CN111803458B - Ezetimibe pharmaceutical preparation - Google Patents
Ezetimibe pharmaceutical preparation Download PDFInfo
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- CN111803458B CN111803458B CN202010793721.8A CN202010793721A CN111803458B CN 111803458 B CN111803458 B CN 111803458B CN 202010793721 A CN202010793721 A CN 202010793721A CN 111803458 B CN111803458 B CN 111803458B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/143—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/145—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 compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The invention relates to an ezetimibe pharmaceutical preparation which specifically comprises ezetimibe solid dispersoid, a filler, a disintegrating agent and an adhesive, wherein the ezetimibe solid dispersoid comprises ezetimibe, microcrystalline cellulose and a dispersing agent, and the particle size d0.5 of the microcrystalline cellulose is less than or equal to 30 mu m. The ezetimibe medicinal preparation prepared by the invention has better dissolution rate, has the same dissolution effect with the original product sold in the market, has smooth process in the preparation process, meets the standard requirement of the quality of the obtained product, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to a novel pharmaceutical preparation of a cholesterol absorption inhibitor, in particular to an ezetimibe pharmaceutical preparation and a preparation method of the pharmaceutical preparation.
Background
Ezetimibe (ezetimibe) is a novel class of cholesterol absorption inhibitors that can be used alone or in combination with HMG-CoA reductase inhibitors (statins) for the treatment of primary (heterozygous familial or non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH), homozygous sitosterolemia (or phytosterolemia). Ezetimibe has an action mechanism of attaching to the brush border of villus of the small intestine and inhibiting the absorption of cholesterol, thereby reducing the transportation of the cholesterol in the small intestine to the liver, reducing the storage amount of the cholesterol in the liver and increasing the removal of the cholesterol in the blood. Ezetimibe tablets were first produced by the companies Milingpauya (Schering Corporation) and Merck (Merck)&Co), marketed in the united states in 2002 (trade name: ZETIA), imported into the market in china in 2008 (trade name:
)。
ezetimibe has the chemical name 1- (4-fluorophenyl) - (3R) - [3- (4-fluorophenyl) - (3S) -hydroxypropyl ] - (4S) - (4-hydroxyphenyl) -2-azetidine (azetidine) one and the structural formula:
ezetimibe is white crystalline powder, is almost insoluble in water, is an insoluble drug, belongs to BCS II class, namely a low-solubility high-permeability drug, and the dissolution of the drug is often the rate-limiting process of absorption. As is well known, the dissolution of the drug is the precondition of exerting the therapeutic effect, and how to improve the dissolution of the ezetimibe oral solid preparation by the preparation technology ensures that the product effectively exerts the therapeutic effect, has very important significance and value, and simultaneously, the mobility of the ezetimibe is very poor, which brings difficulty to the preparation process of the ezetimibe preparation.
Patent CN103655481A provides a preparation method of an ezetimibe oral preparation. After the ezetimibe, lactose and sodium dodecyl sulfate are mixed and granulated, the ball milling is carried out by adopting a ball milling solid dispersion technology, and then the ball milled powder and other auxiliary materials are prepared into a solid oral preparation, so that the dissolution rate of the preparation is improved. However, as seen from the dissolution data, the cumulative dissolution release amount in example 7 was 41.7% higher than that in example 1 within 15 minutes, and the dissolution curves were significantly different among the examples, resulting in non-uniform preparation quality; moreover, the dissolution release of the example 7 is too fast, which is inconsistent with the dissolution curve of the original product on the market, and the equivalent effect can not be realized, thereby affecting the safety and effectiveness of the patient for taking the medicine. In addition, the drug is ground with the ball milling material, which may be carried into the drug ball milling fine powder, and thus, the patient may have a safety risk when taking the drug.
