CN110433163B - Levamlodipine besylate composition and preparation method thereof - Google Patents
Levamlodipine besylate composition and preparation method thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A—HUMAN NECESSITIES
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- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention relates to a benzene sulfonic acid levo-amlodipine composition and a preparation method thereof. The composition comprises the following components in parts by weight: 2-8 parts of levamlodipine besylate, 3-18 parts of a glidant, 80-150 parts of a filler, 3-18 parts of a disintegrant and 0.3-1.7 parts of a lubricant. The composition has obviously improved dissolution curve, related substances, content uniformity, content measurement and data in influence factor test investigation in different media, has obviously improved administration convenience and taste compared with tablets, improves administration compliance of patients, and does not resist administration.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a benzene sulfonic acid levorotatory amlodipine composition and a preparation method thereof.
Background
The levamlodipine besylate is obtained by effectively splitting amlodipine as a parent drug, is an original fourth-generation calcium antagonist in China, and is clinically used for treating hypertension, chronic stable angina and variant angina. By adopting a chiral drug resolution technology, a dextrorotatory part which has almost no pharmacological activity and is relatively high in toxicity in amlodipine is removed, only a levorotatory part with antihypertensive activity is reserved, and the drug effect of the same dose of levorotatory amlodipine is 2 times that of a racemate and is 1000 times that of a dextrorotatory body. The dosage can be halved, the antihypertensive curative effect is consistent with that of amlodipine, and the adverse reaction is correspondingly reduced.
Levamlodipine besylate
At present, the variety of the levamlodipine besylate which is mainly sold in the market is the levamlodipine besylate tablet produced by Shihuida pharmaceutical industry group (Jilin) limited company, the trade name is Shihuida, and the specification is 2.5 mg. By referring to the technical guide principle of the stability research of chemical drugs (bulk drugs and preparations), the technical guide principle of the dissolution test of a general oral solid preparation, the technical documents of 'Chinese pharmacopoeia' of 2015 edition and the like, the research on the dissolution curves of the levoamlodipine besylate tablets (Shihuida) from different media, related substances (namely impurities), content uniformity, content measurement, influence factors and the like. The fact that the data of related substances and content uniformity of the levamlodipine besylate tablet (Shihuida) in the stability investigation test shows that the data gradually decline along with the prolonging of the storage time is discovered. In the influencing factor test, the data of related substances and optical purity of the levamlodipine besylate tablet (Shihudada) are greatly changed. In the examination of the dissolution curves of different media, the difference of data and RSD (%) between the accumulative dissolution points of the levamlodipine besylate tablet (Shihudada) are also quite large.
In addition, the levamlodipine besylate tablet (Shihuida) is a tablet without a film coating, and a patient is easy to stick in the oral cavity when taking the tablet, so that the patient can feel bitter in mouth obviously.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a benzene sulfonic acid levamlodipine composition and a preparation method thereof.
The invention aims to provide a levamlodipine besylate composition, which has obviously improved dissolution curves, related substances (namely impurities), content uniformity, content measurement and data in influence factor test investigation in different media, has obviously improved administration convenience and mouthfeel compared with tablets, improves the medication compliance of patients and does not resist administration.
The invention also aims to provide a preparation method of the levamlodipine besylate composition.
In order to achieve the above object of the present invention, the present invention adopts the following technical solutions.
On one hand, the invention provides a levamlodipine besylate composition, which comprises the following components in parts by weight: 2-8 parts of levamlodipine besylate, 3-18 parts of a glidant, 80-150 parts of a filler, 3-18 parts of a disintegrant and 0.3-1.7 parts of a lubricant.
Preferably, in the composition, the levamlodipine besylate is 3.47-6.94 parts, preferably 3.47 parts.
Preferably, in the above composition, the glidant is 5 to 15 parts, preferably 5 parts.
Preferably, in the above composition, the filler is 90 to 130 parts, preferably 126.03 parts.
