CN117462503A - Celecoxib quick-release and slow-release double-release preparation and preparation method thereof - Google Patents
Celecoxib quick-release and slow-release double-release preparation and preparation method thereof Download PDFInfo
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- CN117462503A CN117462503A CN202311416889.7A CN202311416889A CN117462503A CN 117462503 A CN117462503 A CN 117462503A CN 202311416889 A CN202311416889 A CN 202311416889A CN 117462503 A CN117462503 A CN 117462503A
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- Prior art keywords
- release
- celecoxib
- slow
- quick
- double
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Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a celecoxib quick-release and slow-release double-release preparation and a preparation method thereof, wherein the preparation comprises a quick-release part and a slow-release part; the quick-release part comprises the following components in percentage by mass: 10-80% of an alkaline blank pill core and 20-90% of a drug layer; the slow release part comprises the components: 8 to 77.6 percent of alkaline blank pill core, 19.4 to 72 percent of drug layer and 3 to 20 percent of slow release coating layer; the medicine layer comprises the components: 20 to 70 percent of celecoxib, 0.2 to 40 percent of stabilizer, 0.01 to 40 percent of protective agent I and 0.01 to 20 percent of protective agent II. The solubility and bioavailability of celecoxib in the double-release preparation are improved, the celecoxib can be quickly released to reach higher initial drug concentration after oral administration, the curative effect is quickly exerted, and the stable blood concentration can be maintained, so that the celecoxib sustained-release preparation takes effect continuously.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a celecoxib quick-release and slow-release double-release preparation and a preparation method thereof.
Background
Celecoxib (celecoxib) is a non-steroidal anti-inflammatory drug (NSAIDs) and is also a high-selectivity cyclooxygenase-2 (COX-2) inhibitor, and can prevent the production of prostaglandins, so that the effects of anti-inflammation, pain relieving and antipyretic are achieved. The traditional Chinese medicine composition is mainly used for relieving symptoms and signs of Osteoarthritis (OA), adult Rheumatoid Arthritis (RA) and ankylosing spondylitis clinically. Meanwhile, the traditional Chinese medicine composition is also widely applied to the analgesic treatment of adult Acute Pain (AP) such as acute trauma, postoperative pain and the like. This has the advantage of alleviating symptoms without causing related gastrointestinal complications. The poor solubility of the liquid medicine results in low oral bioavailability, and becomes a significant limiting factor for clinical application.
Celecoxib has poor solubility, belongs to BCS II medicines, and is dissolved out to be the speed limiting step of in vivo absorption, so that the bioavailability of the medicines is low and the absorption difference is large. Celecoxib is a poorly soluble weak acid compound that is practically insoluble in water, with solubility increasing with increasing pH. To improve celecoxib solubility and in vivo absorption, many researchers use different techniques such as solid dispersion, cyclodextrin inclusion, microsphere and the like to improve the adverse characteristics. The patent CN103585164B grinds celecoxib, a dispersion promoter and an alkaline compound under the protection of nitrogen to obtain a solid mixture of celecoxib D90 of 5-20 mu m. Patent CN103263385B prepares celecoxib long-acting nano injection by jet milling and high-pressure homogenization. Patent CN110840850B prepares celecoxib into a nano drug delivery system with the particle size of 10-1000 nm after nano micronization treatment, and then prepares a freeze-dried tablet, so that the solubility and dissolution speed of the drug can be improved, the absorption speed and bioavailability of gastrointestinal tract are improved, but the drug is difficult to continuously play a role, the domestic freeze-dried tablet production line is rare, the equipment requirement is high, the production process, the packaging, the storage environment and the like of the freeze-dried tablet product are required to be strictly controlled, and the processing is complex, the production cost is high, and the quality stability of the product is poor.
At present, the domestic celecoxib commercial preparation only has capsule preparations with quick release by oral administration, and has various defects of low bioavailability, large administration dosage, slow absorption, large fluctuation of blood concentration, cardiovascular and gastrointestinal adverse reactions and the like. Therefore, the celecoxib preparation with high bioavailability, quick absorption, quick response, stable blood concentration and prolonged action time is developed through a more effective means, and more choices are brought to clinical application of celecoxib.
