CN110946830A - Fenofibrate solid dispersion preparation capable of being rapidly dissolved and preparation method thereof - Google Patents
Fenofibrate solid dispersion preparation capable of being rapidly dissolved and preparation method thereof Download PDFInfo
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- CN110946830A CN110946830A CN201911415324.0A CN201911415324A CN110946830A CN 110946830 A CN110946830 A CN 110946830A CN 201911415324 A CN201911415324 A CN 201911415324A CN 110946830 A CN110946830 A CN 110946830A
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- 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
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- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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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 belongs to the technical field of medicine preparation, and relates to a fenofibrate solid dispersion preparation capable of being rapidly dissolved and a preparation method thereof. The preparation comprises, by mass, 50 parts of fenofibrate, 50-250 parts of a high-molecular solid dispersion carrier and more than 10 parts of dry ice powder; the polymer solid dispersion carrier is Poloxamer407, PEG6000, TPGS,
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and relates to a fenofibrate solid dispersion preparation capable of being rapidly dissolved and a preparation method thereof.
Background
Fenofibrate was a clofibrate derivative, originally developed in 1974 by group Fournier SA, france, and originally marketed in france for use in lowering cholesterol levels in patients at risk for underlying cardiovascular disease. Similar to fibrates, it reduces Low Density Lipoprotein (LDL) and Very Low Density Lipoprotein (VLDL), increases High Density Lipoprotein (HDL) levels, and reduces triglyceride levels. Alone or in combination with statins, for the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate has been well-proven in curative effect and tolerance since the market, and is one of the most commonly used fibrates at present.
Solid dispersions are those in which the drug is highly dispersed in a suitable carrier for the purpose of immediate or sustained release. Commonly used carriers include water-soluble, poorly soluble and enteric carriers. The solid dispersion technology can obviously reduce the particle size of the medicament, change the physical state of the medicament, inhibit recrystallization and increase the wettability of the medicament, thereby obviously improving the dissolution rate of the insoluble medicament and playing an important role and position in improving the solubility and the dissolution rate of the insoluble medicament. Fenofibrate has good curative effect, but the bioavailability is low after oral administration due to the fact that fenofibrate is not easy to dissolve in water and is not enough in dissolution rate. The bioavailability is improved by improving the characteristic of low solubility of fenofibrate. However, the currently published formulations and production processes have respective limitations, and the dissolution rate is relatively low.
Disclosure of Invention
In order to solve the technical problems, the invention provides a fenofibrate solid dispersion preparation capable of being rapidly dissolved and a preparation method thereof.
The fenofibrate solid dispersion preparation capable of being rapidly dissolved comprises, by mass, 50 parts of fenofibrate, 50-250 parts of a high-molecular solid dispersion carrier and more than 10 parts of dry ice powder; the polymer solid dispersion carrier is Poloxamer407, PEG6000, TPGS,
The preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, which is disclosed by the invention, comprises the following specific steps of: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a sieve of 80-120 meshes, and mixing uniformly; 2) setting the extrusion temperature to 85-105 ℃ and controlling the rotating speed to 80-100 r/min; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding other adjuvants, and making into capsule or tablet.
According to the preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, other auxiliary materials comprise a disintegrating agent, an adhesive and a lubricating agent.
According to the preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, the filling agent is one or more of pregelatinized starch, dextrin and powdered sugar.
According to the preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, the filling disintegrating agent is one or more of sodium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone.
According to the preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, the adhesive is one or more of starch slurry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, water, ethanol and dextrin.
According to the preparation method of the fenofibrate solid dispersion preparation capable of being rapidly dissolved, the lubricant is one or more of magnesium stearate, talcum powder, silicon dioxide and stearic acid.
Compared with the prior art, the fenofibrate solid dispersion preparation is added with the dry ice powder during preparation, the dry ice is sublimated into gas to prevent the raw material, particularly fenofibrate, from being stained on the wall and forming lumps, and the air flow dispersion and pulverization processes are increased to obtain a more uniform solid dispersion, so that the fenofibrate can be dissolved out of the fenofibrate solid dispersion preparation more favorably.
