CN114533686B - Oral solid preparation of dihydropyridines medicine and preparation method thereof - Google Patents
Oral solid preparation of dihydropyridines medicine and preparation method thereof Download PDFInfo
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- 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
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- 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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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61P9/12—Antihypertensives
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Abstract
The application belongs to the field of pharmaceutical preparations, and in particular relates to an oral solid preparation of dihydropyridine drugs, which comprises dihydropyridine drugs with D50 of 0.1-28 mu m, water-soluble polyhydroxy compounds, water-insoluble fillers and water-soluble polymer binders. The application further controls the structure, compatibility and grading of the components. The research shows that the components and the compositions under parameters can synergistically improve the dissolution and stability of the medicine, the dissolution of the medicine in vitro is consistent with that of a reference preparation, the oral administration absorption is good, and the bioavailability is good.
Description
Technical field:
the application belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral solid preparation of felodipine serving as a dihydropyridine drug and a preparation method thereof.
The background technology is as follows:
dihydropyridines are important drugs in calcium antagonists, mainly comprising nifedipine, nimodipine, nitrendipine, amlodipine besylate, lacidipine, nicardipine, felodipine, cilnidipine and the like.
Taking felodipine ((±) -2, 6-dimethyl-4- (2, 3-dichlorophenyl) -1, 4-dihydro-3, 5-pyridinedicarboxylic acid methyl ester ethyl ester) as an example, it has a compound represented by the following general formula i:
felodipine is a drug with poor water solubility and good permeability of BCS II, and the solubility in water is 0.00058mg/ml, so that the improvement of felodipine dissolution is important and difficult to prepare felodipine preparations.
Patent CN102462663a discloses a pharmaceutical composition of felodipine as antihypertensive agent and a preparation method thereof, the composition comprises felodipine, a filler, a dispersing agent, a disintegrating agent, a solubilizer, an adhesive and a lubricant, wherein felodipine and the dispersing agent are micronized together, and then dry granulation is adopted to prepare the pharmaceutical composition of felodipine, wherein mannitol is used as the solubilizer, and the prior developing agent does not use the solubilizer.
Patent CN102462663a discloses a felodipine pharmaceutical solid dispersion and a preparation method thereof, wherein the insoluble pharmaceutical felodipine is used as an active ingredient, the active pharmaceutical and a high molecular carrier are uniformly mixed according to a certain proportion, and the felodipine solid dispersion is prepared by a hot melt extrusion method.
Patent CN104758938A discloses a felodipine tablet for treating hypertension and a preparation method thereof, the tablet contains felodipine, tween 80, crospovidone and a filler. The preparation method comprises the following steps: dissolving felodipine in ethanol, adding tween 80 and crospovidone, stirring, granulating with the suspension as binder on filler, drying to obtain granule, mixing with lubricant, and tabletting.
The above prior art method has a solubilization effect on the dissolution of felodipine drug to a certain extent, but has factors which cause drug instability to different extents, and in order to increase drug dissolution, patent document 1 uses mannitol as a solubilizing agent; in order to increase the dissolution of the drug, the patent document 2 prepares the drug into a solid dispersion, which is easy to form an unstable crystal form and is not beneficial to the stability of the drug, and the solid dispersion has a complex technical process and high requirements on production equipment and operation; patent document 3 discloses that felodipine is dissolved in ethanol, and the use of tween 80 as a surfactant not only tends to cause felodipine to form unstable crystal forms, but also causes inconsistent dissolution behavior in vitro and in vivo.
Disclosure of Invention
The application aims to provide a dihydropyridine drug oral solid preparation which does not contain a solubilizer, a surfactant, and has the advantages of simple preparation process, rapid dissolution and long-term stability.
Another object of the present application is to provide a method for preparing the above oral preparation.
An oral solid preparation of dihydropyridine medicine contains dihydropyridine medicine with D50 of 0.1-28 μm, water-soluble polyhydroxy compound, water-insoluble filler and water-soluble polymer adhesive.
It is found that the dissolution performance of the preparation can be improved under the control of the particle size bulk drug and the components.
According to the application, under the combination of the components, the particle size range of the dihydropyridine drugs is further controlled, so that the synergy can be further realized, and the dissolution effect is further improved.
