CN117982443A - A dapagliflozin metformin sustained-release tablet - Google Patents
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Abstract
The invention relates to a dapagliflozin and metformin sustained-release tablet which consists of a metformin hydrochloride tablet layer, a dapagliflozin tablet layer and a gastric-soluble film coating. The metformin hydrochloride tablet layer contains 1000mg of metformin hydrochloride, magnesium stearate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose 2208 and silicon dioxide. The dapagliflozin tablet layer contains 5-25mg of amorphous dapagliflozin, 6-15mg of sodium carboxymethyl starch, anhydrous lactose, microcrystalline cellulose, magnesium stearate and silicon dioxide. The sustained release tablet has good stability under high temperature, high humidity and illumination. The invention also provides a preparation method of the dapagliflozin metformin sustained-release tablet.
Description
Technical Field
The invention relates to a dapagliflozin and metformin solid preparation, in particular to a dapagliflozin and metformin sustained-release tablet.
Background
Dapagliflozin (Dapagliflozin) is an SGLT-2 inhibitor developed by the company Aspirin and used for treating diabetes, and has a molecular formula of C 21H25ClO6 and CAS number 461432-26-8, and a structural formula shown in the specification. Metformin is a classical drug for treating diabetes mellitus, and is used for forming a compound preparation with various diabetes mellitus treatment drugs.
There are many documents reporting compound dosage forms of dapagliflozin and metformin at present, according to the action mechanism and in vivo metabolism characteristics of dapagliflozin and metformin, dapagliflozin is required to be released quickly, release is basically completed within the first 30 minutes, metformin hydrochloride is released slowly, and only XIGDUO of the slow release dosage forms of the prior art are available on the market.
XIGDUO the drug substance used is dapagliflozin propylene glycol water in the form of hydrate crystals, see CN101479287B. Taking 5mg as an example, the tablet comprises a dapagliflozin layer and a metformin sustained-release layer, wherein the dapagliflozin layer contains 6.15mg of dapagliflozin propylene glycol monohydrate (5 mg of dapagliflozin), microcrystalline cellulose, lactose, crospovidone, silicon dioxide and magnesium stearate; the metformin sustained release layer contains 1000mg of metformin hydrochloride, magnesium stearate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose 2208 and silicon dioxide; film coating is carried out byII pink 85F94592 (5 mg specification) orII yellow 85F12372 (10 mg gauge). The preparation has a shelf life of 2 years under good storage condition, and has good performance when subjected to accelerated test under the conditions of 40+/-2 ℃/75%RH+/-5%RH.
However, in the actual use process of the medicine, the medicine is difficult to be stored in ideal environments of shade, dryness and light shielding all the time, and the current 40 ℃ 75% RH acceleration test is not consistent with the actual situation of medicine storage. As a chronic disease drug, according to the current prescription management method, the drug is not more than 12 weeks per prescription, and patients need to take the drug daily, so the drug is generally not invalid due to the fact that the shelf life is exceeded. In life, the medicines often deteriorate in a purely high-temperature or high-humidity scene, for example, in summer sunlight, the temperature in a vehicle often reaches more than 70 ℃ and is kept for a plurality of hours, and when in rainy season or when the medicine package is wet, the medicines are also in a high-humidity environment of more than 90% RH for a long time. The stability of the original grinding formulation under the high temperature or high humidity condition is not ideal, and the quality guarantee period and the medication safety of the medicine are affected.
Chinese patent CN106924208a describes a sustained release tablet of dapagliflozin hydrochloride with dapagliflozin, propylene glycol, and hydroxypropyl cellulose as the immediate release layer. In CN13398097a, dapagliflozin, propylene glycol, crystal and opard, arginine were used as the dapagliflozin immediate release layer. The above products are also poor in high temperature or high humidity stability.
Disclosure of Invention
In order to solve the problems, the invention provides a dapagliflozin metformin sustained-release tablet.
The tablet consists of a metformin hydrochloride tablet layer, a dapagliflozin tablet layer and a gastric-soluble film coating, wherein each dapagliflozin tablet layer of the tablet contains 5-25mg of dapagliflozin in an amorphous form and 6-15mg of sodium carboxymethyl starch.
