CN110283142B - Febuxostat-indomethacin co-amorphous substance and preparation method thereof - Google Patents
Febuxostat-indomethacin co-amorphous substance and preparation method thereof Download PDFInfo
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- CN110283142B CN110283142B CN201910505651.9A CN201910505651A CN110283142B CN 110283142 B CN110283142 B CN 110283142B CN 201910505651 A CN201910505651 A CN 201910505651A CN 110283142 B CN110283142 B CN 110283142B
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
- C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a febuxostat-indometacin co-amorphous substance and a preparation method thereof; the febuxostat and indometacin are mixed according to a molar ratio of 1:0.5 to 2, and no sharp diffraction peak is observed in the powder X-ray diffraction spectrum expressed by a degree 2 theta by using Cu-Ka radiation. The research shows that after febuxostat and indometacin are prepared into a co-amorphous substance, the dissolution rates of the two medicines are obviously improved compared with those of the bulk drugs, and the two medicines have the characteristic of synergistic release and have better application prospects. The mode of combined medication provides a new idea for the subsequent preparation research.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a febuxostat-indomethacin co-amorphous solid dispersion and a preparation method thereof.
Background
Febuxostat (Febuxostat) is a clinically common anti-gout drug, has obvious inhibition effect on the XOR of an oxidized form and a reduced form, has stronger and lasting effect of reducing uric acid, and can be used for treating chronic hyperuricemia of gout. However, rapid reduction of uric acid concentration during anti-hyperuricemia therapy is highly likely to lead to acute episodes of ventilation, and non-steroidal anti-inflammatory drugs are clinically recommended for synergistic treatment of gout and relief of pain from acute episodes of gout. According to a biological pharmaceutics classification system, febuxostat belongs to BCS II drugs, and has the characteristics of low solubility, high permeability and low bioavailability.
Indomethacin (Indomethacin), a classic non-steroidal anti-inflammatory drug, has antipyretic, inflammatory pain-relieving effects. The same as febuxostat, the same belongs to BCS II medicines. Can be used for relieving pain of gout acute attack.
Disclosure of Invention
The invention aims to provide a febuxostat-indometacin amorphous substance, which can improve the dissolution rate of two medicaments, play the synergistic effect of the two medicaments and improve the curative effect and the compliance of patients.
The invention also aims to provide a preparation method of the febuxostat-indometacin co-amorphous substance.
The object of the invention can be achieved by the following measures:
a febuxostat-indometacin co-amorphous substance is prepared by mixing febuxostat and indometacin according to a molar ratio of 1: 0.5-2, using Cu-K α The powder X-ray diffraction spectrum expressed by the degree 2 theta of radiation has no sharp diffraction peak.
We found that febuxostat (abbreviated as FEB) and indomethacin (abbreviated as IND) were mixed at a molar ratio of 1: the ratio of 0.5 to 2 can be combined to form a co-amorphous substance. In a preferred scheme, the molar ratio of febuxostat to indomethacin is 2: 1. 1:1 or 1:2, the glass transition temperature of the co-amorphous obtained at this ratio was 52.77 ℃, 50.11 ℃ or 38.48 ℃ respectively.
The preparation method of the febuxostat-indometacin co-amorphous substance comprises the following steps: the febuxostat and the indometacin are mixed in proportion to prepare the co-amorphous substance by a grinding method, spray drying or hot-melt extrusion method.
In a preferred embodiment, a grinding method can be used, in particular: mixing febuxostat and indometacin in proportion, continuously grinding in a mechanical grinding mode, and continuously destroying the crystal structure of the medicine until a co-amorphous state is formed.
The mechanical milling in the milling method includes but is not limited to freeze milling, and in a preferred embodiment, the milling is performed in a liquid nitrogen environment or at-205 ℃ to-190 ℃.
Preferably, the grinding frequency in the grinding method is 5 to 10Hz, and the grinding time is 10 to 60min.
In a more preferred embodiment, the milling process is: mixing febuxostat and indometacin in proportion, adding into a container of a freezing grinding device, grinding in the environment of liquid nitrogen for 5-15 cycles, wherein each cycle comprises grinding for 2 minutes and cooling for 2 minutes.
The invention also comprises a pharmaceutical composition which comprises the febuxostat-indometacin amorphous substance and a pharmaceutically acceptable carrier.
