A stable irbesartan and levamlodipine pharmaceutical composition

Abstract

The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a stable irbesartan and levamlodipine besylate pharmaceutical composition. The irbesartan and levamlodipine besylate pharmaceutical composition of the present application comprises irbesartan, levamlodipine besylate and pharmaceutically acceptable excipients; the pharmaceutical composition can solve the problem of poor single treatment, has good stability, and can reduce the occurrence of adverse reactions; the irbesartan and levamlodipine besylate pharmaceutical composition of the present application is packaged by using plastic bottles and cooperating with suitable desiccants, so that the degradation rate of the packaged irbesartan and levamlodipine besylate pharmaceutical composition during storage can be significantly reduced, impurities can be reduced, meanwhile, the dissolution and other properties of the medicine are not affected, and the safety of the medicine is significantly improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a stable irbesartan-levamlodipine pharmaceutical composition. Background Technology

[0002] The irbesartan-levamlodipine combination comprises two antihypertensive active ingredients: irbesartan and levamlodipine besylate. Levoamlodipine besylate is a calcium channel blocker (CCB) that blocks the entry of extracellular calcium ions into myocardial and vascular smooth muscle cells via calcium channels in the cell membrane, directly relaxing vascular smooth muscle and producing an antihypertensive effect. Irbesartan is an angiotensin II receptor blocker (ARB) that selectively blocks the binding of Ang II to AT1 receptors, inhibiting vasoconstriction and aldosterone release, thus producing an antihypertensive effect. These two ingredients have complementary mechanisms of action in controlling blood pressure, and the combined use of both ingredients is more effective than either ingredient alone as a monotherapy.

[0003] Given the current situation of unsatisfactory hypertension control, authoritative hypertension guidelines both domestically and internationally recommend combination therapy to improve control rates, and point out that single-pill combination therapy (SPC) should be the first choice. For example, the 2018 ESC / ESH European Hypertension Guidelines made significant changes, recommending that most patients begin treatment with a combination of two drugs, with single-pill combination therapy being the first choice. Initial treatment recommends dual SPC with ACEI / ARB + ​​CCB / diuretic, while the second step of treatment recommends triple SPC with ACEI / ARB + ​​CCB + diuretic. The National Center for Cardiovascular Diseases' "Chinese Hypertension Clinical Practice Guidelines" (2022) recommends initial combination antihypertensive drug therapy for uncomplicated hypertension patients with blood pressure ≥140 / 90 mmHg (1B), and for hypertension patients requiring combination antihypertensive drug therapy, it is recommended to prioritize SPC (2C). When choosing an SPC, it is recommended to prioritize the combination of renin-angiotensin system inhibitor (RASI) + CCB / diuretic (2C). The 2020 ISH guidelines state that, except in certain special circumstances (advanced age, CCB intolerance, etc.), ACEI / ARB+CCB is the preferred dual therapy for hypertension. This indicates that ARB+CCB is one of the preferred dual SPCs recommended by authoritative guidelines both domestically and internationally.

[0004] A common adverse reaction of CCBs is ankle edema, which can be reduced or offset by ARBs by dilating peripheral veins. ARBs can also partially block the reflexive increase in sympathetic tone and heart rate caused by CCBs. In addition, angioedema induced by ARBs can be partially relieved by CCBs. It is evident that the combination of the two can mutually offset or reduce adverse reactions.

[0005] The above analysis shows that my country has a heavy burden of hypertension, unsatisfactory hypertension control, and a large unmet clinical need. SPC is a key measure recommended by authoritative guidelines at home and abroad to improve the rate of hypertension control. Among them, ARB+CCB is one of the preferred dual SPCs recommended by authoritative guidelines at home and abroad. Therefore, it is very necessary to develop SPCs based on ARB+CCB.

