Arginine perindopril solid dispersion and compound preparation thereof

Abstract

The invention discloses an arginine perindopril solid dispersion and a compound preparation thereof, and belongs to the technical field of pharmaceutical preparations. The arginine perindopril solid dispersion provided by the invention is prepared from the following components in parts by mass: 1 part of arginine perindopril, 0.1 to 0.3 part of calcium acetate and 5.2 to 5.4 parts of microcrystalline cellulose. The arginine perindopril solid dispersion and the compound perindopril amlodipine tablet prepared from the arginine perindopril solid dispersion have excellent stability, the preparation methods of the arginine perindopril solid dispersion and the compound perindopril amlodipine tablet are simple to operate, actual production is facilitated, and a drying agent can be prevented from being used during preparation packaging.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to an arginine perindopril solid dispersion and its compound formulation. Background Technology

[0002] Perindopril is a sustained-acting, potent angiotensin-converting enzyme inhibitor (ACEI). It converts angiotensin I into angiotensin II, which has vasoconstrictive effects. Furthermore, this enzyme stimulates the renal cortex to secrete aldosterone and degrades bradykinin, a vasodilator, into an inactive heptapeptide. It can reduce peripheral vascular resistance without changing heart rate and cardiac output, and is primarily used to treat hypertension and congestive heart failure. Perindopril exerts its effect through its active metabolite, perindoprilat. This drug can be used to treat hypertension of various degrees, reaching peak efficacy 4–6 hours after administration and lasting for 24 hours.

[0003] Perindopril has poor water solubility, which can seriously affect drug absorption and distribution during formulation. Therefore, it often exists in the form of salts with organic bases, such as tert-butylamine salt, arginine salt, sodium salt, and maleate salt. Since the sodium salt will be converted into oil upon contact with air and the maleate salt is extremely unstable, researchers in various countries have mainly focused on the research of perindopril tert-butylamine salt and arginine salt.

[0004] According to various patents and literature reports, arginine perindopril has four crystal forms: α, β, γ, and δ. Currently, Servier, a French company, has authorized patents in China that protect three crystal forms: α (CN 101389603B), β (CN101389604B), and δ (CN 103193864B). These are still under the patent protection period of the original research company. Only the metastable γ crystal form is not patented in China and can be used for commercial purposes.

[0005] Due to patent protection of the arginine perindopril crystal form, domestic researchers currently focus mainly on the study of perindopril tert-butylamine salt and its compound preparations, such as patents CN106606492A, CN103861081A, CN104436155A, CN106727376A, CN104586800A, CN111419810A, CN1658898A, CN111298096A, CN111956779A, CN107166876A, and CN103861080A. However, according to patent CN1211365C, perindopril arginine salt has superior stability under high temperature and high humidity conditions compared to tert-butylamine salt. Therefore, driven by patent protection and the desire to obtain formulations with better stability, researchers are compelled to investigate the metastable γ-crystalline form of arginine perindopril and its formulations.

[0006] Based on reports from various patents and literature, perindopril is sensitive to moisture and heat and is prone to degradation. Under high humidity conditions, the side chain ester bonds hydrolyze (impurity A), and under high temperature conditions, it undergoes intramolecular cyclization (impurity E). The possible degradation pathways are shown in Equation 1 below. Therefore, improving the stability of arginine perindopril formulations presents a certain challenge.

[0007]

[0008] Patent EP 3842035A1 discloses a method for preparing arginine perindopril granules and its formulation: calcium chloride is dissolved in purified water at 40°C, and after the solution is clear, arginine perindopril is added and stirred to dissolve, resulting in a pale yellow and transparent arginine perindopril solution. This solution is then sprayed onto microcrystalline cellulose 102 and wet-granulated. After fluidized bed drying, arginine perindopril granules (0.5%–1.5% moisture content) are obtained. XRD analysis shows that the arginine perindopril granules are amorphous. After accelerated treatment at 40°C and 75% RH for 3 months, the impurity E content is 0.21%, and the total impurities are 0.70%. Furthermore, arginine perindopril granules are combined with indapamide and / or amlodipine besylate and bisoprolol fumarate to form a compound preparation for the treatment of hypertension. The improved stability of the arginine perindopril granules obtained in this patent may be related to the formation of a stable complex between arginine perindopril and calcium chloride. However, calcium chloride is highly hygroscopic and may provide a possible moisture environment for the degradation of the active ingredient. Therefore, there is still some uncertainty regarding the stability of the active ingredient and the compound preparation.

