High drug loading celecoxib solid dispersion with solubilizing properties and methods of making same

Abstract

The application discloses a high drug loading celecoxib solid dispersion with solubilization performance and a preparation method thereof, the solid dispersion is made of the following components with mass percentage: celecoxib 50%, carrier material 40-47%, crystal inhibitor 3-10%, and all the components are 100% in total; wherein the carrier material is polyacrylic resin; the crystal inhibitor is selected from one or more of copolyvidone VA64, polyvidone K30, hydroxypropyl methyl cellulose E5 and hydroxypropyl methyl cellulose E50; the solid dispersion provided by the application has a faster dissolution rate and good stability, can effectively inhibit the recrystallization of the drug in the supersaturated solution, and maintain the supersaturation of the drug in the solution; the carrier-crystal inhibitor binary polymer combination is adopted so as to achieve complete drug release, and a new idea is provided for the preparation or process innovation of the high drug loading celecoxib preparation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a high-drug-loading celecoxib solid dispersion with solubilizing properties and its preparation method. Background Technology

[0002] Celecoxib is a 1,5-diaryl-substituted pyrazole compound, chemically named 4-[5-(4-tolyl)-3-(trifluoromethyl)-1-hydro-1-pyrazole-1-yl]benzenesulfonamide. It is the world's first selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), primarily used clinically to treat acute pain and relieve symptoms and signs of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Its advantage lies in relieving symptoms without causing related gastrointestinal complications. Its chemical structure is as follows:

[0003]

[0004] Celecoxib has poor solubility, exhibiting high hydrophobicity and high permeability, classifying it as a BCS class II drug. Its solubility in water at 25°C is only 0.007 mg / mL, and its slow dissolution rate in gastrointestinal fluids after oral administration results in low oral bioavailability, severely impacting its efficacy and significantly limiting its clinical application. Therefore, improving the solubility and dissolution rate of celecoxib is the primary challenge to overcome in the research and development of its oral formulations.

[0005] Currently, various drug solubilization technologies have been applied to celecoxib formulation development to improve its dissolution and in vivo absorption, such as nanocrystals, amorphous solid dispersions, inclusion complexes, and liposomes. Among these, amorphous solid dispersions are a typical supersaturated drug delivery system, increasing drug absorption by generating a supersaturated concentration through increased drug solubility or dissolution rate. However, such supersaturated solutions are thermodynamically metastable, and the drug easily transforms into a stable crystalline state in the gastrointestinal tract. Therefore, to maintain a highly dispersed state and the stability of the supersaturated solution, a large amount of polymer carrier is often added during the preparation of solid dispersions, resulting in a typically low drug loading. When the drug loading is too high, the dissolution rate of the solid dispersion changes from carrier-controlled to drug-controlled, leading to a sharp decrease in dissolution rate and even the loss of the solubilizing advantages of solid dispersions. Therefore, low drug loading is a common problem with amorphous solid dispersions, and the reported celecoxib solid dispersions are no exception. Chinese patent CN103655478A discloses a celecoxib solid dispersion, its preparation method, and its application. Celecoxib and poloxamer 188 are prepared into a solid dispersion using a melt method or a solvent method, increasing drug dissolution. However, the drug loading is only 4.7%–16.6%. Chinese patent CN102000018A discloses a celecoxib-containing solid dispersion, its preparation method, and its application, with a preferred drug loading of 33.3%. The resulting tablets and capsules are relatively large. This requires patients to ingest large amounts of excipients when taking therapeutic doses, often leading to reduced patient compliance due to excessive dosage and increased excipient costs. Therefore, developing a high-drug-loading celecoxib solid dispersion with good solubility is of great significance.

