CN110283142B - A kind of co-amorphous substance of febuxostat-indomethacin and preparation method thereof - Google Patents

Abstract

The invention provides a co-amorphous substance of febuxostat-indomethacin and a preparation method thereof; it is formed by combining febuxostat and indomethacin in a molar ratio of 1:0.5-2, The powder X-ray diffraction spectrum expressed in degrees 2θ has no sharp diffraction peaks using Cu‑Kα radiation. Our research found that after preparing febuxostat and indomethacin into a co-amorphous substance, the dissolution rate of the two drugs was significantly improved compared with the raw drug, and the two drugs had the characteristics of synergistic release. It has a good application prospect. This combination of drugs provides a new idea for future preparation research.

Description

A kind of co-amorphous substance of febuxostat-indomethacin and preparation method thereof

technical field

The technical field of medicine of the present invention, in particular, relates to a febuxostat-indomethacin co-amorphous solid dispersion and a preparation method thereof.

Background technique

Febuxostat, a commonly used anti-gout drug in clinical practice, has a significant inhibitory effect on both oxidized and reduced XOR, so its effect of lowering uric acid is more powerful and durable, and it can be used to treat chronic high blood pressure of gout. uric acidemia. However, the rapid reduction of uric acid concentration during antihyperuricemia treatment is likely to lead to acute attacks of ventilation. Clinically, non-steroidal anti-inflammatory drugs are recommended for synergistic treatment of gout and pain relief of acute attacks of gout. According to the classification system of biopharmaceutics, febuxostat belongs to BCS Ⅱ drug, which has the characteristics of low solubility, high permeability and low bioavailability.

Indomethacin is a classic non-steroidal anti-inflammatory drug, which has the functions of antipyretic and relieving inflammatory pain. Like febuxostat, it belongs to the BCS class II drugs. It can be used to relieve the pain of acute attacks of gout.

Contents of the invention

The object of the present invention is to provide a febuxostat-indomethacin co-amorphous substance, which can increase the dissolution rate of the two drugs, exert the synergistic effect of the two, and improve the curative effect and patient compliance.

Another object of the present invention is to provide a method for preparing the above-mentioned febuxostat-indomethacin co-amorphous substance.

The purpose of the present invention can be achieved through the following measures:

A febuxostat-indomethacin co-amorphous substance, which is formed by combining febuxostat and indomethacin at a molar ratio of 1:0.5-2, using Cu-K _α radiation to The powder X-ray diffraction spectrum expressed in degrees 2θ has no sharp diffraction peaks.

We found that febuxostat (abbreviated as FEB) and indomethacin (abbreviated as IND) can be combined to form a co-amorphous substance at a molar ratio of 1:0.5-2. In a preferred embodiment, the molar ratio of febuxostat to indomethacin is 2:1, 1:1 or 1:2 respectively, and the glass transition temperatures of the co-amorphous substances obtained at this ratio are respectively It is 52.77°C, 50.11°C or 38.48°C.

The preparation method of the febuxostat-indomethacin co-amorphous substance of the present invention is: after mixing febuxostat and indomethacin in proportion, the co-amorphous substance is prepared by grinding, spray drying or hot-melt extrusion. Shaped objects.

In a preferred scheme, a grinding method can be used, specifically: after febuxostat and indomethacin are mixed in proportion, the grinding is continued by means of mechanical grinding, and the crystal structure of the drug is continuously destroyed until a co-amorphous mixture is formed. form.

The mechanical grinding in the grinding method includes but not limited to freezing grinding. In a preferred solution, the grinding is carried out in a liquid nitrogen environment or at -205°C to -190°C.

Preferably, the grinding frequency in the grinding method is 5-10 Hz, and the grinding time is 10-60 min.

In a more preferred scheme, the grinding method is: after mixing febuxostat and indomethacin in proportion, add them to the container of the frozen grinding device, and grind in a liquid nitrogen environment for 5 to 15 minutes. Each cycle consists of grinding for 2 minutes and cooling for 2 minutes.

The present invention also includes a pharmaceutical composition, which comprises the above-mentioned co-amorphous febuxostat-indomethacin and a pharmaceutically acceptable carrier.

The febuxostat-indomethacin co-amorphous substance of the present invention can be used in the preparation of anti-gout drugs or preparations.

In order to better understand the essence of the present invention, the following experiments are used to evaluate the present invention.

(1) Powder X-ray Diffraction Analysis of the state of matter in the pharmaceutical composition during milling.

高压强度：40KV；扫描范围：3-40°)分别对研磨不同时间的药物组合物进行分析。Adopt powder X-ray diffraction analysis method (PXRD analysis condition is Cu Kα radiation; Wavelength:

High voltage strength: 40KV; scanning range: 3-40°) respectively analyze the pharmaceutical composition ground for different times.