The dapagliflozin in an amorphous form is a dapagliflozin compound, the molecular formula is C 21H25ClO6, the dapagliflozin does not contain lattice water or other lattice solvent components, and the content of dapagliflozin in each tablet is preferably 5-10mg, particularly preferably 5mg or 10mg.
Preferably, 12mg of sodium carboxymethyl starch is contained in the dapagliflozin tablet layer of each tablet.
Preferably, the auxiliary materials of the dapagliflozin layer comprise lactose anhydrous, microcrystalline cellulose, magnesium stearate and silicon dioxide, wherein the preferable content is 48mg of lactose anhydrous, 227.5mg of microcrystalline cellulose (5 mg specification) or 222.5mg (10 mg specification), 3mg of magnesium stearate and 4.5mg of silicon dioxide in each tablet.
The metformin hydrochloride layer of each tablet contains 1000mg of metformin hydrochloride, sodium carboxymethyl cellulose, hypromellose, silicon dioxide and magnesium stearate.
The film coating is made of gastric-soluble film coating material, and the components are one or more selected from hydroxypropyl methylcellulose, polyvinyl alcohol or hydroxypropyl cellulose, preferably commercially availableII (Opadry). The content of the film coating material in each tablet is 48-50mg.
The invention also provides a preparation process of the dapagliflozin and metformin sustained-release tablet, which comprises the steps of respectively preparing dapagliflozin particles and metformin particles, mixing the dapagliflozin particles and the metformin particles, tabletting and coating.
The preparation method of the dapagliflozin particles is dry granulation. Weighing raw materials and auxiliary materials with a prescription amount, mixing the weighed raw materials with 60-80% of silicon dioxide, anhydrous lactose, carboxymethyl starch sodium and microcrystalline cellulose with the prescription amount for 1min, sieving with a 20-mesh sieve, mixing for 10min, and adding magnesium stearate and mixing for 5min. Granulating the premixed powder by adopting a dry granulator. And mixing the prepared granules with silicon dioxide, anhydrous lactose, carboxymethyl starch sodium, microcrystalline cellulose and other auxiliary materials with the prescription amount of 20-40% to obtain dapagliflozin granules.
The preparation method of the metformin granulate is wet granulation. Mechanically crushing the raw materials for 10s; weighing raw materials with a prescription amount, adding sodium carboxymethylcellulose with the prescription amount of 50% and metformin hydrochloride with the prescription amount of 50% into a 4L wet granulation pot, starting a stirring knife and a cutting knife, and mixing for 5-10min; starting a spray gun, spraying purified water into the mixed powder, spraying for 4min, adjusting the rotation speeds of a stirring knife and a cutting knife, and granulating for 3min; wet granulating the granulated wet granules by adopting a movable granulator with a 6X 6mm pore size screen, and drying in a fluidized bed until the water content is less than 3%; and (5) drying and granulating the dried granules by adopting a mobile granulator with a 1.5mm aperture screen. And adding 50% of metformin hydrochloride in the prescription amount, 50% of carboxymethylcellulose sodium in the prescription amount and other auxiliary materials into the prepared granules, and mixing to obtain the metformin granules.
The specification of 5mg and the specification of 10mg refer to that each tablet contains 5mg and 10mg of dapagliflozin.
The dapagliflozin particles and the metformin hydrochloride particles are compressed together to form tablets, and the obtained tablets have the parts enriched by the dapagliflozin and the metformin hydrochloride respectively, which are called as dapagliflozin tablets and metformin hydrochloride tablets for convenience of description, and the description does not mean that obvious layering exists in the tablets.
The invention has the advantages that:
Compared with the original grinding agent type, the stability under high temperature and high humidity conditions is improved, thereby being beneficial to preventing the deterioration of medicines under extreme conditions.
The crystal form of the raw material medicine is changed, and the light stability of the whole preparation is ensured to meet the standard.
In a preferred embodiment, the dissolution profile similar to that of the original study is also achieved without adverse effects from patient replacement of the drug.
