Etodolac amorphous solid dispersion and preparation method thereof

Abstract

The invention discloses an etodolac amorphous solid dispersion and a preparation method thereof. The etodolac amorphous solid dispersion comprises etodolac and polyvinylpyrrolidone, and the mass ratio of the etodolac to the polyvinylpyrrolidone is 1: (2-10). According to the prepared amorphous solid dispersion of the etodolac, the solubilization of the etodolac is realized through the polymer auxiliary material, the release rate and the stability are improved, and various adverse effects caused by multiple times of administration every day, especially the adverse effect on gastrointestinal tracts, can be reduced.

Description

Technical Field

[0001] The invention belongs to the field of poorly soluble drug preparations, and in particular relates to an etodolac amorphous solid dispersion and a preparation method thereof. Background Art

[0002] Etodolac, also known as 1,8-diethyl-1,3,4,9-tetrahydrofurano[3,4-b]indole-1-acetic acid, is an acetic acid nonsteroidal anti-inflammatory drug (NSAIDs). It can achieve the effects of analgesia and treatment of arthritis and other diseases by inhibiting COX-2 receptors, and it has fewer side effects, is safer and easier to tolerate. Etodolac belongs to Class II drugs in the biopharmaceutics classification system, which is a drug with low solubility and high permeability and a short half-life, resulting in the need for multiple daily dosing to maintain effective drug concentrations. However, in long-term treatment, the use of conventional oral dosage forms of etodolac multiple times a day can lead to various adverse reactions, especially a high impact on the gastrointestinal tract.

[0003] Amorphous solid dispersions refer to solid dispersion systems in which drugs or other active ingredients are dispersed in a matrix material in an amorphous (non-crystalline) form. Compared with crystalline drugs, amorphous drugs generally have higher solubility and faster dissolution rate, and are therefore widely used in the field of pharmaceutical preparations, especially in the preparation of poorly soluble drugs.

[0004] Polyvinylpyrrolidone (PVP) is a polymer compound obtained by polymerization of vinylpyrrolidone monomers and is a hydrophilic polymer. PVP has good water solubility, biocompatibility and chemical stability, so it is widely used in pharmaceutical, cosmetic, food and industrial fields.

[0005] At present, domestic etodolac tablets, capsules and sustained-release tablets have been approved for marketing, but their low solubility affects their absorption in the body. Chinese patent 201110163297.X discloses a method for preparing hydrophobic drug nanoparticle solid dispersions by high-voltage electrostatic spraying, wherein the drugs involved include etodolac, and the purpose is to prepare a solid dispersion of polymers and drugs with nanostructure characteristics, but the preparation method is complicated, requires the use of special equipment, and uses highly toxic organic solvents including chloroform and dimethyl sulfoxide. Summary of the invention

[0006] Purpose of the invention: In order to solve the above technical problems, the present invention aims to provide an amorphous solid dispersion of etodolac, which solves the problems of poor solubility and low bioavailability of etodolac and has high stability.

[0007] The present invention also provides a method for preparing the etodolac amorphous solid dispersion.

[0008] Technical solution: In order to achieve the above-mentioned purpose, the present invention provides an amorphous solid dispersion of etodolac, comprising etodolac and polyvinyl pyrrolidone, wherein the mass ratio of etodolac to polyvinyl pyrrolidone is 1:2-10.

[0009] Preferably, the mass ratio of etodolac to polyvinyl pyrrolidone is 1:2-4.

[0010] Preferably, the mass ratio of etodolac to polyvinyl pyrrolidone is 3:7 to 1:4.

[0011] Furthermore, the polyvinyl pyrrolidone is PVP K25 or PVP K30.

[0012] The method for preparing the amorphous solid dispersion of etodolac of the present invention comprises the following steps:

[0013] (1) etodolac and polyvinyl pyrrolidone are weighed separately, mixed, dissolved in an organic solvent, and subjected to ultrasonic homogenization to obtain a solution A;

[0014] (2) The organic solvent in solution A is removed to obtain a sample, and the obtained sample is ground and sieved to obtain an amorphous solid dispersion of etodolac.

[0015] Furthermore, the organic solvent in step (1) is any one of anhydrous ethanol, methanol, acetone, n-propanol and n-butanol.

[0016] Furthermore, the volume of the organic solvent in step (1) is 15-40 mL.

[0017] Preferably, the volume of the organic solvent is 20 mL.

[0018] Furthermore, the ultrasonic time in step (1) is 15 to 30 minutes.

[0019] Furthermore, the method of removing the organic solvent in solution A in step (2) is rotary evaporation and vacuum drying.

