CN112516097B - Levamlodipine besylate composition - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention relates to a levamlodipine besylate tablet composition, and belongs to the technical field of pharmaceutical preparations. The technical scheme of the invention is as follows: a levamlodipine besylate composition comprises 3.5% of levamlodipine besylate, 2-8% of taurine, 70-90% of a filler, 3-9% of propylene glycol, 5-10% of a disintegrant and 0.5-2% of a lubricant. The invention provides the levamlodipine besylate medicinal composition which can be quickly released in a human body after being taken and has excellent stability.
Description
Technical Field
The invention relates to a levamlodipine besylate tablet composition, and belongs to the technical field of pharmaceutical preparations.
Background
Amlodipine besylate is a third-generation 1, 4-dihydropyridine calcium ion antagonist successfully developed by the U.S. feverfew pharmaceutical company Limited in the middle of the 80 th century, has the action mechanism of relaxing vascular smooth muscle, expanding coronary artery, improving collateral circulation and improving myocardial ischemia and anoxia, has mild and lasting action, is convenient to take and slight in adverse reaction, and is mainly used for treating hypertension, angina pectoris, heart failure complicated with hypertension or coronary heart disease and the like clinically. The calcium antagonistic activity of the amlodipine besylate levorotatory body is 1000 times that of a dextrorotatory body and 2 times that of a racemic body. Levamlodipine besylate can be used as an antianginal drug and is also effective on coronary artery spastic angina. Racemic tablets typically are administered orally at a starting dose of 5mg (in amlodipine) once daily; in contrast, levorotatory tablets are usually administered orally at a starting dose of 2.5mg (calculated as levamlodipine) once a day.
Levamlodipine besylate is almost insoluble in water, is slowly absorbed by a human body, generally reaches the peak value of blood concentration 6 to 12 hours after being taken, has low total level of the blood concentration, and particularly has very low blood concentration at the initial stage after being taken. Therefore, people need to improve the dissolution behavior of the preparation by technical means to meet the requirement of lowering blood pressure, and meanwhile, the levamlodipine besylate has poor stability, so that impurities grow rapidly after the preparation is prepared, and the problem needs to be solved in the preparation process.
Patent document CN101947210A discloses a levamlodipine besylate liposome tablet and its application in preparing a medicament for treating essential hypertension, which is mainly prepared from levamlodipine besylate, egg yolk lecithin, cholesterol, poloxamer and pharmaceutically acceptable excipients. The levamlodipine besylate liposome tablet improves the dissolution rate and increases the stability, but the process is complex, and a large amount of lipid materials are added, so that great potential safety hazard can be brought to patients with high cholesterol when the tablet is taken.
Patent document CN1686121A discloses a method for preparing amlodipine besylate dispersible tablets, which is prepared from amlodipine, lactose, microcrystalline cellulose, carboxymethyl starch sodium, aerosil and magnesium stearate, and the dispersible tablets can be dispersed in water for administration, so as to improve the convenience of administration.
Although the prior literature discloses a preparation method of various dosage forms containing levamlodipine besylate, the levamlodipine besylate belongs to an insoluble drug, so that the levamlodipine besylate is slowly absorbed after being taken, has long time to peak and very low blood concentration at the initial stage of taking, and cannot play a role in controlling blood pressure immediately after taking. Through the change of the dosage form, the hydrophilicity of the medicine is only improved, the disintegration time of the medicine in vivo is shortened, no evidence shows that the solubility in digestive juice can be increased, and in order to promote the disintegration of the medicine, a large amount of disintegrant components are added in the prescription, so that the medicine is easy to absorb moisture in the storage process, the stability of the preparation is reduced, and the packaging cost is increased.
Disclosure of Invention
The invention aims to provide the levamlodipine besylate medicinal composition which can be quickly released in a human body after being taken and has excellent stability.
The applicant finds that the solubility of the levamlodipine besylate in digestive juice can be obviously improved by adding the filler after grinding and mixing the taurine and the levamlodipine besylate, granulating by using a propylene glycol aqueous solution and tabletting.
