CN115944639A - Amorphous macaroovir composition and preparation method and pharmaceutical preparation thereof - Google Patents
Amorphous macaroovir composition and preparation method and pharmaceutical preparation thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention provides an amorphous mabalovir composition, a preparation method thereof and a pharmaceutical preparation, and belongs to the technical field of medicines. The amorphous mabulaosavir composition comprises mabulaosavir and a carrier, wherein the carrier comprises a povidone polymer and/or a cellulose polymer, and the mabulaosavir accounts for 0.01-70% by mass. The amorphous mabulaosavir composition prepared by the method can be prepared by a solvent evaporation method, a spray drying method or a melt extrusion method. The amorphous mabroxavir composition provided by the invention has greatly improved dissolution rate in a medium with pH of 6.8 and water, which is far higher than that of a raw material medicine, namely mabroxavir, wherein 80.7 percent of amorphous mabroxavir composition can be dissolved in the medium with pH of 6.8 for 90min, and 31.3 percent of amorphous mabroxavir composition can be dissolved in water for 90min.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an amorphous mabulaosvir composition, a preparation method thereof and a pharmaceutical preparation.
Background
Mabarovir (Baloxavir, BAL), a drug against influenza viruses, was discovered by Shionogi & co.ltd, japan and was co-developed with Roche as a new small molecule inhibitor against cap-dependent endonucleases of influenza a or B viruses. It can be rapidly hydrolyzed into active component S-033447 by arylacetamide deacylase in small intestine/blood/liver etc. S-033447 inhibits the activity of endonuclease in influenza virus (RNA virus) infected cells, cracks the cap structure of host pre-mRNA, inhibits the virus from synthesizing mRNA, and further blocks the virus replication. The abacavir is an innovative Cap-dependent endonuclease inhibitor and is a small number of new drugs which can inhibit the proliferation of influenza viruses in the world. And the existing non-clinical research data show that the compound also has activity on avian influenza subtype A/H7N9 of oseltamivir resistant diseases (WHO 2017). Meanwhile, only single medication is needed, so that better convenience and treatment compliance are achieved. Baloxavir has very good market potential because of the large patient base. Compared with oseltamivir, the Baloxavir has the advantages of faster antiviral curative effect, simple administration scheme, less adverse reaction and the like. However, the bioavailability of Baloxavir in rats and monkeys is only about 10% in the existing pharmacokinetic studies, mainly because of the relatively poor solubility of maboxavir, and therefore, there is an urgent need to develop a maboxavir composition and a preparation method thereof, which can improve the solubility and bioavailability of active ingredients.
Disclosure of Invention
The invention aims to provide an amorphous mabulaosvir composition, a preparation method thereof and a pharmaceutical preparation, and aims to solve the technical problem of poor solubility of mabulaosvir in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an amorphous mabulaosavir composition, which comprises mabulaosavir and a carrier; the carrier comprises a povidone-based polymer and/or a cellulose-based polymer.
Further, the povidone-based polymer comprises PVPK30 or PVPVA64; the cellulosic polymer comprises HPMC-AS.
Further, the mass percent of the mabarosavir is 0.01-70%.
The invention provides a preparation method of an amorphous mabulaosvir composition, which comprises one of a solvent evaporation method, a spray drying method and a melt extrusion method.
Further, the solvent evaporation method comprises the following steps: firstly, dispersing the abacavir and the carrier in a solvent, and then removing the solvent to obtain the amorphous abacavir composition.
Further, the solvent comprises one or more of methanol, ethanol, isopropanol, dichloromethane and acetone.
Further, the mass-volume ratio of the mabarosavir to the solvent is 20-70mg.
Further, the method for removing the solvent comprises one of natural airing, drying and drying under reduced pressure.
The invention also provides a pharmaceutical preparation of the mabulaosvir, which comprises an amorphous mabulaosvir composition, and the pharmaceutical preparation is granules, dry suspension, tablets or capsules.