Detailed Description
The fast dissolving fenofibrate solid dispersion formulation and the preparation method thereof according to the present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited thereto.
Example 1: fenofibrate capsule (specification: 50mg (in fenofibrate), 1000 capsules in total).
Prescription: 50g of fenofibrate, 407125 g of Poloxamer (Poloxamer), 20 parts of dry ice powder, 7g of colloidal silicon dioxide and 22g of pregelatinized starch.
The preparation method comprises the following steps: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a 100-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature to 95 ℃ and controlling the rotating speed to 90 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding the formula amount of pregelatinized starch and colloidal silicon dioxide, mixing well, and filling the granules into No. 2 capsules. The total volume is 1000.
Example 2: fenofibrate tablet (specification: 50mg (in fenofibrate) for 1000 tablets in total).
Prescription: 50g of fenofibrate,
50g, 10 parts of dry ice powder, 11g of colloidal silicon dioxide, 79g of pregelatinized starch, 7g of croscarmellose sodium and 3g of magnesium stearate.
The preparation method comprises the following steps: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a 100-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature to 85 ℃ and controlling the rotating speed to 80 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding the pregelatinized starch, the colloidal silicon dioxide and the croscarmellose sodium according to the prescription amount, uniformly mixing, adding the magnesium stearate, and mixing for 2 min; 6)7.5mm shallow concave punch tablet pressing is carried out, and the hardness is controlled to be 6-8 Kp. The total amount of the product is 1000.
Example 3: fenofibrate tablet (specification: 50mg (in fenofibrate) 1000 tablets in total)
Prescription: 50g of fenofibrate, PEG 6000235 g, 15 parts of dry ice powder, 5g of colloidal silicon dioxide, 7g of croscarmellose sodium and 3g of magnesium stearate.
The preparation method comprises the following steps: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a 80-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature at 105 ℃ and controlling the rotating speed at 100 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding colloidal silicon dioxide and croscarmellose sodium according to the prescription amount, mixing uniformly, adding magnesium stearate, and mixing for 2 min; 6) tabletting by using a 9mm shallow concave punch, and controlling the hardness to be 7-10 Kp. The total amount of the product is 1000.
Example 4: fenofibrate capsule (specification: 50mg (in fenofibrate), 1000 capsules in total).
Prescription: 50g of fenofibrate, 125g of TPGS, 15 parts of dry ice powder, 7g of colloidal silicon dioxide and 23g of pregelatinized starch.
The preparation method comprises the following steps: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a 120-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature at 90 ℃ and controlling the rotating speed at 90 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding the formula amount of pregelatinized starch and colloidal silicon dioxide, mixing well, and filling the granules into No. 2 capsules. The total volume is 1000.
Example 5: fenofibrate capsule (specification: 50mg (in fenofibrate), 1000 capsules in total).
Prescription: 50g of fenofibrate, 407125 g of poloxamer, 20 parts of dry ice powder, 7g of colloidal silicon dioxide and 22g of pregelatinized starch.
The preparation method comprises the following steps: 1) firstly, putting fenofibrate and a solid dispersion carrier into a crusher, adding dry ice powder, crushing together, sieving by a 100-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature to 95 ℃ and controlling the rotating speed to 90 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding the formula amount of pregelatinized starch and colloidal silicon dioxide, mixing well, and filling the granules into No. 2 capsules. The total volume is 1000.
Example 6: fenofibrate capsule (specification: 50mg (in fenofibrate), 1000 capsules in total).
Prescription: 50g of fenofibrate, 407125 g of poloxamer, 20 parts of dry ice powder, 7g of colloidal silicon dioxide and 22g of pregelatinized starch.
The preparation method comprises the following steps: 1) coating the dry ice powder on the inner wall of a grinder, then adding a solid dispersion carrier, finally adding fenofibrate, grinding together, sieving by a 100-mesh sieve, and uniformly mixing; 2) setting the extrusion temperature to 95 ℃ and controlling the rotating speed to 90 revolutions per minute; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding the formula amount of pregelatinized starch and colloidal silicon dioxide, mixing well, and filling the granules into No. 2 capsules. The total volume is 1000.