[0006] Irbesartan and levamlodipine are both widely recognized mainstream drugs in their respective classes. They are complementary in their mechanisms of action, synergistically enhancing efficacy and reducing toxicity. They also share consistent administration methods and exhibit no drug interactions. Compared to amlodipine, levamlodipine removes the almost ineffective dextrorotatory component, retaining only its levorotatory isoform. Therefore, the efficacy of an equivalent amount of levamlodipine is twice that of amlodipine. Furthermore, the removal of the dextrorotatory isoform reduces adverse reactions and improves safety, giving the irbesartan-levamlodipine combination a significant clinical advantage. However, compared to the irbesartan-amlodipine combination, the irbesartan-levamlodipine combination has a higher proportion of irbesartan, introducing more impurities, and a lower proportion of levamlodipine besylate, making it more unstable in high humidity and high temperature environments and more prone to degradation. Due to the significant differences in the specifications of the two active ingredients, irbesartan and levamlodipine, there are many challenges in researching and developing stable irbesartan-levamlodipine drug combinations. Currently, irbesartan amlodipine tablets are available overseas, but there are no irbesartan levamlodipine combination products available globally. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a stable irbesartan-levamlodipine pharmaceutical composition. It solves the clinical problem of ineffective treatment with irbesartan or levamlodipine besylate alone, achieving the combined use of irbesartan and levamlodipine, which has a superior antihypertensive effect compared to using either drug alone. Furthermore, compared to irbesartan-amlodipine combination therapy, irbesartan-levamlodipine combination therapy achieves the same efficacy with half the amlodipine dose, significantly reducing adverse reactions. Simultaneously, the inventors discovered during their research that irbesartan-levamlodipine combination therapy degrades faster and has poorer stability during storage compared to irbesartan-amlodipine combination therapy, irbesartan, and levamlodipine besylate alone. When compared with the already marketed irbesartan-amlodipine combination tablets (APREXEVO... ® Levoamlodipine besylate tablets (Shihuida) ®When packaged under the same conditions, the levamlodipine content in the irbesartan-levamlodipine combination showed a significant decreasing trend during the stability study, indicating a potential quality risk during its shelf life. Based on this, the inventors, after extensive investigation, discovered that packaging the irbesartan-levamlodipine pharmaceutical composition in plastic bottles with a suitable desiccant can significantly improve the formulation stability of the packaged irbesartan-levamlodipine besylate pharmaceutical composition, thereby enhancing medication safety.

[0008] Specifically, to solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0009] In a first aspect, this application provides an irbesartan-levamlodipine pharmaceutical composition comprising irbesartan and levamlodipine besylate, wherein the pharmaceutical composition is packaged in a plastic bottle containing a desiccant.

[0010] In some exemplary embodiments, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-levamlodipine drug composition is 1:1.1-7.8 (g / g); preferably, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-levamlodipine drug composition is 1:1.56-5.2 (g / g); more preferably, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-levamlodipine drug composition is 1:2.6-3.9 (g / g).

[0011] In some exemplary embodiments, the desiccant may be selected from silica gel desiccant and / or molecular sieve desiccant; in some exemplary embodiments, the desiccant is silica gel desiccant or molecular sieve desiccant; in some exemplary embodiments, the desiccant is a mixed desiccant containing silica gel desiccant and molecular sieve desiccant.

[0012] In some exemplary embodiments, when the desiccant is a mixed desiccant comprising silica gel desiccant and molecular sieve desiccant, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:0.42-2.35 (g / g); in some exemplary embodiments, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:0.67-1.5 (g / g); in some exemplary embodiments, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:1 (g / g).

[0013] In some exemplary embodiments, the plastic bottle includes a bottle body and a bottle cap, wherein the bottle body is made of materials including but not limited to polyethylene, polypropylene, and polyester; and the bottle cap is made of materials including but not limited to polyethylene and polypropylene.

[0014] In some exemplary embodiments, the desiccant may be placed inside the bottle or in the cap; preferably, the desiccant is placed in the cap to prevent accidental ingestion and improve medication safety; in some exemplary embodiments, the cap may be a moisture-proof combination cap containing the desiccant.