Preferably, the dihydropyridine drug D50 is 0.5-20 mu m; more preferably 1 to 10. Mu.m, still more preferably 2 to 5. Mu.m.
The application researches find that under the preferable particle size, the combination of the components can further realize the synergy and further improve the dissolution effect of the dihydropyridine drug preparation.
In the application, the dihydropyridine drug is at least one of felodipine, nifedipine, nitrendipine and cilnidipine.
Preferably, the water-soluble polyhydroxy compound is one or more of lactose, sorbitol or glucose.
Preferably, the water-soluble polyhydroxy compound is lactose and further comprises at least one of sorbitol and glucose.
Preferably, the weight percent of lactose in the water-soluble polyol is not less than 40wt.%; further preferably 50 to 80wt.%.
In the application, the water-insoluble filler is one or more of microcrystalline cellulose, corn starch, dextrin, polyvinylpyrrolidone, sucrose or mannitol; preferably, the water-insoluble filler is microcrystalline cellulose and corn starch; preferably, the weight ratio of the two is 1:1-2.
Preferably, the water-soluble polymer binder is at least one of hydroxypropyl cellulose and hypromellose.
In the application, other auxiliary components can be added into the solid preparation according to the preparation requirement, for example, the auxiliary components comprise at least one of lubricant, colorant, flavoring agent and the like;
the lubricant may be a lubricating ingredient known in the industry, such as magnesium stearate, among others.
The colorant is a coloring component well known in the industry, and may be, for example, iron oxide, titanium dioxide, or the like.
The flavoring agent is common flavoring agent, such as aspartame, menthol, sucrose, fructose, steviosin, fruit flavor, etc.
In the dihydropyridine drug oral solid preparation, the content of dihydropyridine drugs is 1-10 wt.%, and the content of water-insoluble filler is 20-40 wt.%; the content of the water-soluble polymer binder is 0.1 to 1wt.%; the balance being water-soluble polyhydroxy compound; the total content of each component is 100wt.%;
preferably, in the dihydropyridine drug oral solid preparation, the content of the auxiliary component is 0.5-2.5 wt.%;
further preferably, in the dihydropyridine drug oral solid preparation, the content of the dihydropyridine drug is 3 to 7wt percent, and the content of the water-insoluble filler is 30 to 35wt percent; the content of the water-soluble polymer binder is 0.1 to 0.4wt.%; the content of the auxiliary components is 1 to 1.5wt.%; the balance being water-soluble polyhydroxy compound; the total content of each component was 100wt.%.
Another embodiment of the technical scheme of the application: the water-soluble polyhydroxy compound is coated on the surface of the dihydropyridine drugs to construct the core-shell structure particles.
According to the application, the dihydropyridine drug core is coated by the water-soluble polyhydroxy compound shell, and the particle size of the dihydropyridine drug core is controlled in a combined manner, so that the synergy can be realized, and the dissolution performance and stability of the dihydropyridine drug can be effectively improved.
The present inventors have found that the combination of the particle size of the core and the core-shell structure is a key to further improve the dissolution property and stability. The research of the application also discovers that the composition and the particle size distribution of the core and the shell are further conducive to further realizing synergy, and the dissolution performance and the stability of the dihydropyridine drugs are further improved.
Preferably, the core comprises dihydropyridine drug particles a and dihydropyridine drug particles B;
wherein, the D50 of the dihydropyridine drug particles A is 0.5-6 μm, more preferably 2-3 μm; the D50 of the dihydropyridine drug particles B is 15-28 mu m. More preferably 20 to 26. Mu.m. The application discovers that the combination of the cores with the grain size grading can further realize the synergy and further improve the dissolution performance and the stability of dihydropyridine medicines.
Preferably, the weight ratio of the dihydropyridine drug particles A to the dihydropyridine drug particles B is 1:0.5-2; further preferably 1:1 to 1.5.
Preferably, the core further comprises water-soluble fiber C. It was found that, under the gradation of the core, the water-soluble fiber C in the form of microfiber was further blended, and a three-dimensional elution channel was unexpectedly further constructed, and the elution property and stability were unexpectedly further synergistically improved.
Preferably, the water-soluble fiber C is at least one of hydroxypropyl cellulose and hypromellose.