[0020] Furthermore, the rotary evaporation temperature is 38-40° C., and the rotation speed is 90-100 rpm / min.

[0021] Furthermore, the vacuum drying temperature is 35-40° C., and the time is 36-72 hours.

[0022] Furthermore, the sample in step (2) is sieved through a 55-65 mesh sieve.

[0023] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0024] (1) In the amorphous solid dispersion of etodolac prepared by the present invention, the drug etodolac and the water-soluble carrier material are dispersed in an amorphous form through intermolecular hydrogen bonds. The amorphous drug has a higher Gibbs free energy, and thus has a higher solubility and dissolution rate;

[0025] (2) The present invention adopts a solvent evaporation method to prepare an amorphous solid dispersion of etodolac. The preparation method is simple, and the prepared solid dispersion has good stability, which can ensure that it remains stable during storage and transportation. The present invention has the advantages of both high dissolution rate and stability. While ensuring drug release and high bioavailability, it also ensures the shelf life of the product obtained, which is beneficial to the market promotion and application of drug products. The amorphous solid dispersion of etodolac prepared by the solvent evaporation method is in the form of a white powder, which can reduce various adverse effects of multiple daily administrations, especially adverse effects on the gastrointestinal tract. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The in vitro release curves of etodolac amorphous solid dispersions with different ratios of PVP K25 and etodolac;

[0027] Figure 2 The in vitro release curves of etodolac amorphous solid dispersions of polyvinyl pyrrolidone with different molecular weights under the condition of etodolac: carrier material ratio of 1:4;

[0028] Figure 3 The in vitro release curves of etodolac amorphous solid dispersions of polyvinyl pyrrolidone with different molecular weights under the condition of etodolac: carrier material ratio of 3:7;

[0029] Figure 4 The in vitro release curves of etodolac amorphous solid dispersions with different ratios of PVP K30 and etodolac;

[0030] Figure 5 is the X-ray diffraction pattern of etodolac amorphous solid dispersion;

[0031] Figure 6 This is the X-ray diffraction pattern of the stability experiment of the amorphous solid dispersion of etodolac;

[0032] Figure 7 The X-ray diffraction patterns of Comparative Examples 1 and 2 were not formed into amorphous solid dispersions. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further described below in conjunction with the accompanying drawings.

[0034] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources. Experimental methods without specific conditions specified in the examples are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0035] In the embodiment, the method for determining the release rate of the drug in vitro in a simulated intestinal environment is as follows: the prepared solid dispersion is placed in a dissolution cup, and the release rate determination method in the Chinese Pharmacopoeia is determined according to the second method apparatus, with a phosphate buffer solution of pH = 6.8 as the medium, a rotation speed of 75 rpm / min, and the operation is carried out according to the law. 2 mL of samples are taken at the dissolution time of 5min, 8min, 15min, 30min, 45min, 60min, 120min, 180min, 240min, and 300min, and 2 mL of the same solvent at 37°C is quickly added, and the concentration is analyzed by a 0.45 micron filter membrane. The drug release amount at different times is calculated.

[0036] Example 1

[0037] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0038] Solid dispersion formulation:

[0039] 1 Etodolac 0.2g

[0040] 2PVP K250.8g

[0041] 0.2 g of etodolac and 0.8 g of PVP K25 were mixed and dissolved in 20 mL of ethanol and ultrasonicated for 30 min to obtain solution A. Solution A was poured into a 50 mL eggplant flask and most of the organic solvent was removed using a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90 rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72 h to remove the remaining organic solvent. The obtained sample was ground and passed through a 60-mesh sieve to obtain an amorphous solid dispersion of etodolac. Figure 1 and Figure 2 As shown in Figure 2, the sample released more than 45% in 30 min in a phosphate buffer solution at 37°C and pH 6.8. Figure 5 As shown, after X-ray diffraction analysis of the sample, the characteristic peak of X-ray diffraction disappeared and turned into a bun peak, and the sample was in an amorphous state.

[0042] Example 2

[0043] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0044] Solid dispersion formulation:

[0045] 1 Etodolac 0.3g

[0046] 2PVP K250.7g

[0047] 0.3 g of etodolac and 0.7 g of PVP K25 were mixed and dissolved in 20 mL of ethanol and ultrasonicated for 30 min to obtain solution A. Solution A was poured into a 50 mL eggplant flask and most of the organic solvent was removed using a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90 rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72 h to remove the remaining organic solvent. The obtained sample was ground and passed through a 60-mesh sieve to obtain an amorphous solid dispersion of etodolac. Figure 1 and Figure 3 As shown in Figure 2, the sample released more than 30% in 30 min in a phosphate buffer solution at 37°C and pH 6.8. Figure 5 As shown, after X-ray diffraction analysis of the sample, the characteristic peak of X-ray diffraction disappeared and turned into a bun peak, and the sample was in an amorphous state.

