dried under vacuum, and then dried at 60°C for 12h to obtain a white powder, which is the amino-modified silica.

[0028] Those skilled in the art will understand that, for the purpose of preparing different dosage forms, the compositions of the present invention may be further supplemented with one or more pharmaceutically acceptable excipients.

[0029] In a further embodiment of the present invention, the weight ratio of the amino-modified silica to the excipient is 0.2-6:100, for example, 0.2:100, 0.5:100, 1:100, 1.5:100, 2:100, 2.5:100, 3:100, 3.5:100, 4:100, 4.5:100, 5:100, 5.5:100, or 6:100. In some preferred embodiments, the weight ratio of the amino-modified silica to the excipient is 1:100, 1.5:100, 2:100, 2.5:100, or 3:100.

[0030] In a further embodiment of the invention, the weight ratio of the sum of the weights of perindopril or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof to the excipient is 1:7-9, for example 1:7, 1:7.5, 1:8, 1:8.5 or 1:9, preferably 1:8 or 1:8.5.

[0031] In a further embodiment of the invention, the weight ratio of perindopril or a pharmaceutically acceptable salt thereof to amlodipine or a pharmaceutically acceptable salt thereof is 1:2-2:1, 1:1.8-1.8:1, 1:1.5-1.5:1, or 1:1.2-1.2:1. For example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, or 1.9:1. In a preferred embodiment, the weight ratio of perindopril or a pharmaceutically acceptable salt thereof to amlodipine or a pharmaceutically acceptable salt thereof is 1:1. In another preferred embodiment, the perindopril or a pharmaceutically acceptable salt thereof is expressed in a weight ratio of 2:1 to the amlodipine or a pharmaceutically acceptable salt thereof.

[0032] In a further embodiment of the invention, the composition is selected from tablets, capsules, granules or dry suspensions, preferably tablets.

[0033] A second aspect of the present invention provides a method for preparing a perindopril-amlodipine composition, the method comprising: (a) mixing perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, and optionally one or more pharmaceutically acceptable excipients to obtain a mixture, or further forming the mixture into granules; and optionally (b) compressing the mixture or granules into tablets or filling the granules into capsules.

[0034] In one embodiment, the method includes the steps of sieving, mixing, compacting, and homogenizing perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, and excipients together.

[0035] In one embodiment, the process includes sieving, mixing, compacting, and homogenizing perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, together with fillers, binders, disintegrants, and lubricants.

[0036] In another embodiment, the steps of mixing and compacting perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica with microcrystalline cellulose, sodium glycolate starch, and sodium stearoyl fumarate are included.

[0037] In another embodiment, the steps of mixing and compacting perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica with microcrystalline cellulose, pregelatinized starch, and magnesium stearate are included.

[0038] In a further embodiment, perindopril or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt, amino-modified silica, and excipients are sieved, mixed evenly, and then granulated using wet or dry granulation. In a preferred embodiment, the present invention uses wet granulation; however, considering that perindopril or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt are sensitive to moisture and heat, 50% ethanol is used to induce the viscosity of the pregelatinized starch to achieve the purpose of granulation. In a more preferred embodiment, the present invention uses dry granulation to reduce the generation of related substances during the preparation process.

[0039] A third aspect of the present invention provides the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention, delay of progression or treatment of hypertension and related diseases in patients.

[0040] Example

[0041] Example 1 Tablets

[0042] prescription:

[0043]

[0044] Process:

[0045] Mix corn starch, perindopril arginine, and amlodipine besylate evenly, then add microcrystalline cellulose, amino-modified silica, and magnesium stearate and mix evenly before compressing into tablets.

[0046] Comparative Example 1: Tablets

[0047] The amino-modified silica in the formulation of Example 1 was replaced with colloidal silica, and everything else remained the same.

[0048] Comparative Example 2: Tablets

[0049] Based on the prescription of Comparative Example 1, 2g of sodium thiosulfate was added to the prescription, and everything else was the same as Comparative Example 1.

[0050] Process:

[0051] Mix corn starch, sodium thiosulfate, perindopril arginine and amlodipine besylate evenly, then add microcrystalline cellulose, colloidal silica and magnesium stearate and mix evenly, then compress into tablets.

[0052] Example 1: High-temperature stability test

[0053] The samples from Example 1, Comparative Example 1, and Comparative Example 2 were subjected to high-temperature stability (60℃) studies. The specific data are shown in Table 1.

[0054] Table 1 Comparative data of high-temperature stability studies of tablets

[0055]

[0056] Note: * indicates the USP2023 standard.

