Sacubitril valsartan sodium hydrochlorothiazide tablet and preparation method thereof
By optimizing the prescription dosage and selection of auxiliary materials for sakubalivalsartan sodium and hydrochlorothiazide, the problem of inconsistent dissolution and disintegration effects in compound antihypertensive drugs is solved, rapid disintegration and efficient dissolution are achieved, significantly improving the therapeutic effect of hypertension and reducing side effects.
Patent Information
- Application Number
- CN202510385665.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-29
- Publication Date
- 2025-07-11
AI Technical Summary
The dissolution effect and disintegration effect of different active ingredients in existing compound antihypertensive drugs is difficult to coordinate, resulting in unstable efficacy and increased risk of side effects, which complicates drug development.
By limiting the prescription dosage range of sakubalivalsartan sodium and hydrochlorothiazide, and combining specific pharmaceutical excipients such as refined microcrystalline cellulose and modified microcrystalline cellulose, the dissolution and dissolution characteristics are optimized, so that they completely dissolution within 5 minutes and achieve more than 75% in 60 minutes.
The rapid disintegration and efficient dissolution of sakubadder valsartan sodium hydrochlorothiazide tablets were achieved, which significantly improved the effect of hypertension control, reduced adverse reactions, and improved patient compliance.
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Abstract
Description
Technical Field
[0001] The present application relates to the field of pharmaceutical technology, and more specifically, it relates to a sacubitril / valsartan sodium and hydrochlorothiazide tablet and a preparation method thereof. Background Art
[0002] In contemporary medical practice, hypertension has become a global challenge affecting human health. Persistent high blood pressure not only increases the load on the cardio-cerebral system but also easily induces multiple organ function damage. Especially when combined with chronic diseases such as diabetes and kidney disease, the treatment difficulty increases significantly, which not only restricts the implementation of conventional treatment methods but also poses higher requirements for medication safety.
[0003] For the clinical intervention of hypertensive patients, it is usually necessary to comprehensively consider the individual differences of patients to implement precise treatment, and pay attention to key indicators such as the basic blood pressure value, cardiovascular risk coefficient, and combined symptom status at any time. The current treatment system mainly relies on five major categories of antihypertensive preparations, namely calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB), diuretics, and β-receptor antagonists. For severe cases with systolic blood pressure ≥ 160 mmHg or exceeding the target value by more than 20 mmHg, a dual-drug synergistic regimen is usually recommended. During the implementation of the treatment regimen, a dynamic monitoring mechanism needs to be established, and the dose combination should be adjusted in a timely manner according to the drug response of the patient.
[0004] Regarding the related technologies mentioned above, the inventor believes that although traditional single-component preparations can achieve the basic antihypertensive goal, there is generally an accumulation of side effect risks, which may cause disorders in the body's compensatory functions. The physical and chemical property differences of different active ingredients in compound preparations often make it difficult to coordinate the dissolution rate and disintegration properties, which not only affects the stability of drug efficacy but also increases the process complexity of new drug development. Summary of the Invention
[0005] In the related technologies, it is difficult to coordinate the dissolution effect of different active ingredients in compound antihypertensive drugs and the disintegration effect of the whole tablet, which causes difficulties in drug development. To improve this defect, the present application provides a sacubitril / valsartan sodium and hydrochlorothiazide tablet and a preparation method thereof.
[0006] In the first aspect, the present application provides a sacubitril / valsartan sodium and hydrochlorothiazide tablet, adopting the following technical solution: A sacubitril / valsartan sodium and hydrochlorothiazide tablet, the components of the sacubitril / valsartan sodium and hydrochlorothiazide tablet include sacubitril / valsartan sodium, hydrochlorothiazide, and pharmaceutical excipients. The prescribed amount of sacubitril / valsartan sodium is 10 - 200 mg, and the prescribed amount of hydrochlorothiazide is 6.25 - 25 mg; the pharmaceutical excipients include fillers, binders, disintegrants, glidants, and lubricants.