[0015] In some exemplary embodiments, the dosage of irbesartan is 75-300 mg and the dosage of levamlodipine besylate is 1-10 mg. Preferably, the dosage of irbesartan is 75-150 mg and the dosage of levamlodipine besylate is 1-5 mg. More preferably, the dosage of irbesartan is 150-300 mg and the dosage of levamlodipine besylate is 2.5-5 mg. Further, the dosage of irbesartan is 150 mg and the dosage of levamlodipine besylate is 5 mg, or the dosage of irbesartan is 150 mg and the dosage of levamlodipine besylate is 2.5 mg. All dosages of levamlodipine besylate are calculated as levamlodipine.

[0016] In some exemplary embodiments, the pharmaceutical composition is in tablet form.

[0017] In some exemplary embodiments, the irbesartan-amlodipine pharmaceutical composition further comprises pharmaceutically acceptable fillers, disintegrants, binders, flow aids, lubricants, and coating materials.

[0018] In some exemplary embodiments, the filler is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl methylcellulose, the flow aid is colloidal silica, the lubricant is magnesium stearate, and the coating material is a film coating premix.

[0019] In some exemplary embodiments, the dosage of irbesartan is 150 mg, and the dosage of amlodipine besylate is 2.5 mg or 5 mg; it also includes microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, colloidal silica, magnesium stearate, and film coating premix.

[0020] In some exemplary embodiments, the pharmaceutical composition comprises, relative to the tablet core, 24.96%-30.58% by mass of filler, 3.60%-4.80% by mass of disintegrant, 2.00%-2.70% by mass of binder, 1.00%-1.50% by mass of flow aid, and 1.00%-1.50% by mass of lubricant.

[0021] In some exemplary embodiments, the pharmaceutical composition comprises, relative to the tablet core, 27.72%-29.11% by mass of filler, 4.80% by mass of disintegrant, 2.50% by mass of binder, 1.00% by mass of flow aid, and 1.20% by mass of lubricant.

[0022] Secondly, the present invention provides a packaging method for improving the stability of an irbesartan-levamlodipine drug composition, characterized in that the drug composition is packaged in a plastic bottle containing a desiccant, and the ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-levamlodipine drug composition is 1:1.1-7.8 (g / g).

[0023] Preferably, the ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:1.56-5.2 (g / g); more preferably, the ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:2.6-3.9 (g / g).

[0024] In some exemplary embodiments, the desiccant may be selected from one or both of silica gel desiccant and molecular sieve desiccant; in some exemplary embodiments, the desiccant is silica gel desiccant or molecular sieve desiccant; in some exemplary embodiments, the desiccant is a mixed desiccant containing silica gel desiccant and molecular sieve desiccant.

[0025] In some exemplary embodiments, when the desiccant is a mixed desiccant comprising silica gel desiccant and molecular sieve desiccant, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:0.42-2.35 (g / g); in some exemplary embodiments, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:0.67-1.5 (g / g); in some exemplary embodiments, the mass ratio of silica gel desiccant to molecular sieve desiccant in the mixed desiccant is 1:1 (g / g).

[0026] In some exemplary embodiments, the plastic bottle includes a bottle body and a bottle cap, wherein the bottle body is made of materials including but not limited to polyethylene, polypropylene, and polyester; and the bottle cap is made of materials including but not limited to polyethylene and polypropylene.

[0027] In some exemplary embodiments, the desiccant may be placed inside the bottle or in the cap; preferably, the desiccant is placed in the cap to prevent accidental ingestion and improve medication safety; in some exemplary embodiments, the cap may be a moisture-proof combination cap containing the desiccant.

