A solid dispersion containing piroxicam and its preparation method

Abstract

This invention discloses a piroxicam-containing solid dispersion and its preparation method. The piroxicam-containing solid dispersion of this invention constructs drug-carrier and carrier-carrier interactions from different dimensions, synergistically promoting the solubilizing ability of each carrier for the drug, improving the stability of the amorphous solid dispersion, and significantly increasing its apparent solubility. Furthermore, numerous in vivo experiments demonstrate that the quaternary system of the solid dispersion of this invention improves the bioavailability of piroxicam. The preparation technology of the piroxicam solid dispersion provided by this invention is simple, highly reproducible, and has good prospects for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a solid dispersion containing piroxicam and its preparation method. Background Technology

[0002] Piroxicam, also known as piroxicam, with the chemical name 2-methyl-4-hydroxy-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, is a nonsteroidal anti-inflammatory drug (NSAID) with antipyretic, analgesic, and anti-inflammatory effects. It is widely used to treat diseases of the muscles, bones, and joints, such as osteoarthritis, rheumatoid arthritis, and acute gout. However, due to its strong inhibitory effect on COX-2, piroxicam causes significant gastrointestinal irritation after oral administration. Furthermore, as a BCS class II drug, its low solubility results in low bioavailability, limiting its clinical application.

[0003] Solid dispersion technology can effectively improve the solubility of poorly soluble drugs. Its binary system typically consists of the drug and a polymeric carrier material. Water-insoluble or lipid-soluble carriers are often used in the preparation of sustained-release and controlled-release solid dispersions, while water-soluble polymeric carriers can accelerate the dissolution rate and solubility of the drug. However, the solubility of piroxicam solid dispersions in binary systems remains low, and their bioavailability is poor, failing to meet the requirements of formulations. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide a solid dispersion containing piroxicam and a method for preparing the same, so as to improve the water solubility and bioavailability of piroxicam.

[0005] To achieve the above objectives, the present invention provides the following technical solutions.

[0006] In a first aspect, the present invention provides a solid dispersion containing piroxicam.

[0007] The solid dispersion containing piroxicam provided by the present invention is characterized by comprising the following components: 20-60% piroxicam, 40-70% first excipient component, 9-30% second excipient component, and 1-5% third excipient component.

[0008] The first excipient component includes one or a combination of several of the following: hydroxypropyl methylcellulose, acrylic resin, hydroxypropyl methylcellulose acetate succinate, polyethylene glycol (such as polyethylene glycol 6000, polyethylene glycol 4000), urea, ethyl cellulose, polyvinylpyrrolidone K30, porous silica, microcrystalline cellulose, and copovidone VA64.

[0009] The second excipient component includes one or a combination of several of the following: lecithin, sodium lauryl sulfate, poloxamer (such as poloxamer 188, poloxamer 407), polycaprolactone-polyethylene glycol, polylactic acid-polyethylene glycol, Tween (such as Tween 20, Tween 60, Tween 80), and Span (such as Span 60, Span 80, Span 85).

[0010] The third excipient component includes one or more of the following: mannitol, sodium alginate, L-arginine, xylitol, N-methyl-D-glucosamine, aspartame, sodium benzoate, anhydrous dipotassium hydrogen phosphate, anhydrous sodium carbonate, anhydrous dipotassium hydrogen phosphate, anhydrous sodium carbonate, starch, sucrose, sodium bicarbonate, vitamin A, vitamin C, and vitamin E.

[0011] Preferably, the piroxicam-containing solid dispersion of the present invention is characterized by comprising the following components: 20-35% piroxicam, 50-65% of a first excipient component, 10-20% of a second excipient component, and 1-5% of a third excipient component.

[0012] Preferably, the first excipient component of the present invention is selected from one or a combination of several of the following: copovidone VA64, polyethylene glycol 6000, polyethylene glycol 4000, hydroxypropyl methylcellulose, and polyvinylpyrrolidone K30.

[0013] Preferably, the second excipient component of the present invention is selected from one or a combination of several of sodium dodecyl sulfate, poloxamer 188, and Tween 80.