Preferably, in the above composition, the disintegrant is 5 to 15 parts, preferably 5 parts.
Preferably, in the above composition, the lubricant is 0.5 to 1.5 parts, preferably 0.5 parts.
Preferably, in the above composition, the glidant is selected from anhydrous calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate, preferably calcium hydrogen phosphate dihydrate.
Preferably, in the above composition, the filler is selected from the group consisting of microcrystalline cellulose SH-102 and starch, preferably microcrystalline cellulose SH-102.
Preferably, in the above composition, the disintegrant is selected from croscarmellose sodium, hydroxypropylmethyl cellulose and crospovidone, preferably croscarmellose sodium.
Preferably, in the above composition, the lubricant is selected from talc and magnesium stearate, preferably magnesium stearate.
Preferably, the composition is a capsule formulation.
On the other hand, the invention provides a preparation method of the levamlodipine besylate composition, which comprises the following steps:
(1) sieving the levamlodipine besylate, the filler, the glidant, the disintegrant and the lubricant for later use;
(2) weighing levamlodipine besylate and a disintegrating agent according to a formula, filling into the same clean plastic bag, manually shaking, and preliminarily mixing; then, weighing a part of filler and the mixed powder, and putting the mixture and the mixed powder into a three-dimensional operation mixer for mixing; adding a flow aid and a part of the rest filling agent, and continuously mixing; finally adding the lubricant and the rest of the filler, mixing, and sieving the mixture;
(3) and (5) carrying out intermediate detection. Measuring the content of the main drug in the mixed powder, calculating the theoretical loading, filling into capsules, and subpackaging the finished products.
Preferably, in the above production method, in the step (1), the sieving means sieving with a 60-100 mesh sieve; preferably, the levoamlodipine besylate passes through a 100-mesh sieve, the filler passes through a 60-mesh sieve, and the flow aid, the disintegrant and the lubricant pass through a 80-mesh sieve.
Preferably, in the above preparation method, in the step (2), the amount of the filler added for the first time among the three times of adding the filler is 30 to 35 w/w% of the total filler, and the amount of the filler added for the second time is 45 to 55 w/w% of the total filler.
In a specific embodiment, the preparation method of the present invention comprises the steps of:
the levoamlodipine besylate is sieved by a 100-mesh sieve, the filling agent is sieved by a 60-mesh sieve, and the glidant, the disintegrating agent and the talcum powder are sieved by a 80-mesh sieve for later use.
0.347kg of levamlodipine besylate and 0.500kg of disintegrant are weighed and put into the same clean plastic bag, and shaken by hand for preliminary mixing. Weighing 4.000kg of filler and the mixed powder, putting into a three-dimensional running mixer, and mixing at the frequency of 40Hz for 10 min; adding 6.000kg of filler and 0.500kg of glidant, and running for 5min at the frequency of 40 Hz; adding the rest filler, and mixing at 40Hz frequency for 30 min; adding pulvis Talci 0.050kg, mixing for 10min, and sieving the mixture with 60 mesh sieve once.
And (5) detecting an intermediate. Measuring the content of the main drug in the mixed powder, calculating the theoretical loading, filling into capsules, and subpackaging the finished products.
In a specific embodiment, the composition is a capsule formulation, formulated as follows:
the preparation method of the capsule comprises the following steps:
the levoamlodipine besylate is sieved by a 100-mesh sieve, the microcrystalline cellulose is sieved by a 60-mesh sieve, and the calcium hydrogen phosphate dihydrate, the cross-linked sodium carboxymethyl cellulose and the magnesium stearate are sieved by a 80-mesh sieve for later use.
0.347kg of levamlodipine besylate and 0.500kg of croscarmellose sodium are weighed, put into the same clean plastic bag, shaken by hand and mixed preliminarily. Weighing 4.000kg of microcrystalline cellulose and the mixed powder, putting into a three-dimensional running mixer, and mixing at the frequency of 40Hz for 10 min; adding microcrystalline cellulose 6.000kg and calcium hydrogen phosphate dihydrate 0.500kg, and running at 40Hz frequency for 5 min; adding the rest microcrystalline cellulose, and mixing at 40Hz frequency for 30 min; adding magnesium stearate 0.050kg, mixing for 10min, and sieving the mixture with 60 mesh sieve once.