Patent CN101394837A provides an ezetimibe composition, which achieves the purpose of increasing dissolution by co-grinding ezetimibe and hydrophilic excipient (such as starch, pregelatinized starch, mannitol, sorbitol, etc.) to 20 μm or less, but from the patent figure 2, it can be found that even if the ezetimibe and starch are co-ground to 5 μm or less, the dissolution is significantly improved, but the dissolution effect of the ezetimibe and the original product on the market can not be achieved.
Patent CN103877051A provides a preparation method of ezetimibe tablets, which adopts supercritical carbon dioxide fluid to carry out primary processing on ezetimibe, hydroxypropyl cellulose and mannitol to obtain superfine particle mixed powder, and then auxiliary materials are directly added to carry out tabletting treatment, and the obtained tablets can be completely dissolved out in 15 min. Although the method can ensure that the particle size distribution is uniform in the implementation process, the particle agglomeration phenomenon is obvious, the material dispersibility is poor, and a nozzle is easy to block in the preparation process, so that the method is not suitable for large-scale industrial application.
Therefore, how to overcome the defects of poor water solubility and poor fluidity of ezetimibe and obtain a medicinal preparation which has good dissolution rate, is consistent with the dissolution effect of the original commercially available product, has simple preparation process and uniform product quality is used for the problem to be solved.
Disclosure of Invention
The invention provides an ezetimibe pharmaceutical preparation, aiming at overcoming the problems of poor dissolution effect and poor fluidity of ezetimibe. Dissolution is an in vitro test method that simulates the disintegration and dissolution of an oral solid formulation in the gastrointestinal tract, and has a certain correlation with the bioavailability of the drug in vivo. The ezetimibe medicinal preparation prepared by the invention has better dissolution rate, can be consistent with the dissolution effect of the original product sold in the market, overcomes the problem of difficult preparation caused by the poor flowability of the ezetimibe, has smooth process in the preparation process, ensures that the quality of the obtained product meets the standard requirement, ensures the safety and effectiveness of the administration of patients, and is suitable for industrial large-scale production.
The invention provides an ezetimibe medicinal preparation which specifically comprises an ezetimibe solid dispersion, a filler, a disintegrating agent and an adhesive, wherein the ezetimibe solid dispersion comprises ezetimibe, microcrystalline cellulose and a dispersing agent; the microcrystalline cellulose has a particle diameter d0.5 of 30 μm or less. Preferably, the microcrystalline cellulose has a particle size d0.5 of 20 μm or less.
The microcrystalline cellulose particles having the above-mentioned particle size can be obtained by purchasing, for example, Avicel PH 105,
105, and the like, or can be processed by other modes to prepare the microcrystalline cellulose meeting the grain size requirement of the invention.
The dispersant in the ezetimibe solid dispersion is one or more selected from calcium carbonate, calcium hydrophosphate, magnesium silicate and calcium sulfate; calcium hydrogen phosphate is preferred.
The ezetimibe solid dispersion also comprises a solubilizer, wherein the solubilizer is selected from one or more of sodium dodecyl sulfate, poloxamer and tween 80; a preferred solubilizer is sodium lauryl sulfate.
In the ezetimibe medicinal preparation, the filler is selected from one or more of lactose, mannitol, sorbitol, pregelatinized starch, starch and sucrose; lactose is preferred. The adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and povidone; povidone is preferred. The disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; preferred is croscarmellose sodium.
In the ezetimibe medicinal preparation, the mass dosage of each component is as follows: 10 parts of ezetimibe, 20-50 parts of microcrystalline cellulose, 10-50 parts of a dispersing agent, 30-60 parts of a filler, 2-10 parts of a disintegrating agent and 2-8 parts of an adhesive.
Further preferably, in the ezetimibe pharmaceutical preparation of the present invention, the mass amounts of the components are: 10 parts of ezetimibe, 30-40 parts of microcrystalline cellulose, 25-35 parts of a dispersing agent, 40-60 parts of a filler, 6-10 parts of a disintegrating agent and 3-6 parts of an adhesive.