[0007] By adopting the above technical solution, the present application defines the prescription dosage ranges of sacubitril / valsartan sodium and hydrochlorothiazide. At the preferred ratio of the present application, the dissolution and disintegration characteristics of sacubitril / valsartan sodium and hydrochlorothiazide can reach a balance, with less interference between them. Overall, disintegration and release can be completed at a relatively fast speed, and complete disintegration can be achieved within 5 minutes, and a dissolution rate of more than 75% can be achieved within 60 minutes. On the one hand, sacubitril / valsartan sodium and hydrochlorothiazide can synergistically lower blood pressure. The vasodilatory effect of sacubitril / valsartan sodium can relieve the RAAS system that may be activated by thiazide drugs, reducing compensatory blood pressure rebound. Therefore, it has a good therapeutic effect on hypertensive patients. On the other hand, the potassium-preserving effect of sacubitril / valsartan sodium can partially offset the risk of electrolyte disorders caused by thiazide drugs, helping to avoid hypokalemia. Through the synergistic cooperation of the two, the hypertensive symptoms of patients can be effectively controlled, and the adverse reactions are not obvious. Using a compound preparation can also improve the compliance of patients, thereby strengthening the control effect on the hypertensive symptoms of patients.
[0008] Preferably, the prescription dosages of sacubitril / valsartan sodium and hydrochlorothiazide tablets are as follows: 10 - 200 mg of sacubitril / valsartan sodium, 6.25 - 25 mg of hydrochlorothiazide, 55 - 85 mg of filler, 2 - 15 mg of binder, 1 - 7 mg of disintegrant, 0.1 - 1.5 mg of glidant, and 0.5 - 2.0 mg of lubricant.
[0009] By adopting the above technical solution, the present application optimizes the prescription dosages of sacubitril / valsartan sodium and hydrochlorothiazide tablets. Through the synergistic cooperation of each component, good dissolution and disintegration effects can be achieved, and the vascular tension can be significantly improved, showing a significant therapeutic effect on hypertension.
[0010] Preferably, the binder is at least one of povidone, hypromellose, hydroxypropyl cellulose, and hydroxyethyl cellulose.
[0011] By adopting the above technical solution, within the dosage range defined in the present application, the above several binders can increase the binding effect between the drug powders, facilitating granulation and tableting, and improving the success rate of tableting.
[0012] Preferably, the disintegrant is at least one of crospovidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium.
[0013] By adopting the above technical solution, within the dosage range defined in the present application, the above several disintegrants can make the tablets quickly break into fine particles in gastrointestinal fluid, so that the functional components can be quickly dissolved and absorbed to play a role.
[0014] Preferably, the glidant is at least one of talc powder and silicon dioxide.
[0015] By adopting the above technical solution, within the dosage range defined in the present application, the above-mentioned several glidants can reduce the friction between particles, improve the powder fluidity, and increase the success rate of tabletting.
[0016] Preferably, the lubricant is at least one of magnesium stearate and stearic acid.
[0017] By adopting the above technical solution, within the dosage range defined in the present application, the above-mentioned several lubricants can reduce the friction between particles / particles and the die punch, reduce the sticking phenomenon, and increase the success rate of tabletting.
[0018] Preferably, the filler is at least one of microcrystalline cellulose, lactose, pregelatinized starch, calcium hydrogen phosphate, and starch.
[0019] By adopting the above technical solution, within the dosage range defined in the present application, the above-mentioned several fillers can play an ideal filling role, which is beneficial to the formation of tablets.
[0020] Preferably, the microcrystalline cellulose is refined microcrystalline cellulose, and the refined microcrystalline cellulose is prepared according to the following method: (1) Add refined cotton into hydrochloric acid, react under steam heating conditions, dilute with water after the reaction ends, and let it stand for stratification to obtain a slurry for standby; (2) Take the upper-layer slurry for centrifugal washing, and then dry it to obtain refined microcrystalline cellulose.
