CN111920804A - Canagliflozin solid dispersion, preparation method and application thereof - Google Patents
Canagliflozin solid dispersion, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a canagliflozin solid dispersion, a preparation method and application thereof. The solid dispersion comprises canagliflozin, a hydrophilic high polymer material and a solubilizer; the mass ratio of the solubilizer to the canagliflozin is 1:4-1:1, and the mass ratio of the hydrophilic high polymer material to the canagliflozin is 1:2-2: 1; the hydrophilic polymer material is poloxamer. The solubilizer is polyethylene glycol, microcrystalline cellulose or trimethyl chitosan, and has a good solubilizing effect on canagliflozin. The preparation method is characterized by being prepared by a hot-melt extrusion method, reducing the hot-melt temperature to 100-130 ℃, having simple process, low energy consumption and no solvent residue, and being easy for industrial mass production.
Description
Technical Field
The invention belongs to the field of pharmacy, relates to a solid dispersion and a preparation method thereof, and particularly relates to a solid dispersion of canagliflozin and a hot-melt extrusion method thereof.
Background
Canagliflozin (Canagliflozin), marketed under the name Inovokana, is the first SGLT2 inhibitor approved by the FDA for use in the treatment of type ii diabetes in adult patients. Sodium-glucose co-transporter (SGLT) is a glucose transporter, and has two subtypes, SGLT1 and SGLT2, which are distributed in the small intestinal mucosa and renal tubule, respectively, and can transport glucose into the blood. Canagliflozin (Canagliflozin) inhibits SLCT2, prevents glucose in the renal tubules from being successfully reabsorbed into the blood and excreted with urine, thereby reducing blood glucose concentration.
Canagliflozin (canagliflozin) is a white or off-white powder, is non-hygroscopic, readily soluble in ethanol and practically insoluble in water. The chemical name is (1S) -1, 5-dehydrogenation-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol hemihydrate, and the molecular formula is as follows: C24H25FO5S · 1/2H2O, molecular weight: 453.53, the structural formula is as follows:
the canagliflozin has poor water solubility and is almost insoluble in an aqueous medium with the pH value of 1.1-12.9, and how to improve the in vitro dissolution rate of the preparation is the key point influencing the curative effect of the preparation.
The commonly used methods for improving the bioavailability of poorly soluble drugs are micronization technology and solid dispersion technology. However, after the drug is micronized, the surface free energy is larger, and the drug tends to spontaneously agglomerate, so that the micronization effect is reduced. The conventional solid dispersion preparation methods include: although the melting method, the solvent method, the grinding method and the spray drying method can improve the dissolution rate of the medicine, the preparation methods have the problems of complex process, low reproducibility, organic solvent residue and the like, so that the industrial popularization difficulty is high.
The patent application with the publication number of CN 103655539A relates to a canagliflozin oral solid pharmaceutical composition and a preparation method thereof, the composition contains canagliflozin and pharmaceutic adjuvant, wherein the canagliflozin is in an amorphous form, and the average particle size of particles of the canagliflozin is 2.5-30 mu m. The composition effectively solves the technical problems of crystal transformation and poor compressibility of amorphous canagliflozin in the preparation process of solid preparations. Micronization is one of effective ways for improving the dissolution of the medicine, but the micronization has the defects of being not favorable for uniform mixing due to stronger electrostatic adsorption effect, being easy to re-aggregate, causing the dissolution to be reduced and the like.
Patent application publication No. CN 102985075a discloses a canagliflozin-containing tablet containing a high drug-loading amount of canagliflozin and a pharmaceutically acceptable additive, in particular, containing canagliflozin in a range of 30% to 95% by weight of the tablet. The present invention uses a surfactant such as phospholipid, glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, or the like. The surfactant can improve the hydrophilicity of the medicine and increase the dissolution rate of the medicine, but some surfactants have stronger gastrointestinal irritation and have larger side effect after long-term use.