In-vitro dissolution experiments with artificial gastric juice and artificial intestinal juice as media prove that the solubility of the tablet obtained by the scheme in digestive juice is obviously improved, the stability of the medicine can be obvious due to the addition of the propylene glycol, moisture-absorbable components do not exist in the prescription, and the risk of medicine moisture absorption is greatly reduced.
Analyzing the principle, it may be: taurine is widely used as free amino acid in human tissues, has strong hydrophilicity and wettability, can obviously reduce the hydrophobicity of the medicament after being fully combined with the levamlodipine besylate, changes the solubility of the levamlodipine besylate in digestive juice, increases the concentration of the medicament in the digestive juice, and has strong affinity to human cells, thereby further promoting the absorption of human bodies, improving the blood concentration at the initial administration stage and achieving the purpose of quick response. And the propylene glycol is used as a plasticizer, has excellent hydrophilicity, and is combined with the taurine, so that the release capacity of the medicine is further enhanced. During the stability investigation process, we have unexpectedly found that the addition of propylene glycol can significantly improve the stability of the drug.
The technical scheme of the invention is as follows: a levamlodipine besylate composition comprises 3.5% of levamlodipine besylate, 2-8% of taurine, 70-90% of a filler, 3-9% of propylene glycol, 5-10% of a disintegrant and 0.5-2% of a lubricant.
The filler is selected from lactose and mannitol.
The disintegrant is selected from carboxymethylcellulose calcium and microcrystalline cellulose.
The lubricant of the invention is selected from magnesium stearate and stearic acid.
Preferably, the levamlodipine besylate composition disclosed by the invention comprises 3.5% of levamlodipine besylate, 5-6% of taurine, 76.5-82.5% of a filler, 5-7% of propylene glycol, 7-8% of a disintegrant and 1% of a lubricant.
Preferably, the levamlodipine besylate composition disclosed by the invention comprises 3.5% of levamlodipine besylate, 5% of taurine, 77% of a filler, 6% of propylene glycol, 7% of a disintegrant and 1% of a lubricant.
Preferably, the levamlodipine besylate composition provided by the invention comprises 3.5% of levamlodipine besylate, 6% of taurine, 79.5% of filler, 7% of propylene glycol, 7.5% of disintegrant and 1% of lubricant.
The preparation method of the levamlodipine besylate composition comprises the following steps:
the first step is as follows: weighing levamlodipine besylate and taurine according to the prescription amount, grinding and mixing;
the second step is that: adding the filler and the mixed material prepared in the first step into a wet mixing granulator, mixing for 5min, and adding 20% (w/w) propylene glycol aqueous solution to prepare a proper soft material;
the third step: sieving the soft material with 24 mesh sieve, and drying at 50 deg.C to water content of less than 5%;
the fourth step: adding a disintegrating agent and a lubricating agent into the dried granules, and uniformly mixing by using a three-dimensional motion mixer;
the fifth step: the granules are compressed by using a 6mm shallow concave die, and the hardness of the tablets is 50-60N.
Has the advantages that: the invention provides the levamlodipine besylate medicinal composition which can be quickly released in a human body after being taken and has excellent stability.
Examples and comparative examples
Example 1. recipe:
1000 tablets are prepared according to the preparation method of the technical scheme.
Example 2. recipe:
1000 tablets are prepared according to the preparation method of the technical scheme.
Example 3. recipe:
1000 tablets are prepared according to the preparation method of the technical scheme.
Example 4. prescription:
1000 tablets are prepared according to the preparation method of the technical scheme.
Example 5. recipe:
1000 tablets are prepared according to the preparation method of the technical scheme.
Comparative example 1. taurine was not present in the formulation, as follows:
the first step is as follows: weighing lactose and levamlodipine besylate with the formula amount, adding into a wet mixing granulator, mixing for 5min, and adding 20% (w/w) propylene glycol aqueous solution to prepare a proper soft material; (ii) a
The second step is that: sieving the soft material with 24 mesh sieve, and drying at 50 deg.C to water content of less than 5%;
the third step: adding the carboxymethyl cellulose and the magnesium stearate in the prescription amount into the dried granules, and uniformly mixing by using a three-dimensional motion mixer;
the fourth step: the granules are compressed into tablets, 6mm shallow concave dies are adopted, and the hardness of the tablets is 50-60N, so that 1000 tablets are prepared.