The febuxostat-indometacin co-amorphous substance can be applied to the preparation of anti-gout drugs or preparations.
In order to better understand the essence of the present invention, the following experiments were conducted to evaluate the present invention.
(1) Powder X-ray diffraction analysis of the state of matter in the pharmaceutical composition during milling.
A powder X-ray diffraction analysis method (PXRD analysis conditions are Cu Ka radiation; wavelength:
high-pressure strength: 40KV; scanning range: 3-40 deg.C) the pharmaceutical compositions were each analyzed at different times of milling.
The results of the analysis are shown in FIG. 1. From the X-ray pattern, it can be observed that the unmilled pharmaceutical composition has a strong diffraction peak with crystal characteristics, indicating that it has a typical crystal structure. And as the milling progresses, the crystal diffraction peak gradually decreases. At 60min, the X-ray spectrum of the pharmaceutical composition has no sharp diffraction peak, which indicates that febuxostat and indometacin form a co-amorphous substance.
(2) Differential Scanning Calorimetry (DSC) evaluated the state of matter in the co-amorphous material.
Thermal analysis of both the crystalline and amorphous pure drugs and the co-amorphous form in each ratio was performed using differential scanning calorimetry. The analysis method comprises the following steps: about 5mg of the sample was weighed, placed in an aluminum crucible, and heated to a suitable temperature at 10 ℃/min in a nitrogen atmosphere.
The results of the analysis are shown in FIG. 2: febuxostat and indomethacin showed sharp melting endothermic peaks at 205 ℃ and 157 ℃ respectively. The glass transition temperatures of the two were 64.22 ℃ and 36.08 ℃, respectively. And the molar ratio is 2:1,1:1 and 1: the febuxostat-indometacin co-amorphous substance 2 has a single glass transition temperature, which indicates that the febuxostat-indometacin co-amorphous substance forms a uniform co-amorphous substance.
(3) And (5) physical stability investigation.
For better comparison, we prepared the pure drug in amorphous form, then put it into a 40 ℃ desiccator, and remove the sample at a preset time to analyze its crystallinity with PXRD.
As shown in fig. 3: on day 5, the amorphous febuxostat has only weak crystal diffraction peak, while the amorphous indomethacin is obviously crystallized, which indicates that the indomethacin has stronger crystallization tendency than febuxostat.
In addition, in order to examine the physical stability of the co-amorphous form, co-amorphous forms of different molar ratios were put into dryers at 25 ℃ and 40 ℃ and taken out at an appropriate time to analyze the crystallinity thereof by powder X-ray diffraction.
The results are shown in FIG. 4: the molar ratio of febuxostat to indometacin is 1:1 and 2: the co-amorphous form of 1 remains stable for 30 days at both 25 ℃ and 40 ℃. The molar ratio is 1:2 can keep stable at 25 ℃, and weak crystal diffraction peaks appear at 40 ℃ for 30 days.
(4) Fourier Transform Infrared (FTIR) spectroscopy analyzes interactions between drug molecules.
Preparing sample by potassium bromide (KBr) tabletting method, collecting small amount of sample, mixing with KBr, tabletting, and taking KBr as blank control at 4000-400cm -1 Infrared absorption spectra were measured in the wavenumber range.
The results are shown in FIG. 5: crystalline febuxostat at 1678.7cm -1 A strong carbonyl absorption peak at wavenumber, while the absorption peak of amorphous febuxostat splits to 1680.1cm -1 And 1706.5cm -1 Two separate peaks, attributable to hydrogen-bonded and non-hydrogen-bonded carbonyl peaks, respectively. Crystalline indometacin at 1713.8 and 1690.4cm -1 Two carbonyl stretching vibration peaks are formed and respectively belong to carbonyl groups of carboxyl and benzoyl. The carbonyl peaks of amorphous indometacin are 1739.2, 1709.0 and 1683.1cm respectively -1 At wavenumbers, the groups are assigned to non-hydrogen bonding associated carbonyl groups, carbonyl groups of carboxyl groups forming dimers, and carbonyl groups of benzoyl groups, respectively. To study the intermolecular interaction in the co-amorphous form, by comparing the IR spectra of the febuxostat-indomethacin co-amorphous form and the physical mixture, the absorption peak of the carbonyl group was found to be from 1707cm -1 Blue to 1719cm -1 Here, it is shown that strong hydrogen bond interaction is formed between febuxostat and indomethacin.