Drawings
Other features, objects and advantages of the present application will become more apparent upon reading of the detailed description of non-limiting embodiments, made with reference to the accompanying drawings in which:
figure 1 is an XRD pattern of dapagliflozin in amorphous form.
Detailed Description
The application is described in further detail below with reference to the drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the application and are not limiting of the application. It should be noted that, for convenience of description, only the portions related to the present application are shown in the drawings.
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The application will be described in detail below with reference to the drawings in connection with embodiments.
Example 1
Preparation of dapagliflozin in amorphous form.
Dapagliflozin is dissolved in isopropyl acetate, the solvent is removed by rotary evaporation, and the dapagliflozin is dried in vacuum at room temperature for two days to obtain dapagliflozin amorphous form solid. The X-ray diffraction pattern is shown in figure 1 of the specification of the application, no obvious characteristic peak exists, and the product is proved to be in a typical amorphous form. The elemental analysis results are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum data are shown in Table 2.
TABLE 1 elemental analysis (detection of only C and H)
| Element(s) | C | H |
| Theoretical value | 61.69 | 6.16 |
| Actual measurement value | 61.77 | 6.19 |
TABLE 2 Nuclear magnetic resonance Hydrogen Spectrometry data
Description: dapagliflozin has a molecular formula of C 21H25ClO6, 4H on the sugar ring are active protons, and no peak appears in a hydrogen spectrum.
The experiment is carried out according to the guiding principle of the four 9103 medicines moisture absorption test of Chinese pharmacopoeia 2020 edition, a proper amount of dapagliflozin raw material medicine is taken, the dapagliflozin raw material medicine is placed under the condition of 80% ± 2% relative humidity, and the dapagliflozin raw material medicine is weighed after 24 hours, and the moisture absorption weight gain is calculated as shown in Table 3.
Table 3 moisture absorption test of bulk drug
The result shows that the average moisture absorption weight gain of the dapagliflozin bulk drug is 7.8%, and the amorphous dapagliflozin has stronger moisture absorption property.
According to the Inlet registration standard (JX 20140204) of dapagliflozin tablets, related substances in the preparation are required to be less than or equal to 0.9 percent, and further stability test is carried out on the amorphous bulk drug.
The amorphous dapagliflozin crude drug is used for testing, the dapagliflozin crude drug is stored for 30 days at 60 ℃, the total impurity is 0.86%, and the dapagliflozin crude drug has good stability at high temperature; the RH of 92.5% is preserved for 30 days, becomes viscous semi-fluid after 5 days, loses solid form, has more than 3% of impurities, and is stopped, so that the RH is extremely unstable to high-humidity environment due to strong water absorption; 4500 lx.+ -. 500lx light for 30 days, total impurities 0.55%, worse than original grinding tablet.
Example 2
Preparation of dapagliflozin particles and metformin hydrochloride particles.
In this example, the amounts of the raw materials and the auxiliary materials were calculated according to the scale of 1000 tablets each having 5mg and 10mg specifications.
Table 4 prescription information
The preparation method of the dapagliflozin particles comprises the following steps: weighing raw materials and auxiliary materials according to the prescription, mixing the weighed raw materials with 50% of silicon dioxide, anhydrous lactose, 50% of carboxymethyl starch sodium and microcrystalline cellulose according to the prescription for 1min, sieving with a 20-mesh sieve, mixing for 10min, and finally adding 50% of magnesium stearate and mixing for 5min. Granulating the premixed powder by adopting a dry granulator. Total mixing: adding the granulated material into a mixing barrel, weighing 50% of carboxymethyl starch sodium with the prescription amount, adding into the mixing barrel, mixing for 10min, adding 50% of colloidal silica and 50% of magnesium stearate, adding into the mixing barrel, and mixing for 5min.