[0028] In some exemplary embodiments, the dosage of irbesartan in the pharmaceutical composition is 75-300 mg and the dosage of levamlodipine besylate is 1-10 mg. Preferably, the dosage of irbesartan is 75-150 mg and the dosage of levamlodipine besylate is 1-5 mg. More preferably, the dosage of irbesartan is 150-300 mg and the dosage of levamlodipine besylate is 2.5-5 mg. Further, the dosage of irbesartan is 150 mg and the dosage of levamlodipine besylate is 5 mg, or the dosage of irbesartan is 150 mg and the dosage of levamlodipine besylate is 2.5 mg. All dosages of levamlodipine besylate are calculated as levamlodipine.

[0029] In some exemplary embodiments, the pharmaceutical composition is in tablet form.

[0030] In some exemplary embodiments, the pharmaceutical composition comprises irbesartan, levamlodipine besylate, and pharmaceutically acceptable fillers, disintegrants, binders, flow aids, lubricants, and coating materials.

[0031] In some exemplary embodiments, the filler is microcrystalline cellulose, the disintegrant is croscarmellose sodium, the binder is hydroxypropyl methylcellulose, the flow aid is colloidal silica, the lubricant is magnesium stearate, and the coating material is a film coating premix.

[0032] In some exemplary embodiments, the pharmaceutical composition comprises, relative to the tablet core, 24.96%-30.58% by mass of filler, 3.60%-4.80% by mass of disintegrant, 2.00%-2.70% by mass of binder, 1.00%-1.50% by mass of flow aid, and 1.00%-1.50% by mass of lubricant.

[0033] In some exemplary embodiments, the pharmaceutical composition comprises, relative to the tablet core, 27.72%-29.11% by mass of filler, 4.80% by mass of disintegrant, 2.50% by mass of binder, 1.00% by mass of flow aid, and 1.20% by mass of lubricant.

[0034] Based on the above technical solution, the beneficial effects of the present invention are as follows:

[0035] 1. The irbesartan-amlodipine drug composition of the present invention is a new compound that can solve the problem of poor monotherapy; compared with irbesartan-amlodipine compound, it significantly reduces the dosage, achieves equivalent efficacy, and reduces adverse drug reactions.

[0036] 2. This invention provides a novel packaging method for stabilizing irbesartan-levamlodipine drug compositions. By using a plastic bottle and an appropriate desiccant, the degradation rate of levamlodipine in the irbesartan-levamlodipine drug composition can be significantly controlled, reducing impurity generation without affecting the drug's dissolution and other properties. This ensures that the irbesartan-levamlodipine drug composition meets legal quality standards and significantly improves the safety of the drug composition. Detailed Implementation

[0037] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0038] In this application, the terms “comprising,” “including,” and “containing,” and their equivalents, shall be understood in an open, non-exclusive sense, meaning “including but not limited to,” implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0039] The term "plastic bottle" refers to pharmaceutical packaging bottles made of plastic, which are commonly used in this field.

[0040] In this application, irbesartan tablets (batch number: DA281, specification: 0.15g), levamlodipine besylate tablets (batch number: 230701, specification: 5mg; batch number: 230352, specification: 2.5mg), and other pharmaceutical excipients or reagents involved can all be obtained from commercial sources.

[0041] Preparation Example

[0042] The prescription composition is shown in Table 1:

[0043] Table 1

[0044]

[0045] [Note 1] This component is removed during the process.

[0046] [Note 2] 1.39 mg levamlodipine besylate is equivalent to 1.00 mg levamlodipine; 3.47 mg levamlodipine besylate is equivalent to 2.50 mg levamlodipine; 6.93 mg levamlodipine besylate is equivalent to 5.00 mg. The dosage is calculated based on levamlodipine.

[0047] The preparation method is as follows:

[0048] (1) Premixing: Weigh the prescribed amounts of irbesartan, microcrystalline cellulose 101, and croscarmellose sodium; add the weighed materials to a wet granulator in sequence, stir, shear, and premix to obtain premixed powder.