Furthermore, the ezetimibe pharmaceutical preparation further comprises a glidant, wherein the glidant is one or more selected from superfine silica gel powder, talcum powder, magnesium stearate and sodium stearyl fumarate; magnesium stearate is preferred.
The ezetimibe pharmaceutical preparation provided by the invention is an orally-administered dosage form, such as granules, tablets, capsules, powder and the like.
The invention also aims to provide a method for preparing the ezetimibe pharmaceutical preparation, which comprises the steps of preparing ezetimibe, microcrystalline cellulose and a dispersing agent into an ezetimibe solid dispersion, uniformly mixing the ezetimibe solid dispersion with a filler, a disintegrating agent and an adhesive, carrying out wet granulation, and tabletting to obtain the ezetimibe pharmaceutical preparation.
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose and a dispersing agent into an organic solvent to obtain a suspension;
(2) removing the organic solvent by spray drying to obtain an ezetimibe solid dispersion;
(3) uniformly mixing the ezetimibe solid dispersion with a filler, a disintegrating agent and an adhesive, performing wet granulation, drying, granulating and tabletting;
among them, the microcrystalline cellulose has a particle diameter d0.5 of 30 μm or less, preferably d0.5 of 20 μm or less.
Preferably, the step (1) further comprises a step of adding a solubilizer.
Preferably, the organic solvent in the step (1) may be absolute ethanol, acetone, or the like.
Preferably, the step (3) further comprises the step of uniformly mixing the ezetimibe solid dispersion with the glidant.
Compared with the prior art, the invention has the beneficial effects that:
1. the ezetimibe is insoluble in water and poor in flowability, and the solid dispersion is prepared by matching microcrystalline cellulose (the grain diameter d0.5 of the microcrystalline cellulose is less than or equal to 30 mu m) and a dispersing agent with the ezetimibe, so that the problems of poor dissolution effect and poor flowability of the ezetimibe can be well solved, and the uniform solid dispersion with good flowability can be prepared.
2. The ezetimibe medicinal preparation can obtain the effect consistent with that of the original product on the market after being dissolved out, and ensures the safety and the effectiveness of patients after being taken.
3. In the ezetimibe solid dispersion, the dispersing agent has a porous structure and a large specific surface area, and can adsorb ezetimibe on the surface or in the pore channel to play roles in protecting and solubilizing the drug.
4. In the ezetimibe solid dispersion, the microcrystalline cellulose (the grain diameter d0.5 of the microcrystalline cellulose is less than or equal to 30 mu m) is matched with the dispersing agent, so that the prepared ezetimibe solid dispersion has better formability, and solid dispersion particles with uniform and stable grain size can be formed.
5. In the ezetimibe solid dispersion, the microcrystalline cellulose (the grain diameter d0.5 of the microcrystalline cellulose is less than or equal to 30 microns) and the dispersing agent are matched for use, so that the prepared ezetimibe solid dispersion is not easy to age, has good stability and is suitable for long-term storage.
6. In some embodiments, a solubilizer can be further added to the ezetimibe solid dispersion of the present invention to be used in combination with the microcrystalline cellulose (the particle size d0.5 of the microcrystalline cellulose is less than or equal to 30 μm) and the dispersant, the solubilizer is selected from one or more of sodium dodecyl sulfate, poloxamer and tween 80, and the addition of the solubilizer can further increase the dissolution effect of the ezetimibe.
Detailed Description
Examination of auxiliary Material for solid Dispersion
Experimental example 1
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of microcrystalline cellulose (d0.5 is 30 mu m) in 1L of ethanol to obtain a mixed solution, and removing anhydrous ethanol by spray drying to obtain the ezetimibe solid dispersion.
Experimental example 2
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of microcrystalline cellulose (d0.5 is 65 mu m) in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol by spray drying to obtain the ezetimibe solid dispersion.
Experimental example 3
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of microcrystalline cellulose (d0.5 is 130 μm) in 1L of ethanol to obtain a mixed solution, and removing anhydrous ethanol by spray drying to obtain the ezetimibe solid dispersion.