[0009] Arginine perindopril is sensitive to moisture and heat. Amlodipine in compound preparations is unstable after absorbing moisture, and drug interactions exist. Instability exists when amlodipine besylate is directly mixed with arginine perindopril. Furthermore, according to literature reports, amlodipine besylate, under certain humidity conditions, can undergo a Maillard reaction catalyzed by magnesium when coexisting with lactose and the lubricant magnesium stearate, forming an adduct of amlodipine and lactose (impurity G). The possible degradation pathway is shown in Equation 2 below. Therefore, moisture control and lubricant selection are extremely important in compound preparations.

[0010]

[0011] Patent CN 114668736A discloses a method for preparing perindopril-amlodipine bilayer tablets: Arginine perindopril, microcrystalline cellulose, lactose, magnesium stearate, and colloidal silica are mixed to obtain arginine perindopril granules; amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, magnesium stearate, and colloidal silica are mixed to obtain amlodipine granules. These two granule fractions are then compressed separately using a bilayer tableting machine to obtain perindopril-amlodipine bilayer tablets. However, the method does not delve into the product's long-term stability, requires a relatively expensive bilayer tableting machine, and necessitates improvements in production efficiency.

[0012] Patent CN 116763897 A discloses a perindopril amlodipine tablet and its preparation method: The active ingredients (arginine perindopril and amlodipine besylate) with a D90 of 15-180 μm are mixed with diluent I (at least one of lactose, microcrystalline cellulose, dicalcium phosphate, starch, and pregelatinized starch), followed by the addition of diluent II (at least one of spray-dried lactose, microcrystalline cellulose, dicalcium phosphate dihydrate, directly compressed starch, and pregelatinized starch), lubricant, glidant, and / or disintegrant, and then compressed into tablets to obtain perindopril amlodipine tablets. However, the stability of the product in the later stages is not discussed in detail, and the formulation process has certain requirements on the particle size of the active pharmaceutical ingredient.

[0013] Based on the currently available technical information, arginine perindopril raw material is sensitive to moisture and heat and has poor stability. The γ-crystalline form of arginine perindopril raw material must be stored in a low-temperature sealed environment, which is not practically suitable for formulation production. Even the relatively stable α, β, and δ crystalline forms require formulation products to be packaged with desiccants. Therefore, improving the stability of arginine perindopril raw material and formulations is of paramount importance. Summary of the Invention

[0014] The purpose of this invention is to overcome the shortcomings of the prior art and provide an arginine perindopril solid dispersion and its compound preparation that have excellent stability, simple preparation method and wide availability of raw materials.

[0015] To achieve the above objectives, in a first aspect, the present invention provides an arginine perindopril solid dispersion, the arginine perindopril solid dispersion comprising the following components in parts by weight:

[0016] Arginine perindopril 1 part, calcium acetate 0.1-0.3 parts, microcrystalline cellulose 5.2-5.4 parts.

[0017] The present invention provides an arginine perindopril solid dispersion in which calcium acetate is selected as a stabilizer, resulting in a significant improvement in product stability. Specifically, the calcium ions in the arginine perindopril raw material and calcium acetate can form a complex with excellent stability. Furthermore, since the calcium acetate monohydrate no longer has hygroscopic properties after the complex is formed, the resulting solid dispersion has excellent storage stability.

[0018] Furthermore, this invention has discovered that not all salts containing calcium ions can achieve excellent stabilization effects. A surprising finding during the experiment was that when calcium acetate was used as a stabilizer in conjunction with microcrystalline cellulose to prepare an arginine perindopril solid dispersion, the increase in impurity content after standing was minimal, indicating excellent stability. Specifically, on the one hand, calcium sulfate has low solubility in water and is almost insoluble in ethanol; calcium salts of carbonic acid include calcium carbonate and calcium bicarbonate. While calcium bicarbonate is soluble in water, it easily decomposes at room temperature to produce insoluble calcium carbonate; calcium salts of phosphate include calcium phosphate, calcium hydrogen phosphate, and calcium dihydrogen phosphate. Calcium phosphate and calcium hydrogen phosphate are slightly soluble in water but insoluble in ethanol, while calcium dihydrogen phosphate, although having better solubility, will dissociate arginine perindopril in acidic conditions. Therefore, these calcium salts cannot be used as stabilizers in this invention. On the other hand, although water-soluble calcium chloride can be used as a stabilizer, it is highly hygroscopic and deliquesces easily when exposed to moisture, challenging its applicability to arginine perindopril and amlodipine besylate.