The preparation method of the metformin granule comprises the following steps: mechanically crushing the raw materials and sieving with a 80-mesh sieve; weighing raw materials and auxiliary materials with a prescription amount, sequentially adding metformin hydrochloride with the prescription amount of 50 percent and magnesium stearate with the prescription amount of 50 percent into a 4L wet granulation pot, premixing for 3min, adding sodium carboxymethylcellulose with the prescription amount, premixing for 5min, starting a stirring knife and a cutting knife, starting a spray gun, spraying purified water into the mixed powder, spraying in 4min, adjusting the rotation speeds of the stirring knife and the cutting knife, and granulating for 3min; wet granulating the granulated wet granules by adopting a movable granulator with a 6X 6mm pore size screen, and drying in a fluidized bed until the water content is less than 3%; and (5) drying and granulating the dried granules by adopting a mobile granulator with a 1.5mm aperture screen. Total mixing: adding the granulated material into a mixing barrel, weighing the hydroxypropyl methylcellulose with the prescription amount, adding the hydroxypropyl methylcellulose into the mixing barrel, and mixing for 20min; finally, adding the colloidal silica with the prescription amount and magnesium stearate with the prescription amount of 50% into a mixing barrel, and mixing for 5min.
Example 3
Preparation of 5 mg-sized tablet
Tabletting the dapagliflozin granules (5 mg gauge) and metformin hydrochloride granules prepared in example 2 were taken and the tablet weights were converted according to the actual contents of dapagliflozin granules and metformin hydrochloride granules, and tabletting was performed using a high-speed rotary tablet press 20.3X10.8 mm die.
Coating: preparing the Opadry film coating liquid, controlling the temperature of the tablet bed at 40-45 ℃ and increasing the weight of the coating by 3%.
Example 4
Preparation of a 10mg gauge tablet.
Tabletting the dapagliflozin granules (10 mg gauge) and metformin hydrochloride granules prepared in example 2 were taken and tabletting was performed using a high-speed rotary tablet press 20.3 x 10.8mm die according to the actual content conversion tablet weights of dapagliflozin granules and metformin hydrochloride granules.
Coating: preparing the Opadry film coating liquid, controlling the temperature of the tablet bed at 40-45 ℃ and increasing the weight of the coating by 3%.
Examples 5 to 9
A5 mg size tablet was prepared by the method of examples 2 and 3, but the sodium carboxymethyl starch content was changed to 3mg, 6mg, 9mg, 15mg and 18mg, respectively.
Examples 10 to 14
Tablets of 10mg size were prepared by the method of examples 2 and 4, but the sodium carboxymethyl starch content was changed to 3mg, 6mg, 9mg, 15mg and 18mg, respectively.
Comparative example 1
A 5mg gauge tablet was prepared using the amorphous form dapagliflozin prepared in example 1, the excipients and process were as described in examples 2 and 3, but the disintegrant used 12mg crospovidone instead of sodium carboxymethyl starch.
Comparative example 2
A 10mg gauge tablet was prepared using the amorphous form dapagliflozin prepared in example 1, the excipients and process were as described in examples 2 and 4, but the disintegrant used 12mg crospovidone instead of sodium carboxymethyl starch.
The tablets prepared in examples 3 to 14 and comparative examples 1 and 2 were tested for their properties by test examples 1 to 4, and all reference formulations were, unless otherwise specified, aspartame XIGDUO (5 mg gauge).
Experimental example 1: high temperature stability test
The samples were left at 60℃for 30 days and tested for single and total impurities, the results are shown in Table 5.
Table 5 stability test results at 60℃in the table/representation were not detected.
As can be seen from the table, the compounds of examples 3-14 and comparative example 1 exhibited high temperature stability superior to XIGDUO, and the reason for this result may be that under higher temperature conditions, the XIGDUO form loses crystal water to undergo crystal transformation, and the crystal water forms a solution environment at a part of the sites, resulting in accelerated degradation of dapagliflozin.
Experimental example 2: high wet stability experiment
The total impurity content was determined by standing at 25℃and 92.5% RH for 30 days, and the results are shown in Table 6.
Table 6:25 ℃,92.5% rh stability test results.
It can be seen from the table that the high wet stability of the tablets is independent of the dapagliflozin content.