The invention has the beneficial effects that:
(1) According to the amorphous mabalavir composition, the mabalavir, the povidone polymers and/or the cellulose polymers are dispersed in the solvent, and the drug-loading rate of the amorphous mabalavir composition can reach 60% by using any one of a solvent evaporation method, a spray drying method and a melt extrusion method.
(2) The dissolution rate of the amorphous mabalovir composition provided by the invention is greatly improved: 80.7 percent of the crude drug can be dissolved out in a medium with pH of 6.8 for 90min, which is far higher than the dissolution rate of the raw drug material of the mabalosavir, and is as high as 70.8 percent; 31.3 percent of the crude drug ma baroxavir can be dissolved out in water within 90min, 14.8 percent of the crude drug ma baroxavir can be dissolved out, and the dissolution rate of the amorphous ma baroxavir composition is improved by 16.5 percent compared with the dissolution rate of the crude drug ma baroxavir.
Drawings
FIG. 1 is a drying chart of a raw material drug of Marbaloxavir (BAL-SD);
FIG. 2 is a diagram of the oven drying of an amorphous mabulaosvir composition with HPMC-AS AS a carrier;
FIG. 3 is a diagram of an amorphous mabroxavir composition oven-dried with PVPK30 as a carrier;
FIG. 4 is a drying diagram of an amorphous mabusavir composition with PVPVA64 as a carrier;
fig. 5 is a DSC diagram of an amorphous mabulaosvir composition with HPMC-AS carrier: wherein, the sample A is a DSC spectrogram heated to 235 ℃, and the sample B is a DSC spectrogram which is heated to 235 ℃, then cooled to minus 40 ℃ and heated again to 235 ℃;
fig. 6 is a DSC profile of an amorphous mabulaosavir composition with HPMCK30 as carrier: wherein, the sample A is heated to a DSC spectrogram of 235 ℃, and the sample B is heated to 235 ℃, then cooled to-40 ℃ and heated again to the DSC spectrogram of 235 ℃;
fig. 7 is a DSC diagram of an amorphous mabusavir composition with PVPVA64 as a carrier, wherein: a DSC spectrogram of a sample A heated to 235 ℃, and a DSC spectrogram of a sample B heated to 235 ℃, cooled to-40 ℃ and heated to 235 ℃ again;
figure 8 is an XRD pattern of an amorphous mabulaosvir composition with HPMC-AS carrier;
figure 9 is an XRD pattern of an amorphous mabarosavir composition with PVPK30 as a carrier;
fig. 10 is an XRD pattern of an amorphous mabulaosvir composition with PVPVA64 as a carrier;
figure 11 is a graph comparing the dissolution profiles of the amorphous mabusavir composition with HPMC-AS 50% drug loading AS the carrier and the bulk drug mabusavir in a medium with pH6.8 prepared in example 3;
figure 12 is a comparison of the dissolution curves of the amorphous mabroxavir composition with HPMC-AS carrier loading of 50% and the raw material mabroxavir in aqueous medium prepared in example 3.
Detailed Description
The invention provides an amorphous mabulaosavir composition, which comprises mabulaosavir and a carrier; the carrier comprises a povidone-based polymer and/or a cellulose-based polymer.
In the present invention, the povidone-based polymer comprises PVPK30 or PVPVA64, preferably PVPK30; the cellulosic polymer comprises HPMC-AS.
In the present invention, the mass percentage of the mabulaosavir is 0.01 to 70%, preferably 20 to 60%, and more preferably 40 to 60%.
The invention provides a preparation method of an amorphous mabalavir composition, which comprises one of a solvent evaporation method, a spray drying method and a melt extrusion method.
In the present invention, the amorphous mabroxavir composition refers to the abacavir contained in the composition in an amorphous state, wherein amorphous refers to a solid without crystallization, and preferably, X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) are adopted to detect and judge whether a sample is in an amorphous state.
In the present invention, the amorphous mabulaosavir composition is preferably prepared by a solvent evaporation method or a spray drying method, and more preferably by a solvent evaporation method.