[0019] In a preferred embodiment of the arginine perindopril solid dispersion of the present invention, the arginine perindopril solid dispersion comprises the following components in parts by weight:

[0020] Arginine perindopril 1 part, calcium acetate 0.2-0.28 parts, microcrystalline cellulose 5.22-5.30 parts.

[0021] This invention has found that the mass fraction of components in arginine perindopril solid dispersions also affects the stability of the product. When the mass fraction of components is further selected within the above-mentioned range, under the same conditions and after the same period of time, the arginine perindopril solid dispersion formed by components within the above-mentioned range produces less impurities, i.e., it has better stability.

[0022] In a preferred embodiment of the arginine perindopril solid dispersion of the present invention, the arginine perindopril in the solid dispersion has an amorphous structure.

[0023] Research has shown that the crystal form data of the active ingredient arginine perindopril used in this invention is consistent with the crystal form data published in CN112047999B, CN114149357A and WO2009 / 157018A2, and is in the γ crystal form, which is not protected by patent.

[0024] In a second aspect, the present invention provides a method for preparing the arginine perindopril solid dispersion, the method comprising the following steps:

[0025] Arginine perindopril and calcium acetate were dissolved in water, followed by wet granulation with microcrystalline cellulose. Finally, the granules were sieved and dried to obtain arginine perindopril solid dispersion.

[0026] The present invention has found that the preparation method provided by the present invention can yield products with excellent stability.

[0027] In a preferred embodiment of the preparation method described in this invention, the mass ratio of arginine perindopril to water is 1:(1.2-1.5).

[0028] This invention has found that by selecting an appropriate mass ratio of arginine perindopril and water, the amount of water added can be reduced as much as possible while ensuring sufficient dissolution of arginine perindopril and calcium acetate, thereby reducing subsequent drying time and the possibility of degradation of arginine perindopril.

[0029] In a preferred embodiment of the preparation method described in this invention, the drying temperature is 40–70°C.

[0030] Preferably, the drying temperature is 60–70°C.

[0031] Drying after granulation and sieving, preferably using a fluidized bed drying device with high drying efficiency, can improve drying efficiency and reduce the degradation of arginine perindopril.

[0032] In a preferred embodiment of the preparation method described in this invention, the moisture content of the arginine perindopril solid dispersion is ≤2%.

[0033] The present invention has found that when the moisture content of the arginine perindopril solid dispersion is controlled to be ≤2%, it can achieve relatively excellent stability.

[0034] As a preferred embodiment of the preparation method described in this invention, a pharmaceutically recognized and conventionally used wet granulation technique and parameters are selected.

[0035] In a third aspect, the present invention provides the application of the arginine perindopril solid dispersion in the preparation of a compound antihypertensive drug in combination with other conventional antihypertensive drugs.

[0036] For example, the other conventional antihypertensive drugs include at least one of amlodipine besylate, indapamide, and bisoprolol fumarate.

[0037] The arginine perindopril solid dispersion provided by this invention has excellent stability and can be used in combination with amlodipine besylate to obtain compound perindopril-amlodipine tablets of different specifications to achieve the corresponding antihypertensive effect. For example, there are two specifications of perindopril-amlodipine tablets (I), with the active ingredients being 5 mg of arginine perindopril and 5 mg of amlodipine besylate (calculated as amlodipine), or 10 mg of arginine perindopril and 10 mg of amlodipine besylate (calculated as amlodipine); perindopril-amlodipine tablets (II), with the active ingredients being 5 mg of arginine perindopril and 10 mg of amlodipine besylate (calculated as amlodipine); and perindopril-amlodipine tablets (III), with the active ingredients being 10 mg of arginine perindopril and 5 mg of amlodipine besylate (calculated as amlodipine).

[0038] In a fourth aspect, the present invention provides a compound perindopril-amlodipine tablet comprising arginine perindopril solid dispersion, amlodipine besylate, calcium stearate, and excipients.

[0039] As a preferred embodiment of the compound perindopril-amlodipine tablets of the present invention, the compound perindopril-amlodipine tablets comprise the following components in parts by weight:

[0040] Arginine perindopril solid dispersion (containing 10 mg arginine perindopril), 6.935 parts amlodipine besylate (5 mg amlodipine), 0.3–5 parts calcium stearate and excipients.