[0049] (2) Wet granulation and sieving:

[0050] Adhesive preparation: Weigh the prescribed amount of hydroxypropyl methylcellulose, dissolve it in an appropriate amount of hot purified water, and cool it to room temperature before use;

[0051] The wet granulator mixes and shears the material, then gradually adds the binder.

[0052] A wet granulator is used in conjunction with a granulator for granulation.

[0053] (3) Drying: After the fluidized bed is preheated, the wet granules after granulation in step (2) are put into the fluidized bed for drying. The air volume is adjusted until the material exhibits a good fluidization state. The appropriate drying temperature is set to obtain irbesartan dried granules.

[0054] (4) Mixing: Mix amlodipine benzylsulfonic acid, microcrystalline cellulose 112, colloidal silica, and the dried particles obtained in step (3); finally add magnesium stearate and mix to obtain a total powder.

[0055] (5) Tableting: The weight of tablets to be compressed should be calculated based on the total mixed particle content.

[0056] (6) Coating: Prepare coating solution and coat.

[0057] Experimental Example 1: Stability Study

[0058] The irbesartan-amlodipine compound tablets prepared in Examples 1-9 above were subjected to accelerated testing at a temperature of 40±2℃ and a relative humidity of 75%±5%RH. After placement, samples were taken to detect their properties, content and related substances, and the results were compared with those of day 0. The data are detailed in Table 2.

[0059] Table 2. Accelerated test results of irbesartan-amlodipine tablets (naked exposure)

[0060]

[0061]

[0062] The results showed that after being placed at 40℃ for 3 months, the content of levamlodipine besylate in samples from Experimental Examples 1 to 9 decreased, while the content of related substances increased. Based on this, the effect of packaging method on the stability of irbesartan-levamlodipine compound tablets was further investigated to improve medication safety.

[0063] Experimental Example 2: Tablet Dissolution Study

[0064] The irbesartan-amlodipine compound tablets prepared in Examples 1-9 above were subjected to accelerated testing at a temperature of 40±2℃ and a relative humidity of 75%±5%RH. After standing, samples were taken to examine the dissolution rate. The test method was as follows: the dissolution curve was determined according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), and the dissolution quantification was performed using high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The data are detailed in Table 3.

[0065] Currently, there are no approved compound tablets combining irbesartan and amlodipine besylate for marketing in China or abroad. Irbesartan and amlodipine besylate tablets are already marketed both domestically and internationally, and amlodipine besylate tablets that have passed consistency evaluation are available in China (using amlodipine besylate tablets as a reference). Original imported irbesartan tablets and original domestically produced amlodipine besylate tablets are included in the generic drug reference formulation list, but amlodipine besylate tablets are not currently included. Based on the reference formulation list information, this invention intends to use irbesartan tablets (original imported) and amlodipine besylate tablets (original domestically produced) disclosed in the reference formulation list as reference drugs.

[0066] Table 3 Dissolution results of Irbesartan and Lemmodipine Tablets

[0067]

[0068]

[0069] The results showed that after being placed at 40℃ for 3 months, the dissolution rate of levamlodipine besylate in experimental groups 1-9 all decreased, failing to meet the stability requirements. Therefore, the effect of packaging method on the stability of irbesartan-levamlodipine compound tablets was further investigated to improve medication safety.

[0070] Example 3: Initial stability study of packaged products

[0071] Irbesartan-Amlodipine compound tablets were prepared according to the formulations in Examples 1-9. Referring to the packaging materials of commercially available irbesartan-amlodipine compound tablets, an opaque white blister pack (PVC / PE / PVDC / aluminum) was chosen as the packaging material. The packaged irbesartan-amlodipine compound tablets (PVC / PE / PVDC / aluminum) were subjected to accelerated testing at a temperature of 40℃±2℃ and a relative humidity of 75%±5%RH. The test results are shown in Tables 4-5.

[0072] Table 4. Accelerated Test Results of Irbesartan / Levoamlodipine Compound Tablets (150mg / 2.5mg)

[0073]

[0074] Table 5. Accelerated Test Results of Irbesartan / Levoamlodipine Compound Tablets (150mg / 5mg) 2

[0075]

[0076] [Note] The content and related substance change trends of other specifications of products are similar to those in Table 4-5.

