Compound antihypertensive pharmaceutical composition

Abstract

The invention relates to the technical field of medicines, and particularly discloses a compound antihypertensive pharmaceutical composition. The pharmaceutical composition provided by the invention selects sacubitril valsartan sodium and indapamide as active ingredients, and within a prescription dosage range limited by the application, the two medicines can fully realize an antihypertensive effect through a synergistic effect, and the renal function of a patient is effectively improved. Through cooperation of the two components, the hypertension symptom of a patient can be effectively controlled, the adverse reaction is not obvious, and the compliance of the patient can be improved by adopting the compound preparation, so that the control on the blood pressure of the patient is enhanced.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and more specifically, it relates to a compound antihypertensive drug composition. Background Art

[0002] In the field of modern medicine, hypertension has become a global public health problem. Hypertension will increase the burden on important organs such as the heart and cerebrovascular vessels, and trigger a series of serious complications. When hypertension coexists with other stubborn diseases, the threat to the health of patients is even greater, which restricts the surgery and medication of patients and brings huge challenges to treatment.

[0003] When treating hypertension, it is necessary to select appropriate antihypertensive drugs according to the specific conditions of patients, such as blood pressure level, cardiovascular risk factors, and comorbidities. Commonly used antihypertensive drugs include calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB), diuretics, β-receptor antagonists, etc. For patients with blood pressure ≥160 / 100 mmHg or 20 / 10 mmHg higher than the target blood pressure, combination therapy can be adopted, such as a single-pill combination of two antihypertensive drugs. In clinical treatment, it is often necessary to adjust the drug dosage and treatment plan in a timely manner according to the blood pressure changes and drug reactions of patients to obtain better treatment effects.

[0004] Regarding the related technologies described above, the inventor believes that although the single-component antihypertensive drugs on the market at present can lower blood pressure, they are likely to deteriorate the physical condition of patients due to adverse reactions, increasing the risk of subsequent treatment. When using compound drugs, not only are the adverse reaction situations more complex, but it is often difficult to achieve ideal dissolution and disintegration effects due to the different physicochemical properties of different active ingredients, causing certain difficulties in drug development. Summary of the Invention

[0005] In the related technologies, the adverse reactions of single-component antihypertensive drugs will increase the risk of subsequent treatment, while compound antihypertensive drugs not only have more complex adverse reactions, but also the dissolution and disintegration effects are difficult to reach an ideal state, causing difficulties in drug development. To improve the above defects, this application provides a compound antihypertensive drug composition.

[0006] This application provides a compound antihypertensive drug composition, adopting the following technical solution: A compound antihypertensive drug composition, the components of the compound antihypertensive drug composition include sacubitril / valsartan sodium, indapamide and pharmaceutical excipients, and each tablet of the compound antihypertensive drug composition contains 50 - 500 mg of sacubitril / valsartan sodium and 1 - 10 mg of indapamide.

[0007] By adopting the above technical solutions, the pharmaceutical composition of the present application selects sacubitril / valsartan sodium and indapamide as active ingredients, and limits the content ranges of the two in each tablet. Under the preferred ratio conditions of the present application, the dissolution and disintegration characteristics of sacubitril / valsartan sodium and indapamide can achieve a balance, with less interference between them, and the whole can complete disintegration and release at a relatively fast speed. Sacubitril / valsartan sodium can inhibit the degradation of natriuretic peptides by neprilysin, thereby exerting diuretic, natriuretic, vasodilating, and anti-sympathetic effects. Its angiotensin receptor blocking effect can avoid the compensatory activation of the RAS after neprilysin is inhibited; indapamide exerts its antihypertensive effect by inhibiting the reabsorption of water and electrolytes in the cortical diluting segment of the distal renal tubule. Within the prescribed dosage range of the present application, these two drugs can produce a synergistic antihypertensive effect, and due to the specific combination method of the present application, the synergistic antihypertensive effect of these two components can take effect quickly. Therefore, the composition of the present application has a high antihypertensive efficiency. In addition, the adverse reactions of sacubitril / valsartan sodium include hyperkalemia and an increased risk of cardiovascular diseases, while indapamide is a non-thiazide diuretic with a long half-life and cardiovascular protective effects, and can reduce blood potassium. Therefore, they can achieve good complementarity in terms of adverse reactions, reducing the occurrence of adverse reactions. Through the synergistic cooperation of the two, the hypertension symptoms of patients can be effectively controlled, and the adverse reactions are not obvious. The use of a compound preparation can also improve the compliance of patients, thereby strengthening the control effect on the hypertension symptoms of patients.