[0041] This invention has found that selecting components in the above-mentioned mass fractions of the compound perindopril-amlodipine tablets can improve the stability of the tablets. Specifically, when arginine perindopril is prepared into an arginine perindopril solid dispersion, its stability is improved while reducing its contact with amlodipine besylate raw material, thus avoiding instability factors in mixed formulations and improving the stability of the compound perindopril-amlodipine tablets. Furthermore, selecting calcium stearate as a lubricant avoids the Maillard reaction catalyzed by conventional lubricants such as magnesium stearate with excipients like lactose and amlodipine, which is more conducive to improving product stability.

[0042] In a preferred embodiment of the compound perindopril amlodipine tablets of the present invention, the excipients include fillers and glidants.

[0043] Preferably, the filler includes at least one of microcrystalline cellulose, lactose, and starch.

[0044] The present invention has found that when the above-mentioned type of filler is selected, it has better flowability and compressibility.

[0045] Preferably, the flow aid comprises silicon dioxide.

[0046] This invention has found that selecting silica as a flow aid has excellent flow aid effect and can improve tablet hardness, thereby ensuring uniform dispersion of components and improving product stability during the preparation process.

[0047] In a fifth aspect, the present invention provides a method for preparing the compound perindopril amlodipine tablets, the method comprising the following steps:

[0048] The components were mixed, compressed into tablets, and dried to obtain compound perindopril amlodipine tablets.

[0049] This invention improves the stability of the active ingredient and reduces the possibility of degradation by further reducing the moisture content in the tablets after mixing and compressing the components and then drying them. Furthermore, amlodipine besylate raw material is less prone to Maillard reaction with lactose in a dry environment, which reduces the degradation of impurity G and improves product stability.

[0050] In a preferred embodiment of the preparation method described in this invention, the drying temperature is 40–70°C.

[0051] In a preferred embodiment of the preparation method described in this invention, the moisture content of the compound perindopril amlodipine tablets is ≤1.5%. This invention has found that further controlling the moisture content of the compound perindopril amlodipine tablets within the above-mentioned range can effectively improve the stability of the product.

[0052] As a preferred embodiment of the preparation method described in this invention, the compound perindopril amlodipine tablets can be packaged and stored in various ways in PET, HDPE or PP bottles that do not require desiccant, as well as in aluminum / aluminum blister packs, double soft aluminum blister packs, PVC / aluminum foil blister packs in composite aluminum bags.

[0053] Preferably, the compound perindopril amlodipine tablets are packaged in a pillow-type package using polyvinyl chloride solid pharmaceutical rigid sheet (PVC) / pharmaceutical aluminum foil blister pack + composite aluminum bag.

[0054] The present invention found that, after a 6-month accelerated test at 40°C and 70% RH, the related substances in solid pharmaceutical rigid sheets (PVC) / pharmaceutical aluminum foil blister packs and composite aluminum bags did not increase significantly, and all quality control items, such as content determination, dissolution curve and content uniformity, were qualified.

[0055] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0056] 1. The arginine perindopril solid dispersion provided by this invention is prepared by using calcium acetate as a stabilizer for the first time, compounding it with arginine perindopril and microcrystalline cellulose. Furthermore, the arginine perindopril in the solid dispersion has an amorphous structure, avoiding conflict with the original patent. In addition, this patent uses previously unreported calcium acetate as a stabilizer, significantly improving the stability of the prepared arginine perindopril solid dispersion.

[0057] 2. The compound perindopril amlodipine tablets provided by the present invention use the arginine perindopril solid dispersion prepared by the present invention, combined with calcium stearate as a lubricant, which avoids the Maillard reaction catalyzed by the common lubricant magnesium stearate between lactose and amlodipine, and is more conducive to improving product stability.

[0058] 3. The compound perindopril amlodipine tablets provided by the present invention utilize the arginine perindopril solid dispersion prepared by the present invention, combined with other components, and employ a tablet drying process during preparation, which greatly improves the stability of the compound perindopril amlodipine tablets.