In recent years, hot melt extrusion has received attention from pharmaceutical researchers at home and abroad as a novel method for preparing solid dispersions. The method realizes the transfer conveying, shearing mixing and melt extrusion of materials in a single screw or double screw extruder heated section by section. Compared with the traditional preparation method, the hot-melt extrusion method has the characteristics of high production efficiency, no need of organic solvent, suitability for industrial production and the like. However, for such a drug having a higher melting point, the hot-melt extrusion method easily causes thermal decomposition of the drug and the carrier, thereby limiting the wide use of this method.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a solid dispersion of canagliflozin and a preparation method thereof, which are safe, effective, easy for large-scale production and have higher dissolution rate and bioavailability.
In order to achieve the purpose, the inventor adopts the following technical scheme:
a solid dispersion of canagliflozin comprises the canagliflozin, a hydrophilic high polymer material and a solubilizer. Wherein the mass ratio of the solubilizer to the canagliflozin is 1:4-1:1, and the mass ratio of the hydrophilic polymer material to the canagliflozin is 1:2-2: 1.
The hydrophilic polymer material is poloxamer.
The solubilizer is any one of polyethylene glycol, microcrystalline cellulose and trimethyl chitosan.
By adopting the combination of poloxamer and solubilizer, the hot-melt extrusion temperature can be reduced, the extrusion process is simplified, and the screw shearing function with enough strength can be obtained, so that the dispersion state of the drug in the carrier is effectively improved, and the solubilization function can be achieved.
The preparation method of the solid dispersion of canagliflozin is prepared by a hot-melt extrusion method, and specifically comprises the steps of simultaneously adding the canagliflozin, a hydrophilic high polymer material and a solubilizer into an extruder, enabling the materials to undergo three stages of solid conveying, melting and melt conveying, and obtaining the highly mixed and dispersed solid dispersion of canagliflozin under the action of strong shearing of a kneader and a screw element, wherein most of the medicine is dispersed in an amorphous state in a carrier in the solid dispersion, and the content of the medicine does not substantially influence the dispersed state.
Specifically, the components are crushed and sieved by a 60-100-mesh sieve, then the components are uniformly mixed for later use, the temperature of an extruder is set to be 100 ℃, after the temperature is raised to a set value and is stable, the mixture is added at a constant speed, the temperature is raised to 130 ℃, the mixture is completely melted, a double-screw hot-melt extruder is used for extruding to obtain a strip-shaped object, the rotating speed of a screw is 30 rpm, the surface of the extruded object is smooth and compact, the existence of a pore channel cannot be observed, the extruded object is cooled to room temperature, and the extruded object is crushed and sieved by a 20-80-mesh.
A pharmaceutical composition comprises a solid dispersion of canagliflozin and a pharmaceutically acceptable carrier thereof, and specifically, the dosage form can be granules, powder, capsules and tablets.
The obtained granules or powder can be directly subpackaged as granules or powder, or processed into capsules, tablets, coated on pellets by a lamination method or coated on the outer surface of the preparation, and then the corresponding solid preparation is prepared.
Compared with the traditional process, the invention has the following outstanding beneficial effects:
1. the invention takes polyethylene glycol, microcrystalline cellulose and trimethyl chitosan as solubilizer and plasticizer of the Kagliflozin hot melt extrusion method, and reduces the hot melt temperature to 100-130 ℃. Ensures the stability of the medicine.
2. In the obtained solid dispersion, the canagliflozin is uniformly dispersed in the carrier material and is quickly dissolved in a dissolving medium, so that the bioavailability of the insoluble drug is improved, the administration dosage is reduced, and the adverse reaction of the drug is reduced.
3. The method has the advantages of simple process, low energy consumption, no solvent residue, no other impurities introduced in the whole process, and easy realization of continuous large-scale production.
Drawings
FIG. 1: drug dissolution profiles of canagliflozin bulk drug and canagliflozin solid dispersions (examples 1 to 4, comparative examples 1 to 3).
Detailed Description
The invention is further described with reference to the following figures and detailed description. It is to be understood that the following description is only for the purpose of illustrating the present invention and is not to be construed as limiting the scope thereof. Unless otherwise specified, the contents of the respective components used below are percentages by weight.