And (5) detecting an intermediate. Measuring the content of the main drug in the mixed powder, calculating the theoretical loading, filling into capsules, and subpackaging the finished products.
Compared with the prior art, the composition has small batch difference of dissolution curves in different media, and good quality controllability; the data of related substances, content uniformity, content measurement and influence factor test investigation are obviously improved, and the composition is more stable than the levamlodipine besylate tablets in the prior art under high temperature, high humidity and illumination; the composition is obviously improved in the aspects of convenience in taking and mouthfeel compared with tablets, improves the medication compliance of patients, and does not resist taking.
Drawings
FIG. 1: dissolution profile of levamlodipine besylate capsules in ph2.0 hydrochloric acid (n ═ 12) (similar);
FIG. 2: dissolution profile of levamlodipine besylate capsules in ph4.5 acetate (n ═ 12) (similar);
FIG. 3: dissolution profile of levamlodipine besylate capsules in ph6.8 phosphate (n ═ 12) (similar); and
FIG. 4: the dissolution curve of levamlodipine besylate capsules in water (n-12) is similar,
wherein, the self-made capsule 161101 in fig. 1 to 4 refers to the prescription 10, and the reference preparation 161509-2 refers to levamlodipine besylate tablet (shihudada).
Detailed Description
The impurities D, E, F referred to in the following examples are as follows:
example 1 Levamlodipine besylate composition
A levamlodipine besylate capsule preparation is disclosed, and the formula is as follows:
the preparation method of the capsule comprises the following steps:
the levoamlodipine besylate is sieved by a 100-mesh sieve, the microcrystalline cellulose is sieved by a 60-mesh sieve, and the calcium hydrogen phosphate dihydrate, the cross-linked sodium carboxymethyl cellulose and the magnesium stearate are sieved by a 80-mesh sieve for later use.
0.347kg of levamlodipine besylate and 0.500kg of croscarmellose sodium are weighed, put into the same clean plastic bag, shaken by hand and mixed preliminarily. Weighing 4.000kg of microcrystalline cellulose and the mixed powder, putting into a three-dimensional running mixer, and mixing at the frequency of 40Hz for 10 min; adding microcrystalline cellulose 6.000kg and calcium hydrogen phosphate dihydrate 0.500kg, and running at 40Hz frequency for 5 min; adding the rest microcrystalline cellulose, and mixing at 40Hz frequency for 30 min; adding magnesium stearate 0.050kg, mixing for 10min, and sieving the mixture with 60 mesh sieve once.
And (5) detecting an intermediate. Measuring the content of the main drug in the mixed powder, calculating the theoretical loading, filling into capsules, and subpackaging the finished products.
Example 2 Levamlodipine besylate composition
A levamlodipine besylate capsule preparation is disclosed, and the formula is as follows:
the preparation method of the capsule comprises the following steps:
the levoamlodipine besylate is sieved by a 100-mesh sieve, the microcrystalline cellulose is sieved by a 60-mesh sieve, and the calcium hydrogen phosphate dihydrate, the cross-linked sodium carboxymethyl cellulose and the magnesium stearate are sieved by a 80-mesh sieve for later use.
0.347kg of levamlodipine besylate and 1.000kg of croscarmellose sodium are weighed, put into the same clean plastic bag, shaken manually and mixed preliminarily. Weighing 4.000kg of microcrystalline cellulose and the mixed powder, putting into a three-dimensional running mixer, and mixing at the frequency of 40Hz for 10 min; adding microcrystalline cellulose 6.000kg and calcium hydrogen phosphate dihydrate, mixing to 1.000kg, and running at 40Hz frequency for 5 min; adding the rest microcrystalline cellulose, and mixing at 40Hz frequency for 30 min; adding 0.100kg of magnesium stearate, mixing for 10min, and sieving the mixture once with a 60-mesh sieve.
