CN112121022A - Fenofibrate tablet composition and preparation method thereof - Google Patents
Fenofibrate tablet composition and preparation method thereof Download PDFInfo
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- CN112121022A CN112121022A CN202011019023.9A CN202011019023A CN112121022A CN 112121022 A CN112121022 A CN 112121022A CN 202011019023 A CN202011019023 A CN 202011019023A CN 112121022 A CN112121022 A CN 112121022A
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- fenofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The invention relates to a fenofibrate composition, and belongs to the technical field of pharmaceutical preparations. The technical scheme of the invention is as follows: a fenofibrate tablet composition, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 6-10 microns, 36-60g of food-grade chitosan oligosaccharide, 30-50g of microcrystalline cellulose, 520-30 g of hydroxypropyl cellulose E, 808-16 g of polysorbate, 6-12g of aerosil and 1-2g of magnesium stearate. The invention provides a norfibrate composition with uniform content and low adverse reaction incidence.
Description
Technical Field
The invention relates to a fenofibrate tablet composition, and belongs to the technical field of pharmaceutical preparations.
Background
Fenofibrate tablet is first applied to clinic in 1975, is mainly used for treating hyperlipidemia with unsatisfactory adult diet control therapy, is one of the first-choice medicines for reducing triglyceride, has obvious effect of reducing triglyceride and mixed hyperlipidemia compared with cholesterol, can reduce the level of hematuria, has good effect on treating type 2 diabetes and metabolic syndrome, is one of the most commonly used fibrate medicines, and has good effect and tolerance.
According to the biopharmaceutical classification system, fenofibrate belongs to the classical class ii drug. Due to the difficult solubility and the poor dissolution rate of fenofibrate, the bioavailability of fenofibrate is low, and the oral bioavailability of fenofibrate is only 35%. Many documents currently describe how to improve the bioavailability of fenofibrate formulations.
According to clinical findings, after some patients take the fenofibrate sold on the market, the most common adverse reactions of abdominal discomfort, diarrhea and constipation occur, the adverse reactions increase the discomfort of the patients, and the clinical popularization and application of the medicament are seriously influenced.
Disclosure of Invention
The purpose of the invention is as follows: the common adverse reactions such as abdominal discomfort, diarrhea, constipation and the like generated after the existing fenofibrate tablets are taken are solved, and the comfort level of patients after the tablets are taken is improved.
The technical scheme of the invention is as follows: a fenofibrate tablet composition, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 6-10 microns, 36-60g of food-grade chitosan oligosaccharide, 30-50g of microcrystalline cellulose, 520-30 g of hydroxypropyl cellulose E, 808-16 g of polysorbate, 6-12g of aerosil and 1-2g of magnesium stearate.
In the technical scheme of the invention, the polysorbate-80 plays a positive role in improving the dissolution of fenofibrate; the combined action of the food-grade chitosan oligosaccharide, the microcrystalline cellulose and the hydroxypropyl cellulose E5 overcomes the common adverse reactions of abdominal discomfort, diarrhea, constipation and the like caused by fenofibrate to patients, and can meet the requirement of dissolution consistency evaluation. The problem of content uniformity of fenofibrate is solved by adding the micro silica gel powder.
The preferred technical scheme of the invention is as follows: a fenofibrate tablet composition, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 8-9 microns, 45-55g of food-grade chitosan oligosaccharide, 38-45g of microcrystalline cellulose, 525-28 g of hydroxypropyl cellulose E, 2-15g of polysorbate-8012, 8-10g of aerosil and 1.5g of magnesium stearate.
The molecular weight of the food-grade chitosan oligosaccharide is 1800-2200.
The preferred technical scheme of the invention is as follows: a fenofibrate tablet composition, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 8.5 microns, 50g of food-grade chitosan oligosaccharide, 42g of microcrystalline cellulose, hydroxypropyl cellulose E526 g, polysorbate-8014 g, 9g of aerosil and 1.5g of magnesium stearate.
The preparation method of the fenofibrate tablet composition comprises the following steps:
step 1, grinding the fenofibrate raw material medicine to a required particle size, and sieving other solid auxiliary materials by a 80-mesh sieve;
step 2, uniformly mixing fenofibrate, polysorbate-80 and micropowder silica gel according to the prescription amount, and then placing the mixture and food-grade chitosan oligosaccharide, microcrystalline cellulose and hydroxypropyl cellulose E5 according to the prescription amount in a fluidized bed for uniformly mixing;
step 3, spraying 30-45% ethanol water solution to the granules obtained in the step 2, and granulating;
step 4, granulating and drying at 60 ℃;
and 5, adding magnesium stearate in the prescription amount, and tabletting.