The analysis results are shown in Figure 1. It can be observed from the X-ray spectrum that the unground pharmaceutical composition has strong crystal characteristic diffraction peaks, indicating that it has a typical crystal structure. With the grinding process, the crystal diffraction peaks gradually weakened. At 60 minutes, the X-ray spectrum of the pharmaceutical composition has no sharp diffraction peaks, indicating that febuxostat and indomethacin form a co-amorphous substance.

(2) Differential Scanning Calorimetry (DSC) to evaluate the state of matter in the co-amorphous substance.

Thermal analysis of both pure drugs in crystalline and amorphous form as well as various proportions of co-amorphous species was performed using differential scanning calorimetry. Analysis method: Weigh about 5 mg of sample, place it in an aluminum crucible, and raise the temperature to a suitable temperature at 10°C/min in a nitrogen atmosphere.

The analysis results are shown in Figure 2: Febuxostat and indomethacin have sharp melting endothermic peaks at 205°C and 157°C, respectively. The glass transition temperatures of the two are 64.22°C and 36.08°C, respectively. However, febuxostat-indomethacin co-amorphous substances with molar ratios of 2:1, 1:1 and 1:2 all had a single glass transition temperature, indicating that they formed uniform co-amorphous substances.

(3) Physical stability inspection.

For a better comparison, we prepared the pure drug into an amorphous form, then placed it in a desiccator at 40°C, and took out samples at a preset time to analyze its crystallinity by PXRD.

As shown in Figure 3: On the 5th day, the amorphous febuxostat had only weak crystal diffraction peaks, while the amorphous indomethacin had obvious crystallization, indicating that indomethacin had a stronger effect than febuxostat. crystallization tendency.

In addition, in order to investigate the physical stability of the co-amorphous substance, put the co-amorphous substance in different molar ratios into a desiccator at 25°C and 40°C, take it out at an appropriate time, and analyze its crystallinity by powder X-ray diffraction.

The results are shown in Figure 4: the co-amorphous substances with febuxostat-indomethacin molar ratios of 1:1 and 2:1 were stable at 25°C and 40°C for 30 days. The co-amorphous substance with a molar ratio of 1:2 can remain stable at 25°C, and a weak crystal diffraction peak appears at 40°C after 30 days.

(4) Fourier transform infrared (FTIR) spectroscopy to analyze the interaction between drug molecules.

Potassium bromide (KBr) tablet method was used to prepare samples. A small amount of sample was mixed with KBr evenly and pressed into tablets. The KBr sheet was used as a blank control, and the infrared absorption spectrum was measured in the wavenumber range of 4000-400cm ^-1 .

The results are shown in Figure 5: crystalline febuxostat has a strong carbonyl absorption peak at the wavenumber of 1678.7cm ^-1 , while the absorption peak of amorphous febuxostat is split into 1680.1cm ^-1 and 1706.5cm ^- 1 ¹ Two separate peaks, assigned to hydrogen-bonded and non-hydrogen-bonded carbonyls, respectively. Crystalline indomethacin has two carbonyl stretching vibration peaks at 1713.8 and 1690.4 cm ^-1 , which belong to the carbonyl of carboxyl and benzoyl respectively. The carbonyl peaks of amorphous indomethacin are at 1739.2, 1709.0 and 1683.1 cm ^-1 respectively, which belong to non-hydrogen-bonded carbonyl, dimer-forming carboxyl carbonyl and benzoyl carbonyl. In order to study the intermolecular interactions in the co-amorphous substance, by comparing the infrared spectra of the febuxostat-indomethacin co-amorphous substance and the physical mixture, it was found that the absorption peak of the carbonyl group blue-shifted from 1707cm ^-1 to 1719cm ^- 1 ¹ , indicating that a strong hydrogen bond interaction is formed between febuxostat and indomethacin.

(5) Intrinsic dissolution (IDR) experiment.

Investigate the dissolution rate of the drug within 30min. About 200mg of the drug was compressed into a tablet in the IDR mold (tabletting condition: 5MPa, 40s), and then the dissolution test was carried out in the dissolution apparatus. The dissolution conditions are: dissolution medium, 500ml pH 7.4 phosphate buffer; dissolution temperature: 37°C; rotation speed, 50rpm. Samples were taken at preset times and analyzed for drug concentration in the samples by high performance liquid chromatography (HPLC). HPLC conditions: instrument, Shimadzu SPD 20A; chromatographic column: Agilent C18ODS column (250×4.6mm); column temperature: 30°C; mobile phase: acetonitrile and pH 5 phosphate buffer; flow rate: 1ml/min; injection volume: 20 μL.