Preferably, the weight ratio of the water-soluble fiber C in the solid preparation is not higher than 1wt.%; preferably 0.1 to 0.3wt.%.
In the present application, the water-soluble polyhydroxy compound is used as a shell. Preferably, the water-soluble polyhydroxy compound is lactose and further comprises at least one of sorbitol and glucose. Preferably, the weight percent of lactose in the shell is not less than (greater than or equal to) 40wt.%; further preferably 50 to 80wt.%. Further preferably, the shell comprises lactose and sorbitol in a weight ratio of 1-3:1; further preferably 1.5 to 2:1. It was found that the dissolution effect can be further improved by further synergy with the combination of the structure and composition of the core-shell, the graded core and the combined shell.
In the preferred dihydropyridine drug oral solid preparation, the content of the core is 3-7wt% and the content of the water-insoluble filler is 30-35wt%; the content of the water-soluble polymer binder is 0.1 to 0.4wt.%; the content of the auxiliary components is 1 to 1.5wt.%; the balance being a shell; the total content of each component was 100wt.%.
According to the preferred scheme, the core-shell structure, the core grading and the shell components are controlled in a combined mode, so that the coordination can be realized, the dissolution of dihydropyridine drugs can be improved, and good dissolution and stability can be obtained without adding a solubilizer or surfactant. In addition, the preparation has excellent stability.
In the application, the oral solid preparation is at least one of tablets, granules, capsules and the like.
The application also provides a preparation method of the dihydropyridine oral solid preparation, which is prepared by mixing the components.
For example, the preparation is as follows: uniformly mixing dihydropyridine drug particles, water-soluble polyhydroxy compound and non-water-soluble filler, adding water-soluble polymer adhesive for granulating, and then mixing with other components (such as auxiliary components) to prepare the dihydropyridine drug oral solid preparation.
The preferred dihydropyridine drug oral solid preparation with a coating structure comprises the following preparation method: coating water-soluble polyhydroxy compound on the surface of dihydropyridine drugs in advance to construct core-shell structure particles, and then mixing the core-shell structure particles with other components to prepare the dihydropyridine drug oral solid preparation;
further preferably, the dihydropyridine drug particles A and the dihydropyridine drug particles B are mixed to form a core, then the surface of the core is coated with water-soluble polyhydroxy compound to form core-shell structure particles, and then the core-shell structure particles are mixed with other components to prepare the dihydropyridine drug oral solid preparation;
still more preferably, the dihydropyridine drug particles A, the dihydropyridine drug particles B and the water-soluble fibers C are mixed to form a core, and then the surface of the core is coated with the water-soluble polyhydroxy compound to form core-shell structure particles, and then the core-shell structure particles are mixed with other components to prepare the dihydropyridine drug oral solid preparation.
Taking felodipine oral preparation as an example, the preparation process comprises the following steps:
(1) Obtaining the required felodipine particles;
(2) The felodipine particles are graded or selectively mixed with the water-soluble fiber C and then placed in a wet granulator together with a water-soluble polyhydroxy compound, so that the felodipine particles are fully coated by the water-soluble polyhydroxy compound to form core-shell particles.
(4) Granulating: adding water-insoluble filler and core-shell particles into a granulator, uniformly mixing, adding water-soluble polymer binder solution, and granulating.
(5) And (3) drying: drying the granules obtained in step (4) to control the moisture content to be within 3wt%, preferably 0.5 to 1.5wt%.
(6) Finishing: and (5) finishing the dried granules by adopting a screen.
(7) Tabletting: mixing the obtained granule with magnesium stearate with prescribed amount, tabletting, and making tablet with tablet weight difference meeting requirement (tablet weight difference less than 7.5%).
Advantageous effects
1. It is found that the dissolution performance of the preparation can be improved under the control of the particle size bulk drug and the components. Further, the combination control of the components and the particle size is beneficial to further improving the dissolution performance of the preparation, reducing the generation of impurities in the preparation and improving the safety of the medicine.
2. The preparation disclosed by the application not only has the same dissolution in vitro as a reference preparation, but also has good oral absorption and better bioavailability. 3. The preparation provided by the application has the advantages that the preparation process is simple and feasible, the quality of the prepared preparation is stable and controllable, and the preparation is beneficial to industrial mass production.