The starting materials and their components used in examples 1-4 are shown in Table 1:
TABLE 1
The preparation method comprises the following steps: crushing the components, sieving the components with a 60-mesh sieve, uniformly mixing the components to prepare a physical mixture, setting the temperature of an extruder at 100 ℃, adding the physical mixture at a constant speed after the temperature is raised to a set value and is stable, heating the mixture to 130 ℃, completely melting the mixture, extruding the mixture by using a double-screw hot-melt extruder to obtain a strip-shaped object, wherein the rotating speed of a screw is 30 rpm, the surface of an extruded object is smooth and compact, no pore channel is observed, cooling the extruded object to room temperature, and crushing and sieving the extruded object with a 40-mesh sieve to obtain the canagliflozin solid dispersion.
In the solid dispersion obtained in examples 1-4, the drug is dispersed in the carrier in an amorphous state in the solid dispersion, preferably, a mixture of poloxamer and microcrystalline cellulose is used as the carrier, the hot-melt extrusion operation is easier to perform in the extrusion process, the screw torque value in the extrusion process is less than 30%, and the melt pressure in the die is less than 15 bar. The obtained solid dispersion is easy to crush, and the mass ratio of the poloxamer to the microcrystalline cellulose is 2:1, the supersaturation degree reaches 5500 mug. multidot.mL-1, and the dissolution is rapid.
And the solid dispersion obtained by taking the mixture of the poloxamer and the microcrystalline cellulose as a carrier can keep good stability under the acceleration condition of 2 months.
The starting materials and their components used in comparative examples 1-3 are shown in Table 2:
TABLE 2
Preparation of comparative example 1:
crushing the components, sieving the components with a 60-mesh sieve, uniformly mixing the components to prepare a physical mixture, setting the temperature of an extruder at 100 ℃, adding the physical mixture at a constant speed after the temperature is raised to a set value and is stable, heating the mixture until the temperature is 160 ℃, completely melting the mixture, extruding the mixture to obtain a strip-shaped object, cooling the strip-shaped object to room temperature, crushing the strip-shaped object, and sieving the obtained object with a 40-mesh sieve to obtain the canagliflozin solid dispersion particles.
Preparation of comparative example 2:
crushing the components, sieving the components with a 60-mesh sieve, uniformly mixing the components to prepare a physical mixture, setting the temperature of an extruder at 100 ℃, adding the physical mixture at a constant speed after the temperature is raised to a set value and is stable, heating the mixture until the temperature is up to 180 ℃, completely melting the mixture, extruding the mixture to obtain a strip-shaped object, cooling the strip-shaped object to room temperature, crushing the strip-shaped object, and sieving the obtained object with a 40-mesh sieve to obtain the canagliflozin solid dispersion particles.
Preparation of comparative example 3: mixing uniformly to prepare a physical mixture.
Example 5 dissolution test:
chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler, 0.02% phosphate buffer (pH 6.5 adjusted to acetonitrile (40: 60)) was used as a mobile phase, the flow rate was 1ml/min, and the detection wavelength was 254 nm.
Taking the product, according to a dissolution determination method (XC second method in appendix of year 2015 edition of Chinese pharmacopoeia), taking 900ml of phosphate buffer (containing 0.5% of sodium dodecyl sulfate) with pH of 6.8 as a solvent, rotating at 75 r/min, taking 5ml of solution respectively at 5min, 10 min, 15 min, 30 min and 45min, filtering, and taking a subsequent filtrate as a test solution; and taking about 10mg of canagliflozin reference substance, precisely weighing, putting into a 100ml measuring flask, adding a small amount of ethanol, performing ultrasonic dissolution, and diluting with the dissolution liquid to a scale. Shake up to serve as a control solution. Precisely measuring 20 μ l of each of the sample solution and the reference solution, injecting into a liquid chromatograph, recording chromatogram, and calculating according to peak area by external standard method. The results of the assay are shown in the following table:
the canagliflozin bulk drug, and the canagliflozin solid dispersion particles and the mixtures obtained in examples 1 to 4 and comparative examples 1 to 3 were subjected to dissolution experiments, and the corresponding data are shown in table 3 and fig. 1.