[0006] This invention, by selecting a carrier with good solubilizing properties and adding a small amount of crystal inhibitor, extends the supersaturation period by interfering with the formation and growth of crystal nuclei and inhibiting or slowing down the precipitation process of the drug in a supersaturated solution, thus exerting a good "spring-parachute" effect. Through the rational combination of binary polymers of carrier and crystal inhibitor, a celecoxib solid dispersion with a drug loading of up to 50% and good dissolution performance was successfully prepared. Summary of the Invention

[0007] The purpose of this invention is to provide a high-drug-loading celecoxib solid dispersion with good solubilizing properties and its preparation method, overcoming the current limitation of low drug loading in celecoxib solid dispersions.

[0008] The solid dispersion prepared by this invention can rapidly dissolve celecoxib even under high drug loading, and improves the storage stability of the celecoxib solid dispersion.

[0009] The technical solution of the present invention is as follows:

[0010] A celecoxib solid dispersion is made of the following components in mass percentage:

[0011] Celecoxib 50%, carrier material 40-47%, crystal inhibitor 3-10%; total of all components 100%;

[0012] in,

[0013] The carrier material is polyacrylic acid resin, preferably. EPO;

[0014] The crystallization inhibitor is selected from one or more of copovidone VA64 (PVP VA64), povidone K30 (PVP K30), hydroxypropyl methylcellulose E5 (HPMC E5), and hydroxypropyl methylcellulose E50 (HPMC E50); copovidone VA64 is preferred.

[0015] Particularly preferred, the celecoxib solid dispersion of the present invention is made of the following components in mass percentage:

[0016] Celecoxib 50%, EPO 45%, copovidone VA64 5%.

[0017] The preparation method of the celecoxib solid dispersion of the present invention is as follows:

[0018] Weigh out celecoxib, carrier material, and crystal inhibitor, mix them evenly in a solvent, then remove the solvent by rotary evaporation, vacuum dry, grind and sieve to obtain celecoxib solid dispersion;

[0019] The solvent is a mixture of anhydrous ethanol and dichloromethane, preferably with a volume ratio of 3:1 for anhydrous ethanol and dichloromethane;

[0020] The preferred temperatures for rotary evaporation are 50°C and for vacuum drying are 50°C.

[0021] It is preferred to grind the material through a 120-mesh sieve.

[0022] The beneficial effects of this invention are reflected in:

[0023] This invention fully leverages the supersaturation advantage of high drug loading solid dispersions by using suitable carriers and crystal inhibitors. It can effectively inhibit crystal nucleation and growth of drugs in supersaturated solutions, enabling rapid and complete drug dissolution and overcoming the "cliff effect" of a sharp drop in dissolution that is common when drug loading increases. Attached Figure Description

[0024] Figure 1 Example 1: Dissolution curve of solid dispersion in pH=1 medium.

[0025] Figure 2Dissolution curves of solid dispersions in Example 2 and Example 3 in medium with pH=1.

[0026] Figure 3 Dissolution curves of solid dispersions in Examples 4 and 5 in a medium of pH=1.

[0027] Figure 4 Differential scanning calorimetry (DSC) spectra of the active pharmaceutical ingredient and the solid dispersion of Example 4.

[0028] Figure 5 X-ray diffraction patterns of the active pharmaceutical ingredient and the solid dispersion of Example 4

[0029] Figure 6 Example 4: Powder X-ray diffraction pattern of the stability test of the solid dispersion.

[0030] Figure 7 Example 4: Dissolution curves from the stability test of the solid dispersion.

[0031] Figure 8 Example 4: Dissolution curves of solid dispersions of Comparative Example 1 and Comparative Example 2 in pH=1 medium. Detailed Implementation

[0032] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. It should be noted that the following description is for illustrative purposes only and does not limit its scope. Unless otherwise specified, the content of each component used below is a weight percentage.