Drawings
FIG. 1 is a graph showing the dissolution profiles of examples 1 to 4, which were obtained by fitting the cumulative dissolution data.
FIG. 2 shows dissolution curves of examples 5 to 14, which were obtained by fitting cumulative dissolution data.
Detailed description of the preferred embodiments
Felodipine particle size control: particle size control was performed using a YQ-200 jet mill (manufactured by Shanghai Sishan powder machine Co., ltd.) under the following conditions: the feed pressure was 0.8MPa, the pulverizing pressure was 0.8MPa, and the feed rate was 5Hz.
Measurement of the average particle size of felodipine: taking a proper amount of crushed felodipine, adding a proper amount of water, stirring, adding a proper amount of tween-80, uniformly dispersing felodipine by ultrasound, and measuring by using a 3000E type laser particle size analyzer (manufactured by Malvern corporation).
Sample preparation the sample was prepared by a wet granulation process using a G10 wet mixing granulator (manufactured by Zhejiang Galan technologies Co., ltd.) in a granulation pan 1L.
The dissolution test can better simulate the release behavior of the oral solid preparation in the digestive tract, is an in vitro test method for simulating the disintegration and dissolution of the oral solid preparation in the gastrointestinal tract, is an important index for evaluating the quality and daily supervision of the pharmaceutical preparation, and is also an important tool for developing and screening prescriptions of the preparation. The product is subjected to dissolution test according to the second method (oar method) of the method for measuring the dissolution rate and the release rate of the general rule 0931 of the 2020 edition of Chinese pharmacopoeia. Test dissolution solution was prepared with reference to the dissolution solution used in the japanese orange book "felodipine tablet 5mg dissolution test" as 0.02% tween 80 (W/V) -ph4.0 solution and 0.02% tween 80 (W/V) -ph1.2 solution, 50rpm, test solution: 900ml.
Example 1
Prescription:
| felodipine particles (average particle size: 20 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
Sample preparation: adding felodipine particles, microcrystalline cellulose, corn starch, and lactose into wet granulator, stirring and shearing to obtain granule, granulating with 3% (wt/wt) hydroxypropyl cellulose aqueous solution, drying the granule, and granulating with waterThe sieve is granulated, the sieve and the magnesium stearate with the prescription amount are evenly mixed, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 1. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 2
Prescription:
| felodipine particles (average particle size: 10 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
The difference compared to example 1 is that felodipine has a D50 of 10 μm and the other parameters are the same as in example 1.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 1. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 3
Prescription:
| felodipine particles (average particle size: 5 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
The difference compared to example 1 is that felodipine has a D50 of 5 μm and the other parameters are the same as in example 1.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 1. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 4
Prescription:
| felodipine particles (average particle size: 2.3 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
The difference compared to example 1 is only that felodipine has a D50 of 2.3 μm and the other parameters are the same as in example 1.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 1. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 5
Prescription:
| felodipine particles (average particle size: 2.3 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
The recipe is identical to example 4, except that the core-shell structure is preformed:
sample preparation: and (3) placing felodipine particles (cores) and lactose (shells) in a wet granulator, and starting a stirring function and a shearing function to fully coat the felodipine particles by the lactose to form a coating community. Adding the coated community, microcrystalline cellulose and corn starch into a wet granulator, mixing uniformly, adding a hydroxypropyl cellulose aqueous solution with the concentration of 3% (wt/wt), granulating, drying the drug-containing granules, then adopting a phi 0.8mm screen to carry out granule finishing, mixing uniformly with the prescribed amount of magnesium stearate, tabletting, and ensuring that the tablet weight difference of the prepared tablet meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 6
The only difference compared to example 5 is that the felodipine particles have a D50 of 26 μm.