Disclosure of Invention
In order to improve the bioavailability of the medicine, improve the medicine taking limit of the common capsule preparation, enable the medicine to take effect quickly, obtain stable blood concentration and prolong the acting time of the medicine, the invention provides a celecoxib quick-release and slow-release double-release preparation and a preparation method thereof.
The technical scheme for solving the technical problems is as follows:
the first aspect of the invention provides a celecoxib quick-release and slow-release double-release preparation, which comprises a quick-release part and a slow-release part;
the quick-release part comprises the following components in percentage by mass:
10 to 80 percent of alkaline blank pill core,
20% -90% of a medicine layer;
the slow-release part comprises the following components in percentage by mass:
8 to 77.6 percent of alkaline blank pill core,
19.4 to 72 percent of medicine layer,
3% -20% of slow-release coating layer;
wherein, based on 100% of the drug layer, the drug layer comprises the following components:
the mass ratio of the celecoxib in the quick-release part to the celecoxib in the slow-release part is 1:1-1:5.
Further, in the in vitro release process, the release rate of 5 minutes reaches more than 30%, the slow release is carried out within 5 minutes to 24 hours, and the release rate of 24 hours reaches more than 85%.
Further, the protective agent I is one or more selected from glycine, mannitol, sorbitol, maltitol, xylitol, erythritol, dextran, maltose, sucrose, glucose, lactose, galactose, trehalose and polyethylene glycol.
Further, the protective agent II is selected from one or more of microcrystalline cellulose-sodium carboxymethyl cellulose, microcrystalline cellulose and silicon dioxide.
The invention also provides a preparation method of the celecoxib quick-release and slow-release double-release preparation, which comprises the following steps:
(1) Mixing blank auxiliary materials with an alkaline material, and preparing an alkaline blank pill core through centrifugal granulation or extrusion spheronization;
(2) Adding celecoxib and a stabilizer into water, fully and uniformly mixing, and carrying out wet grinding to obtain grinding liquid;
(3) Adding a protective agent I and a protective agent II into water, stirring at a high speed, dispersing uniformly, and mixing uniformly with grinding liquid to obtain celecoxib suspension;
(4) Adding an alkaline blank pill core into a fluidized bed, slowly layering celecoxib suspension for drug loading to the alkaline blank pill core, and drying to obtain celecoxib quick-release pellets;
(5) Preparing a slow-release layer coating liquid;
(6) Adding the celecoxib quick-release pellets into a fluidized bed, spraying liquid coating by using a slow-release layer coating liquid, and drying to obtain a slow-release part, namely the celecoxib slow-release pellets;
(7) And mixing the celecoxib quick-release pellets with celecoxib slow-release pellets to obtain the double-release preparation.
Further, the blank auxiliary material is selected from one or more of microcrystalline cellulose, starch, sucrose and lactose; the alkaline material is one or more selected from potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide and sodium carbonate.
In the step (5), the slow-release material is dissolved in a proper solvent, and an anti-adhesion agent, a plasticizer and a pore-forming agent are added and stirred uniformly to obtain the slow-release layer coating liquid.
Further, the slow release layer coating liquid comprises one or more of slow release materials, plasticizers, pore-forming agents and anti-adhesion agents; wherein, the mass ratio of the slow-release material, the plasticizer, the pore-forming agent and the anti-adhesion agent is (5-15): (0-5): (0-5): (0-5).
Further, the pH of the aqueous solution of the alkaline blank pellet core is 8-11. Wherein the concentration of the aqueous solution of the basic blank pellet core is 50% (w/w).
Further, the particle size of the alkaline blank pill core is 20-100 meshes.
Further, in the grinding fluid in the step (2), the mass and volume concentration of the stabilizing agent is 3-8%, and the mass and volume concentration of the celecoxib is 15-25%; the wet grinding condition is 3000 rpm-4000 rpm for grinding for 60-120 min.
Further, the particle size of the celecoxib in the celecoxib suspension is 10-1000 nm.
Further, the wet grinding technique of step (2) is implemented using a nano grinder or sand mill.