[0059] 4. This invention can convert metastable γ-crystalline arginine perindopril into a stable amorphous arginine perindopril solid dispersion. The obtained arginine perindopril solid dispersion and its compound oral preparation have good stability and stable quality, and all test items are qualified. At the same time, the preparation process provided by this invention is simple, has high production efficiency, and is suitable for industrial and large-scale production. Attached Figure Description

[0060] Figure 1 The images show the PXRD patterns of the arginine perindopril active pharmaceutical ingredient, microcrystalline cellulose excipient, and the arginine perindopril solid dispersion prepared in Example 1, as well as those from Example 3. Detailed Implementation

[0061] To better illustrate the objectives, technical solutions, and advantages of this invention, the invention will be further described below with reference to specific embodiments. It should be noted that these descriptions of embodiments are intended to aid in understanding the invention but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the invention described below can be combined with each other as long as they do not conflict with each other.

[0062] The accelerated testing conditions and quality testing methods in the parallel experiments of the following examples and comparative examples are consistent. The quality testing methods refer to the import drug registration standard (standard number: JX20170213) of perindopril amlodipine tablets (trade name: Coveram) developed and marketed by Les Laboratoires Servier, France.

[0063] Impurity A (perindopril) is the result of hydrolysis of the side chain ester bond of perindopril under high humidity conditions, with a limit of ≤0.8%; Impurity E is the result of intramolecular cyclization of perindopril under high temperature conditions, with a limit of ≤0.7%; Impurity F is the degradation product of amlodipine, with a limit of ≤0.4%; Impurity G is the adduct of amlodipine and lactose, with a limit of ≤0.2%; the limit for a single unknown impurity is ≤0.2%, and the limit for total impurities is ≤3.0%.

[0064] Examples 1-3 and Comparative Examples 1-2

[0065] The present invention provides an arginine perindopril solid dispersion, the components (parts by mass) of which are shown in Table 1.

[0066] Table 1

[0067] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Arginine perindopril 1.0 1.0 1.0 1.0 1.0 Calcium chloride / / / 0.20 / Calcium acetate 0.20 0.28 0.24 / 0.10 microcrystalline cellulose 5.30 5.22 5.26 5.30 5.40 Moisture content of solid dispersion 1.6 1.5 1.4 1.6 1.5

[0068] The preparation method of the arginine perindopril solid dispersion provided in Example 3 includes the following steps:

[0069] 500.0g of arginine perindopril and 120.0g of calcium acetate were dissolved in 750.0g of purified water. After stirring and dissolving until clear and transparent, 2630.0g of microcrystalline cellulose was added and wet-granulated. The material had uniform moisture content, could be formed into a ball by hand, and easily dispersed by light touch. After granulation and sieving, the material was uniformly dispersed without small lumps or hard cores. Fluidized bed drying was used at a temperature of 60±5℃ to obtain arginine perindopril solid dispersion with uniform particle size distribution, good flowability, and a moisture content of 1.4%.

[0070] The preparation methods of arginine perindopril solid dispersions provided in Examples 1-2 and Comparative Examples 1-2 are consistent with those in Example 3.

[0071] The stability of the arginine perindopril solid dispersions prepared in Examples 1-2 and Comparative Examples 1-2 was assessed by placing the prepared products in a stability test chamber at 70°C for 4 days and testing their related substances. The test results are shown in Table 2.

[0072] Table 2

[0073]

[0074] As can be seen from Table 2, the impurity contents of the solid dispersions prepared in Examples 1-2 and Comparative Examples 1-2 were similar at day 0, with no significant difference. However, after heating at 70°C for 4 days, the impurity E content showed a significant difference. Specifically, when the examples adopted the technical solution provided by this invention, the resulting products exhibited excellent stability, with only a small increase in impurity content after heating at 70°C for 4 days.

[0075] Comparing the related substance detection results of Example 1 and Comparative Example 1, it can be seen that when the ratio of calcium chloride and calcium acetate to arginine perindopril raw material is the same, the content of impurities A and E in Example 1 is significantly lower than that in Comparative Example 1. Calcium acetate is significantly more effective than calcium chloride in improving the stability of arginine perindopril as a stabilizer. The reason for this is that calcium chloride is more hygroscopic than calcium acetate, which has an adverse effect on the stability of arginine perindopril solid dispersion. In addition, calcium acetate monohydrate containing water of crystallization no longer has hygroscopicity, making it very suitable for water-sensitive arginine perindopril raw material. Therefore, this patent selects calcium acetate as a stabilizer to prepare arginine perindopril solid dispersion.