Prescription:
| felodipine particles (D50: 26.0 μm) | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
Sample preparation: and (3) placing felodipine particles (cores) and lactose (shells) in a wet granulator, and starting a stirring function and a shearing function to fully coat the felodipine particles by the lactose to form a coating community. Mixing the coated aggregate with microcrystalline cellulose and corn starch, granulating with 3% (wt/wt) hydroxypropyl cellulose aqueous solution, drying, and granulatingThe sieve is granulated, the sieve and the magnesium stearate with the prescription amount are evenly mixed, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 7
The only difference compared to example 5 is that the felodipine particles comprise particles a and B, wherein particle a has a D50 of 2.3 μm and particle B has a D50 of 26 μm. The mass ratio of particles A and B is 1:1.
prescription:
| felodipine granule A (D50: 2.3 μm) | 7.5g |
| Felodipine granule B (D50: 26.0 μm) | 7.5g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
Sample preparation: the felodipine particles A (core) and the felodipine particles B (core) are pre-mixed and then are mixed with lactose (shell) in a wet granulator, and the stirring function and the shearing function are started, so that the lactose fully coats felodipine particles to form a coated aggregate. Mixing the coated aggregate with microcrystalline cellulose and corn starch, granulating with 3% (wt/wt) hydroxypropyl cellulose aqueous solution, drying, and granulatingThe sieve is granulated, the sieve and the magnesium stearate with the prescription amount are evenly mixed, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 8
The only difference compared to example 7 is that the felodipine particles comprise particles a and B, wherein particle a has a D50 of 2.3 μm and particle B has a D50 of 26 μm. The mass ratio of particles A and B is 1:2.
prescription:
sample preparation: the felodipine particles A (core) and the felodipine particles B (core) are pre-mixed and then are mixed with lactose (shell) in a wet granulator, and the stirring function and the shearing function are started, so that the lactose fully coats felodipine particles to form a coated aggregate. Mixing the coated aggregate with microcrystalline cellulose and corn starch, granulating with 3% (wt/wt) hydroxypropyl cellulose aqueous solution, drying, and granulatingThe sieve is granulated, the sieve and the magnesium stearate with the prescription amount are evenly mixed, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 9
The only difference compared to example 7 is that the felodipine particles comprise particles a and B, wherein particle a has a D50 of 5.2 μm and particle B has a D50 of 21.0 μm. The mass ratio of particles A and B is 1:1.
prescription:
| felodipine granule A (D50: 5.2 μm) | 7.5g |
| Felodipine granule B (D50: 21.0 μm) | 7.5g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 1.0g |
| Magnesium stearate | 3.0g |
Sample preparation: the felodipine particles A (core) and the felodipine particles B (core) are pre-mixed and then are mixed with lactose (shell) in a wet granulator, and the stirring function and the shearing function are started, so that the lactose fully coats felodipine particles to form a coated community. Adding the coated aggregate and microcrystalline cellulose and corn starch into a wet granulator, mixing uniformly, adding 3% (wt/wt) hydroxypropyl cellulose water solution, granulating, drying the above granule,then adoptThe sieve is granulated, the sieve and the magnesium stearate with the prescription amount are evenly mixed, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 10
The difference compared to example 7 is only that a water-soluble fiber polymer C (hydroxypropyl cellulose) was also added to the core, wherein the water-soluble fiber polymer C was 50% of the total amount of hydroxypropyl cellulose in the formulation. That is, the hyprolose in the formulation was 50% pre-mixed into the core, the remainder being used as a water soluble binder.
Sample preparation: felodipine particles A+B (cores) are pre-mixed with hydroxypropyl cellulose, and then are further mixed with lactose (shells) in a wet granulator, and the stirring function and the shearing function are started, so that the felodipine particles are fully coated by the lactose to form a coating community. Mixing the coated aggregate with microcrystalline cellulose and corn starch, granulating with 1.5% (wt/wt) hydroxypropyl cellulose aqueous solution, drying, and granulatingThe screen is granulated, the screen and magnesium stearate with the prescription amount are evenly mixed to obtain preparation powder, a rotary tablet press is used for preparing tablets with felodipine content of 5mg, the tabletting process is smooth, and the tablet weight difference of the prepared tablets meets the regulation (the tablet weight difference is less than 7.5%).