Further, the stabilizer is one or more of the following materials: poloxamer, tween 80, sodium dodecyl sulfate, celluloses and derivatives thereof, and polyvinylpyrrolidone.
Further, the slow release coating layer at least comprises a slow release material for controlling the release of the drug, the slow release material comprises one or more of polyvinyl acetate, acrylic resin or ethyl cellulose, preferably one or more of kollicoat SR30D (polyvinyl acetate 30% aqueous dispersion), eudragit NE30D, eudragit RS30D, eudragit RL30D, aixiazu or Sulisi, more preferably Eudragit RS30D and Eudragit RL30D, and the release rate of the celecoxib of the slow release part is controlled by the cooperation of two slow release materials with different porosities; the plasticizer is one or more selected from triethyl citrate, propylene glycol, triacetin, methyl phthalate, dibutyl sebacate, diethyl phthalate and dibutyl phthalate; the pore-forming agent is one or more selected from lactose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone K30, polyethylene glycol and sodium dodecyl sulfate; the anti-sticking agent is one or more selected from pulvis Talci, magnesium stearate, silica gel micropowder or glyceryl monostearate.
Further, the mass ratio of the quick-release part to the slow-release part is 1: (1-5), preferably 1: (1.5-2.5).
Further, the dual release formulation is packaged or filled in divided doses into hard capsules.
Compared with the prior art, the invention has the following technical effects:
(1) The quick-release part and the slow-release part adopt specific mass ratio, and simultaneously match with specific compositions of the quick-release part and the slow-release part, so that the in-vitro release rate of the preparation reaches more than 30% within 5 minutes, the preparation takes effect rapidly, and then the preparation is released slowly, and the in-vitro release rate reaches more than 85% within 24 hours;
(2) The celecoxib quick-release and slow-release double-release preparation provided by the invention not only has the advantages of high solubility and high bioavailability of nanocrystalline medicaments, but also can prolong the action time of medicaments, the medicaments in quick-release parts can be quickly dissolved out after entering gastrointestinal tracts, the bioavailability is high, the absorption is quick, the effect is quick, the subsequent slow-release parts are gradually released, the blood concentration is maintained within the effective medicament concentration range, the stable blood concentration is provided, the adverse reaction of the medicaments is reduced, and the action time of the medicaments is prolonged;
(3) The dispersed drug pellets after the dissolution of the capsules can be distributed in a large area in the gastrointestinal tract, so that the local irritation to the gastrointestinal tract is reduced, and the individual difference is reduced;
(4) The alkaline pellet core can provide local alkaline environment when the water solution permeates into the pellet, so that the solubility of celecoxib is improved;
(5) The drug is subjected to nano-micronization treatment to prepare a nano drug delivery system with the particle size of 10-1000 nm, so that the solubility and dissolution speed of the drug can be obviously improved, and the bioavailability is obviously improved;
(6) The stable nanocrystalline drug prepared by wet grinding in the invention can obtain a solid preparation with stable quality and quick release in a common fluidized bed drug loading mode without freeze-drying and other means, provides a novel nanocrystalline drug preparation mode, avoids the problems of poor placement stability of liquid preparation, complex freeze-drying process of freeze-drying tablets and high quality control difficulty of freeze-drying products, and has the advantages of simple auxiliary materials, high safety, simple and convenient process and easy production and amplification.
Drawings
FIG. 1 shows a graph comparing in vitro release curves of examples 1-5 of the present invention with commercially available products;
fig. 2 shows the blood concentration profile in beagle dogs over time.
Detailed Description
Further advantages and effects of the present invention will become apparent to those skilled in the art from the disclosure of the present specification, by describing the embodiments of the present invention with specific examples. While the description of the invention will be described in connection with the preferred embodiments, it is not intended to limit the inventive features to the implementation. Rather, the purpose of the invention described in connection with the embodiments is to cover other alternatives or modifications, which may be extended by the claims based on the invention. The following description contains many specific details for the purpose of providing a thorough understanding of the present invention. The invention may be practiced without these specific details. Furthermore, some specific details are omitted from the description in order to avoid obscuring the invention. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Example 1
The formula comprises the following components:
(1) Quick release part (30%)
(2) Sustained release portion (70%)
The preparation process comprises the following steps:
dissolving disodium hydrogen phosphate in water, mixing with microcrystalline cellulose to obtain soft material, extruding, rolling to obtain 40 mesh micropill, drying, sieving, and selecting 40-60 mesh micropill as basic blank core.