[0048] Example 3

[0049] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0050] Solid dispersion formulation:

[0051] 1 Etodolac 0.2g

[0052] 2PVP K300.8g

[0053] 0.2 g of etodolac and 0.8 g of PVP K30 were mixed and dissolved in 20 mL of ethanol and ultrasonicated for 30 min to obtain solution A. Solution A was poured into a 50 mL eggplant flask and most of the organic solvent was removed using a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90 rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72 h to remove the remaining organic solvent. The obtained sample was ground and passed through a 60-mesh sieve to obtain an amorphous solid dispersion of etodolac. Figure 2 and Figure 4 As shown in Figure 2, the sample released more than 45% in 30 min in a phosphate buffer solution at 37°C and pH 6.8. Figure 5 As shown, after X-ray diffraction analysis of the sample, the characteristic peak of X-ray diffraction disappeared and turned into a bun peak, and the sample was in an amorphous state.

[0054] Example 4

[0055] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0056] Solid dispersion formulation:

[0057] 1 Etodolac 0.3g

[0058] 2PVP K300.7g

[0059] 0.3 g of etodolac and 0.7 g of PVP K30 were mixed and dissolved in 20 mL of ethanol and ultrasonicated for 30 min to obtain solution A. Solution A was poured into a 50 mL eggplant flask and most of the organic solvent was removed using a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90 rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72 h to remove the remaining organic solvent. The obtained sample was ground and passed through a 60-mesh sieve to obtain an amorphous solid dispersion of etodolac. Figure 3 and Figure 4 As shown in Figure 2, the sample released more than 30% in 30 min in a phosphate buffer solution at 37°C and pH 6.8. Figure 5 As shown, after X-ray diffraction analysis of the sample, the characteristic peak of X-ray diffraction disappeared and turned into a bun peak, and the sample was in an amorphous state.

[0060] Comparative Example 1

[0061] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0062] Solid dispersion formulation:

[0063] 1 Etodolac 0.8g

[0064] 2PVP K250.2g

[0065] 0.8 g of etodolac and 0.2 g of PVP K25 were mixed and dissolved in 20 mL of ethanol and ultrasonicated for 30 min to obtain solution A. Solution A was poured into a 50 mL eggplant flask and most of the organic solvent was removed using a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90 rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72 h to remove the remaining organic solvent. The obtained sample was analyzed by X-ray diffraction test, and the sample had a clear crystalline structure and did not form an amorphous solid dispersion. Figure 7 As shown, there are obvious diffraction peaks in the X-ray diffraction pattern, indicating that the sample has a crystalline structure.

[0066] Comparative Example 2

[0067] The preparation method of the etodolac amorphous solid dispersion is as follows:

[0068] Solid dispersion formulation:

[0069] 1 Etodolac 0.8g

[0070] 2PVP K300.2g

[0071] 0.8g of etodolac and 0.2g of PVP K30 were mixed and dissolved in 20mL of ethanol and ultrasonicated for 30min to obtain solution A. Solution A was poured into a 50mL eggplant-shaped flask and most of the organic solvent was removed by a rotary evaporator. The operating conditions were a water bath at 40°C and a rotation speed of 90rpm / min. The sample was placed in a vacuum drying oven and dried at 35°C for 72h to remove the remaining organic solvent. The obtained sample was analyzed by X-ray diffraction test, and the sample had a clear crystalline structure and did not form an amorphous solid dispersion. Figure 7 As shown, there are obvious diffraction peaks in the X-ray diffraction pattern, indicating that the sample has a crystalline structure.

[0072] Comparative Example 3

[0073] The preparation method of Example 1 or Example 3 is adopted, except that the sample is dried at 45° C. for 72 h and other conditions remain unchanged. The sample becomes a molten state and forms a hard solid block after cooling.

[0074] Comparative Example 4

[0075] The preparation method of Example 1 or Example 3 was used, except that the sample was dried at 30°C for 72 hours, and other conditions remained unchanged. The 72-hour drying time failed to completely remove the remaining organic solvent in the sample. When the temperature was too low, the drying efficiency was limited, resulting in incomplete removal of the organic solvent.

[0076] Comparative Example 5

[0077] The preparation method of Example 1 or Example 3 is adopted, except that the water bath is at 45° C. and other conditions remain unchanged. The liquid in the eggplant-shaped flask boils, resulting in uneven evaporation of the solvent and product loss, and there are hidden dangers to operational safety.