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 11
The difference compared to example 10 is that sorbitol is used instead of lactose as the shell, and the other parameters are the same as in example 10.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 12
In comparison with example 10, the only difference is that a mass ratio of 1:1 (total content of water-soluble polyhydroxy compound in the formulation was 163 g) was used as a shell instead of lactose, and the other parameters were the same as in example 10.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 13
The only difference compared to example 12 is that a mass ratio of 2:1 as shell, and other parameters were the same as in example 12.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 14
Compared with example 13, the difference is that the mass ratio is 2:1 as a shell, and other parameters were the same as in example 13.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 15
The only difference compared to example 13 is that dextrin replacement (microcrystalline cellulose-corn starch) is used as the non-water soluble filler. Other parameters were the same as in example 13.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Example 16
The only difference compared to example 13 is that the formulation was prepared into capsules by the steps of:
sample preparation: and the preparation powder is filled into a capsule with felodipine content of 5 mg/granule by adopting a No. 3 capsule shell, and the filling process is smooth.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 2. From the dissolution results, the samples were rapidly dissolved in the above 2 media.
Comparative example 1
The difference compared to example 1 is that the D50 particle diameter of the core is 32.0. Mu.m, and the other operations are the same as in example 1.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 3. From the dissolution results, the samples were dissolved slowly in the above 2 media, and the purpose of rapid dissolution was not achieved.
Comparative example 2:
the difference compared with example 1 is that the D50 particle diameter of the core is 0.06. Mu.m, and the other operations are the same as in example 1.
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 3. From the dissolution results, the samples were dissolved slowly in the above 2 media, and the purpose of rapid dissolution was not achieved.
Comparative example 3
The only difference compared to example 1 is that the binder, hydroxypropyl cellulose, is outside the scope of the present application,
prescription:
| felodipine particles | 15g |
| Lactose and lactose | 163g |
| Microcrystalline cellulose | 32g |
| Corn starch | 56g |
| Hydroxypropyl cellulose | 4.0g |
| Magnesium stearate | 3.0g |
The dissolution profile of the samples in 0.02% Tween 80-pH4.0 medium and 0.02% Tween 80-pH1.2 medium was determined and the results are shown in Table 3. From the dissolution results, the samples were dissolved slowly in the above 2 media, and the purpose of rapid dissolution was not achieved.
3. Effect data
1. Dissolution data
The dissolution profile was determined by taking samples of the examples: dissolution medium 1 was 0.02% tween 80 (W/V) -ph4.0 and dissolution medium 2 was 0.02% tween 80 (W/V) -ph 1.2; the paddle method, the rotating speed is 50 revolutions per minute, the dissolution curves of 5, 10, 15, 20, 30, 45, 60 and 90 minutes are set for measuring the sampling time points, sampling is carried out at each time point, the dissolution medium with the same temperature and the same volume is timely supplemented, filtering is carried out, the subsequent filtrate is taken, and the dissolution rate is measured by adopting a high performance liquid chromatography. The cumulative dissolution rate was calculated from the dissolution rates, and a dissolution curve was drawn, with the following results:
table 1 dissolution profile measurement results table of examples 1 to 4
Table 2 dissolution curve measurement results of examples 5 to 16
TABLE 3 dissolution profile measurement results Table for comparative examples 1 to 3
Conclusion of the test:
from the experimental data of examples 1 to 4, it can be seen that the size of the API particle has an effect on the dissolution of the sample in 0.02% Tween 80 (W/V) -pH4.0 medium and 0.02% Tween 80 (W/V) -pH1.2 medium, the smaller the API particle size, the greater the dissolution.
From the experimental data of examples 5 to 10, it can be seen that in the core-shell structure, the particle size of the bulk drug with single particle size has obvious influence on dissolution (examples 5 and 6), and the smaller the particle size, the faster the dissolution; the combination of the crude drugs with different particle sizes according to a certain proportion obviously improves the dissolution of the samples prepared by the single particle size raw materials (examples 5-9), wherein the optimal particle size composition is particle A (D50=2.3 μm): particles B (d50=26 μm) =1:1 (example 7); the dissolution was further enhanced by adding a water-soluble fiber polymer C to the core (example 10).
Examples 10 to 14 mainly screened the shells covering the community (core-shell structure) and examined the effect of lactose, sorbitol and glucose as shells on the dissolution of the sample, the results of the examination were that different shells had a significant effect on the dissolution, with the optimal shell composition being lactose: sorbitol=2:1 (example 13).
2. Stability investigation
The stability of the felodipine-containing preparation is examined according to the "Chinese pharmacopoeia 2020 edition 9001" raw material medicine and preparation stability test guiding principle ".
A batch of samples was prepared according to the method of the examples of the present application, and stability was examined, and sample placement conditions and examination items are shown in the following table.