Adding polyvinylpyrrolidone and sodium dodecyl sulfate into 300mL purified water, stirring and dissolving to obtain a dispersion medium, slowly pouring celecoxib raw material into the dispersion medium, stirring for 5min, and fully wetting celecoxib and dispersing in the dispersion medium to obtain a primary suspension; adding the primary suspension into a nano grinder, adjusting the rotating speed to 3000rpm, and carrying out wet grinding for 60min to obtain nano-scale medicine grinding liquid; adding the prescription amount of mannitol and microcrystalline cellulose-sodium carboxymethyl cellulose into 150ml of water, stirring and mixing at high speed until the mixture is fully dispersed, adding the mixture into a medicine grinding liquid, and stirring the mixture uniformly to obtain celecoxib suspension.
Adding the basic blank pellet core into a fluidized bed, controlling the temperature of the material to be 32-37 ℃, slowly spraying celecoxib suspension, and drying to obtain a quick-release part (celecoxib quick-release pellets).
Adding the povidone K30 with the prescription amount into purified water, stirring and dissolving; adding kollicoat SR30D and talcum powder with prescribed amounts, stirring to fully dissolve or disperse, and obtaining the slow-release coating liquid.
And (3) weighing the prescription-quantity celecoxib quick-release pellets, adding the quick-release pellets into a fluidized bed coating machine, spraying the prepared slow-release layer coating liquid, and drying to obtain the celecoxib slow-release pellets.
The pellets were mixed in the immediate release portion: the slow release part is 30%: and (5) filling 70% of the capsules to obtain the finished product.
Example 2
The formula comprises the following components:
(1) Quick release part (40%)
(2) Sustained release portion (60%)
The preparation process comprises the following steps:
dissolving sodium hydroxide in water, mixing with microcrystalline cellulose to obtain soft material, extruding, rolling to obtain 60 mesh micropill, drying, sieving, and selecting 60-80 mesh micropill as basic blank core.
Adding hydroxypropyl cellulose and sodium dodecyl sulfate into 200mL purified water, stirring and dissolving to obtain a dispersion medium, slowly pouring celecoxib raw material into the dispersion medium, stirring for 5min, and fully wetting celecoxib and dispersing in the dispersion medium to obtain an initial suspension. And adding the primary suspension into a nano grinder, adjusting the rotating speed to 3500rpm, and carrying out wet grinding for 60min to obtain the nano-scale medicine grinding liquid. Adding prescription amount of trehalose and microcrystalline cellulose-sodium carboxymethyl cellulose into 200ml of water, stirring and mixing at high speed until the mixture is fully dispersed, adding the mixture into a medicine grinding liquid, and stirring the mixture uniformly to obtain celecoxib medicine suspension.
Adding the basic blank pill core into a fluidized bed, controlling the temperature of the materials to be 32-37 ℃, slowly spraying celecoxib drug suspension, and drying to obtain a quick-release part (celecoxib quick-release pellets).
Adding the triethyl citrate with the prescription amount into purified water, stirring and dissolving; adding Eudragit RS30D, eudragit RL30D and talcum powder with the prescribed amounts, stirring to fully dissolve or disperse, and obtaining the slow-release coating liquid.
And (3) weighing the prescription-quantity celecoxib quick-release pellets, adding the pellets into a fluidized bed coating machine, spraying the prepared coating liquid, and drying to obtain the slow-release pellets.
The pellets were mixed in the immediate release portion: the slow release part is 40%:60% of the capsules are filled in the capsule, obtaining the product.
Example 3
The formula comprises the following components:
(1) Quick release part (25%)
(2) Sustained release portion (75%)
The preparation process comprises the following steps:
dissolving disodium hydrogen phosphate in water, mixing with microcrystalline cellulose and lactose to obtain soft material, extruding, rolling to obtain 60 mesh micropill, drying, sieving, and selecting 60-80 mesh micropill as basic blank core.