[0077] The results showed that after 3 months of storage, the irbesartan content in the irbesartan-levamlodipine combination tablets met the quality requirements, but the levamlodipine content changed significantly (decreased by >5%). This indicates that irbesartan-levamlodipine combination tablets packaged using the same packaging materials as those already on the market do not meet the stability requirements. Therefore, further investigation is needed to explore packaging methods that can stabilize irbesartan-levamlodipine combination tablets to improve medication safety.

[0078] Experiment Example 4: Examination of Packaging Forms

[0079] Referring to the packaging materials of irbesartan-amlodipine tablets and levamlodipine besylate tablets already on the market, this study designed to investigate the impact of different packaging formats on the product quality of irbesartan-levamlodipine combination tablets (150mg / 2.5mg). The investigation was conducted according to the table below:

[0080] Table 6

[0081]

[0082] [Note] Silica gel desiccant is used for all desiccants, with an amount of approximately 1g.

[0083] The influencing factors of the above samples under 50℃ conditions were studied, and the data are as follows:

[0084] Table 7. Results of stability study of irbesartan-levamlodipine compound tablets in different packaging forms

[0085]

[0086] The results showed that after 15 days of storage at 50℃, the content of aluminum-plastic samples did not change significantly, but related substances increased; the content of levamlodipine in cold aluminum samples decreased significantly; adding desiccants to aluminum-plastic and cold aluminum packaging did not significantly improve stability; the stability of bottled samples in group 5 was worse than that of aluminum-plastic and cold aluminum packaging, but unexpectedly, the content of bottled samples with desiccant in group 6 did not change significantly, and overall there was no significant difference from aluminum-plastic packaging. Based on these results, it is indicated that adding desiccants can improve product stability to a certain extent, and the effect of desiccants is more significant in bottling devices. Therefore, further investigation is needed regarding the bottled + desiccant packaging format.

[0087] Test Example 5: Investigation of Packaging Materials

[0088] For bottled packaging, the impact of the inner packaging material on the quality of irbesartan-amlodipine combination tablets (150mg / 2.5mg) was investigated according to the table below:

[0089] Table 8

[0090]

[0091] The influencing factors of the above samples under 50℃ conditions were studied, and the data are as follows:

[0092] Table 9. Results of stability studies on irbesartan-levamlodipine compound tablets packaged in different bottle materials.

[0093]

[0094] The results showed that after being placed at 50℃ for 15 days, there were no significant differences in the content and related substances of samples in groups 5, 7, 8, and 9, indicating that the material of the bottle body and cap has no significant impact on the stability of the product, and commonly used solid medicine bottle packaging materials can be considered.

[0095] Experimental Example 6: Investigation of Desiccant Types

[0096] For the "bottled + desiccant" packaging format, the impact of desiccant type on the product quality of irbesartan-amlodipine compound tablets (150mg / 2.5mg) was investigated according to the table below:

[0097] Table 10

[0098]

[0099] [Note] All oral solid medicine bottles are made of polypropylene + desiccant + oral solid medicine bottle cap.

[0100] The influencing factors of the above samples under 50℃ conditions were studied, and the data are as follows:

[0101] Table 11. Results of stability study of irbesartan-levamlodipine compound tablets in "bottled + desiccant" packaging.

[0102]

[0103] The results showed that after being placed at 50℃ for 15 days, the content of silica gel samples in group 6 did not change significantly, but the content of related substances showed an increasing trend. The content of molecular sieve samples in group 10 and mixed desiccants of silica gel and molecular sieve in groups 11-15 did not change significantly. The increase in related substances in molecular sieve samples in group 10 was the lowest, and the increase in related substances in mixed desiccants of silica gel and molecular sieve also decreased significantly. This indicates that molecular sieve desiccants and mixed desiccants of silica gel and molecular sieve are both superior for this product.