[0008] Preferably, the pharmaceutical excipients include fillers, binders, disintegrants, glidants, and lubricants.

[0009] By adopting the above technical solutions, the present application preferably selects the types of components included in the pharmaceutical excipients. Fillers can increase the weight or volume of tablets, facilitating the formation of tablets; binders can increase the binding effect between drug powders, facilitating granulation and tableting; disintegrants can cause tablets to quickly break into fine particles in gastrointestinal fluids, enabling the rapid dissolution and absorption of the active ingredients of the drug, and fully exerting the efficacy of the active ingredients; glidants can reduce the friction between particles, improving the fluidity of powders (granules); lubricants reduce the friction between particles / particles and the die, contributing to the smooth formation of tablets. Through the synergistic cooperation of the above components and the active ingredients, the tablets of the present application can achieve good release effects, continuously and steadily release the active ingredients after disintegration, thereby reducing the uncertain factors for the treated patients, contributing to the rapid control of the condition of patients with hypertension complicated with diabetes, and overcoming the inconveniences of existing drugs.

[0010] Preferably, the filler includes one or more of microcrystalline cellulose, lactose, pregelatinized starch, calcium hydrogen phosphate, and starch.

[0011] By adopting the above technical solution, components such as microcrystalline cellulose, pregelatinized starch, lactose, and starch can associate hydrogen bonds inside the tablet, enabling the tablet to have a relatively large hardness after being compression-molded. When the tablet absorbs moisture, the hydrogen bonds formed by the above components are damaged, so the hindrance to tablet disintegration is relatively small. Under the action of hydrogen bonds, it can produce a synergistic effect with the disintegrant, which is beneficial to the dissolution of the active ingredient. Among the above several fillers, microcrystalline cellulose, pregelatinized starch, and lactose all have good compression moldability. Pregelatinized starch itself also has a certain disintegrating effect, which helps to improve the dissolution effect of the active ingredient. Calcium hydrogen phosphate has the characteristic of not absorbing moisture, which can reduce the adhesion between components and is beneficial to the rapid dispersion after tablet disintegration.

[0012] Preferably, the binder includes one or more of povidone, hypromellose, and hydroxypropyl cellulose.

[0013] By adopting the above technical solution, povidone, hypromellose, and hydroxypropyl cellulose have good film-forming properties and adhesiveness, can effectively bond the drug powder together, and can overcome the defect of poor compression moldability of starch when starch is used as the disintegrant, improving the compressibility of the tablet, thereby helping to obtain a tablet with good mechanical strength. While ensuring the molding effect, the influence of these binders on the release kinetic characteristics of the active ingredient is relatively small, so the prepared tablets can better meet the pharmacopoeia standards.

[0014] Preferably, the disintegrant includes one or more of cross-linked povidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0015] By adopting the above technical solution, cross-linked povidone has a relatively high drug release amount. When sodium carboxymethyl starch, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose are mixed with cross-linked povidone, the disintegration effect can be effectively improved by capillary and swelling effects, so as to achieve rapid and controllable disintegration behavior, enabling the tablet to be rapidly dispersed in the gastrointestinal tract, which helps to improve the bioavailability of sacubitril / valsartan sodium and indapamide.

[0016] Preferably, the glidant includes one or more of talc powder and colloidal silicon dioxide.

[0017] By adopting the above technical solution, these types of glidants can significantly improve the powder fluidity, reduce the weight difference during the tableting process, and improve the production efficiency and the appearance uniformity of the tablets.

[0018] Preferably, the lubricant includes one or more of magnesium stearate and stearic acid.

[0019] By adopting the above technical solutions, these types of lubricants can effectively reduce the frictional resistance of the mold during tablet pressing, prevent sticking and punching phenomena, and at the same time regulate the dissolution curve of the tablets to meet the design requirements.

[0020] Preferably, the tablet core of the compound antihypertensive drug composition comprises the following components in parts by weight: 10 - 200 parts of sacubitril / valsartan sodium, 0.5 - 5 parts of indapamide, 60 - 80 parts of filler, 1 - 10 parts of binder, 1 - 5 parts of disintegrant, 0.1 - 1.0 part of glidant, and 0.8 - 1.5 parts of lubricant.

[0021] By adopting the above technical solutions, the tablets of the present application can achieve good release effects, and the drug efficacy is stable, and the active ingredients can be continuously and steadily released after disintegration.