And (5) detecting an intermediate. Measuring the content of the main drug in the mixed powder, calculating the theoretical loading, filling into capsules, and subpackaging the finished products.
EXAMPLE 3 screening of glidant classes
The same formulation and preparation as in example 1 was used, except that the glidants used were tested in the presence of anhydrous dibasic calcium phosphate as a glidant in addition to the dibasic calcium phosphate dihydrate used in example 1.
The flowability (angle of repose) and the content uniformity of the formulation were measured, and the results were as follows:
angle of repose, content uniformity data comparison
| Classes of glidants | Anhydrous calcium hydrogen phosphate | Dibasic calcium phosphate dihydrate |
| Fluidity (angle of repose) | 40.2° | 34.6° |
| Content uniformity | 12 | 3 |
In the capsule filling step in the investigation process, we find that the phenomenon that the content of the capsule gradually increases occurs in the filling process by using anhydrous calcium hydrogen phosphate as a flow aid without adjusting filling parameters, while the content of the capsule is kept stable by using calcium hydrogen phosphate dihydrate as the flow aid, and specific data are as follows.
Content data comparison in filling process
Example 4 screening experiment of disintegrant types
The same formulation and preparation method as in example 1 were used except that the disintegrant used was determined to be hydroxypropylmethylcellulose and crospovidone, respectively, in addition to croscarmellose sodium in example 1.
The dissolution curves of the above formulations in hydrochloric acid of pH2.0 were determined, wherein the formulations using croscarmellose sodium had significant advantages over the other two disintegrants in the respective cumulative dissolution point values and the respective RSD (%) data, as shown in the following table
Dissolution profile in hydrochloric acid at pH2.0
EXAMPLE 5 screening experiment of adjuvant amount
The inventors designed multiple sets of experiments and measured the dissolution profiles of each formulation and control by HPLC. Finally, the inventors have unexpectedly discovered the prescription 10 for further investigation.
Prescription design summary of levamlodipine besylate capsules
The inventor determines the dissolution curves of the prescription 10 and the levoamlodipine besylate tablet (shihuida) in different mediums by a high performance liquid chromatography method and calculates a similarity factor. 10000 lab scale-up were performed for recipe 10, and the dissolution profiles (see fig. 1 to 4 for details) of different media (ph2.0 hydrochloric acid, ph4.5 acetate, ph6.8 phosphate and water) were measured to calculate similarity factors, which were determined as the final recipe.
Example 6 stability experiment
1. Experimental sample
Levamlodipine besylate capsules, prepared from example 1 of this patent.
Levamlodipine besylate tablets (Shihuida) were purchased from Shihuida pharmaceutical group (Jilin) Limited.
2. Investigation of high temperature, high humidity, and light stability
2.1 investigation project and method
According to the guiding principle of the stability test of the raw material medicaments and the pharmaceutical preparations of 9001 in the pharmacopoeia of the people's republic of China, the stability of the levamlodipine besylate capsules and the levamlodipine besylate tablets is investigated, and the method comprises the following steps:
investigation of influence factors
2.2 test results
Results of Levamlodipine besylate capsules
Results of Levamlodipine besylate tablets
And (4) conclusion: levamlodipine besylate capsule: when the film is placed under the condition of high humidity of 92.5% for 5 days, the moisture absorption weight gain is 9.30%, and the moisture absorption weight gain exceeds 5%, so other items under the condition are not considered; the product is placed for 30 days under the condition of high humidity of 75 percent, and related substances, dissolution, content and optical purity are not changed; standing at 60 deg.C for 30 days, increasing impurity D from 0.09% to 0.28%, increasing amplitude to 0.19%, increasing total impurity from 0.22% to 0.57%, increasing amplitude to 0.35%, and keeping other impurities unchanged; the content, the dissolution degree and the optical purity have no obvious change; placing the mixture at the high temperature of 40 ℃ for 30 days, wherein the impurity D is increased from 0.09% to 0.12%, the amplification is 0.03%, the total impurity is increased from 0.22% to 0.24%, other impurities are almost unchanged, and the content, the dissolution rate and the optical purity are not obviously changed; when the product is placed under the condition of strong light irradiation for 30 days, the impurity D is increased from 0.09% to 0.82%, the amplification is 0.73%, the maximum unknown single impurity is increased from 0.04% to 0.12%, the amplification is 0.08%, the total impurity is increased from 0.22% to 1.68%, and the amplification is 1.46%. The content is reduced from 101.5 percent to 96.9 percent, and the reduction amplitude is 4.6 percent. The dissolution rate is reduced from 95.6 percent to 85.9 percent, the reduction amplitude is 9.7 percent, and the optical purity is not changed.
