CN113712927B - Compound valsartan levoamlodipine tablet and preparation method thereof - Google Patents
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Abstract
The invention discloses a compound valsartan levoamlodipine tablet and a preparation method thereof. The formula of the compound valsartan levamlodipine tablet is 1) or 2) as follows: 1) 160 parts of valsartan, 3.47 parts of levamlodipine besylate, 80-120 parts of diluent, 30-50 parts of disintegrant, 2-4 parts of glidant, 8-12 parts of lubricant and 20-40 parts of coating agent; 2) 80 parts of valsartan, 3.47 parts of levamlodipine besylate, 40-60 parts of diluent, 10-30 parts of disintegrant, 1-3 parts of glidant, 3-5 parts of lubricant and 5-15 parts of coating agent; the diluent is one or two of microcrystalline cellulose, lactose and calcium hydrophosphate, and the water content is 0.1-1.0%. The invention adopts the dry granulation process, and the valsartan has higher viscosity and is more viscous when meeting water, so the dry granulation process avoids adding a wetting agent during granulation, is easy for large-scale production operation, reduces the production time and improves the production efficiency; in addition, the drying agent is added in the package, so that the stability of the product is improved.
Description
Technical Field
The invention relates to a compound valsartan levoamlodipine tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
The activator of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from angiotensin I under the action of Angiotensin Converting Enzyme (ACE). Angiotensin II binds to specific receptors on the cell membrane of tissues and has a number of physiological roles, which can be directly or indirectly involved in blood pressure regulation. Angiotensin II has a strong vasoconstrictor effect, has a direct pressure-boosting effect, and can promote sodium reabsorption, stimulate aldosterone secretion, and the like.
Valsartan is a highly specific Angiotensin (AT) II receptor antagonist which acts selectively on the AT1 receptor subtype, the AT1 receptor subtype being responsive to the known effects of angiotensin II, the AT2 receptor subtype being not associated with cardiovascular effects, and valsartan being devoid of any partial agonist activity AT the AT1 receptor. Valsartan has 20000 times stronger affinity for the AT1 receptor than the AT2 receptor.
According to clinical research, valsartan is proved to be effective in reducing blood pressure and controlling blood pressure, and can prevent hypertension from being combined with kidney diseases or diabetic renal nephropathy from progressing. The valsartan can be replaced for patients with systolic heart failure who cannot tolerate ACE I, the combination of the valsartan and ACE I can be considered for patients with systolic heart failure who are contraindicated by a beta receptor blocker, the valsartan has an obvious curative effect, and the valsartan can be used as a first-choice medicine of compound combination medicines.
Amlodipine is a dihydropyridine calcium antagonist. It is characterized by slow speed of binding and dissociation with receptor, so that the action of the medicine is maintained for a long time. For patients with myocardial ischemia, it can increase cardiac output and coronary blood flow, increase myocardial oxygen supply, reduce oxygen consumption, and improve exercise ability.
After amlodipine is singly used or valsartan is singly used, the blood pressure of patients can be converted into a valsartan amlodipine tablet for combined administration when the blood pressure of the patients is not properly controlled, and the amlodipine tablet is mainly used for treating essential hypertension and patients who cannot sufficiently control the blood pressure by single medicine treatment.
The valsartan amlodipine tablets have good clinical use effect, and the literature reports that the valsartan amlodipine tablets have more obvious curative effect on treating the senile hypertension and have no obvious adverse drug reaction problem, so that the valsartan amlodipine tablets are the first choice for the quality of the senile hypertension patients.
Disclosure of Invention
The invention aims to provide a compound valsartan levamlodipine tablet, which is prepared by compounding valsartan with levamlodipine besylate, and the application of the levamlodipine besylate improves the compound drug effect and avoids adverse reaction caused by the levamlodipine besylate; the invention adopts dry granulation, improves the stability of the product, reduces the production time, improves the production efficiency and is convenient for large-scale production.