Tests of examples 3-14 show that the tablets have a strong water absorption when the sodium carboxymethyl starch content is 18mg, and that the stability of the tablets at high humidity can be effectively improved by using a lower dose of sodium carboxymethyl starch.
Experimental example 3: light stability test
The test results are shown in Table 7 after 30 days at 4500 lx.+ -. 500 lx. The example formulation is not as stable as the reference formulation in light but is still within acceptable limits. Also, the example formulations exhibited superior photostability to comparative examples 1 and 2.
TABLE 7 light stability test results
Experimental example 4: dissolution test
Since dapagliflozin requires immediate release, bioequivalence experiments require release of over 85% at 15 minutes, this example focused on examining the dissolution profiles of the examples, comparative examples and reference under acidic conditions that mimic gastric environments.
TABLE 8 dissolution test results, 5mg specification
TABLE 9 dissolution test results, 10mg specification
The dissolution rates of comparative example 1 and comparative example 2 were too fast, and although the BE test could BE passed, the dissolution profile was widely separated from the reference, possibly affecting registration.
Further testing of examples 5-14 found that when the sodium carboxymethyl starch content was 3mg, the 15min dissolution rate was below 80% and failed the bioequivalence test. In order to ensure the dissolution rate, the content of sodium carboxymethyl starch should be above 6 mg/tablet.
Claims (10)
1. A dapagliflozin metformin sustained release tablet, characterized in that:
The tablet consists of a metformin hydrochloride tablet layer, a dapagliflozin tablet layer and a gastric-soluble film coating, wherein each dapagliflozin tablet layer of the tablet contains 5-25mg of dapagliflozin in an amorphous form and 6-15mg of sodium carboxymethyl starch.
2. The sustained release tablet of claim 1, wherein:
The dapagliflozin amorphous form is dapagliflozin compound, the molecular formula is C 21H25ClO6, and the dapagliflozin amorphous form does not contain lattice water or other lattice solvent components.
3. The sustained release tablet of claim 1, wherein:
The amorphous form of dapagliflozin content in each tablet is 5mg or 10mg.
4. The sustained release tablet of claim 1, wherein: each of the dapagliflozin tablets contained 12mg of sodium carboxymethyl starch.
5. The extended release tablet formulation of claim 1, wherein the dapagliflozin layer of excipients further comprises anhydrous lactose, microcrystalline cellulose, magnesium stearate, and silicon dioxide.
6. The sustained release tablet of claim 5 wherein the dapagliflozin tablet layer of each tablet comprises 48mg of anhydrous lactose, 3mg of magnesium stearate, 4.5mg of silicon dioxide;
the conditions are as follows: each tablet of 5mg specification contains 227.5mg of microcrystalline cellulose and each tablet of 10mg specification contains 222.5mg of microcrystalline cellulose.
7. The sustained release tablet of claim 1, wherein:
the metformin hydrochloride layer of each tablet contains 1000mg of metformin hydrochloride, and the auxiliary materials comprise sodium carboxymethyl cellulose, hypromellose, silicon dioxide and magnesium stearate.
8. The sustained release tablet of claim 1, wherein: the film coating is made of gastric-soluble film coating material, and the components are one or more selected from hydroxypropyl methylcellulose, polyvinyl alcohol or hydroxypropyl cellulose, preferably commercially availableII (Opadry), the content of film coating material in each tablet is 48-50mg.
9. A process for the preparation of dapagliflozin and metformin extended release tablet as claimed in claim 1, comprising preparing dapagliflozin particles and metformin particles separately, mixing dapagliflozin particles and metformin particles, tabletting and coating.
10. The method of preparing as claimed in claim 9, wherein: the dapagliflozin granules are prepared by dry granulation, and the metformin granules are prepared by wet granulation.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN118634201A (en) * | 2024-08-13 | 2024-09-13 | 惠升生物制药股份有限公司 | A kind of janagliflozin metformin tablets and preparation method thereof |
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| CN118634201B (en) * | 2024-08-13 | 2024-11-15 | 惠升生物制药股份有限公司 | A kind of janagliflozin metformin tablets and preparation method thereof |
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