In the present invention, the solvent evaporation method comprises the steps of: firstly, dispersing the abacavir and the carrier in a solvent, and then evaporating to remove the solvent to obtain the amorphous abacavir composition.
In the present invention, the solvent includes one or more of methanol, ethanol, isopropanol, dichloromethane and acetone, preferably one or more of ethanol, isopropanol and dichloromethane, and more preferably ethanol and/or dichloromethane.
In the present invention, the mass-to-volume ratio of the mabulaosavir to the solvent is 20 to 70mg, preferably 30 to 60mg, and more preferably 40 to 50mg.
In the present invention, the method for removing the solvent includes one of natural airing, drying and drying under reduced pressure, preferably natural airing or drying, and more preferably drying.
In the present invention, the amorphous mabulaosavir composition provided remains in an amorphous state for 1 week or more, preferably 2 weeks or more, and more preferably 6 weeks or more.
In the invention, the specific parameters of the spray drying method are that the inlet temperature is 80-95 ℃, the gas flow is 50-40, and the sample injection rate is 8-15%.
In the invention, the specific parameters of the melt extrusion method are that the heating temperature is 140-190 ℃, the rotating speed is 19-25 r/min, and the torque is 12-45 Ncm.
The invention also provides a pharmaceutical preparation of the mabroxavir, which comprises the amorphous mabroxavir composition and is a granule, a dry suspension, a tablet or a capsule.
In the invention, the pharmaceutical preparation is granules, dry suspensions, tablets or capsules, preferably granules, dry suspensions or tablets, and more preferably granules or tablets.
In the present invention, a preferred preparation method of the pharmaceutical preparation of mabulaosavir comprises:
weighing the following raw materials in proportion:
mixing the mabalavir and the HPMC-AS, and then spray-drying to obtain an amorphous mabalavir composition; mixing filler, binder, disintegrant and amorphous Marbalozavir composition uniformly to obtain mixture, mixing lubricant and mixture, tabletting to obtain plain tablet, and coating with coating powder to obtain pharmaceutical preparation.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Dispersing HPMC-AS and the mabusavir in 20mL of dichloromethane-ethanol (volume ratio is 1.
Example 2
Dispersing HPMC-AS and the mabroxavir in 20mL of dichloromethane-ethanol (volume ratio is 1).
Example 3
Dispersing HPMC-AS and the mabusavir in 20mL of dichloromethane-ethanol (volume ratio is 1.
Example 4
Dispersing HPMC-AS and the mabusavir in 20mL of dichloromethane-ethanol (volume ratio is 1.
Example 5
Dispersing HPMC-AS and the mabusavir in 20mL of dichloromethane-ethanol (volume ratio is 1.
Example 6
Dispersing PVPVA64 and the mabalasacvir into 50mL of dichloromethane-ethanol (volume ratio is 4.
Example 7
Dispersing PVPVA64 and the mabalasacvir into 50mL of dichloromethane-ethanol (volume ratio is 4.
Example 8
Dispersing PVPVA64 and the Marbafloxacin in 50mL of dichloromethane-ethanol (volume ratio is 4.
Example 9
Dispersing PVPVA64 and the mabalasacvir into 50mL of dichloromethane-ethanol (volume ratio is 4.
Example 10
Dispersing PVPVA64 and the mabalasacvir into 50mL of dichloromethane-ethanol (volume ratio is 4.
Example 11
Dispersing PVPK30 and the Marbasavir in 30mL of acetone, wherein the total mass of the dispersed PVPK30 and the dispersed Marbasavir is 100mg, the mass ratio of the PVPK30 to the Marbasavir is 8.
Example 12
Dispersing PVPK30 and the Marbaloxavir in 30mL of acetone, wherein the total mass of the dispersed PVPK30 and the dispersed Marbaloxavir is 100mg, the mass ratio of the PVPK30 to the Marbaloxavir is 6.
Example 13
Dispersing PVPK30 and the Marbasavir in 30mL of acetone, wherein the total mass of the dispersed PVPK30 and the dispersed Marbasavir is 100mg, and the mass ratio of the PVPK30 to the Marbasavir is 5.