[0033] Example 1:

[0034] Weigh out 3g of celecoxib. 2.7 g of EPO and 0.3 g of HPMC E50 were mixed thoroughly and added to 30 mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50 °C under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50 °C and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0035] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution (pH=1). Dissolution tests were performed using the paddle method according to the 2020 edition of the Chinese Pharmacopoeia, with a paddle rotation speed of 50 rpm. Samples were taken at 2, 5, 10, 20, 30, 45, and 60 min, and after rapid filtration, the drug concentration was determined by UV-Vis spectrophotometry. The cumulative dissolution percentage at each time point was calculated. Three 50 mg portions of celecoxib raw material were also taken and subjected to the same procedure to determine the cumulative dissolution percentage at each time point. Results are shown below. Figure 1 .from Figure 1 As can be seen, the dissolution rate of celecoxib active pharmaceutical ingredient in hydrochloric acid is very low, with only 0.7% dissolution after 60 minutes. Meanwhile, with... Using EPO as a carrier and HPMC E50 as a crystal inhibitor, the dissolution rate of celecoxib increased dramatically after being made into a solid dispersion. At 60 minutes, the dissolution rate of celecoxib was 68.97%, which was much higher than that of the active pharmaceutical ingredient.

[0036] Example 2:

[0037] Weigh out 3g of celecoxib. 2.7 g of EPO and 0.3 g of HPMC E5 were mixed thoroughly and added to 30 mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50 °C under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50 °C and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0038] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 2 .from Figure 2 As can be seen, after adding HPMC E5 as a crystal inhibitor, the dissolution rate of celecoxib was 79.13% at 60 min.

[0039] Example 3:

[0040] Weigh out 3g of celecoxib. EPO 2.7g and PVP K30 0.3g were mixed thoroughly and added to 30mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50℃ under reduced pressure. Then, the mixture was transferred to a vacuum drying oven at 50℃ and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0041] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 2 .from Figure 2 As can be seen, after adding PVP K30 as a crystal inhibitor, the dissolution rate of celecoxib was 83.16% at 60 min, showing good dissolution performance.

[0042] Example 4:

[0043] Weigh out 3g of celecoxib. EPO 2.7g and PVP VA64 0.3g were mixed thoroughly and added to 30mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50℃ under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50℃ and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0044] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 3 .from Figure 3 As can be seen, after adding PVP VA64 as a crystal inhibitor, the dissolution rate of celecoxib was 90.73% at 60 min, showing excellent dissolution performance. Moreover, at the same ratio, the crystal inhibition performance of PVP VA64 was better than that of HPMC E50, HPMC E5 and PVP K30.

[0045] Example 5:

[0046] Weigh out 3g of celecoxib. EPO 2.82g and VA64 0.18g were mixed thoroughly and added to 30mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50℃ under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50℃ and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0047] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 3 .from Figure 3 As can be seen, after adding 3% PVP VA64, the dissolution rate of celecoxib was 80.88% at 60 min, showing good dissolution performance.

[0048] Example 6:

[0049] Approximately 5 mg of the solid dispersion prepared in Example 4 was weighed into an aluminum pot, and the thermal behavior of the sample was detected using a differential scanning calorimeter. The nitrogen flow rate was 50 mL / min, the heating rate was 10 °C / min, and the scanning range was 25 °C–200 °C. Separately, 5 mg each of a physical mixture of the same proportions as in Example 4 and celecoxib raw material were processed using the same method. The resulting chromatograms are shown in [Figure number missing]. Figure 4 .

[0050] As shown in the figure, celecoxib active pharmaceutical ingredient exhibits a strong endothermic peak at 161.6℃, which is its melting point. The absence of this endothermic peak in the solid dispersion indicates that the celecoxib crystals have disappeared, and the drug is dispersed amorphously in the carrier material, resulting in an amorphous solid dispersion. The disappearance of the drug's melting point peak in the physical mixture suggests that the drug melted within the polymer material during heating.

[0051] Separately, appropriate amounts of celecoxib raw material and a physical mixture of the same proportions as in Example 4 and Example 4 were taken, and their diffraction patterns were determined by powder X-ray diffraction. The results are shown in [Figure 1]. Figure 5 .from Figure 5 As can be seen, within the scanning range, celecoxib active pharmaceutical ingredient exhibits strong crystal diffraction peaks at 2θ values ​​of 10.74°, 14.9°, 16.16°, 19.7°, and 21.54°. The solid dispersion obtained in Example 4 did not show the strong, sharp diffraction peaks characteristic of celecoxib active pharmaceutical ingredient, indicating that the product obtained in Example 4 is an amorphous solid dispersion. The crystal peaks appearing in the physical mixture largely overlap with the crystal peaks of the active pharmaceutical ingredient.