(5) Intrinsic Dissolution (IDR) experiments.
The dissolution rate of the drug within 30min was examined. About 200mg of the drug was tabletted in an IDR mold (tabletting conditions: 5MPa, 40s), and then subjected to a dissolution test in a dissolution apparatus. The dissolution conditions were: dissolution medium, 500mlpH 7.4 phosphate buffer; dissolution temperature: 37 ℃; rotational speed, 50rpm. Samples were taken at predetermined times and analyzed for drug concentration in the samples by High Performance Liquid Chromatography (HPLC). HPLC conditions are as follows: instrument, shimadzu SPD 20A; and (3) chromatographic column: agilent C18ODS column (250X 4.6 mm); column temperature: 30 ℃; mobile phase: acetonitrile and pH 5 phosphate buffer; flow rate: 1ml/min; sample introduction volume: 20 μ L.
Dissolution rate results are shown in figure 6: febuxostat from crystalline febuxostat and amorphous febuxostatDissolution rates in the form febuxostat, crystalline physical mixture (molar ratio 1, i.e. febuxostat to indomethacin, the same below), amorphous physical mixture (molar ratio 1: 0.395,0.521,0.394,0.582,0.589mg min -1 cm -2 . The dissolution rate of indometacin from crystalline indometacin, amorphous indometacin, crystalline physical mixture, amorphous physical mixture and co-amorphous substance is 0.0899,0.228,0.272,0.325 and 0.489mg min -1 cm -2 . As can be seen from the dissolution rate results, the dissolution rates of the two drugs are obviously improved after the febuxostat and the indometacin form a co-amorphous substance.
Meanwhile, the dissolution rates of febuxostat and indometacin from the amorphous substance are 0.589 mgmin and 0.489mgmin respectively - 1 cm -2 The synergistic release effect of the two drugs after preparation into the co-amorphous substance is demonstrated. The results are shown in FIG. 7.
The febuxostat and the indometacin have the potential of synergistic gout resistance, and the curative effect can be improved by preparing the febuxostat and the indometacin into a co-amorphous form. The patent provides a febuxostat-indometacin amorphous substance. In the co-amorphous substance, the application further provides that the molar ratio of febuxostat to indomethacin is 1: 1. 1:2 and 2:1, which can be prepared using cryo-milling, spray drying or hot melt extrusion techniques. The research shows that after febuxostat and indometacin are prepared into a co-amorphous substance, the dissolution rates of the two medicines are obviously improved compared with those of the bulk drugs, and the two medicines have the characteristic of synergistic release and have better application prospects. The mode of combined medication provides a new idea for the subsequent preparation research.
Drawings
Fig. 1 is a PXRD pattern of a febuxostat-indomethacin mixture ground for different times;
FIG. 2 is a DSC profile;
FIG. 3 is a pure drug stability test PXRD pattern;
FIG. 4 is a co-amorphous stability test PXRD pattern;
FIG. 5 is an infrared spectrum;
in the figure, a crystalline febuxostat, b amorphous febuxostat, c crystalline indomethacin, d amorphous indomethacin, e crystalline physical mixture (molar ratio 1
FIG. 6 is an IDR dissolution test profile;
figure 7 is a febuxostat-indomethacin synergistic release profile.
Detailed Description
This is further illustrated in the following examples. The examples are intended to illustrate the invention, but not to limit it in any way. All parameters in the examples and the remaining descriptions are based on mass, unless otherwise specified. Various raw materials of the preparation method which are not described in the specification can be commercially obtained.
Example 1: preparation of febuxostat-indometacin co-amorphous substance
Respectively weighing 0.50g of febuxostat and 0.57g of indomethacin, adding into a cryo-grinding tube, and grinding in a liquid nitrogen environment, wherein the cryo-grinding parameters are set to 5 cycles, each cycle comprises 2min grinding and 2min cooling, and the grinding frequency is 10Hz. After grinding was complete, the cryo-grinding tubes were immediately removed and placed in a desiccator to return to room temperature.
Example 2: preparation of febuxostat-indometacin co-amorphous substance
1.0g of febuxostat and 0.57g of indomethacin are respectively weighed and added into a cryogrinding tube, and grinding is carried out in the environment of liquid nitrogen, the cryogrinding parameters are set to 5 cycles, each cycle comprises 2min grinding and 2min cooling, and the grinding frequency is 10Hz. After the grinding was completed, the cryogrinding tube was immediately taken out and placed in a desiccator to return to room temperature.