Levamlodipine besylate tablets: when the film is placed under the condition of high humidity of 92.5% for 5 days, the moisture absorption weight gain is 13.59%, and is more than 5%, so other items under the condition are not considered; placing the mixture for 30 days under the condition of 75% high humidity, wherein the impurity D is increased to 0.03% from undetected content, the maximum unknown single impurity is increased to 0.22% from 0.10%, the amplification is 0.12%, the total impurity is increased to 0.53% from 0.15%, the amplification is 0.38%, the content, the dissolution rate and the optical purity are unchanged; when the product is placed at the high temperature of 60 ℃ for 30 days, the impurity D is increased to 0.71 percent from undetected value, the amplification is 0.71 percent, the total impurity is increased to 1.34 percent from 0.15 percent, the amplification is 1.19 percent, the content is reduced to 96.2 percent from 100.7 percent, the reduction is 4.5 percent, and the dissolution rate and the optical purity are almost unchanged; standing at 40 deg.C for 30 days, the impurity D increases from no detection to 0.07%, the amplification is 0.07%, the total impurity increases from 0.15% to 0.26%, the amplification is 0.11%, the content, dissolution rate, and optical purity almost have no change; when the product is placed under the condition of strong light irradiation for 30 days, the impurity D is increased from undetected value to 1.58 percent, the increase is 1.58 percent, the maximum unknown single impurity is increased from 0.10 percent to 0.29 percent, the increase is 0.19 percent, the content is reduced from 100.7 percent to 88.5 percent, the reduction is 12.2 percent, the dissolution rate is reduced from 92.7 percent to 81.6 percent, the reduction is 11.1 percent, and the optical purity is reduced from 99.437 to 98.954 percent.
And (4) conclusion: the result shows that the impurity D of the levamlodipine besylate capsule related substance has the greatest influence on single impurity under high temperature and illumination. The dissolution rate of the levamlodipine besylate tablets has influence on the content and related substances of the levamlodipine besylate tablets under high temperature and high humidity and illumination, but the influence on the levamlodipine besylate tablets is larger than that of the levamlodipine besylate capsules, and the change trend is consistent.
3. Accelerated, long term stability study
3.1 investigation items and methods
3.2 accelerated test investigation
Acceleration test result of levamlodipine besylate capsule
Results of accelerated test of levoamlodipine besylate tablets
3.3 Long term test investigation
Long-term test results of levamlodipine besylate capsules
Long-term test results of levamlodipine besylate tablets
3.4 comparative data analysis
And (4) conclusion: through the investigation of stability tests, the levamlodipine besylate capsules have stable indexes, and related substances and content data have no obvious change. The levo-amlodipine besylate tablet (Shihuida) has obvious increase of related substance data from 3 months of acceleration, partial data exceeds qualified limit, content data change is obvious, and content uniformity data change amplitude is large.