[0078] Comparative Example 6

[0079] The preparation method of Example 1 or Example 3 is adopted, except that the water bath is at 35° C. and other conditions remain unchanged. The solvent removal rate is slow and the evaporation rate of the solvent is not effectively increased, resulting in a low efficiency of the solvent removal process.

[0080] Example 5

[0081] In vitro dissolution test:

[0082] The powders of the amorphous solid dispersion of etodolac in Examples 1 to 4 were taken in the following amounts: 150 mg, 100 mg, 150 mg, and 100 mg, each containing an equivalent amount of 30 mg of etodolac. The powders were pressed into tablets, and 30 mg of the raw material of etodolac was used as a control. The in vitro release of the prepared samples was investigated by the in vitro drug release determination method. The results are shown in Tables 1 and Figure 1-4 .

[0083] Table 1 Release results of solid dispersions in vitro in simulated intestinal environment pH 6.8

[0084]

[0085] From Table 1 and Figure 1-4 It can be seen that the etodolac amorphous solid dispersion improves the release effect of etodolac in the simulated intestinal environment. Example 1 and Example 3 can release more than 5% at 5 minutes, and Examples 1-4 can release more than 30% at 30 minutes. The release rate is better than that of the etodolac raw material, among which Example 1 has the best release effect.

[0086] Example 6

[0087] X-ray diffraction analysis of etodolac amorphous solid dispersion:

[0088] The samples of the amorphous solid dispersion of etodolac in Examples 1 to 4 and the raw material of etodolac were subjected to X-ray diffraction analysis. The scanning range was 5-40° and the speed was 15° / min. The results are as follows: Figure 5 The characteristic peak of X-ray diffraction of the amorphous solid dispersion of etodolac disappears and turns into a steamed bun peak, indicating that etodolac is loaded in the carrier in an amorphous state.

[0089] Example 7

[0090] Stability test of amorphous solid dispersion of etodolac:

[0091] Samples of the amorphous solid dispersion of etodolac from Examples 1 to 4 were placed in a constant temperature and humidity chamber at 25°C and 75% relative humidity. After 15 days, X-ray diffraction analysis was performed. The scanning range was 5-40° and the speed was 15° / min. The results are as follows: Figure 6 The amorphous solid dispersion samples of etodolac in Examples 1 to 4 remained in an amorphous state after being stored at 25° C. and 75% relative humidity for 15 days, indicating that they have good stability.

[0092] This indicates that the solid dispersion prepared by the present invention can have a higher dissolution rate and better stability.

Claims

1. An amorphous solid dispersion of etodolac, characterized in that: The etodolac amorphous solid dispersion comprises etodolac and polyvinyl pyrrolidone, and the mass ratio of the etodolac to the polyvinyl pyrrolidone is 1:2-10.

2. The amorphous solid dispersion of etodolac according to claim 1, characterized in that: The polyvinyl pyrrolidone is PVP K25 or PVP K30.

3. A method for preparing the amorphous solid dispersion of etodolac according to claim 1, characterized in that: The steps include: (1) etodolac and polyvinyl pyrrolidone are weighed separately, mixed, dissolved in an organic solvent, and subjected to ultrasonic homogenization to obtain a solution A; (2) The organic solvent in solution A is removed to obtain a sample, and the obtained sample is ground and sieved to obtain an amorphous solid dispersion of etodolac.

4. The method for preparing the amorphous solid dispersion of etodolac according to claim 3, characterized in that: The organic solvent in step (1) is any one of anhydrous ethanol, methanol, acetone, n-propanol and n-butanol.

5. The method for preparing the amorphous solid dispersion of etodolac according to claim 4, characterized in that: The volume of the organic solvent in step (1) is 15-40 mL.

6. The method for preparing the amorphous solid dispersion of etodolac according to claim 3, characterized in that: The ultrasonic time in step (1) is 15 to 30 minutes.

7. The method for preparing the amorphous solid dispersion of etodolac according to claim 3, characterized in that: The method of removing the organic solvent in solution A in step (2) is rotary evaporation and vacuum drying.

8. The method for preparing the amorphous solid dispersion of etodolac according to claim 7, characterized in that: The rotary evaporation temperature is 38-40° C., and the rotation speed is 90-100 rpm / min.

9. The method for preparing the amorphous solid dispersion of etodolac according to claim 7, characterized in that: The vacuum drying temperature is 35-40° C. and the time is 36-72 hours.

10. The method for preparing the amorphous solid dispersion of etodolac according to claim 3, characterized in that: The sample in step (2) is sieved through a 55-65 mesh sieve.

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