TABLE 3
As can be seen in table 1 and fig. 1:
examples 1-4, dissolution was rapid, and substantially all dissolution was achieved in 60 min;
comparative example 1, no solubilizer was added, the melting temperature was high, and the dissolution of the formed dispersion was slow due to the lack of plasticizer and porogen;
comparative example 2, only solubilizer was used as solid dispersion carrier, melting temperature was high, dissolution was slower;
comparative example 3, which is a physical mixture system only, does not form a solid dispersion, and shows poor dissolution;
because of poor solubility of the canagliflozin bulk drug, the dissolution is the worst when the dissolution is measured by using a simple raw material.
The examples and the comparative examples show that the combined use of the solubilizer and the poloxamer can not only lower the melting temperature of the system, but also facilitate the operation of the melt extrusion process and energy conservation, and also facilitate the dissolution of the canagliflozin.
Claims (6)
1. A solid dispersion of canagliflozin is characterized by comprising the canagliflozin, a hydrophilic high polymer material and a solubilizer;
wherein the mass ratio of the solubilizer to the canagliflozin is 1:4-1:1, and the mass ratio of the hydrophilic polymer material to the canagliflozin is 1:2-2: 1;
the hydrophilic polymer material is poloxamer;
the solubilizer is any one of polyethylene glycol, microcrystalline cellulose and trimethyl chitosan.
2. The solid dispersion of canagliflozin according to claim 1, characterized in that the mass ratio of poloxamer to microcrystalline cellulose is 2: 1.
3. the method for preparing a solid dispersion of canagliflozin of claim 1, wherein the preparation is carried out by a hot-melt extrusion method.
4. The process for preparing a solid dispersion of canagliflozin of claim 3, wherein the canagliflozin, the hydrophilic polymeric material and the solubilizer are simultaneously fed into an extruder, the material is subjected to three stages of solid conveying, melting and melt conveying, and under the action of powerful shearing of a kneader and a screw element, a highly mixed and dispersed solid dispersion of canagliflozin is obtained, most of the drug is dispersed in the solid dispersion in an amorphous state in the carrier and the content does not substantially affect the dispersed state.
5. The method for preparing a solid dispersion of canagliflozin of claim 4, wherein the extruder temperature is set to 100 ℃ to 130 ℃ and the screw rotation speed is 30 rpm.
6. A pharmaceutical composition comprising a solid dispersion of canagliflozin of claim 1 and a pharmaceutically acceptable carrier therefor.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721142A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Rivaroxaban solid dispersion and preparation method thereof |
| WO2016098016A1 (en) * | 2014-12-17 | 2016-06-23 | Dr. Reddy’S Laboratories Limited | Process for the preparation of sglt2 inhibitors |
| CN105769803A (en) * | 2014-12-16 | 2016-07-20 | 康普药业股份有限公司 | Medicinal composition for treating 2-diabetes mellitus and preparation method of medicinal composition |
| CN106474484A (en) * | 2015-09-02 | 2017-03-08 | 常州方楠医药技术有限公司 | Compositionss of unformed canagliflozin and pharmaceutic adjuvant and preparation method thereof |
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- 2020-09-10 CN CN202010945234.9A patent/CN111920804A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721142A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Rivaroxaban solid dispersion and preparation method thereof |
| CN105769803A (en) * | 2014-12-16 | 2016-07-20 | 康普药业股份有限公司 | Medicinal composition for treating 2-diabetes mellitus and preparation method of medicinal composition |
| WO2016098016A1 (en) * | 2014-12-17 | 2016-06-23 | Dr. Reddy’S Laboratories Limited | Process for the preparation of sglt2 inhibitors |
| CN106474484A (en) * | 2015-09-02 | 2017-03-08 | 常州方楠医药技术有限公司 | Compositionss of unformed canagliflozin and pharmaceutic adjuvant and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| NABIL K. ALRUWAILI等: "Formulation of amorphous ternary solid dispersions of dapagliflozin using PEG 6000 and Poloxamer 188: solid-state characterization, ex vivo study, and molecular simulation assessment", 《DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY》 * |
| 孟胜男等主编: "《药剂学》", 31 May 2017, 中国医药科技出版社 * |
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