Table 4 examines items and conditions
The stability test results are shown in the following table:
TABLE 5 stability test data
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Test conclusion the stability data of each example in the table meets the requirements.
Claims (12)
1. An oral solid preparation of dihydropyridines, which is characterized by comprising dihydropyridines with D50 of 0.1-28 mu m, water-soluble polyhydroxy compound, water-insoluble filler and water-soluble polymer adhesive;
the dihydropyridine medicine is at least one of felodipine, nifedipine, nitrendipine and cilnidipine, the water-soluble polyhydroxy compound is one or more of lactose, sorbitol and glucose, the water-insoluble filler is one or more of microcrystalline cellulose, corn starch and dextrin, and the water-soluble polymer adhesive is at least one of hydroxypropyl cellulose and hypromellose; in the dihydropyridine drug oral solid preparation, the content of the dihydropyridine drug is 1-10 wt.%, and the content of the water-insoluble filler is 20-40 wt.%; the content of the water-soluble polymer binder is 0.1 to 1wt.%; the balance being water-soluble polyhydroxy compound; the total content of each component is 100wt.%;
the preparation method comprises the following steps: coating water-soluble polyhydroxy compound on the surface of dihydropyridine drugs in advance to construct core-shell structure particles, and then mixing the core-shell structure particles with other components to prepare the dihydropyridine drug oral solid preparation; the preparation method of the core-shell structure particle comprises the step of placing the dihydropyridine drug and the water-soluble hydroxyl compound in a wet granulator to fully coat the dihydropyridine drug particles with the water-soluble polyhydroxy compound to form the core-shell particle.
2. The dihydropyridine oral solid preparation of claim 1, wherein the dihydropyridines are in the form of
The D50 of the medicine is 0.5-20 mu m.
3. The dihydropyridine oral solid preparation of claim 1, wherein the dihydropyridines are in the form of
The D50 of the medicine is 1-10 mu m.
4. The dihydropyridine oral solid preparation of claim 1, wherein the dihydropyridines are in the form of
The D50 of the medicine is 2-5 mu m.
5. The dihydropyridine oral solid preparation of claim 1, wherein the water-soluble polyhydroxy compound comprises a water-soluble polyhydroxy compound
The base compound is lactose and also contains at least one of sorbitol and glucose.
6. The dihydropyridine oral solid preparation according to claim 5, wherein the weight percentage of lactose in the water-soluble polyhydroxy compound is not less than 40 wt.%.
7. The dihydropyridine oral solid preparation according to claim 5, wherein the weight percentage of lactose in the water-soluble polyhydroxy compound is 50 to 80wt.%.
8. The oral solid dihydropyridine pharmaceutical formulation according to any one of claims 1 to 7, further comprising an adjunct ingredient, wherein the adjunct ingredient comprises at least one of a lubricant, a colorant, and a flavoring agent.
9. The oral solid preparation of dihydropyridine according to claim 8, wherein the dihydropyridine oral solid preparation has a dihydropyridine content of 1 to 10wt.% and a water-insoluble filler content of 20 to 40wt.%; the content of the water-soluble polymer binder is 0.1 to 1wt.%; the content of the auxiliary components is 0.5 to 2.5wt.%; the balance being water-soluble polyhydroxy compound; the total content of each component was 100wt.%.
10. The oral solid preparation of dihydropyridine according to claim 8, wherein the dihydropyridine oral solid preparation has a dihydropyridine content of 3 to 7wt.% and a water-insoluble filler content of 30 to 35wt.%; the content of the water-soluble polymer binder is 0.1 to 0.4wt.%; the content of the auxiliary components is 1 to 1.5wt.%; the balance being water-soluble polyhydroxy compound; the total content of each component was 100wt.%.
11. The oral solid preparation of dihydropyridines according to claim 8, wherein the oral solid preparation of dihydropyridines is at least one of tablets, granules and capsules.
12. A method for preparing the dihydropyridine pharmaceutical oral solid preparation according to any one of claims 1 to 11, which is characterized in that the method comprises the following steps: coating water-soluble polyhydroxy compound on the surface of dihydropyridine drugs in advance to construct core-shell structure particles, and then mixing the core-shell structure particles with other components to prepare the dihydropyridine drug oral solid preparation.
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