[0022] Preferably, the pharmaceutical excipient further comprises a solubilizer, and the solubilizer comprises hydroxypropyl-β-cyclodextrin.

[0023] By adopting the above technical solutions, hydroxypropyl-β-cyclodextrin has good hydrophilicity itself and can form an inclusion complex with indapamide. The dissolution effect of this inclusion complex in the gastrointestinal tract is significantly better than that of indapamide, thereby overcoming the defect of poor solubility of indapamide. Therefore, the addition of hydroxypropyl-β-cyclodextrin improves the release effect of indapamide, helps to fully exert the synergistic effect of indapamide and sacubitril / valsartan sodium, and can effectively relieve the symptoms of hypertensive patients.

[0024] Preferably, the solubilizer further comprises poloxamer.

[0025] By adopting the above technical solutions, poloxamer is a surfactant molecule, in which the lipophilic group is polyoxypropylene group and the hydrophilic group is polyoxyethylene group. When cooperating synergistically with the inclusion solubilization effect of hydroxypropyl-β-cyclodextrin, it can further improve the solubility of indapamide, which is beneficial to fully exert the synergistic effect of indapamide and sacubitril / valsartan sodium, and can effectively relieve the symptoms of hypertensive patients.

[0026] In summary, the present application has the following beneficial effects: 1. The drug composition of the present application selects sacubitril / valsartan sodium and indapamide as active ingredients. Within the prescribed dosage range of the present application, these two drugs can fully achieve the antihypertensive effect through synergistic effects and effectively improve the renal function of patients. Through their synergistic cooperation, the hypertensive symptoms of patients can be effectively controlled, and the adverse reactions are not obvious. Using the compound preparation can also improve the compliance of patients, thereby strengthening the control of patients' blood pressure.

[0027] 2. Through the synergistic cooperation of pharmaceutical excipients and active ingredients, the tablets of the present application can achieve good release effects, continuously and steadily release the active ingredients after disintegration, thereby reducing the uncertainties for the treated patients, helping to quickly control the conditions of patients with hypertension complicated with diabetes, and overcoming the inconveniences of existing drugs. Detailed implementation manners

[0028] The present application will be further described in detail below with reference to examples and comparative examples. All raw materials involved in the present application are commercially available. Examples

[0029] Examples 1 - 5 Taking Example 1 as an example for illustration below.

[0030] Example 1 This example provides a compound antihypertensive drug composition in the form of plain tablets, which includes the following components (calculated according to the prescription dosage): 50 mg of sacubitril / valsartan sodium, 1 mg of indapamide, 120 mg of filler, 2 mg of binder, 2 mg of disintegrant, 0.2 mg of glidant, and 1.6 mg of lubricant; the filler is selected as microcrystalline cellulose, the binder is hydroxypropyl methylcellulose, the disintegrant is sodium carboxymethyl starch, the glidant is talc powder, and the lubricant is magnesium stearate.

[0031] The compound antihypertensive drug composition of this example is prepared according to the following steps: (1) Mix sacubitril / valsartan sodium, indapamide, filler, binder, and disintegrant, mix at a rotation speed of 10 rpm for 15 min, and then pass through a 30 - mesh sieve to obtain a preliminary mixture for standby; (2) Mix the preliminary mixture, glidant, and lubricant, mix at a rotation speed of 8 rpm for 20 min, and then perform tabletting treatment with a hardness of 15 kg, controlling the weight difference to be ±5%, to obtain tablet cores; (3) Perform film - coating processing on the tablet cores to obtain the compound antihypertensive drug composition.

[0032] As shown in Table 1, the main difference between Examples 1 - 5 lies in the different raw material ratios of the tablet cores.

[0033] Table 1 Raw material ratios of tablet cores Example 6 The difference between this example and Example 5 is that the filler is composed of lactose and pre - gelatinized starch mixed in a weight ratio of 3:5.

[0034] Example 7 The difference between this example and Example 5 is that the filler is composed of lactose, pregelatinized starch, and dibasic calcium phosphate mixed in a weight ratio of 3:5:1.

[0035] Example 8 The difference between this example and Example 7 is that the binder is composed of povidone and hypromellose mixed in a weight ratio of 1:1.

[0036] Example 9 The difference between this example and Example 8 is that the disintegrant is crospovidone.

[0037] Example 10 The difference between this example and Example 8 is that the disintegrant is composed of sodium carboxymethylcellulose and low-substituted hydroxypropyl cellulose mixed in a weight ratio of 2:1.