Example 14
Dispersing PVPK30 and the Marbaloxavir in 30mL of acetone, wherein the total mass of the dispersed PVPK30 and the dispersed Marbaloxavir is 100mg, the mass ratio of the PVPK30 to the Marbaloxavir is 4.
Example 15
Dispersing PVPK30 and the Marbasavir in 30mL of acetone, wherein the total mass of the dispersed PVPK30 and the dispersed Marbasavir is 100mg, and the mass ratio of the PVPK30 to the Marbasavir is 3.
Example 16
Dispersing HPMC-AS and mabusavir in 50mL of methanol, wherein the total mass of the dispersed HPMC-AS and mabusavir is 250mg, the mass ratio of the HPMC-AS to the mabusavir is 4, performing ultrasonic treatment until the HPMC-AS and the mabusavir are completely dissolved, and then placing the mixture in a spray dryer for treatment, wherein the specific spray drying parameters are shown in Table 1.
Table 1 spray drying parameter settings:
| inlet temperature/. |
80 |
| Flow of |
45 |
| |
15 |
| ASPIRATOR％ | |
| 100 | |
| |
10 |
Collecting spray-dried samples to obtain the amorphous Marbalozavir composition.
And (3) dissolution rate determination:
taking the amorphous madarosavir composition prepared in example 3 AS an example, the dissolution rate of the amorphous madarosavir composition in ph6.8 medium and aqueous medium was determined, and 40mg of a solid dispersion powder using HPMC-AS a carrier was weighed, wherein the content of madarosavir was 20mg, and 60mg of a physical mixture of HPMC-AS and madarosavir was weighed, AS a control group, wherein the content of madarosavir was 20mg.
The dissolution medium is degassed water and phosphate medium with pH of 6.8, and the sampling time points are 5min, 10min, 15min, 20min, 30min, 45min, 60min and 90min. 900ml of the degassed solvent was measured, and the solution was poured into each operating vessel, and the temperature of the solvent was maintained at 37 ℃. + -. 0.5 ℃. The test sample was taken and put into 6 handling containers, and 4.5mL of the solution was aspirated at a predetermined sampling point, and 4.5mL of the solution was replenished. 2mL of the taken solution was transferred to a dissolution tube to which 1mL of methanol was added, the solution was vortexed, mixed uniformly, and filtered through a 0.45 μm nylon filter (organic filter), the ultraviolet absorption of the filtrate was measured at 260nm, and the dissolution of the test sample was measured three times, wherein the specific dissolution method and detection method are shown in Table 1.
TABLE 1 particular parameters of dissolution method and detection method
TABLE 2 DSC and XRD profile characterization of examples 1-15 and control
Wherein BAL-SD in Table 2 represents pure mabulaosavir bulk drug, AS-SD, K30-SD and VA64-SD represent pure carriers.
As can be seen from the table 2, when the drug-loading rate of the amorphous mabarosavir composition with HPMC-AS AS a carrier is 60%, a small amount of the amorphous mabarosavir composition is separated out, and when the drug-loading rate is 70%, the amorphous mabarosavir composition is obviously separated out, so that the effect is optimal; when the drug-loading rate of the amorphous Marbalozavir composition taking PVP K30 and PVPVA64 as carriers is 40%, obvious precipitation is generated, and the amorphous requirement cannot be met. The amorphous mabalavir composition can be prepared by using the three carriers, wherein the maximum drug-loading rate of PVPK30 and PVPVA64 is at least 20%, and the maximum drug-loading rate of HPMC-AS is at least 60%.
As can be seen from the figure, fig. 1 shows that white crystals are obviously separated from the solid dispersion of the individual mabalavir bulk drug, and fig. 2 shows that the mass ratio of the mabalavir to the HPMCAS is 2:8 to 6: the solid dispersion prepared at 4 was colorless and transparent, and no white crystal precipitated, and the ratio was 7: in case 3, white crystals precipitated. Fig. 3 shows that the mass ratio of the mabarosavir to the PVPK30 is 4: obvious precipitation occurs when the temperature is 6 hours, and an amorphous sample cannot be prepared. Fig. 4 shows that the mass ratio of mabularoside to VA64 is 4: the precipitation phenomenon appeared obvious when the sample was 6 hours, and the amorphous sample could not be prepared.