Experimental example 4
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of copovidone in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol through spray drying to obtain the ezetimibe solid dispersion.
Experimental example 5
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of polyethylene glycol 6000 in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol through spray drying to obtain the ezetimibe solid dispersion.
Experimental example 6
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of hydroxypropyl methyl cellulose in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol through spray drying to obtain the ezetimibe solid dispersion.
Experimental example 7
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of croscarmellose sodium in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol by spray drying to obtain the ezetimibe solid dispersion.
Experimental example 8
Dissolving 10g of ezetimibe, 15g of calcium hydrogen phosphate and 20g of lactose in 1L of ethanol to obtain a mixed solution, and removing absolute ethanol through spray drying to obtain the ezetimibe solid dispersion.
EXAMPLE 9 determination of dissolution Rate of Ezetimibe solid Dispersion
The samples prepared in examples 1-8 were taken and the dissolution liquid was taken at 5min and 30min for HPLC measurements using acetate buffer (pH 4.5) containing 0.2% sodium dodecyl sulfate as dissolution medium by dissolution method (slurry method) at 50 rpm, and the experimental results were as follows:
experimental example 10 aging test of ezetimibe solid Dispersion
The samples prepared in the experimental examples 1-8 were placed in an accelerated test (40 ℃/RH 75%) for 6 months to determine the dissolution rate, acetate buffer (pH 4.5) containing 0.2% sodium dodecyl sulfate was used as dissolution medium, the dissolution liquid was taken at 5min and 30min for HPLC determination according to the dissolution rate determination method (slurry method) with the rotation speed of 50 rpm, and the experimental results were as follows:
according to the invention, the auxiliary material investigation of the ezetimibe solid dispersion discovers that when the auxiliary material selects a dispersing agent and microcrystalline cellulose, and the particle size d0.5 of the microcrystalline cellulose is less than or equal to 30 micrometers, the prepared ezetimibe solid dispersion has good dissolution rate in an acetate buffer solution (pH value of 4.5) containing 0.2% of sodium dodecyl sulfate, and does not age after 6 months of accelerated experiments, and the good dissolution release is also realized in the acetate buffer solution (pH value of 4.5) containing 0.2% of sodium dodecyl sulfate. When the auxiliary materials are selected from dispersing agents and microcrystalline cellulose with the particle size of more than 30 mu m, and when the auxiliary materials are selected from dispersing agents, copovidone, polyethylene glycol, hydroxypropyl methylcellulose, croscarmellose sodium or lactose, the prepared ezetimibe solid dispersion has poor dissolution effect, and also has aging phenomenon and reduced dissolution rate in an accelerated experiment.
Preparation of ezetimibe medicinal preparation
Example 1
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Microcrystalline cellulose (d0.5 is 25 μm) | 20 |
| Calcium hydrogen phosphate | 15 |
| Lactose | 35 |
| Croscarmellose sodium | 4 |
| Povidone | 3 |
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 25 μm) and calcium hydrogen phosphate into anhydrous ethanol to obtain mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) mixing the ezetimibe solid dispersion with lactose, croscarmellose sodium and povidone uniformly, granulating by a wet method, drying, grading and tabletting.
Example 2
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Microcrystalline cellulose (d0.5 is 30 μm) | 30 |
| Calcium carbonate | 25 |
| Pregelatinized starch | 45 |
| Sodium carboxymethyl starch | 8 |
| Hydroxypropyl methylcellulose | 4 |
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 30 μm) and calcium carbonate into anhydrous ethanol to obtain a mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) uniformly mixing the ezetimibe solid dispersion with pregelatinized starch, sodium carboxymethyl starch and hydroxypropyl methyl cellulose, performing wet granulation, drying, granulating and tabletting.