[0038] Example 11 The difference between this example and Example 8 is that the disintegrant is composed of crospovidone, sodium carboxymethylcellulose, and low-substituted hydroxypropyl cellulose mixed in a weight ratio of 3:2:1.

[0039] Example 12 The difference between this example and Example 11 is that the glidant is composed of talc and colloidal silicon dioxide mixed in a weight ratio of 2:1.

[0040] Example 13 The difference between this example and Example 12 is that the lubricant is composed of magnesium stearate and stearic acid mixed in a weight ratio of 4:1.

[0041] Example 14 The difference between this example and Example 13 is that the pharmaceutical excipients further include a solubilizer, and the solubilizer includes hydroxypropyl-β-cyclodextrin, and the prescribed amount of hydroxypropyl-β-cyclodextrin in the prescription is 15 mg.

[0042] Example 15 The difference between this example and Example 14 is that the solubilizer further includes poloxamer, and the prescribed amount of poloxamer in the prescription is 5 mg.

[0043] Comparative Example Comparative Example 1 The difference between this comparative example and Example 1 is that the compound antihypertensive drug composition includes the following components (calculated according to the prescribed amount in the prescription): sacubitril / valsartan sodium 15 mg, indapamide 0.8 mg, filler 120 mg, binder 2 mg, disintegrant 2 mg, glidant 0.2 mg, lubricant 1.6 mg.

[0044] Comparative Example 2 The difference between this comparative example and Example 1 is that the compound antihypertensive drug composition includes the following components (calculated according to the prescription dosage): sacubitril / valsartan sodium 500 mg, indapamide 15 mg, filler 200 mg, binder 20 mg, disintegrant 2 mg, glidant 0.2 mg, lubricant 2 mg.

[0045] Performance detection test method I. Dissolution test Determined according to the dissolution and release determination method (General Principle 0931, Method 1). Using 900 ml of phosphate buffer solution (pH 6.8) as the dissolution medium, the rotation speed is 100 revolutions per minute. Operate according to the law and sample at 45 minutes. The test results are shown in Table 2.

[0046] II. Disintegration test According to the disintegration time limit inspection method in Part IV of the Chinese Pharmacopoeia 2020 Edition, 0921, the disintegration time limit was detected. The results are shown in Table 1; using water as the dissolution medium, the dissolution volume is 900 mL, and the disintegration time limit t was detected by the paddle method at 50 rpm. Taking t ≤ 5 min and no sudden release phenomenon as the qualified standard, the results are shown in Table 3.

[0047] Table 2 Dissolution Table 3 Disintegration test Sample Test result Sample Test result Example 1 Qualified Example 10 Qualified Example 2 Qualified Example 11 Qualified Example 3 Qualified Example 12 Qualified Example 4 Qualified Example 13 Qualified Example 5 Qualified Example 14 Qualified Example 6 Qualified Example 15 Qualified Example 7 Qualified Comparative Example 1 Unqualified Example 8 Qualified Comparative Example 2 Unqualified Example 9 Qualified / / Combining Examples 1-5 and Comparative Examples 1-2 and combining Tables 2-3, it can be seen that the dissolution degrees measured in Examples 1-5 are higher than those in Comparative Examples 1-2, and the disintegration effect is better. This is because under the preferred ratio conditions of this application, the dissolution and disintegration characteristics of the two components of sacubitril / valsartan sodium and indapamide can reach a balance, with less interference between each other, and the overall can complete disintegration and release at a relatively fast speed. Thanks to the specific combination method of this application, the synergistic antihypertensive effect of these two components can take effect quickly. Therefore, the composition of this application has a high antihypertensive efficiency and effectively strengthens the control effect on the hypertension symptoms of patients.

[0048] Combined with Example 5 and Examples 6 - 13 and in combination with Table 2 - 3, it can be seen that by optimizing the filler, binder, disintegrant, glidant and lubricant, the compound antihypertensive drug composition of the present application can not only maintain a high dissolution rate, but also has a better disintegration effect. This is because within the range of the active ingredient content defined in the present application, the filler can increase the weight or volume of the tablet, which is beneficial to the formation of the tablet; the binder can increase the bonding effect between the powder particles to facilitate granulation and tableting; the disintegrant can make the tablet quickly break into fine particles in the gastrointestinal fluid, so that the active ingredient of the drug can be quickly dissolved and absorbed, and the efficacy of the active ingredient can be fully exerted; the glidant can reduce the friction between particles and improve the fluidity of the powder (granules); the lubricant reduces the friction between particles / particles and the die, which helps the smooth formation of the tablet. Through the synergistic cooperation of the above components and the active ingredient, the tablets of the present application can achieve a good release effect, and can continuously and steadily release the active ingredient after disintegration, thereby reducing the uncertain factors in the treatment process, helping to quickly control the condition of patients with hypertension complicated with diabetes, and overcoming the inconveniences of existing drugs.