In accelerated test investigation, the distribution range of the content uniformity data of the levamlodipine besylate capsules is 6.9-3.32, and no obvious change is caused. The content uniformity of the levamlodipine besylate tablet (Schhuuda) is obviously increased along with the time, and is increased from 4.02 at the beginning to 12.86.
4. Examination of dissolution curves
In order to verify the difference in dissolution curves between the capsule of the present invention and the existing levamlodipine besylate tablet (shihuda) in each lot, the following experiment was performed:
4.1 Levamlodipine besylate capsules production verification batch-to-batch variation analysis
Levamlodipine besylate capsules were prepared from the formulation and method of example 1 in three batches, with the batch numbers 161101, 161102, 161103, respectively. The dissolution curves of 4 media were measured, and the inter-lot differences were analyzed.
4.1.1 Levamlodipine besylate capsules 161101, 161102, 161103pH2.0 hydrochloric acid dissolution Curve determination
The dissolution curves of three batches of levamlodipine besylate capsules 161101, 161102 and 161103 in hydrochloric acid with pH of 2.0 were measured, and the results are as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of single points is about 5 percent; the RSD at each time point is basically consistent and is between 5.66% and 2.22%.
4.1.2 Levamlodipine besylate capsules 161101, 161102, 161103pH4.5 acetate dissolution Curve assay
The dissolution curves of three batches of levamlodipine besylate capsules 161101, 161102 and 161103 in acetate at pH4.5 were measured, and the results are as follows:
and (3) analysis: the accumulated dissolution base of each time point has no difference among batches, and the RSD of each time point is basically consistent and is between 8.65 and 3.41 percent.
4.1.3 Levamlodipine besylate capsules 161101, 161102, 161103pH6.8 phosphate dissolution Curve assay
The dissolution curves of three batches of levamlodipine besylate capsules 161101, 161102 and 161103 in phosphate at pH6.8 were measured, and the results are as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of a single point is about 2 percent; the RSD at each time point was substantially the same, between 8.60% and 3.86%.
4.1.4 determination of Water dissolution Curve of Levamlodipine besylate capsules 161101, 161102, 161103
The dissolution curves of three batches of levamlodipine besylate capsules 161101, 161102 and 161103 in water were measured, and the results are as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of a single point is about 4 percent; RSD of each time point is basically consistent, and the RSD is more than 10 percent except for 5min and 15min individual time points, and all other time points are less than 10 percent and between 14.09 percent and 2.79 percent.
In conclusion, the dissolution curves of the levamlodipine besylate capsules in various media have small batch difference and good quality controllability.
4.2 analysis of the differences between different batches of Levamlodipine besylate tablets (Shihuida)
Levamlodipine besylate tablets (Shihuida) are purchased in two batches, wherein the batches are 160913-2 and 170442 respectively. The dissolution curves of 4 media were measured, and the lot-to-lot variation was analyzed.
4.2.1 Levamlodipine besylate tablet (Shihuida) 160913-2, 170442pH2.0 hydrochloric acid dissolution Curve determination
The dissolution curves of two batches of samples 160913-2 and 170442 of levamlodipine besylate tablet (shihudada) in hydrochloric acid with pH of 2.0 are respectively measured, and the results are as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of single-point dissolution is about 12 percent; the RSD of each time point is basically consistent, and the RSD of the time point of 5min is more than 10 percent and is between 19.05 percent and 3.07 percent.
4.2.2 Levamlodipine besylate tablet (Shihuida) 160913-2, 170442pH4.5 acetate dissolution Curve assay
The dissolution curves of two batches of samples 160913-2 and 170442 of levamlodipine besylate tablet (shihuda) in acetate with pH4.5 are measured, and the results are as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of single-point dissolution is about 8 percent; the RSD of each time point is basically consistent, and the RSD of the time point of 5min is more than 10 percent and is between 9.87 percent and 2.91 percent.