[0076] Comparing the related substance test results of Examples 1, 2, and 2, it can be seen that when the proportion of calcium acetate is less than 0.2 parts, the stability of the arginine perindopril solid dispersion decreases, and the content of impurity E increases significantly, but it is still superior to calcium chloride. This indicates that when calcium acetate is used as a stabilizer, its proportion has a certain impact on stability. Considering the related substance test results of Examples 1 and 2 and the solubility of calcium acetate, this patent preferably uses a ratio of arginine perindopril to calcium acetate of 1:0.2 to 0.3.

[0077] In addition, the PXRD patterns of commercially available arginine perindopril active pharmaceutical ingredient, microcrystalline cellulose excipient, and the arginine perindopril solid dispersion prepared in Example 3 are as follows: Figure 1 As shown, from Figure 1 As can be seen, the PXRD pattern of arginine perindopril active pharmaceutical ingredient is consistent with the γ-crystalline form disclosed in patents CN112047999B, CN114149357A, and WO2009 / 157018A2, and does not conflict with the α, β, and δ-crystalline form patents protected by the original manufacturer. According to the PXRD patterns of Example 3 and microcrystalline cellulose, the arginine perindopril solid dispersion in Example 3 shows the same PXRD pattern as microcrystalline cellulose, rather than the γ-crystalline form pattern of arginine perindopril active pharmaceutical ingredient, indicating that arginine perindopril active pharmaceutical ingredient exhibits an amorphous configuration in the solid dispersion.

[0078] Comparative Example 3

[0079] Les Laboratoires Servier, a French company, developed and marketed perindopril amlodipine tablets (III) (trade name: Coveram). The specifications are: perindopril arginine 10 mg and amlodipine besylate (calculated as amlodipine) 5 mg. The publicly available prescription information includes: perindopril arginine (crystal form unknown), amlodipine besylate, microcrystalline cellulose, lactose, magnesium stearate, and silicon dioxide. It is packaged in a polypropylene bottle with a low-density polyethylene stopper containing a desiccant. The same accelerated testing conditions and related substances detection methods as in the examples were used.

[0080] Examples 4-8 and Comparative Example 4

[0081] The present invention provides a compound perindopril amlodipine tablet, the component content (parts by mass) of the compound perindopril amlodipine tablet is shown in Table 3, wherein the arginine perindopril solid dispersion used is the same batch of arginine perindopril solid dispersion prepared by the preparation method in Example 3.

[0082] Table 3

[0083]

[0084]

[0085] The preparation methods of the compound perindopril-amlodipine tablets provided in Examples 4-7 include the following steps: mixing arginine perindopril solid dispersion, amlodipine besylate, microcrystalline cellulose, lactose, silica, and the lubricant calcium stearate, and then compressing the mixture into tablets to obtain the compound perindopril-amlodipine tablets. Example 7 involves drying the compound perindopril-amlodipine tablets from Example 6 to minimize the moisture content of the tablets.

[0086] The preparation method of the compound perindopril amlodipine tablets provided in Comparative Example 4 includes the following steps: mixing arginine perindopril solid dispersion, amlodipine besylate, microcrystalline cellulose, lactose, silicon dioxide and lubricant magnesium stearate, and then compressing the mixture into tablets to obtain compound perindopril amlodipine tablets.

[0087] In the preparation process of the compound perindopril amlodipine tablets provided in this embodiment of the invention, the material mixing flow is good, the tablets are easily demolded during compression, and there is no sticking or punching phenomenon. The content uniformity, disintegration time and dissolution of the compound perindopril amlodipine tablets all meet the requirements after testing.

[0088] The stability of the prepared product was tested. Specifically, the prepared product was placed in a stability test chamber at 60°C and heated for 7 days. The relevant substances were detected, and the results are shown in Table 4.

[0089] Table 4

[0090]

[0091] As can be seen from Table 4, when the technical solution provided by the present invention is adopted, the impurity content obtained in the stability test can meet the requirements, and the increase of impurities F, G and E is significantly reduced compared with the original product of Comparative Example 3.

[0092] As can be seen from Example 6 and Comparative Example 4, in Comparative Example 4, magnesium stearate was used as a lubricant. After acceleration at 60°C for 7 days, the content of impurity G was significantly higher than that in Example 6 and exceeded the standard limit (≤0.2%). The contents of impurities A, F, and E were not significantly different. The reason for this is that, under certain moisture conditions, magnesium salts can catalyze the Maillard reaction between amlodipine besylate and lactose, thus increasing the content of impurity G. Therefore, this patent preferably uses calcium stearate as a lubricant.