[0049] Combined with Example 14 and Example 13 and in combination with Table 2 - 3, it can be seen that the drug dissolution rate measured in Example 14 is higher. This is because the hydroxypropyl - β - cyclodextrin added in Example 13 has good hydrophilicity itself and can form an inclusion complex with indapamide. The dissolution effect of this inclusion complex in the gastrointestinal tract is significantly better than that of indapamide, thereby overcoming the defect of poor solubility of indapamide. Therefore, the addition of hydroxypropyl - β - cyclodextrin improves the release effect of indapamide, helps to fully exert the synergistic effect of indapamide and sacubitril / valsartan sodium, and can effectively relieve the symptoms of hypertensive patients.

[0050] Combined with Example 14 and Example 15 and in combination with Table 2 - 3, it can be seen that the drug dissolution rate measured in Example 15 is higher. This is because poloxamer is a surface - active molecule, in which the lipophilic group is polyoxypropylene group and the hydrophilic group is polyoxyethylene group. When combined with the inclusion - solubilization effect of hydroxypropyl - β - cyclodextrin, it can further improve the solubility of indapamide, which is beneficial to fully exert the synergistic effect of indapamide and sacubitril / valsartan sodium, and can effectively relieve the symptoms of hypertensive patients.

[0051] Combined with Examples 1 - 15, it can be seen that the compound antihypertensive drug compositions in the examples of the present application can all achieve disintegration within 5 minutes and there is no burst release phenomenon, indicating that the tablets of the present application can achieve a good release effect, and can continuously and steadily release the active ingredient after disintegration, thereby reducing the uncertain factors in the treatment process, helping to quickly control the condition of patients with hypertension complicated with diabetes, and overcoming the inconveniences of existing drugs.

[0052] The above embodiments are merely explanations of the present application and not limitations thereof. After reading this specification, those skilled in the art may make modifications to the embodiments of the present application that do not contribute creatively, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A compound antihypertensive drug composition, characterized in that: The components of the compound antihypertensive pharmaceutical composition include sacubitril valsartan sodium, indapamide and pharmaceutical excipients. Each tablet of the compound antihypertensive pharmaceutical composition contains 50-500 mg of sacubitril valsartan sodium and 1-10 mg of indapamide.

2. The antihypertensive compound composition according to claim 1, characterized in that: The pharmaceutical excipients include fillers, binders, disintegrants, glidants and lubricants.

3. The antihypertensive compound composition according to claim 2, characterized in that: The filler comprises one or more of microcrystalline cellulose, lactose, pregelatinized starch, calcium hydrogen phosphate, and starch.

4. The compound antihypertensive pharmaceutical composition according to claim 2, characterized in that: The binder includes one or more of povidone, hypromellose, and hydroxypropyl cellulose.

5. The compound antihypertensive pharmaceutical composition according to claim 2, characterized in that: The disintegrant comprises one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

6. The compound antihypertensive pharmaceutical composition according to claim 2, characterized in that: The glidant includes one or more of talc and colloidal silicon dioxide.

7. The antihypertensive compound composition according to claim 2, characterized in that: The lubricant includes one or more of magnesium stearate and stearic acid.

8. The compound antihypertensive pharmaceutical composition according to claim 2, characterized in that: The core of the compound antihypertensive drug composition comprises the following components in parts by weight: 10-200 parts of sacubitril-valsartan sodium, 0.5-5 parts of indapamide, 60-80 parts of filler, 1-10 parts of binder, 1-5 parts of disintegrant, 0.1-1.0 parts of glidant, and 0.8-1.5 parts of lubricant.

9. The compound antihypertensive pharmaceutical composition according to claim 2, characterized in that: The pharmaceutical excipients further include a solubilizer, and the solubilizer includes hydroxypropyl-β-cyclodextrin.

10. The compound antihypertensive pharmaceutical composition according to claim 9, characterized in that: The solubilizing agents also include poloxamers.

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