[0021] By adopting the above technical solution, the present application uses refined cotton as the raw material, first acid-hydrolyzes the refined cotton, and extracts the upper-layer slurry with a higher purity of microcrystalline cellulose after the acid-hydrolysis product stands for stratification, and separates refined microcrystalline cellulose from it. Compared with ordinary microcrystalline cellulose, refined microcrystalline cellulose reduces the adsorption of drug molecules caused by incompletely acid-hydrolyzed cotton fibers and free amorphous cellulose, so that drug molecules can have a higher dissolution rate, which is beneficial to the rapid onset of drugs.
[0022] Preferably, the pharmaceutical excipient further includes a dissolution aid, the dissolution aid includes modified microcrystalline cellulose, and the modified microcrystalline cellulose is prepared according to the following method: Take the remaining lower-layer slurry in the process of preparing refined microcrystalline cellulose, dry it after centrifugal washing to obtain crude microcrystalline cellulose, add the crude microcrystalline cellulose, co-reactant and fatty acid into an ethanol aqueous solution under nitrogen protection, mix under water bath heating conditions, and then add an oxidation-type initiator to react. After the reaction ends, perform suction filtration, wash and dry the filter cake to obtain modified microcrystalline cellulose.
[0023] By adopting the above technical solution, the present application reuses the remaining lower-layer slurry in the process of preparing refined microcrystalline cellulose, extracts crude microcrystalline cellulose, and under the action of an oxidative initiator, fatty acids can be grafted onto the glycoside units of the crude microcrystalline cellulose through a free radical reaction, thereby obtaining amphiphilic modified microcrystalline cellulose. The modified microcrystalline cellulose overcomes the adsorption caused by impurities in the crude microcrystalline cellulose and can promote the dissolution and diffusion of drugs through its amphiphilicity, which is beneficial to the rapid onset of drugs.
[0024] In a second aspect, the present application provides a method for preparing sacubitril / valsartan sodium and hydrochlorothiazide tablets, adopting the following technical solution.
[0025] A method for preparing sacubitril / valsartan sodium and hydrochlorothiazide tablets includes the following steps: (1) Mix sacubitril / valsartan sodium, hydrochlorothiazide, a filler, and a binder, add water and mix after stirring and shearing to obtain a soft material, and continue to stir and shear the soft material for later use; (2) Perform wet granulation on the soft material, sieve it, then dry and perform dry finishing, and sieve it again for later use; (3) Mix the dry material obtained after sieving in step (2) with the remaining pharmaceutical excipients, stir, and then press tablets to obtain sacubitril / valsartan sodium and hydrochlorothiazide tablets.
[0026] By adopting the above technical solution, the present application first prepares a soft material containing drug components, then uses the soft material to prepare a dry material, and then mixes the dry material with the remaining pharmaceutical excipients to obtain sacubitril / valsartan sodium and hydrochlorothiazide tablets. With the synergistic cooperation of various excipients, the sacubitril / valsartan sodium and hydrochlorothiazide tablets of the present application have a high tablet pressing success rate and tablet pressing quality.
[0027] In summary, the present application has the following beneficial effects: 1. The present application defines the prescription dosage range of sacubitril / valsartan sodium and hydrochlorothiazide. Under the preferred ratio of the present application, the dissolution and disintegration characteristics of sacubitril / valsartan sodium and hydrochlorothiazide can reach a balance, with less interference between them, and the overall can complete disintegration and release at a relatively fast speed, completely disintegrating within 5 minutes and achieving a dissolution rate of more than 75% within 60 minutes.
[0028] 2. By taking the sacubitril / valsartan sodium and hydrochlorothiazide tablets of the present application, the hypertension symptoms of patients can be effectively controlled, and the adverse reactions are not obvious. Using a compound preparation can also improve the compliance of patients, thereby strengthening the control effect on the hypertension symptoms of patients.