Adding polyvinylpyrrolidone and poloxamer into 250mL purified water, stirring and dissolving to obtain a dispersion medium; slowly pouring celecoxib raw material into a dispersion medium and stirring for 5min to enable celecoxib to be fully wetted and dispersed in the dispersion medium to obtain an initial suspension; and adding the primary suspension into a nano grinder, adjusting the rotating speed to 3500rpm, and carrying out wet grinding for 90min to obtain the nano-scale medicine grinding liquid. Adding the prescription amount of sorbitol and microcrystalline cellulose into 100ml of water, stirring and mixing at high speed until the mixture is fully dispersed, adding the mixture into a medicine grinding liquid, and stirring the mixture uniformly to obtain celecoxib medicine suspension.
Adding the basic blank pill core into a fluidized bed, controlling the temperature of the materials to be 32-37 ℃, slowly spraying celecoxib drug suspension, and drying to obtain a quick-release part (celecoxib quick-release pellets).
Adding the prescription amount of Sulisi into purified water, stirring and dispersing uniformly to obtain the slow-release coating solution.
And (3) weighing the prescription-quantity celecoxib quick-release pellets, adding the pellets into a fluidized bed coating machine, spraying the prepared coating liquid, and drying to obtain the slow-release pellets.
The pellets were mixed in the immediate release portion: the slow release part is 25%: and (5) filling 75% of the capsules to obtain the traditional Chinese medicine.
Example 4
The formula comprises the following components:
(1) Quick release part (45%)
(2) Sustained release portion (55%)
The preparation process comprises the following steps:
dissolving sodium carbonate in water, mixing with microcrystalline cellulose and starch to obtain soft material, extruding, rolling to obtain 40 mesh micropill, drying, sieving, and selecting 40-60 mesh micropill as basic blank core.
Adding hypromellose and tween 80 into 250mL of purified water, stirring and dissolving to obtain a dispersion medium; slowly pouring celecoxib raw material into a dispersion medium and stirring for 5min to enable celecoxib to be fully wetted and dispersed in the dispersion medium, so as to obtain an initial suspension. Adding the primary suspension into a nano grinder, adjusting the rotating speed to 3200rpm, and carrying out wet grinding for 120min to obtain the nano-scale medicine grinding liquid. Adding the prescription amount of lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and silicon dioxide into 150ml of water, stirring and mixing at high speed until the mixture is fully dispersed, adding the mixture into a medicine grinding liquid, and stirring the mixture uniformly to obtain celecoxib medicine suspension.
Adding the basic blank pill core into a fluidized bed, controlling the temperature of the materials to be 32-37 ℃, slowly spraying celecoxib drug suspension, and drying to obtain a quick-release part (celecoxib quick-release pellets).
Adding the triethyl citrate with the prescription amount into purified water, stirring and dissolving; adding Eudragit RS30D, eudragit RL30D and talcum powder with the prescribed amounts, stirring to fully dissolve or disperse, and obtaining the slow-release coating liquid.
And (3) weighing the prescription-quantity celecoxib quick-release pellets, adding the pellets into a fluidized bed coating machine, spraying the prepared coating liquid, and drying to obtain the slow-release pellets.
The pellets were mixed in the immediate release portion: the slow release part is 45%: and (5) filling 55% of capsules to obtain the traditional Chinese medicine.
Example 5
(1) Quick release part (30%)
(2) Sustained release portion (70%)
The preparation process comprises the following steps:
dissolving dipotassium hydrogen phosphate in water, mixing with microcrystalline cellulose to prepare a soft material, extruding, rounding to prepare micropills with about 60 meshes, drying, sieving, and selecting micropills with 60-80 meshes as alkaline blank pill cores.
Adding polyvinylpyrrolidone into 200mL of purified water, stirring and dissolving to obtain a dispersion medium, slowly pouring celecoxib raw material into the dispersion medium, stirring for 5min, and fully wetting and dispersing celecoxib in the dispersion medium to obtain an initial suspension; and adding the primary suspension into a nano grinder, adjusting the rotating speed to 3500rpm, and carrying out wet grinding for 120min to obtain the nano-scale medicine grinding liquid. Adding the prescribed amount of polyethylene glycol, mannitol and microcrystalline cellulose-sodium carboxymethyl cellulose into 100ml of water, stirring at high speed, mixing until the mixture is fully dispersed, adding the mixture into a medicine grinding liquid, and stirring the mixture uniformly to obtain celecoxib medicine suspension.