Has the advantages that:
according to the preparation method, fenofibrate is uniformly mixed with the superfine silica gel powder, and then is uniformly mixed with other auxiliary materials for granulation, so that the content uniformity of the tablet can be improved; the dissolution rate of the tablet can be improved by using 30% ethanol water for granulation. Adopts a mode of spraying 30-45% of ethanol water solution, utilizes the viscosity of chitosan oligosaccharide to granulate, and preferably 35-40% of ethanol water solution.
If the granulation is carried out by spraying with water or an ethanol solution having a concentration of less than 30%, the hardness of the resulting tablet is too high to affect the dissolution of the drug. If the concentration of the ethanol aqueous solution is too high, the production safety control is not facilitated. Therefore, the 30-45% ethanol water solution is selected to be sprayed for granulation.
Has the advantages that: the invention provides a fenofibrate tablet composition, which meets the requirements of pharmacopoeia and can reduce adverse reactions of patients after administration.
Example 1. fenofibrate with particle size of 6 microns 2g, food grade chitosan oligosaccharide 72g, microcrystalline cellulose 100g, hydroxypropyl cellulose E540 g, polysorbate-8032 g, aerosil 12g, magnesium stearate 2 g. The preparation method is characterized in that the preparation method is carried out according to the technical scheme of the specification, 30% ethanol water solution is used for spray granulation, and 2000 tablets are prepared.
Example 2. fenofibrate with particle size of 10 microns 2g, food grade chitosan oligosaccharide 120g, microcrystalline cellulose 60g, hydroxypropyl cellulose E560 g, polysorbate-8016 g, aerosil 24g and magnesium stearate 4 g. According to the preparation method of the technical scheme of the specification, 45% ethanol water solution is used for spray granulation to prepare 2000 tablets.
Example 3 fenofibrate with particle size of 8.5 microns (2 g), food grade chitosan oligosaccharide (100 g), microcrystalline cellulose (84 g), hydroxypropyl cellulose (E552 g), polysorbate-8028 g, aerosil (18 g) and magnesium stearate (3 g). Spraying 35% ethanol water solution for granulation according to the preparation method of the technical scheme of the specification, and preparing 2000 tablets.
Comparative example 1. preparation of 1000 tablets was carried out in the same manner as in example 3.
The preparation method of the fenofibrate tablet composition comprises the following steps:
step 1, grinding the fenofibrate raw material medicine to a required particle size, and sieving other solid auxiliary materials by a 80-mesh sieve;
and 2, placing the fenofibrate, the polysorbate-80, the superfine silica gel powder, the food-grade chitosan oligosaccharide, the microcrystalline cellulose and the hydroxypropyl cellulose E5 in the formula amount into a fluidized bed, and uniformly mixing.
And 3, spraying 12-16g of 30-45% ethanol water solution to the granules obtained in the step 2, and granulating.
And 4, finishing the granules and drying at 60 ℃.
And 5, adding magnesium stearate in the prescription amount, and tabletting.
Comparative example 2 adjustment with reference to the recipe of example 3
2g of fenofibrate with the particle size of 8.5 microns, 20g of food-grade chitosan oligosaccharide, 144g of microcrystalline cellulose, hydroxypropyl cellulose E572 g, polysorbate-8028 g, 18g of aerosil and 3g of magnesium stearate. Spraying 35% ethanol water solution for granulation according to the preparation method of the technical scheme of the specification, and preparing 2000 tablets.
Comparative example 3 adjustment with reference to the recipe of example 3
2g of fenofibrate with the particle size of 8.5 microns, 120g of food-grade chitosan oligosaccharide, 40g of microcrystalline cellulose, hydroxypropyl cellulose E596 g, polysorbate-8028 g, 18g of aerosil and 3g of magnesium stearate. Spraying 35% ethanol water solution for granulation according to the preparation method of the technical scheme of the specification, and preparing 2000 tablets.