[0052] Example 7:

[0053] The solid dispersion obtained in Example 4 was placed in an environment with a temperature of 40°C and a relative humidity of 75% for stability testing. The sample was taken out at 0, 1, 2 and 3 months and the crystal structure of the drug was characterized by powder X-ray diffraction. In addition, 0.100g of the sample was added to 900mL of hydrochloric acid solution with pH=1 for powder dissolution test. The experiment was carried out in three parallel groups. Figure 6 The X-ray diffraction pattern of the obtained powder shows that no strong sharp diffraction peaks appeared in the obtained solid dispersion within three months, proving that the amorphous morphology was maintained. Figure 7 The dissolution curves obtained show no significant differences between them, all exhibiting excellent dissolution performance, which proves the good stability of the solid dispersion obtained in Example 4.

[0054] Comparative Example 1:

[0055] Weigh out 3g of celecoxib. 3g of EPO was thoroughly mixed and added to 30mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50°C under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50°C and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0056] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 8 . While EPO rapidly increases the dissolution rate of celecoxib solid dispersions with a 50% drug loading, exhibiting a typical "spring" effect (drug concentration of 21.54 μg / ml and dissolution rate of 34% at 2 minutes), the high supersaturation and thermodynamically unstable amorphous state lead to a sharp drop in drug concentration after two minutes. However, the addition of 5% PVP VA64 as a crystallization inhibitor demonstrates excellent crystal-inhibiting properties, resulting in a celecoxib dissolution rate of 90.73% at 60 minutes, showcasing superior dissolution performance.

[0057] Comparative Example 2:

[0058] Weigh out 3g of celecoxib. EPO 2.4g and VA64 0.6g were mixed thoroughly and added to 30mL of a mixture of anhydrous ethanol and dichloromethane (mixed in a 3:1 volume ratio). After ultrasonic dissolution, the solvent was removed by rotary evaporation at 50℃ under reduced pressure. The mixture was then transferred to a vacuum drying oven at 50℃ and dried overnight. Finally, the mixture was ground and passed through a 120-mesh sieve to obtain a solid dispersion.

[0059] Three 0.100 g portions of the solid dispersion were weighed and added to 900 mL of hydrochloric acid solution with pH = 1 respectively. The powder dissolution experiment was conducted according to the method in Example 1. The results are shown below. Figure 8 .from Figure 8 As can be seen, after adding 10% PVP VA64, the dissolution rate of celecoxib was only 54.89% at 60 min. Compared with adding 5% PVP VA64, the dissolution rate slowed down significantly with the increase of the proportion of the crystal inhibitor, resulting in a negative impact that hindered drug dissolution.

Claims

1. A celecoxib solid dispersion characterized in that, The celecoxib solid dispersion is made from the following components in mass percentage: Celecoxib 50%, carrier material 45%, crystallization inhibitor 5%; Wherein, The carrier material is Eudragit EPO; The crystallization inhibitor is copovidone VA64.

2. The process for preparing the solid dispersion of celecoxib according to claim 1, wherein The preparation method is as follows: Weigh celecoxib, carrier material, and crystallization inhibitor, mix them in solvent, then remove the solvent by rotary evaporation, vacuum dry, grind and sieve, and we get the celecoxib solid dispersion.

3. The production method according to claim 2, wherein The solvent is a mixture of anhydrous ethanol and dichloromethane.

4. The production method according to claim 3, wherein The solvent is a mixture of anhydrous ethanol and dichloromethane with a volume ratio of 3:

1.

5. The production method according to claim 2, wherein The temperature of rotary evaporation is 50℃, and the temperature of vacuum drying is 50℃.

6. The production method according to claim 2, wherein Grind and sieve through 120 mesh.

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