Comparative example 2 formulation without propylene glycol, formulation was as follows:
preparation process
The first step is as follows: weighing levamlodipine besylate and taurine according to the prescription amount, grinding and mixing;
the second step is that: adding lactose in a prescription amount and the mixed material prepared in the first step into a wet mixing granulator, mixing for 5min, and adding a proper amount of purified water to prepare a proper soft material;
the third step: sieving the soft material with 24 mesh sieve, and drying at 50 deg.C to water content of less than 5%;
the fourth step: adding the carboxymethyl cellulose calcium and the magnesium stearate with the prescription amount into the dried granules, and uniformly mixing by using a three-dimensional motion mixer;
the fifth step: the granules are compressed into tablets, 6mm shallow concave dies are adopted, and the hardness of the tablets is 50-60N, so that 1000 tablets are prepared.
Comparative example 3. example 2 formulation 1000 tablets were prepared as follows
The first step is as follows: adding the formula amount of levamlodipine besylate, taurine and lactose into a wet mixing granulator, mixing for 5min, and adding 20% (w/w) propylene glycol aqueous solution to prepare a proper soft material;
the second step is that: sieving the soft material with 24 mesh sieve, and drying at 50 deg.C to water content of less than 5%;
the third step: adding the carboxymethyl cellulose calcium and the magnesium stearate with the prescription amount into the dried granules, and uniformly mixing by using a three-dimensional motion mixer;
the fourth step: the granules are compressed into tablets, 6mm shallow concave dies are adopted, and the hardness of the tablets is 50-60N, so that 1000 tablets are prepared.
Comparative example 4
1000 tablets are prepared according to the preparation method of the technical scheme.
Comparative example 5. recipe:
1000 tablets are prepared according to the preparation method of the technical scheme.
Test example 1: the release rates of the products of examples 1-5 and comparative examples 1-5 in artificial gastric juice and artificial intestinal juice were measured, respectively, and the results are reported in table 1.
The instrument name: full-automatic dissolution test system
Instrument brand: sotax
The test method comprises the following steps: the method is characterized by referring to dissolution determination method of United states Pharmacopeia, flow cell method and ring opening.
Dissolution medium: artificial gastric juice and artificial intestinal juice.
Taking 16.4 mL of dilute hydrochloric acid, adding 800 mL of water and 10g of pepsin, and adding water to dilute the mixture to 1000 mL; wherein the dilute hydrochloric acid is 234mL of concentrated hydrochloric acid, and water is added to dilute the concentrated hydrochloric acid to 1000mL to obtain 9.5% -10.5% dilute hydrochloric acid.
Dissolving potassium dihydrogen phosphate 6.8g in water 500 mL, and adjusting pH to 6.8 with 0.1mol/L sodium hydroxide solution; taking 10g of pancreatin, adding a proper amount of water for dissolving, mixing the solution 2, and adding water for diluting to 1000mL to obtain the pancreatin-containing oral liquid. .
Sampling time: 1h, 2h, 4h, 6h and 8h (artificial gastric juice test 1-2h, artificial intestinal juice test 3-8 h).
Rotating speed: 50rpm
The test method comprises the following steps: HPLC chromatography.
Detection wavelength: 237 nm.
Preparation of a reference solution: taking a proper amount of a levamlodipine besylate reference substance, precisely weighing, adding a proper amount of methanol for dissolving, and quantitatively diluting with a hydrochloric acid solution with the pH of 1.0 to prepare a solution containing 5 mu g of levamlodipine per 1 ml.
TABLE 1 results of testing the degree of release of the products of examples 1 to 5 and comparative examples 1 to 5
Table 1 the data illustrates:
the release degree of the levamlodipine besylate tablets prepared in the embodiments 1 to 5 by adopting the technical scheme of the invention in the artificial gastric juice and the artificial intestinal juice is obviously higher than that of the levamlodipine besylate tablets obtained in the comparative examples 1 to 5, which shows that the addition of 2 to 8 percent of taurine and 3 to 9 percent of propylene glycol in the technical scheme can obviously promote the release of the drug in the artificial gastric juice and the artificial intestinal juice, improve the blood concentration at the initial administration stage, facilitate the rapid absorption of a human body after the drug administration and achieve the purpose of rapid onset of action. The samples of comparative examples 1 to 5 have low dissolution rate and can not achieve the purpose of quick response after being taken.