[0029] 3. In this application, purified cotton is used as the raw material. First, it is acid-hydrolyzed, and then the acid-hydrolyzed product is used to prepare purified microcrystalline cellulose and modified microcrystalline cellulose respectively, which helps to improve the dissolution effect of drugs and promotes the rapid onset of drugs. Detailed implementation manners
[0030] The following further elaborates on this application with reference to examples, preparation examples and comparative examples. The raw materials involved in this application are all commercially available.
[0031] Preparation examples of purified microcrystalline cellulose and modified microcrystalline cellulose The following takes Preparation Example 1 as an example for illustration.
[0032] Preparation Example 1 In this preparation example, hydrochloric acid is prepared by mixing and diluting a 0.35 mol / L hydrochloric acid solution and water in a weight ratio of 1:30.
[0033] In this preparation example, the purified microcrystalline cellulose is prepared according to the following method: (1) Add purified cotton to hydrochloric acid, preheat to 75 °C first, and then react for 40 min under the condition of steam heating at 100 °C. After the reaction, add 2 volumes of water for dilution, and let it stand for 4 h to obtain a layered slurry for standby; (2) Take the upper-layer slurry (accounting for 75% of the total volume of the slurry) for centrifugal washing until the pH of the discharged water is neutral, and dry the obtained material in a flash drying device with an inlet air temperature of 145 °C to obtain purified microcrystalline cellulose.
[0034] In this preparation example, the modified microcrystalline cellulose is prepared according to the following method: Take the remaining lower-layer slurry (accounting for 25% of the total volume of the slurry) in the process of preparing purified microcrystalline cellulose for centrifugal washing until the pH of the discharged water is neutral, and dry the obtained material in a flash drying device with an inlet air temperature of 145 °C to obtain crude microcrystalline cellulose; under nitrogen protection, according to the molar ratio of glycoside unit: stearic acid: co-reactant = 3:3:1, mix the crude microcrystalline cellulose, stearic acid and the co-reactant trifluoroacetic anhydride together, and add the mixture to an ethanol aqueous solution with an ethanol content of 30 wt% according to the weight ratio of the mixture: ethanol aqueous solution = 1:5, preheat under the condition of water bath heating at 50 °C, and then add a ferrous sulfate / hydrogen peroxide initiator equivalent to 0.8% of the total weight of the crude microcrystalline cellulose, co-reactant and stearic acid, and react for 8 h under the condition of water bath heating at 55 °C. After the reaction, carry out suction filtration, wash and dry the filter cake to obtain modified microcrystalline cellulose. Examples
[0035] Examples 1-5 The following takes Example 1 as an example for illustration.
[0036] Example 1 In this example, calcium hydrogen phosphate is selected as the filler, hydroxyethyl cellulose as the binder, croscarmellose sodium as the disintegrant, silicon dioxide as the glidant, and magnesium stearate as the lubricant.
[0037] This example provides a sacubitril / valsartan sodium and hydrochlorothiazide tablet, whose components include sacubitril / valsartan sodium, hydrochlorothiazide and pharmaceutical excipients. The pharmaceutical excipients include filler, binder, disintegrant, glidant and lubricant. The single - tablet prescription dosage of the sacubitril / valsartan sodium and hydrochlorothiazide tablet is as follows: sacubitril / valsartan sodium 10 mg, hydrochlorothiazide 6.25 mg, filler 55 mg, binder 2 mg, disintegrant 1 mg, glidant 0.1 mg, lubricant 0.5 mg.