The compound valsartan levamlodipine tablet provided by the invention is prepared from valsartan, levamlodipine besylate, a diluent, a disintegrating agent, a glidant, a lubricant and a coating agent, and the mass ratio of the components is 1) or 2);
1) 160 parts of valsartan, 3.47 parts of levamlodipine besylate, 80-120 parts of diluent, 30-50 parts of disintegrant, 2-4 parts of glidant, 8-12 parts of lubricant and 20-40 parts of coating agent;
2) 80 parts of valsartan, 3.47 parts of levamlodipine besylate, 40-60 parts of diluent, 10-30 parts of disintegrant, 1-3 parts of glidant, 3-5 parts of lubricant and 5-15 parts of coating agent.
The diluent can be one or two of microcrystalline cellulose, lactose and calcium hydrophosphate;
the water content of the diluent is 0.1-1.0%, such as microcrystalline cellulose M112, anhydrous calcium hydrogen phosphate and the like.
The disintegrant can be one or two of crospovidone, croscarmellose sodium and sodium carboxymethyl starch;
the glidant may be colloidal silicon dioxide;
the lubricant may be magnesium stearate;
the coating agent may be a film coated premix (gastric soluble).
The invention provides a preparation method of a compound valsartan levoamlodipine tablet, which comprises the following steps:
s1, placing the valsartan, the levamlodipine besylate, the diluent, the disintegrant, the glidant and a part of the lubricant in a wet granulation mixer for mixing;
s2, performing dry granulation on the material obtained in the step S1 to obtain granules;
and S3, mixing the particles with the rest of the lubricant, and then tabletting and coating the mixture to obtain the compound feed.
In the above preparation method, in step S1, the mixing conditions are as follows:
the stirring speed is 200-500 rpm; the shearing rotating speed is 1000-2000 rpm; the mixing time is 3-8 min.
In step S1, the amount of the lubricant is 50 to 80% of the total amount.
In the above preparation method, in step S2, the dry granulation conditions are as follows:
the rotating speed of the press roll is 5-20 rpm; the pressure of the press roll is 40-100 bar; the granulation rotating speed is 100-200 rpm; the aperture of the screen mesh is 0.5-1.5 mm.
In the above preparation method, in step S3, the mixing conditions are as follows:
the mixing speed is 5-15 rpm, and the mixing time is 5-15 min;
the hardness of the tablet obtained by tabletting is 100-150N;
the coating is carried out at the temperature of 60-80 ℃, and the weight of the coated product is increased by 5-10%.
The amlodipine is a racemic compound, contains equal amount of levorotatory isomer and dextrorotatory isomer, namely racemic amlodipine, in the amlodipine, the levorotatory isomer really has pharmacodynamic action with organisms, and the dextrorotatory isomer has no effect and certain side effect, so the invention adopts the levamlodipine besylate to replace the amlodipine besylate in the compound preparation, the pharmacodynamic effect is 2 times of that of the racemate, and the adverse reaction brought by the dextrorotatory isomer is avoided.
The compound valsartan levamlodipine tablet prepared by the method has uniform particles and good fluidity, and the introduction of water is reduced by using the process, so that the relevant substances of the product in stability research can be effectively ensured to meet the requirements, and the product stability is good.
The dry granulation process is adopted, and the valsartan is high in viscosity and is sticky when meeting water, so that a wetting agent is not added during granulation, the large-scale production operation is easy, the production time is shortened, and the production efficiency is improved; in addition, the invention adds desiccant (such as solid medicinal sheet molecular sieve desiccant and solid medicinal paper bagged silica gel desiccant) in the package, thereby improving the stability of the product.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 Dry Process for preparing Valsartan Levamlodipine tablet
This example provides a formulation and method for preparing 1 ten thousand tablets of valsartan levoamlodipine (specification 160mg/2.5 mg) as follows:
the composition of formula 1 is shown in table 1, wherein the microcrystalline cellulose is microcrystalline cellulose M112, and the moisture content is 0.2%. Meanwhile, the recipes using the microcrystalline cellulose pH101 (water content of 4.5%) and the microcrystalline cellulose pH102 (water content of 4.3%) were set as the comparative recipe 1 and the comparative recipe 2, respectively.