As can be seen from the dissolution curves of fig. 11 and 12, 80.7% of the amorphous mabulaosvir composition can be dissolved in a medium with a pH of 6.8 for 90min, 9.9% of the raw material can be dissolved, and the dissolution effect of the amorphous mabulaosvir composition is improved by 70.8% compared with that of the raw material medicine; the amorphous mabalovir composition can be dissolved out by 31.3 percent and the raw material medicine can be dissolved out by 14.8 percent in water for 90min, and the amorphous mabalovir composition is improved by 16.5 percent compared with the raw material medicine. Therefore, the amorphous mabalavir composition prepared by the invention has better dissolution effect than the bulk drugs.
According to the above embodiments, the amorphous mabusavir composition comprises mabusavir and a carrier, wherein the carrier comprises a povidone polymer and/or a cellulose polymer, and the mabusavir is 0.01-70% by mass. The amorphous mabulaosavir composition prepared by the method can be prepared by a solvent evaporation method, a spray drying method or a melt extrusion method. The dissolution rate of the amorphous mabulaosavir composition provided by the invention in a medium with the pH of 6.8 and water is greatly improved and is far higher than that of a raw material medicine mabulaosavir, wherein 80.7% can be dissolved out in the medium with the pH of 6.8 within 90min, and 31.3% can be dissolved out in the water within 90min.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. An amorphous mabulaosavir composition comprising mabulaosavir and a carrier; the carrier comprises a povidone-based polymer and/or a cellulose-based polymer.
2. The amorphous mabulaosavir composition according to claim 1, wherein the povidone-based polymer comprises PVPK30 or PVPVA64; the cellulosic polymer comprises HPMC-AS.
3. The amorphous mabusavir composition according to claim 1 or 2, wherein the mabusavir composition is 0.01-70% by mass.
4. A process for the preparation of an amorphous mabusavir composition as claimed in any one of claims 1 to 3, comprising one of solvent evaporation, spray drying and melt extrusion.
5. The method of claim 4, wherein the solvent evaporation method comprises the steps of: firstly, dispersing the mabulaosvir and the carrier in a solvent, and then removing the solvent to obtain the amorphous mabulaosvir composition.
6. The method according to claim 5, wherein the solvent comprises one or more of methanol, ethanol, isopropanol, dichloromethane, and acetone.
7. The preparation method according to claim 5 or 6, wherein the mass volume ratio of the mabroxavir to the solvent is 20-70mg.
8. The method of claim 7, wherein the solvent removal method comprises one of natural drying, oven drying, and drying under reduced pressure.
9. A pharmaceutical preparation of mabalavir, which comprises the amorphous mabalavir composition as described in any one of claims 1 to 3 or the amorphous mabalavir composition prepared by the preparation method as described in any one of claims 4 to 8, and is a granule, a dry suspension, a tablet or a capsule.
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| CN202211724251.5A CN115944639A (en) | 2022-12-30 | 2022-12-30 | Amorphous macaroovir composition and preparation method and pharmaceutical preparation thereof |
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| CN113101270A (en) * | 2020-01-10 | 2021-07-13 | 广东东阳光药业有限公司 | Baroswarriol composition and preparation method thereof |
| WO2022054096A1 (en) * | 2020-09-14 | 2022-03-17 | Cipla Limited | Solid forms of substituted polycyclic pyridone compounds and prodrugs therof and process of preparation thereof |
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| CN113101270A (en) * | 2020-01-10 | 2021-07-13 | 广东东阳光药业有限公司 | Baroswarriol composition and preparation method thereof |
| WO2022054096A1 (en) * | 2020-09-14 | 2022-03-17 | Cipla Limited | Solid forms of substituted polycyclic pyridone compounds and prodrugs therof and process of preparation thereof |
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