Comparative example 4 adjustment with reference to the recipe of example 3
2g of fenofibrate with the particle size of 8.5 microns, 100g of food-grade chitosan oligosaccharide, 120g of microcrystalline cellulose, hydroxypropyl cellulose E580 g, polysorbate-8028 g, 18g of aerosil and 3g of magnesium stearate, and 35% of ethanol aqueous solution is sprayed for granulation to prepare 2000 tablets.
Comparative example 5. the formulation was the same as in example 3, and the preparation method according to the technical scheme of the specification was carried out by spraying purified water for granulation to prepare 2000 tablets.
Test example 1. the products of examples 1 to 3 and comparative example 1 were each measured for content uniformity by the content uniformity measurement method specified in pharmacopoeia 2015, and the data are shown in table 1.
Content uniformity: taking 1 tablet of the product, placing in a 100ml measuring flask, adding 50ml of water, dissolving with ultrasound for 15min, cooling, diluting with water to scale, shaking, filtering, precisely measuring 5ml of the subsequent filtrate, placing in a 50ml measuring flask, diluting with water to scale, and shaking to obtain sample solution. Precisely measuring 20 mu l of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; and taking an appropriate amount of fenofibrate reference substance, precisely weighing, adding water to dissolve, and quantitatively diluting to prepare a solution containing about 100 mu g of fenofibrate in each 1ml as a reference substance solution. Measuring by the same method, and calculating by peak area according to an external standard method to obtain the product. The results are reported in table 1.
TABLE 1
The data in table 1 show that the tablets prepared by the preparation method of the present invention have content uniformity in compliance with the standard specification. In contrast to the comparative example 1, the content uniformity did not reach the standard when the adjuvants were directly mixed. The preparation method plays a positive role in content uniformity.
Experimental example 2 dissolution of the products of examples 1-3 and comparative examples 2-5 in ph1.0 medium (0.025 mol/SDS (sodium dodecyl sulfate)), ph4.0 medium, ph6.8 medium, and aqueous medium were measured at temperatures set at (37 ± 0.5 ℃) and a rotational speed of 75 r/min according to dissolution measurement method specified in pharmacopoeia appendix XC of 2015 edition, second method, paddle method, dissolution medium of 900ml, and sampling and measuring dissolution at 10min, 15min, 30min, 45min, 60min, and 90min, respectively, and the data are recorded in tables 2-6.
The reference preparation is produced by Beijing Yimin pharmaceutical industry purchased in the market, and the specification is 0.1 g.
TABLE 20.025 summary of pH1.0 hydrochloric acid solution medium cumulative dissolution data for mol/SDS (examples 1-3)
TABLE 30.025 summary of pH1.0 hydrochloric acid solution medium cumulative dissolution data for mol/SDS (control examples 2-5)
Data in tables 2 and 3 show that: dissolution of the samples of the examples of the invention compared to a reference formulation, f2More than 50, meets the requirement of consistency evaluation in hydrochloric acid solution medium with pH of 1.0; comparative examples 2 to 52Are all less than 50, and do not meet the consistency evaluation requirement.
Therefore, the dissolution rate of the products of comparative examples 2-5 was not investigated in the subsequent pH4.0 medium, pH6.8 medium and aqueous medium.
TABLE 4 summary of cumulative dissolution data for acetate buffer medium at pH4.0 (examples 1-3)
The data in Table 4 show that the dissolution behavior of the fenofibrate tablets obtained in examples 1-3 in acetate buffer medium at pH4.0 is consistent with that of the reference.
TABLE 5 summary of cumulative dissolution data for phosphate buffer media at pH6.8 (examples 1-3)
The data in Table 5 show that the dissolution behavior of the fenofibrate tablets obtained in examples 1-3 in phosphate buffer medium at pH6.8 is consistent with that of the reference.
TABLE 6 summary of cumulative dissolution data for aqueous media (examples 1-3)
The data in table 6 show that the dissolution behavior of the fenofibrate tablets obtained in examples 1 to 3 in aqueous medium is consistent with that of the reference.
The dissolution results show that the dissolution behaviors of the finally determined prescription and the reference preparation in water, pH4.0 acetate buffer solution and pH6.8 phosphate buffer solution dissolution media are similar, and the product development target is met.