The dissolution rate results are as shown in Figure 6: Febuxostat is obtained from crystalline febuxostat, amorphous febuxostat, and crystalline physical mixture (molar ratio 1:1, i.e. febuxostat and indomethacin) Molar ratio, the same below), the dissolution rates in amorphous physical mixture (molar ratio 1:1), and co-amorphous substance (molar ratio 1:1) are: 0.395, 0.521, 0.394, 0.582, 0.589 mgmin ^-1 cm ^-2 . The dissolution rates of indomethacin from crystalline indomethacin, amorphous indomethacin, crystalline physical mixture, amorphous physical mixture, and co-amorphous substances were 0.0899, 0.228, 0.272, 0.325, and 0.489 mg min, respectively ^-1 cm ^-2 . It can be seen from the results of the dissolution rate that after febuxostat and indomethacin form a co-amorphous substance, the dissolution rate of the two drugs is significantly increased.

At the same time, the dissolution rates of febuxostat and indomethacin from the co-amorphous substance were 0.589 and 0.489 mgmin ^{- 1} cm ^-2 , respectively, which indicated that the two drugs had a synergistic release effect after being prepared into the co-amorphous substance. The result is shown in Figure 7.

Febuxostat and indomethacin have the potential of synergistic anti-gout, and their preparation as a co-amorphous form can improve the curative effect. This patent provides a febuxostat-indomethacin co-amorphous substance. In this type of co-amorphous substance, the application further provides a co-amorphous substance with a molar ratio of febuxostat to indomethacin of 1:1, 1:2 and 2:1, which can be frozen and ground, Prepared by spray drying or hot melt extrusion technology. Our research found that after preparing febuxostat and indomethacin into a co-amorphous substance, the dissolution rate of the two drugs was significantly improved compared with the raw drug, and the two drugs had the characteristics of synergistic release. It has a good application prospect. This combination of drugs provides a new idea for future preparation research.

Description of drawings

Fig. 1 is the PXRD pattern of febuxostat-indomethacin mixture grinding different time;

Figure 2 is a DSC spectrum;

Fig. 3 is pure drug stability test PXRD collection of patterns;

Fig. 4 is co-amorphous stability test PXRD pattern;

Fig. 5 is infrared spectrum;

In the figure, a crystalline febuxostat, b amorphous febuxostat, c crystalline indomethacin, d amorphous indomethacin, e crystalline physical mixture (molar ratio 1:1), f no Amorphous physical mixture (molar ratio 1:1), g co-amorphous (molar ratio 1:1)

Fig. 6 is IDR dissolution test collection of illustrations;

Figure 7 is the synergistic release profile of febuxostat-indomethacin.

Detailed ways

Further illustration will be given in the following examples. These examples of the present invention are only used to illustrate the present invention, but do not limit the present invention in any way. All parameters in the examples and other descriptions are based on mass unless otherwise stated. Various raw materials whose preparation methods are not described in the instructions can be purchased commercially.

Embodiment 1: Preparation of febuxostat-indomethacin co-amorphous

Weigh 0.50g of febuxostat and 0.57g of indomethacin respectively and add them to the frozen grinding tube, and grind in a liquid nitrogen environment. The frozen grinding parameters are set to 5 cycles, and each cycle includes 2min grinding and 2min cooling. The grinding frequency is 10Hz. After the grinding is completed, immediately take out the frozen grinding tube and put it in a desiccator to return to room temperature.

Embodiment 2: Preparation of febuxostat-indomethacin co-amorphous

Weigh 1.0g of febuxostat and 0.57g of indomethacin respectively and add them to the frozen grinding tube, and grind in a liquid nitrogen environment. The frozen grinding parameters are set to 5 cycles, and each cycle includes 2min grinding and 2min cooling. The grinding frequency is 10Hz. After the grinding is completed, immediately take out the frozen grinding tube and put it in a desiccator to return to room temperature.

Embodiment 3: Preparation of febuxostat-indomethacin co-amorphous

Weigh 0.50g of febuxostat and 1.14g of indomethacin respectively and add them to the frozen grinding tube, and grind in a liquid nitrogen environment. The frozen grinding parameters are set to 5 cycles, and each cycle includes 2min grinding and 2min cooling. The grinding frequency is 10Hz. After the grinding is completed, immediately take out the frozen grinding tube and put it in a desiccator to return to room temperature.

Embodiment 4: physical stability investigation

Take an appropriate amount of febuxostat-indomethacin co-amorphous and place them in a desiccator at 25°C/0%RH and 40°C/0%RH respectively, and take out the powder X-ray diffraction analysis sample at a preset time. crystallinity. The result is shown in Figure 4.

Embodiment 5: intrinsic dissolution test

Weigh 200 mg of the drug and add it to the IDR mold, and press it under the hydraulic press at 5 MPa for 40 s. The exposed surface of the tablet is 0.5 cm ² . Then the mold was fixed on the dissolution apparatus for dissolution test. Samples were taken at 5, 10, 15, 20, 25, and 30 minutes, passed through a 0.45 μm filter membrane, and analyzed for drug concentration by high performance liquid chromatography. The results are shown in Figures 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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