Dissolution determination
According to a dissolution determination method (an appendix XC second method in the Chinese pharmacopoeia 2015 edition), 1000ml of 1.0% sodium dodecyl sulfate solution is used as a dissolution medium, the rotating speed is 100r/min, and sampling is carried out according to the method at 5, 10, 15, 30, 45 and 60 min. The absorbance at 289nm was measured and the dissolution rate for each example was calculated. The results are shown in Table 1.
Table 1 dissolution of examples 1-4
Claims (7)
1. A fenofibrate solid dispersion preparation capable of being rapidly dissolved is characterized by comprising 50 parts of fenofibrate, 50-250 parts of high polymer solid dispersion carrier and more than 10 parts of dry ice powder in parts by mass; the polymer solid dispersion carrier is Poloxamer407, PEG6000, TPGS,
2. The method for preparing a fast dissolving solid dispersion formulation of fenofibrate according to claim 1, comprising the steps of: 1) coating the dry ice powder on the inner wall of a grinder, adding fenofibrate, adding a solid dispersion carrier, grinding together, sieving by a sieve of 80-120 meshes, and mixing uniformly; 2) setting the extrusion temperature to 85-105 ℃ and controlling the rotating speed to 80-100 r/min; 3) after the temperature rise is finished, adding the mixture obtained in the step 1) into an extruder, and carrying out hot melting and extrusion to obtain an extrudate; 4) cooling the extrudate by using ice water, crushing, and sieving by using a 80-mesh sieve to obtain fenofibrate solid dispersion; 5) adding other adjuvants, and making into capsule or tablet.
3. The method for preparing a fast dissolving solid dispersion of fenofibrate of claim 2, wherein the other excipients comprise disintegrants, binders and lubricants.
4. The method for preparing a fast dissolving solid dispersion of fenofibrate according to claim 3, wherein the bulking agent is one or more of pregelatinized starch, dextrin, powdered sugar.
5. The method for preparing a rapidly dissolvable solid dispersion formulation of fenofibrate according to claim 3, wherein the disintegrant is one or more of sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium croscarmellose, and crospovidone.
6. The method for preparing a fast-dissolving fenofibrate solid dispersion formulation of claim 3, wherein the binder is one or more of starch slurry, hypromellose, hyprolose, water, ethanol, dextrin.
7. The method for preparing a fast dissolving solid dispersion of fenofibrate according to claim 3, wherein the lubricant is one or more of magnesium stearate, talc, silica, stearic acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911415324.0A CN110946830A (en) | 2019-12-31 | 2019-12-31 | Fenofibrate solid dispersion preparation capable of being rapidly dissolved and preparation method thereof |
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| CN201911415324.0A CN110946830A (en) | 2019-12-31 | 2019-12-31 | Fenofibrate solid dispersion preparation capable of being rapidly dissolved and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101384250A (en) * | 2005-11-09 | 2009-03-11 | 诺瓦提斯公司 | Process for making pharmaceutical compositions with a transient plasticizer |
| EP2649989A1 (en) * | 2012-04-13 | 2013-10-16 | King Saud University | Method for preparing a solid dispersion, solid dispersion obtained thereby and use thereof |
| CN105748432A (en) * | 2014-12-15 | 2016-07-13 | 蚌埠丰原涂山制药有限公司 | Fenofibrate soft capsule and preparation method thereof |
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- 2019-12-31 CN CN201911415324.0A patent/CN110946830A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101384250A (en) * | 2005-11-09 | 2009-03-11 | 诺瓦提斯公司 | Process for making pharmaceutical compositions with a transient plasticizer |
| EP2649989A1 (en) * | 2012-04-13 | 2013-10-16 | King Saud University | Method for preparing a solid dispersion, solid dispersion obtained thereby and use thereof |
| CN105748432A (en) * | 2014-12-15 | 2016-07-13 | 蚌埠丰原涂山制药有限公司 | Fenofibrate soft capsule and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| STEVANUS HIENDRAWAN等: "Micronization of fenofibrate by rapid expansion of supercritical solution", 《JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY》 * |
| 郑杨等: "非诺贝特固体分散体制备工艺研究及比较", 《中国药剂学杂志(网络版)》 * |
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