Experimental example 3 outpatient clinic treatment 210 patients with mild hyperlipidemia (without other diseases), age 38-65 years, randomly divided into 7 groups, 30 patients each taking commercial fenofibrate tablets, fenofibrate tablets of examples 1-3 and fenofibrate tablets of control examples 2-4, respectively, with the order of reducing stomach discomfort and taking with diet. The preparation is administered orally 1 tablet at a time 3 times daily. The composition is administered 1 tablet at a time 1 time every day from the second day together with morning. The period is 30 days, during the experiment period, cold, cool and spicy food is prohibited to eat, and the feeling after taking the medicine is recorded. On day 30, the summary data was collected and recorded in table 7.
TABLE 7 experience after dosing
The data in table 7 show that the product prepared by the technical scheme of the invention well overcomes the adverse reactions of abdominal discomfort, diarrhea, constipation and the like after being taken by a patient, and well improves the comfort of the patient after being taken.
Claims (4)
1. A fenofibrate tablet composition, which contains per 1000 tablets: 1g of fenofibrate with the particle size of 6-10 microns, 36-60g of food-grade chitosan oligosaccharide, 30-50g of microcrystalline cellulose, 520-30 g of hydroxypropyl cellulose E, 808-16 g of polysorbate, 6-12g of aerosil and 1-2g of magnesium stearate.
2. The fenofibrate tablet composition of claim 1, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 8-9 microns, 45-55g of food-grade chitosan oligosaccharide, 38-45g of microcrystalline cellulose, 525-28 g of hydroxypropyl cellulose E, 2-15g of polysorbate-8012, 8-10g of aerosil and 1.5g of magnesium stearate.
3. The fenofibrate tablet composition of claim 1, comprising per 1000 tablets: 1g of fenofibrate with the particle size of 8.5 microns, 50g of food-grade chitosan oligosaccharide, 42g of microcrystalline cellulose, hydroxypropyl cellulose E526 g, polysorbate-8014 g, 9g of aerosil and 1.5g of magnesium stearate.
4. A method of preparing a fenofibrate tablet composition according to claim 1, comprising the steps of:
step 1, grinding the fenofibrate raw material medicine to a required particle size, and sieving other solid auxiliary materials by a 80-mesh sieve;
step 2, uniformly mixing fenofibrate, polysorbate-80 and micropowder silica gel according to the prescription amount, and then placing the mixture and food-grade chitosan oligosaccharide, microcrystalline cellulose and hydroxypropyl cellulose E5 according to the prescription amount in a fluidized bed for uniformly mixing;
step 3, spraying 30-45% ethanol water solution to the granules obtained in the step 2, and granulating;
step 4, granulating and drying at 60 ℃;
and 5, adding magnesium stearate in the prescription amount, and tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202011019023.9A CN112121022A (en) | 2020-09-25 | 2020-09-25 | Fenofibrate tablet composition and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011019023.9A CN112121022A (en) | 2020-09-25 | 2020-09-25 | Fenofibrate tablet composition and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1360499A (en) * | 1999-07-09 | 2002-07-24 | 埃迪克埃迪法姆药品实验室 | Pharmaceutical composition contg. fenofibrate and preparation method |
| CN101594850A (en) * | 2006-12-21 | 2009-12-02 | 兰贝克赛实验室有限公司 | Antilipidemic pharmaceutical compositions and and preparation method thereof |
| CN101674813A (en) * | 2007-01-22 | 2010-03-17 | 诺瓦瓦克斯股份有限公司 | Multi-phasic pharmaceutical formulations of poorly water-soluble drugs for reduced fed/fasted variability and improved oral bioavailability |
-
2020
- 2020-09-25 CN CN202011019023.9A patent/CN112121022A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1360499A (en) * | 1999-07-09 | 2002-07-24 | 埃迪克埃迪法姆药品实验室 | Pharmaceutical composition contg. fenofibrate and preparation method |
| CN101594850A (en) * | 2006-12-21 | 2009-12-02 | 兰贝克赛实验室有限公司 | Antilipidemic pharmaceutical compositions and and preparation method thereof |
| CN101674813A (en) * | 2007-01-22 | 2010-03-17 | 诺瓦瓦克斯股份有限公司 | Multi-phasic pharmaceutical formulations of poorly water-soluble drugs for reduced fed/fasted variability and improved oral bioavailability |
Non-Patent Citations (1)
| Title |
|---|
| 任秀华等: "非诺贝特固体分散片的试制", 《中国医药工业杂志》 * |
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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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Application publication date: 20201225 |