TABLE 1 composition of valsartan levamlodipine tablet formulation
A dry granulation process was used, as shown in table 2:
TABLE 2 Dry granulation Process steps
TABLE 3 Dry granulation Process conditions
| Rotational speed of feed screw | Parameter(s) |
| Rotational speed of feed | 30-60rpm |
| Rotational speed of the press roll | 5-20rpm |
| Pressure of press roll | 40-100bar |
| Rotational speed of granulator | 100-200rpm |
| Pore diameter of whole grain sieve | 0.5-1.5mm |
The particles prepared by the embodiment are uniform, the flowability is good, the introduction of water is reduced by using the process, the relevant substances of the product can be effectively ensured to meet the requirements, and the product stability is good.
When the valsartan levamlodipine tablet prepared in the example is subjected to influencing factor placement, the results are shown in table 4, and it can be seen that when microcrystalline cellulose M112 with small moisture is used and placed for 10 days under the influencing factor condition, the related substances meet the requirements and are obviously better than the related substances obtained by using the comparative prescription sample.
TABLE 4 detection results of substances related to influence factors of valsartan levamlodipine tablets
The tablets prepared in this example have good mixing uniformity and the contents are all within the qualified range, and the dissolution rate of the coated tablets is detected according to the following data:
TABLE 5 dissolution results of valsartan levoamlodipine tablet formulation
Example 2 Dry Process for preparing Valsartan Levamlodipine tablet
This example provides a formulation and method for preparing 1 ten thousand tablets of valsartan levamlodipine (specification 160mg/2.5 mg), as follows
The formulation is shown in Table 6, in which the microcrystalline cellulose is microcrystalline cellulose M112 and the water content is 0.2%.
TABLE 6 composition of valsartan levoamlodipine tablet formulation
A dry granulation process was used, as shown in table 7:
TABLE 7 Dry granulation Process steps
The samples prepared in this example have good mixing uniformity and the content is within the qualified range, and the dissolution rate detection of the coated tablets in the medium with pH6.8 is carried out, and the data is as follows:
TABLE 8 dissolution results of valsartan levoamlodipine tablet formulation
The study on the dissolution curve shows that the dosage of the disintegrating agent has little influence on the dissolution of the product, and the dissolution can meet the requirement.
Example 3 Dry Process for preparing Valsartan Levamlodipine tablet
This example provides a formulation and method for preparing 1 ten thousand tablets of valsartan levoamlodipine (specification 160mg/2.5 mg) as follows:
the formulation is shown in Table 9, in which the microcrystalline cellulose is microcrystalline cellulose M112 and the water content is 0.2%.
TABLE 9 composition of valsartan levoamlodipine tablet formulation
A dry granulation process was used, as shown in table 10:
TABLE 10 Dry granulation Process steps
The samples prepared in this example were mixed well and contained amounts within a qualified range, and the coated tablets were tested for dissolution, with the following data:
TABLE 11 dissolution of valsartan levoamlodipine tablet formulation
The investigation on the dissolution curve shows that different diluents and disintegrants have small influence on the dissolution of the product, and the dissolution rate can meet the requirement.
Example 4 Dry preparation of Valsartan levoamlodipine tablet tablets
This example provides a formulation and method for preparing 1 ten thousand valsartan levoamlodipine tablets (specification 80mg/2.5 mg) as follows:
the formulation composition is shown in table 12, the microcrystalline cellulose is microcrystalline cellulose M112, and the moisture content is 0.2%.
TABLE 12 composition of valsartan levoamlodipine tablet formulation
A dry granulation process was used, as shown in table 13:
TABLE 13 Dry granulation Process steps
The samples prepared in this example were mixed well and contained amounts within a qualified range, and the coated tablets were tested for dissolution, with the following data:
TABLE 14 dissolution of valsartan levoamlodipine tablet formulation
The invention reduces the dosage by replacing amlodipine besylate in the original compound, improves the drug effect of the compound on the same dosage and avoids the side effect caused by amlodipine besylate.