[0057] As shown in Table 1, on day 30 of the high-temperature experiment, the perindopril impurity F and amlodipine impurity D all increased in Example 1, Comparative Example 1, and Comparative Example 2, but the increase in Example 1 was much lower than that in Comparative Example 1. The increase in amlodipine impurity D in Comparative Example 2 was larger, possibly related to the interaction between sodium thiosulfate and amlodipine. In Example 1 and Comparative Example 2, N-nitrosamine perindopril and N-nitrosamine amlodipine were not detected, while in Comparative Example 1, N-nitrosamine perindopril and N-nitrosamine amlodipine were detectable on day 30. The absence of N-nitrosamines in Example 1 may be related to the fact that amino-modified silica provides a weakly alkaline environment for the tablets, while nitrosation requires an acidic medium. The absence of N-nitrosamines in Comparative Example 2 may be related to the addition of the antioxidant sodium thiosulfate, which blocked the nitrosation reaction.

[0058] Example 2 Capsules

[0059] prescription:

[0060]

[0061] Process:

[0062] Amino-modified silica, arginine perindopril, and amlodipine besylate were mixed, and then cross-linked sodium carboxymethyl cellulose, pregelatinized starch, and magnesium stearate were added and mixed. The mixture was then granulated using a dry granulation machine and filled into capsules.

[0063] Comparative Example 3: Capsules

[0064] The amino-modified silica in the formulation of Example 2 was replaced with colloidal silica, and everything else remained the same.

[0065] Example 2: High-temperature stability test

[0066] The samples from Example 2 and Comparative Example 3 were subjected to high-temperature stability (60°C) studies. The specific data are shown in Table 2.

[0067] Table 2 Comparative data of high-temperature stability studies of capsules

[0068]

[0069] Note: * indicates the USP2023 standard.

[0070] As shown in Table 2, on day 30 of the high-temperature experiment, both perindopril impurity F and amlodipine impurity D increased in Example 2 and Comparative Example 3, but the increase in Example 2 was much lower than that in Comparative Example 3. N-N-nitrite perindopril and N-nitrite amlodipine were undetectable in Example 2, while in Comparative Example 3, N-nitrite perindopril and N-nitrite amlodipine had increased significantly by day 30.

[0071] Based on the high-temperature stability experiments of the above ordinary tablets and capsules, it can be seen that amino-modified silica can stabilize perindopril and amlodipine, and it provides a weakly alkaline environment that basically blocks the nitrosation reaction. The perindopril and amlodipine compound preparation made from the composition of this invention will basically not produce N-nitroso compounds.

[0072] Although the invention has been described with reference to exemplary embodiments, it should be understood that the invention is not limited to the disclosed exemplary embodiments. Various adjustments or changes may be made to the exemplary embodiments described in this specification without departing from the scope or spirit of the invention. The scope of the claims should be interpreted in the broadest possible sense to cover all modifications and equivalent structures and functions.

Claims

1. A pharmaceutical composition for treating cardiovascular diseases, characterized in that, The product comprises perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, and a pharmaceutically acceptable excipient, wherein the amino-modified silica is prepared by modifying the surface of silica with 3-aminopropyltriethoxysilane as a coupling agent, and the pharmaceutically acceptable excipient is selected from at least one of corn starch, microcrystalline cellulose, magnesium stearate, croscarmellose sodium, and pregelatinized starch.

2. The composition according to claim 1, characterized in that, The weight ratio of the amino-modified silica to the excipient is 0.2-6:

100.

3. The composition according to claim 1, characterized in that, The weight ratio of the sum of the weights of the perindopril or its pharmaceutically acceptable salt and the amlodipine or its pharmaceutically acceptable salt to the excipient is 1:7-9.

4. The composition according to claim 1, characterized in that, The weight ratio of perindopril or a pharmaceutically acceptable salt thereof to amlodipine or a pharmaceutically acceptable salt thereof is 1:2 to 2:

1.

5. The composition according to claim 1, characterized in that, The composition is selected from tablets, capsules, granules or dry suspensions.

6. The composition according to claim 5, characterized in that, The composition is a tablet.

7. A method for preparing the composition according to any one of claims 1 to 6, characterized in that, include: (a) mixing perindopril or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, amino-modified silica, and optionally one or more pharmaceutically acceptable excipients to obtain a mixture, or further forming the mixture into granules; and optionally (b) compressing the mixture or granules into tablets or filling the granules into capsules.

8. The method for preparing the composition according to claim 7, characterized in that, The granules are prepared by direct compression, wet granulation, or dry granulation.

9. Use of the composition according to any one of claims 1 to 6 in the preparation of a medicament for delaying the progression or treating hypertension in a subject in need.

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