Adding the basic blank pill core into a fluidized bed, controlling the temperature of the materials to be 32-37 ℃, slowly spraying celecoxib drug suspension, and drying to obtain a quick-release part (celecoxib quick-release pellets).
Adding polyethylene glycol with a prescription amount into purified water, stirring and dissolving; adding Eudragit NE30D and talcum powder with the prescribed amount, stirring to fully dissolve or disperse, and obtaining the slow release layer coating liquid.
And (3) weighing the prescription-quantity celecoxib quick-release pellets, adding the pellets into a fluidized bed coating machine, spraying the prepared coating liquid, and drying to obtain the slow-release pellets.
The pellets were mixed in the immediate release portion: the slow release part is 30%: and (5) filling 70% of the capsules to obtain the finished product.
And (3) effect verification test:
1. in vitro dissolution test comparison
In vitro dissolution tests were performed on 5 capsules and commercial products (celecoxib-containing 200mg celecoxib capsules from the company of the U.S. Pat. No. 5) of the self-made celecoxib immediate-release and sustained-release double-release preparation in examples 1 to 5, respectively.
Taking 5mL (simultaneously supplementing equal isothermal dissolution medium) of 5min, 15min, 30min, 60min, 120min, 240min, 360min, 720min, 960min and 1440min respectively according to the legal operation by taking 900mL of hydrochloric acid solution (pH 1.2) containing 1% sodium dodecyl sulfate as dissolution medium and rotating at 75 revolutions per minute according to the second method (paddle method) of the fourth part 0931 of the 2020 edition of Chinese pharmacopoeia, filtering, and taking the subsequent filtrate as a sample solution; taking a proper amount of celecoxib reference substance, quantitatively diluting into a solution containing 0.1mg of celecoxib reference substance per 1mL, taking the two solutions as reference substance solutions, and detecting at a wavelength of 251nm according to high performance liquid chromatography (the fourth part 0512 of Chinese pharmacopoeia of 2020 edition).
In vitro release data are shown in table 1 and in vitro release curves are shown in figure 1.
TABLE 1 in vitro dissolution test results
Note that: 5, 15, 30, 60, 120, 240, 360, 720, 960, 1440 in Table 1 represent sampling times of 5min, 15min, 30min, 60min, 120min, 240min, 360min, 720min, 960min, 1440min, respectively.
2. Oral bioavailability studies
The high bioavailability celecoxib quick-release and slow-release double-release preparation prepared in example 1 provided by the invention is used as a test preparation (R group) by taking a commercial product (celecoxib) as a reference preparation (T group).
Internal blood concentration determination of beagle dogs
With double crossover administration, 6 male beagle dogs were randomly divided into two groups, three each, each group was given either the reference formulation or the test formulation, and after one week, the administration was exchanged. Fasted overnight one day prior to dosing. Leg vein 1mL of blank whole blood was taken in 1.5mL of EP tube with heparin sodium added. And (5) gastric lavage administration. After administration, 1mL of whole blood was collected from 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, and 72h in an EP tube containing heparin sodium at 1.5 mL. Centrifuging at 8000rpm for 5min, collecting supernatant (blood plasma), and measuring blood concentration by liquid chromatography tandem mass spectrometry (LC-MS/MS). The blood concentration curve is shown in figure 2.
As can be seen from the results of the in-vivo blood concentration curve of animals, the high-bioavailability celecoxib quick-release and slow-release double-release preparation provided by the invention has obviously improved bioavailability and more complete absorption compared with the commercially available product (celecoxib); the self-made preparation can be absorbed more rapidly, can take effect rapidly, can maintain the blood concentration stable in the effective concentration range for a long time after taking effect, and has longer action time.
It should be noted that the above examples are only for illustrating the present invention and are not intended to limit the present invention. Numerous alternatives and modifications of the present invention will be devised by those skilled in the art without departing from the spirit and nature of the invention, which should be construed as being within the scope of the present invention.