Example 5 packaging of Valsartan levoamlodipine tablets
The stability of the valsartan levamlodipine tablets of example 4 in different packages is shown in table 15, and it can be seen that the stability of the product can be improved by placing a desiccant (solid pharmaceutical paper, silica gel desiccant in a bag, in an amount of 1.0 g) in the package.
Table 15 investigation results of influence factors of valsartan levoamlodipine tablets
Claims (3)
1. The compound valsartan levamlodipine tablet is prepared from valsartan, levamlodipine besylate, a diluent, a disintegrant, a glidant, a lubricant and a coating agent, and the mass ratio of the components is as follows:
160 parts of valsartan, 3.47 parts of levamlodipine besylate, 104.53 parts of diluent, 40 parts of disintegrant, 3 parts of glidant, 9 parts of lubricant and 20-40 parts of coating agent;
the diluent is microcrystalline cellulose, and the microcrystalline cellulose is microcrystalline cellulose M112;
the disintegrant is crospovidone;
the glidant is colloidal silicon dioxide;
the lubricant is magnesium stearate;
the coating agent is a film coating premix,
the preparation method of the compound valsartan levoamlodipine tablet comprises the following steps:
s1, placing the valsartan, the levamlodipine besylate, the diluent, the disintegrant, the glidant and a part of the lubricant in a wet granulation mixer for mixing;
s2, performing dry granulation on the material obtained in the step S1 to obtain granules;
s3, mixing the granules with the rest of the lubricant, tabletting and coating to obtain the finished product,
in the step S1, the stirring speed is 300rpm, the shearing speed is 2000rpm, the mixing time is 5min,
in the step S2, the rotating speed of a press roll is 5-20 rpm, the pressure of the press roll is 40-100 bar, the granulating rotating speed is 100-200 rpm, the aperture of a screen mesh is 0.5-1.5 mm,
in the step S3, the mixing speed is 10rpm, the mixing time is 10min, the hardness of the tablet obtained by tabletting is 150N, the coating is performed at 60 to 80 ℃, and the weight gain after the coating is 5%.
2. The method for preparing the compound valsartan levamlodipine tablet as claimed in claim 1, comprising the following steps:
s1, placing the valsartan, the levamlodipine besylate, the diluent, the disintegrant, the glidant and a part of the lubricant in a wet granulation mixer for mixing;
s2, performing dry granulation on the material obtained in the step S1 to obtain granules;
and S3, mixing the granules with the rest of the lubricant, and then tabletting and coating the mixture to obtain the finished product.
3. The method for packaging a compound valsartan levoamlodipine tablet as claimed in claim 1, wherein the method comprises the following steps: and adding a drying agent into the package, wherein the drying agent is a solid medicinal flaky molecular sieve drying agent or a solid medicinal paper bagged silica gel drying agent.
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| CN101843615A (en) * | 2010-06-25 | 2010-09-29 | 包丽昕 | Dispersible tablets containing valsartan and amlodipine besylate and preparation method thereof |
| CN109498626A (en) * | 2017-09-14 | 2019-03-22 | 北京万全德众医药生物技术有限公司 | A kind of stable compound preparation valsartan amlodipine prescription and preparation method thereof |
| CN107951849B (en) * | 2017-12-15 | 2020-07-07 | 湖南千金协力药业有限公司 | Amlodipine besylate tablet and preparation method thereof |
| CN108553435A (en) * | 2018-06-08 | 2018-09-21 | 华益药业科技(安徽)有限公司 | A kind of Valsartan piece and preparation method thereof |
| CN109260160A (en) * | 2018-08-30 | 2019-01-25 | 天津仁生医药科技有限公司 | A kind of valsartan amlodipine tablet and preparation method thereof |
| CN110693884A (en) * | 2019-11-22 | 2020-01-17 | 江苏亚邦强生药业有限公司 | Compound preparation valsartan amlodipine tablet and preparation method thereof |
| CN113181180A (en) * | 2021-05-07 | 2021-07-30 | 苏州康恒研新药物技术有限公司 | Preparation method of valsartan amlodipine sustained-release tablet |
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