[0038] This example provides a preparation method of the sacubitril / valsartan sodium and hydrochlorothiazide tablet, which includes the following steps: (1) According to the specification of 1000 tablets, sacubitril / valsartan sodium, hydrochlorothiazide, filler and binder are mixed, and after stirring and shearing, water is added for mixing to obtain a soft material, and the soft material is continuously stirred and sheared for standby; (2) The soft material is wet - sized, sieved, then dried and dry - sized, and sieved again for standby; (3) The dry material obtained after sieving in step (2) is mixed with the remaining pharmaceutical excipients, and after stirring, tableting is carried out to obtain the sacubitril / valsartan sodium and hydrochlorothiazide tablet.
[0039] As shown in Table 1, the main difference between Examples 1 - 5 lies in the different prescription dosages.
[0040] Table 1 Prescription Dosage (unit: mg) Example 6 The difference between this example and Example 5 is that the filler is a mixture of starch and pre - gelatinized starch in a weight ratio of 5:1, the binder is a mixture of hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of 1:1, the disintegrant is a mixture of crospovidone, sodium carboxymethyl starch and sodium carboxymethyl cellulose in a weight ratio of 1:1:2, the glidant is talc powder, and the lubricant is stearic acid.
[0041] Example 7 The difference between this example and Example 6 is that the disintegrant is crospovidone, and the filler is a mixture of lactose and microcrystalline cellulose ( microcrystalline cellulose) in a weight ratio of 1:1.
[0042] Example 8 The difference between this example and Example 7 is that the microcrystalline cellulose is the refined microcrystalline cellulose of Preparation Example 1.
[0043] Example 9 The difference between this example and Example 8 is that the pharmaceutical excipient further includes a dissolution aid, the prescribed amount of the dissolution aid is 4.5 mg, and the dissolution aid is the modified microcrystalline cellulose of Preparation Example 1.
[0044] Example 10 The difference between this example and Example 9 is that the microcrystalline cellulose selected is microcrystalline cellulose.
[0045] Comparative Example Comparative Examples 1-2 As shown in Table 2, the main difference between Comparative Examples 1-2 and Example 1 lies in the different prescribed amounts of each component.
[0046] Table 2 Prescribed Amounts (unit: mg) Performance Detection Test Method I. Disintegration Test According to the disintegration time limit inspection method 0921 recorded in the fourth part of the Chinese Pharmacopoeia 2020 edition, the disintegration time limit was detected. The results showed that the disintegration time limits of Examples 1-10 were all within 5 minutes.
[0047] II. Dissolution Test It was determined according to the dissolution and release determination method (General Rule 0931, Method 1). Using 900 ml of phosphate buffer solution (pH 6.8) as the dissolution medium and the rotation speed of 100 revolutions per minute, and operating according to this method, the dissolution at 60 minutes was determined. The determination results are shown in Table 3.
[0048] Table 3 Dissolution Combining Examples 1-7 and Comparative Example 1 and combining with Table 3, it can be seen that the dissolution degrees measured in Examples 1-7 are all higher than those in Comparative Example 1 and Comparative Example 2, indicating that within the prescribed amount range defined in this application, both sacubitril / valsartan sodium and hydrochlorothiazide can achieve good dissolution effects, and the dissolution degree of more than 75% can be achieved within 60 minutes, which can produce an effective therapeutic effect on hypertension.
[0049] Combining Example 7 and Example 8 and referring to Table 3, it can be seen that the dissolution rate measured in Example 8 is higher than that in Example 7. This is because compared with ordinary microcrystalline cellulose, the refined microcrystalline cellulose reduces the adsorption of drug molecules caused by incompletely acid-hydrolyzed cotton fibers and amorphous cellulose, so that the drug molecules can have a higher dissolution rate, which is beneficial to the rapid onset of the drug.
[0050] Combining Example 8 and Example 9 and referring to Table 3, it can be seen that the dissolution rate measured in Example 9 is higher than that in Example 8. This is because the modified microcrystalline cellulose has amphiphilicity, which can promote the dissolution and diffusion of the drug, and is beneficial to the rapid onset of the drug.