[0104] Experimental Example 7: Investigation of Desiccant Dosage

[0105] For the packaging format of "bottled + molecular sieve desiccant", the effect of desiccant dosage on the product quality of irbesartan-amlodipine compound tablets (150mg / 2.5mg) was investigated according to the table below:

[0106] Table 12

[0107]

[0108] [Note] All oral solid medicine bottles are made of polypropylene + desiccant + oral solid medicine bottle cap.

[0109] (1) Stability test

[0110] The influencing factors of the above samples under 50℃ conditions were studied, and the data are as follows:

[0111] Table 13. Stability Study Results of Irbesartan-Levoamlodipine Compound Tablets with "Bottled + Molecular Sieve Desiccant"

[0112]

[0113] The results showed that after being placed at 50℃ for 15 days, samples in groups 10 and 16-20 all met the quality standards. However, the related substances in samples in groups 10 and 16 showed an increasing trend, while the related substances in the other groups did not change significantly.

[0114] (2) Dissolution test

[0115] The dissolution curves of amlodipine besylate for samples in groups 10 and 16-20 at pH 6.8 are as follows:

[0116] Table 14 Dissolution curves of levamlodipine besylate in irbesartan-levamlodipine combination tablets

[0117]

[0118] The results showed that, under pH 6.8, the dissolution curves indicated that the 20th group of samples dissolved faster and had a lower f2 value.

[0119] Further testing of other product specifications using the relatively superior packaging methods described in Groups 17-19, and examining their stability and dissolution curves, showed that they all reached a level essentially consistent with those of Groups 17-19.

[0120] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0121] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, all of which fall within the protection scope of this application.

Claims

1. An irbesartan-levamlodipine pharmaceutical composition, characterized in that, The pharmaceutical composition comprises irbesartan and levamlodipine besylate, and is packaged in a plastic bottle containing a desiccant.

2. The pharmaceutical composition according to claim 1, characterized in that, The dosage of irbesartan is 75-300 mg and the dosage of amlodipine besylate is 1-10 mg; preferably, the dosage of irbesartan is 75-150 mg and the dosage of amlodipine besylate is 1-5 mg; more preferably, the dosage of irbesartan is 150-300 mg and the dosage of amlodipine besylate is 2.5-5 mg.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is in tablet form and further comprises pharmaceutically acceptable fillers, disintegrants, binders, flow aids, lubricants, and coating materials.

4. The pharmaceutical composition according to claim 3, characterized in that, The dosage of irbesartan is 150 mg, and the dosage of amlodipine besylate is 2.5 mg or 5 mg; it also includes microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, colloidal silica, magnesium stearate and film coating premix.

5. The pharmaceutical composition according to claim 3, characterized in that, The composition comprises, relative to the core, 24.96%-30.58% filler, 3.60%-4.80% disintegrant, 2.00%-2.70% binder, 1.00%-1.50% flow aid, and 1.00%-1.50% lubricant.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:1.1-7.8; preferably, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:1.56-5.2; more preferably, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:2.6-3.

9.

7. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The desiccant is selected from silica gel desiccant and / or molecular sieve desiccant.

8. The pharmaceutical composition according to claim 7, characterized in that, When the desiccant is a mixed desiccant containing silica gel desiccant and molecular sieve desiccant, the mass ratio of the silica gel desiccant to the molecular sieve desiccant is 1:0.42-2.

35.

9. A packaging method for improving the stability of an irbesartan-levamlodipine pharmaceutical composition, characterized in that, The pharmaceutical composition is packaged in a plastic bottle containing a desiccant. The mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine pharmaceutical composition is 1:1.1-7.

8.

10. The method according to claim 9, characterized in that, The mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:1.56-5.2; preferably, the mass ratio of the amount of desiccant in the bottle to the total amount of the irbesartan-amlodipine drug composition is 1:2.6-3.9.

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