4.2.3 measurement of L-amlodipine besylate tablet (Shihuida) 160913-2, 170442pH6.8 phosphate dissolution Curve
Dissolution curves of two batches of samples 160913-2, 170442 of levamlodipine besylate tablet (shihuida) in ph6.8 phosphate were measured, and the results were as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is basically consistent, and the maximum difference of single-point dissolution is about 9 percent; the RSD of each time point is basically consistent, and the RSD of the time point of 5min is more than 10 percent and is between 20.65 percent and 3.19 percent.
4.2.4 determination of Water dissolution Curve of Levamlodipine besylate tablets (Shihuida) 160913-2, 170442
The dissolution curves of two batches of samples 160913-2 and 170442 of levamlodipine besylate tablet (shihuida) in water were measured, and the results were as follows:
and (3) analysis: the accumulated dissolution of each time point among batches is greatly different, and the maximum difference of single-point dissolution is about 20 percent; the RSD at each time point varied greatly, with RSD at various time points being greater than 10% and between 39.57% and 3.37%.
In conclusion, the dissolution curve of the levamlodipine besylate tablet (shihuida) in the medium in 4 is greatly different among different batches, and especially in an aqueous medium, the difference of the data of the accumulative dissolution rate among different batches is obvious, so that the quality control of the preparation is not facilitated.
4.3 comparison of the capsules of the present invention with Levamlodipine besylate tablets (Shihuida)
The comparison shows that the data difference and RSD (%) of the levamlodipine besylate capsules in different media are obviously superior to those of the levamlodipine besylate tablets (Shihudada).
5 summary of the invention
The test batches 161101, 161102 and 161103 of the levamlodipine besylate capsules and the tablets (shihudada) 160913-2 and 170442 of the levamlodipine besylate capsules are used for carrying out influencing factors, accelerated tests, long-term tests, investigation of dissolution curves in different media and comparison of quality data. The levamlodipine besylate capsules are fully proved to be combined by calcium hydrophosphate dihydrate, microcrystalline cellulose SH-102, croscarmellose sodium and magnesium stearate and mixed by an equivalent incremental method, and the process of filling the powder into the capsules is greatly improved in quality and quality process controllability compared with the levamlodipine besylate tablets.
Claims (6)
1. A levamlodipine besylate composition comprises the following components in parts by weight: 3.47 parts of levamlodipine besylate, 5 parts of a flow aid, 126.03 parts of a filling agent, 5 parts of a disintegrating agent and 0.5 part of a lubricating agent; the glidant is calcium hydrophosphate dihydrate; the filler is microcrystalline cellulose SH-102; the disintegrant is croscarmellose sodium; the lubricant is magnesium stearate.
2. The composition of claim 1, wherein the composition is in the form of a capsule.
3. A preparation method for preparing the levamlodipine besylate composition of claim 1 or 2, comprising the steps of:
(1) sieving the levamlodipine besylate, the filler, the glidant, the disintegrant and the lubricant for later use;
(2) weighing the levamlodipine besylate and the disintegrating agent according to the formula, filling into the same clean plastic bag, manually shaking, and preliminarily mixing; then weighing a part of filler and the mixed powder and putting the part of filler and the mixed powder into a three-dimensional operation mixer for mixing; adding a flow aid and a part of the rest filling agent, and continuously mixing; finally adding the lubricant and the rest of the filler, mixing, and sieving the mixture;
(3) detecting intermediate, measuring the content of main drug in the mixed powder, calculating theoretical loading, encapsulating, and packaging.
4. The method according to claim 3, wherein in the step (1), the sieving is a 60-100 mesh sieving.
5. The preparation method according to claim 3, wherein in step (1), the levamlodipine besylate is sieved through a 100-mesh sieve, the filler is sieved through a 60-mesh sieve, and the glidant, the disintegrant and the lubricant are sieved through a 80-mesh sieve.
6. The method according to claim 3, wherein in the step (2), the amount of the filler added for the first time among the three times of the addition of the filler is 30 to 35 w/w% of the total filler, and the amount of the filler added for the second time is 45 to 55 w/w% of the total filler.
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