Claims (10)
1. The celecoxib quick-release and slow-release double-release preparation is characterized by comprising a quick-release part and a slow-release part;
the quick-release part comprises the following components in percentage by mass:
10 to 80 percent of alkaline blank pill core,
20% -90% of a medicine layer;
the slow-release part comprises the following components in percentage by mass:
8 to 77.6 percent of alkaline blank pill core,
19.4 to 72 percent of medicine layer,
3% -20% of slow-release coating layer;
wherein, based on 100% of the drug layer, the drug layer comprises the following components:
the mass ratio of the celecoxib in the quick-release part to the celecoxib in the slow-release part is 1:1-1:5.
2. The celecoxib quick-release and slow-release double-release preparation according to claim 1, wherein in the in-vitro release process, the release rate of 5 minutes is more than 30%, the celecoxib is slowly released within 5 minutes to 24 hours, and the release rate of 24 hours is more than 85%.
3. The celecoxib quick-release and slow-release double-release preparation according to claim 1, wherein the protective agent I is one or more selected from glycine, mannitol, sorbitol, maltitol, xylitol, erythritol, dextran, maltose, sucrose, glucose, lactose, galactose, trehalose and polyethylene glycol.
4. The celecoxib quick-release and slow-release double-release preparation according to claim 1, wherein the protective agent II is one or more selected from microcrystalline cellulose-sodium carboxymethyl cellulose, microcrystalline cellulose and silicon dioxide.
5. A method for preparing the celecoxib immediate-release and sustained-release double-release preparation as claimed in any one of claims 1 to 4, which comprises the following steps:
(1) Mixing blank auxiliary materials with an alkaline material, and preparing an alkaline blank pill core through centrifugal granulation or extrusion spheronization;
(2) Adding celecoxib and a stabilizer into water, fully and uniformly mixing, and carrying out wet grinding to obtain grinding liquid;
(3) Adding a protective agent I and a protective agent II into water, stirring at a high speed, dispersing uniformly, and mixing uniformly with grinding liquid to obtain celecoxib suspension;
(4) Adding an alkaline blank pill core into a fluidized bed, slowly layering celecoxib suspension for drug loading to the alkaline blank pill core, and drying to obtain celecoxib quick-release pellets;
(5) Preparing a slow-release layer coating liquid;
(6) Adding the celecoxib quick-release pellets into a fluidized bed, spraying liquid coating by using a slow-release layer coating liquid, and drying to obtain a slow-release part, namely the celecoxib slow-release pellets;
(7) And mixing the celecoxib quick-release pellets and the celecoxib slow-release pellets to obtain the double-release preparation.
6. The preparation method of the celecoxib quick-release and slow-release double-release preparation according to claim 5, wherein the blank auxiliary materials are one or more selected from microcrystalline cellulose, starch, sucrose and lactose; the alkaline material is one or more selected from potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide and sodium carbonate.
7. The method for preparing a celecoxib quick-release and slow-release double-release preparation according to claim 5, wherein the slow-release layer coating liquid comprises one or more of slow-release materials, plasticizers, pore-forming agents and anti-adhesion agents.
8. The method for preparing a celecoxib immediate-release and sustained-release double-release preparation according to claim 5, wherein the pH of the aqueous solution of the basic blank pellet core is 8-11.
9. The method for preparing a celecoxib quick-release and slow-release double-release preparation according to claim 5, wherein the particle size of the basic blank pill core is 20-100 meshes.
10. The preparation method of the celecoxib quick-release and slow-release double-release preparation according to claim 5, wherein the mass volume concentration of the stabilizer in the grinding fluid in the step (2) is 3-8%, and the mass volume concentration of celecoxib is 15-25%; the wet grinding condition is 3000 rpm-4000 rpm for grinding for 60-120 min.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311416889.7A CN117462503A (en) | 2023-10-30 | 2023-10-30 | Celecoxib quick-release and slow-release double-release preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311416889.7A CN117462503A (en) | 2023-10-30 | 2023-10-30 | Celecoxib quick-release and slow-release double-release preparation and preparation method thereof |
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