Example 3
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Microcrystalline cellulose (d0.5 is 20 μm) | 26 |
| Calcium sulfate | 30 |
| Sucrose | 20 |
| Lactose | 40 |
| Cross-linked polyvidone | 10 |
| Hydroxypropyl cellulose | 8 |
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 20 μm) and calcium sulfate into ethanol to obtain a mixed solution;
(2) removing ethanol by spray drying to obtain ezetimibe solid dispersoid;
(3) the ezetimibe solid dispersion is uniformly mixed with sucrose, lactose, crospovidone and hydroxypropyl cellulose, and then wet granulation, drying, granule finishing and tablet pressing are carried out.
Example 4
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Microcrystalline cellulose (d0.5 is 18 μm) | 30 |
| Calcium hydrogen phosphate | 10 |
| Poloxamers | 4 |
| Mannitol | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Sodium carboxymethylcellulose | 2 |
| Silica gel micropowder | 1 |
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 18 μm), calcium hydrogen phosphate and poloxamer into acetone to obtain a mixed solution;
(2) removing acetone by spray drying to obtain ezetimibe solid dispersoid;
(3) uniformly mixing the ezetimibe solid dispersion with mannitol, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and superfine silica powder, performing wet granulation, drying, granulating and tabletting.
Example 5
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Avicel PH 105 | 35 |
| Magnesium silicate | 50 |
| Sodium dodecyl sulfate | 2 |
| Tween 80 | 1 |
| Lactose | 30 |
| Cross-linked polyvidone | 2 |
| Povidone | 2 |
The preparation method comprises the following steps:
(1) adding ezetimibe, Avicel PH 105, magnesium silicate, sodium dodecyl sulfate and Tween 80 into absolute ethyl alcohol to obtain a mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) and uniformly mixing the ezetimibe solid dispersion with lactose, crospovidone and povidone, carrying out wet granulation, drying, granulating and tabletting.
Example 6
The preparation method comprises the following steps:
(1) the preparation method comprises the steps of mixing the ezetimibe,
105, adding calcium carbonate and calcium hydrophosphate into absolute ethyl alcohol to obtain mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) uniformly mixing the ezetimibe solid dispersion with sorbitol, croscarmellose sodium, hydroxypropyl cellulose and talcum powder, granulating by a wet method, drying, granulating and tabletting.
Example 7
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 22 μm) and calcium sulfate into anhydrous ethanol to obtain a mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) uniformly mixing the ezetimibe solid dispersion with starch, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl cellulose and magnesium stearate, granulating by a wet method, drying, granulating and tabletting.
Example 8
| Composition of | Dosage (g) |
| Ezetimibe | 10 |
| Microcrystalline cellulose (d0.5 is 20 μm) | 50 |
| Calcium hydrogen phosphate | 20 |
| Lactose | 40 |
| Croscarmellose sodium | 5 |
| Povidone | 2 |
| Hydroxypropyl methylcellulose | 2 |
| Stearic acid sodium fumarate | 1 |
The preparation method comprises the following steps:
(1) adding ezetimibe, microcrystalline cellulose (d0.5 is 20 μm) and calcium hydrogen phosphate into anhydrous ethanol to obtain mixed solution;
(2) removing the absolute ethyl alcohol by spray drying to obtain an ezetimibe solid dispersion;
(3) mixing the ezetimibe solid dispersion with lactose, croscarmellose sodium, povidone, hydroxypropyl methylcellulose and sodium stearyl fumarate uniformly, granulating by a wet method, drying, grading and tabletting.
Comparative examples
The preparation method is the same as example 1.