Example 3: preparation of febuxostat-indometacin co-amorphous substance
0.50g of febuxostat and 1.14g of indomethacin are respectively weighed and added into a cryogrinding tube, and grinding is carried out in the environment of liquid nitrogen, the cryogrinding parameters are set to 5 cycles, each cycle comprises 2min grinding and 2min cooling, and the grinding frequency is 10Hz. After grinding was complete, the cryo-grinding tubes were immediately removed and placed in a desiccator to return to room temperature.
Example 4: physical stability investigation
The appropriate amount of febuxostat-indomethacin co-amorphous was taken and placed in a drier at 25 ℃/0 rh and 40 ℃/0 rh, respectively, and the samples were taken out at a preset time for analysis of crystallinity by powder X-ray diffraction. The results are shown in FIG. 4.
Example 5: intrinsic dissolution test
200mg of the drug is weighed and added into an IDR mould, and tabletting is carried out under the conditions of 5MPa and 40s under a hydraulic press. The exposed surface of the tablet was 0.5cm 2 . The mold was then fixed to a dissolution apparatus for dissolution testing. Samples were taken at 5, 10, 15, 20, 25, 30min, respectively, and passed through a 0.45 μm filter and analyzed for drug concentration by HPLC. The results are shown in FIGS. 6 and 7.
Claims (5)
1. The febuxostat-indometacin co-amorphous substance is characterized by comprising febuxostat and indometacin in a molar ratio of 2:1 or 1:1, using Cu-K α Radiation, powder X-ray diffraction spectrum expressed in degree 2 theta has no sharp diffraction peak; the glass transition temperatures of the two co-amorphous materials are 52.77 ℃ and 50.11 ℃; the preparation method comprises the following steps: mixing febuxostat and indometacin according to a proportion, continuously grinding in a mechanical grinding mode, and continuously destroying the crystal structure of the medicine until a co-amorphous state is formed; the grinding is carried out in a liquid nitrogen environment or at the temperature of minus 205 ℃ to minus 190 ℃.
2. A co-amorphous form of febuxostat-indomethacin according to claim 1, wherein the frequency of milling is 5 to 10Hz and the time of milling is 10 to 60min.
3. The febuxostat-indomethacin co-amorphous substance according to claim 1, wherein the grinding method comprises the steps of mixing febuxostat and indomethacin in proportion, adding the mixture into a container of a freeze grinding device, grinding in a liquid nitrogen environment for 5-15 cycles, wherein each cycle comprises 2 minutes of grinding and 2 minutes of cooling.
4. A pharmaceutical composition comprising the co-amorphous form of febuxostat-indomethacin according to claim 1 and a pharmaceutically acceptable carrier.
5. Use of the febuxostat-indomethacin co-amorphous substance as claimed in claim 1 in the preparation of an anti-gout drug or preparation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012140632A1 (en) * | 2011-04-15 | 2012-10-18 | Ranbaxy Laboratories Limited | Febuxostat solid dispersion |
| CN109336816A (en) * | 2018-09-29 | 2019-02-15 | 中国药科大学 | A kind of total amorphous substance of celecoxib Indomethacin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012140632A1 (en) * | 2011-04-15 | 2012-10-18 | Ranbaxy Laboratories Limited | Febuxostat solid dispersion |
| CN109336816A (en) * | 2018-09-29 | 2019-02-15 | 中国药科大学 | A kind of total amorphous substance of celecoxib Indomethacin |
Non-Patent Citations (6)
| Title |
|---|
| "Advances in coamorphous drug delivery systems";Qin Shi等;《Acta Pharmaceutica Sinica B》;20190131;第9卷(第1期);第19-35页 * |
| "Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen";Korbinian Lӧbmann等;《Mol. Pharmaceutics》;20110804;第8卷;第1919-1928页 * |
| "Pharmacokinetic Interactions of Concomitant Administration of Febuxostat and NSAIDs";Reza Khosravan等;《J. Clin. Pharmacol.》;20060719;第46卷;第855-866页 * |
| "共无定型药物系统的研究进展";姚静 等;《药学学报》;20131231;第48卷(第5期);第648-654页 * |
| "共无定形给药系统研究进展";王星星等;《中国药事》;20190531;第33卷(第5期);第544-554页 * |
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