[0093] As can be seen from Examples 6 and 7, further controlling the moisture content to ≤1.5% after drying improves the stability of the product. After 7 days of accelerated drying at 60°C, the contents of impurities A, F, G, and E are all reduced. After drying, the moisture content in the compound perindopril amlodipine tablets is further reduced, which more effectively improves the stability of the product.

[0094] The preparation method of Example 8 is as follows: Arginine perindopril solid dispersion, amlodipine besylate, microcrystalline cellulose, lactose, silicon dioxide, and lubricant calcium stearate are mixed and then compressed into tablets to obtain compound perindopril-amlodipine tablets. The perindopril-amlodipine tablets are dried at a temperature of 60±5℃ until the moisture content of the tablets is ≤1.5%, and then packaged in a pillow-type packaging using "polyvinyl chloride solid pharmaceutical rigid sheet (PVC) / pharmaceutical aluminum foil blister pack + composite aluminum bag".

[0095] To investigate the stability of the original products of Example 8 and Comparative Example 3, accelerated stability tests were conducted on the original packaged formulation of Comparative Example 3 and the packaged formulation of Example 8. The accelerated test conditions were 40°C and 75%RH for 6 months. Related substances were detected in the formulations of the original products of Example 8 and Comparative Example 3 at 1 month, 3 months and 6 months, respectively. The test results are shown in Table 5.

[0096] Table 5

[0097]

[0098] As shown in Table 5, after accelerated testing at 40℃ and 75% RH, the related substance test results indicate that the content of each impurity and the total impurity content of the product prepared using the technical solution of this invention are far lower than the impurity limit standards of the original drug, perindopril amlodipine tablets. Furthermore, the contents of impurities A, E, and total impurities are close to those of the original drug, while the content of impurity G is significantly lower. This is because the use of calcium stearate as a lubricant in this invention is superior to the use of magnesium stearate as a lubricant in the original product, confirming that the compound perindopril amlodipine tablets obtained using the technical solution provided by this invention have excellent stability. In addition, the technical solution provided by this invention can use blister packs with aluminum bags without desiccant, achieving accelerated test results equivalent to those of the original product with desiccant packaging.

[0099] This invention discloses a method for preparing arginine perindopril solid dispersion and its compound oral formulation. For the first time, calcium acetate is used as a stabilizer to prepare the metastable γ-crystalline arginine perindopril into an amorphous solid dispersion, avoiding conflicts with the original manufacturer's patents and improving the stability of arginine perindopril. Furthermore, the method for preparing the arginine perindopril solid dispersion and its compound oral formulation uses calcium stearate as a lubricant, avoiding the Maillard reaction catalyzed by the common lubricant magnesium stearate between lactose and amlodipine, which is more conducive to improving product stability. Finally, the additional drying process for tablets in this invention further improves product stability.

[0100] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. An arginine perindopril solid dispersion, characterized in that, The arginine perindopril solid dispersion comprises the following components in parts by weight: Arginine perindopril 1 part, calcium acetate 0.1-0.3 parts, microcrystalline cellulose 5.2-5.4 parts.

2. The arginine perindopril solid dispersion according to claim 1, characterized in that, The arginine perindopril solid dispersion comprises the following components in parts by weight: Arginine perindopril 1 part, calcium acetate 0.2-0.28 parts, microcrystalline cellulose 5.22-5.30 parts.

3. The arginine perindopril solid dispersion according to claim 1, characterized in that, The arginine perindopril in the solid dispersion has an amorphous structure.

4. The method for preparing the arginine perindopril solid dispersion according to any one of claims 1 to 3, characterized in that, The preparation method includes the following steps: Arginine perindopril and calcium acetate were dissolved in water, followed by wet granulation with microcrystalline cellulose. Finally, the granules were sieved and dried to obtain arginine perindopril solid dispersion.

5. A compound perindopril-amlodipine tablet, characterized in that, It comprises the arginine perindopril solid dispersion as described in any one of claims 1 to 3, amlodipine besylate, calcium stearate, and excipients.

6. The compound perindopril amlodipine tablets according to claim 5, characterized in that, The excipients include fillers and flow aids.

7. The method for preparing compound perindopril amlodipine tablets as described in claim 5 or 6, characterized in that, The preparation method includes the following steps: mixing the components, compressing them into tablets, and then drying them to obtain compound perindopril amlodipine tablets.

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