Test example 2 stability study
The products of examples 1 to 5 and comparative examples 1 to 5 were respectively subjected to aluminum-plastic packaging, 10 aluminum-plastic plates for each sample and 12 pieces/plate for packaging specification, and placed in an accelerated stability inspection box under the conditions of 40 ℃ of temperature and 75% of humidity, and sampled at the end of 1 st, 2 nd, 3 th and 6 th months, 2 plates for each time point were sampled, and the relevant substances were measured, and the results are shown in Table 2.
TABLE 2 measurement results of substances related to product stability tests of examples 1 to 5 and comparative examples 1 to 5
Table 2 the data illustrates: in an accelerated stability test, the growth rates of related substances of the products of examples 1-5, comparative example 1 and comparative example 3-4 prepared by adopting the technical scheme of the invention are obviously slower than those of the products of comparative example 2 and comparative example 5, which shows that the stability of the levamlodipine besylate can be obviously improved by adding 3-9% of propylene glycol in the technical scheme, and the adverse effect of impurities generated by drug degradation on the health of patients is reduced.
Claims (3)
1. The levamlodipine besylate composition is characterized by comprising 3.5% of levamlodipine besylate, 2-8% of taurine, 70-82.5% of a filler, 3-9% of propylene glycol, 5-10% of carboxymethylcellulose calcium and 0.5-2% of magnesium stearate, wherein the filler is selected from lactose and mannitol;
the first step is as follows: weighing levamlodipine besylate and taurine according to the prescription amount, grinding and mixing;
the second step is that: adding the filler and the mixed material prepared in the first step into a wet mixing granulator, mixing for 5min, and adding 20% (w/w) propylene glycol aqueous solution to prepare a proper soft material;
the third step: sieving the soft material with 24 mesh sieve, and drying at 50 deg.C to water content of less than 5%;
the fourth step: adding a disintegrating agent and a lubricating agent into the dried granules, and uniformly mixing by using a three-dimensional motion mixer;
the fifth step: the granules are compressed by using a 6mm shallow concave die, and the hardness of the tablets is 50-60N.
2. The levamlodipine besylate composition according to claim 1, comprising 3.5% of levamlodipine besylate, 5-6% of taurine, 76.5-77% of a filler, 5-7% of propylene glycol, 7-8% of carboxymethylcellulose calcium, and 1% of magnesium stearate.
3. The levamlodipine besylate composition according to claim 1, comprising 3.5% of levamlodipine besylate, 5% of taurine, 77% of a filler, 6% of propylene glycol, 7% of calcium carboxymethylcellulose and 1% of magnesium stearate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011525154.4A CN112516097B (en) | 2020-12-22 | 2020-12-22 | Levamlodipine besylate composition |
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| CN202011525154.4A CN112516097B (en) | 2020-12-22 | 2020-12-22 | Levamlodipine besylate composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP4439499B2 (en) * | 2005-08-01 | 2010-03-24 | 大日本住友製薬株式会社 | Amlodipine-containing particles and orally disintegrating tablets comprising the same |
| CN101209245A (en) * | 2006-12-29 | 2008-07-02 | 大日本住友制药株式会社 | Particle containing amlodipine and orally disintegrating tablets containing the same |
| CN101711762A (en) * | 2008-10-08 | 2010-05-26 | 鲁南制药集团股份有限公司 | Medicine composition for treating hypertension |
| CN103127018B (en) * | 2013-03-06 | 2014-03-19 | 浙江昂利康制药有限公司 | Levamlodipine besylate tablet and preparation method thereof |
| CN104688734B (en) * | 2013-12-04 | 2017-08-15 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Levamlodipine besylate |
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Effective date of registration: 20210906 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Dijia Pharmaceutical Group Co.,Ltd. |
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