Dissolution study
Samples from examples 1-8 and comparative recipes 1-3 were taken and a commercial product of ezetimibe was taken
Taking acetate buffer solution (pH value 4.5) containing 0.2% sodium dodecyl sulfate as dissolution medium, performing HPLC determination at 5, 10, 15, 20, 30, and 45min according to dissolution determination method (slurry method) at rotation speed of 50 rpm, and the experimental results are as follows:
original product sold in market
In drug registration and years of clinical application, the safety and effectiveness of the drug administration of patients are proved, the dissolution rate is an in vitro test method for simulating the disintegration and dissolution of an oral solid preparation in the gastrointestinal tract, and is an important index for judging the in vivo effectiveness of the drug. The results of dissolution tests are shown in the table above, and the results show that the dissolution rate of the ezetimibe can be improved by the mutual matching of the ezetimibe, microcrystalline cellulose (the grain diameter d0.5 of the microcrystalline cellulose is less than or equal to 30 mu m) and the dispersing agent in the embodiment of the invention, and the dissolution rate of the ezetimibe pharmaceutical preparation and the dissolution rate of the original grindingThe dissolution of the products sold on the market is highly consistent, the effectiveness of the products sold on the market is consistent, and the safety and effectiveness of patients after taking the medicine are ensured. The comparative formula 1 does not contain microcrystalline cellulose, the comparative formula 2 does not contain a dispersing agent, the grain diameter d0.5 of the microcrystalline cellulose in the comparative formula 3 is more than 30 mu m, the dissolution rate of the prepared sample is obviously poor, and the prepared sample is not good as a commercially available product
The dissolution curves are inconsistent, and the safety and the effectiveness of the patients for taking the medicine are influenced.
Claims (10)
1. An ezetimibe pharmaceutical preparation, which is characterized by comprising an ezetimibe solid dispersion, a filler, a disintegrant and a binder, wherein the ezetimibe solid dispersion comprises ezetimibe, microcrystalline cellulose and a dispersant; the grain diameter d0.5 of the microcrystalline cellulose is less than or equal to 30 mu m; the dispersant in the ezetimibe solid dispersion is one or more selected from calcium carbonate, calcium hydrophosphate, magnesium silicate and calcium sulfate.
2. Ezetimibe pharmaceutical formulation according to claim 1, characterized in that the microcrystalline cellulose has a particle size d0.5 of 20 μm or less.
3. The ezetimibe pharmaceutical formulation according to claim 1, wherein the ezetimibe solid dispersion further comprises a solubilizer selected from one or more of sodium dodecyl sulfate, poloxamer and tween 80.
4. The ezetimibe pharmaceutical formulation according to claim 1, wherein the filler is selected from one or more of lactose, mannitol, sorbitol, pregelatinized starch, sucrose.
5. The ezetimibe pharmaceutical formulation according to claim 1, wherein the binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone.
6. The ezetimibe pharmaceutical formulation according to claim 1, wherein the disintegrant is one or more selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium.
7. The ezetimibe pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation comprises the following components in mass: 10 parts of ezetimibe, 20-50 parts of microcrystalline cellulose, 10-50 parts of a dispersing agent, 30-60 parts of a filler, 2-10 parts of a disintegrating agent and 2-8 parts of an adhesive.
8. The ezetimibe pharmaceutical formulation according to claim 1, further comprising a glidant, wherein the glidant is selected from one or more of aerosil, talc, magnesium stearate and sodium stearyl fumarate.
9. A process for preparing a pharmaceutical formulation of ezetimibe according to claim 1, comprising the steps of:
(1) adding ezetimibe, microcrystalline cellulose and a dispersing agent into an organic solvent to obtain a suspension;
(2) removing the organic solvent by spray drying to obtain an ezetimibe solid dispersion;
(3) uniformly mixing the ezetimibe solid dispersion with a filler, a disintegrating agent and an adhesive, performing wet granulation, drying, granulating and tabletting;
wherein the microcrystalline cellulose has a particle diameter d0.5 of 30 μm or less.
10. The method according to claim 9, wherein the step (1) further comprises a step of adding a solubilizing agent.
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| CN115252565B (en) * | 2022-05-30 | 2023-09-19 | 国药集团致君（深圳）制药有限公司 | Ezetimibe tablet and preparation process and dissolution evaluation method thereof |
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