[0051] Combining Example 7, Example 8 - 10 and referring to Table 3, it can be seen that the dissolution rate measured in Example 10 does not increase significantly compared with that in Example 7, indicating that when the refined microcrystalline cellulose and the modified microcrystalline cellulose are not used in combination, the dissolution effect of the sacubitril / valsartan sodium and hydrochlorothiazide tablets is limited.
[0052] The above embodiments are only explanations of the present application, not limitations on the present application. After reading this specification, those skilled in the art can make modifications to the embodiments of the present application without creative contributions according to needs, 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 sacubitril / valsartan sodium and hydrochlorothiazide tablet, characterized in that, The components of the sacubitril / valsartan sodium and hydrochlorothiazide tablets include sacubitril / valsartan sodium, hydrochlorothiazide and pharmaceutical excipients. The prescription dosage of sacubitril / valsartan sodium is 10 - 200 mg, and the prescription dosage of hydrochlorothiazide is 6.25 - 25 mg; the pharmaceutical excipients include fillers, binders, disintegrants, glidants and lubricants.
2. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 1, wherein The prescription dosages of the sacubitril / valsartan sodium and hydrochlorothiazide tablets are as follows: 10 - 200 mg of sacubitril / valsartan sodium, 6.25 - 25 mg of hydrochlorothiazide, 55 - 85 mg of filler, 2 - 15 mg of binder, 1 - 7 mg of disintegrant, 0.1 - 1.5 mg of glidant, and 0.5 - 2.0 mg of lubricant.
3. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 2, characterized in that, The binder is at least one of povidone, hypromellose, hydroxypropyl cellulose, and hydroxyethyl cellulose.
4. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 2, wherein The disintegrant is at least one of crospovidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose sodium.
5. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 2, wherein The glidant is at least one of talc powder and silicon dioxide.
6. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 2, wherein The lubricant is at least one of magnesium stearate and stearic acid.
7. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 2, characterized in that, The filler is at least one of microcrystalline cellulose, lactose, pregelatinized starch, calcium hydrogen phosphate, and starch.
8. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 7, characterized in that, The microcrystalline cellulose is refined microcrystalline cellulose, and the refined microcrystalline cellulose is prepared according to the following method: (1) Add refined cotton to hydrochloric acid, react under steam heating conditions, dilute with water after the reaction ends, stand for layering to obtain a slurry, and set aside; (2) Take the upper-layer slurry for centrifugal washing, and then dry it to obtain refined microcrystalline cellulose.
9. The sacubitril / valsartan sodium and hydrochlorothiazide tablets according to claim 8, characterized in that, The pharmaceutical excipients also include dissolution aids, and the dissolution aids include modified microcrystalline cellulose. The modified microcrystalline cellulose is prepared according to the following method: Take the remaining lower-layer slurry in the process of preparing refined microcrystalline cellulose, centrifugally wash it and then dry it to obtain crude microcrystalline cellulose. Under nitrogen protection, add the crude microcrystalline cellulose, co-reactant and fatty acid to an ethanol aqueous solution, mix under water bath heating conditions, then add an oxidation-type initiator for reaction. After the reaction ends, perform suction filtration, wash and dry the filter cake to obtain modified microcrystalline cellulose.
10. The preparation method of the sacubitril / valsartan sodium and hydrochlorothiazide tablets according to any one of claims 1-9, characterized in that, It includes the following steps: (1) Mix sacubitril / valsartan sodium, hydrochlorothiazide, filler and binder, add water for mixing after stirring and shearing to obtain a soft material, and continue to stir and shear the soft material, and set aside; (2) Perform wet granulation on the soft material, sieve it, then dry and perform dry finishing, and sieve it again for standby; (3) Mix the dry material obtained by sieving in step (2) with the remaining pharmaceutical excipients, stir and then press tablets to obtain sacubitril / valsartan sodium and hydrochlorothiazide tablets.