[0014] Preferably, the third excipient component of the present invention is selected from one or a combination of several of anhydrous dipotassium hydrogen phosphate, anhydrous sodium carbonate, L-arginine, and N-methyl-D-glucosamine.

[0015] Secondly, the present invention provides a method for preparing the above-mentioned piroxicam-containing solid dispersion.

[0016] The present invention provides a method for preparing a piroxicam-containing solid dispersion, comprising the following steps:

[0017] S1. Vacuum dry the piroxicam, the first excipient component, the second excipient component, and the third excipient component to remove moisture.

[0018] S2. Weigh out piroxicam, the first excipient component, the second excipient component, and the third excipient component in proportion, and add them in equal amounts and mix them evenly.

[0019] S3. Dissolve the well-mixed ingredients of the prescription in a solvent.

[0020] S4. Ensure all components are completely dissolved and reacted, then remove the solvent to obtain a dried finished product.

[0021] The solvent mentioned in step S3 includes one or a combination of several of water, acetone, ethanol, and ethylene glycol.

[0022] The solvent removal method described in step S4 includes one or a combination of spray drying, freeze drying, rotary evaporation, and fluidized bed drying.

[0023] Preferably, the solvent in step S3 is ethanol or an aqueous solution containing ethanol (such as a 95% aqueous solution of ethanol).

[0024] Preferably, the solvent removal method in step S4 is rotary evaporation, and the temperature is set to 55-65°C.

[0025] Preferably, the solvent removal method in step S4 is spray drying, with an inlet air temperature of 80-110°C, an outlet air temperature of 50-70°C, and an atomization pressure of 4-10 kPa.

[0026] Preferably, the solvent removal method in step S4 is a fluidized bed drying method, with an inlet air temperature of 40-60℃ and an atomization pressure of 10-20 kPa.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] Compared with the active pharmaceutical ingredient and existing technologies (CN111840231A, CN117138062A), the piroxicam solid dispersion quaternary system prepared by this invention constructs drug-carrier and carrier-carrier interactions from different dimensions, synergistically promoting the solubilization ability of each carrier for the drug, improving the stability of the amorphous solid dispersion, and significantly improving its apparent solubility. Furthermore, numerous in vivo experiments have shown that the solid dispersion quaternary system of this invention improves the bioavailability of piroxicam, thereby enhancing clinical efficacy.

[0029] Addressing the shortcomings of existing technologies, the inventors of this invention, through extensive research and experimentation, discovered a specific quaternary solid dispersion system that can significantly improve the solubility and dissolution rate of piroxicam. Compared with binary and ternary systems, the quaternary system of this invention greatly enhances the solubility and dissolution rate of piroxicam (specific data are provided in the embodiments of this invention). Compared with traditional commercially available formulations or active pharmaceutical ingredients, the highly soluble piroxicam formulation of this invention can improve the in vivo bioavailability in rats and significantly reduce paw edema caused by acute or subacute inflammation. Attached Figure Description

[0030] Figure 1 This is a solubility diagram of the binary system of piroxicam solid dispersion in Example 2.

[0031] Figure 2 This is a solubility diagram of the ternary system of piroxicam solid dispersion in Example 3.

[0032] Figure 3 This is a solubility diagram of the quaternary system of piroxicam solid dispersion in Example 4.

[0033] Figure 4 This is a comparison chart of the solubility of different components of the piroxicam solid dispersion in Example 5.

[0034] Figure 5 This is a comparison of dissolution curves of different components of the piroxicam solid dispersion in Example 5.

[0035] Figure 6 The dissolution curves of the quaternary system of piroxicam solid dispersion in Example 6 in different media are shown.

[0036] Figure 7 This is a powder X-ray diffraction pattern of the quaternary system of piroxicam solid dispersion in Example 7.

[0037] Figure 8 This is a scanning electron microscope image of the quaternary system of piroxicam solid dispersion in Example 7.

[0038] Figure 9 This is an oral plasma concentration-time curve of the piroxicam solid dispersion quaternary system in Example 8.

[0039] Figure 10 This is a diagram illustrating the anti-inflammatory effect of the piroxicam solid dispersion quaternary system in Example 8 on paw swelling caused by acute inflammation in rats.

[0040] Figure 11 This is a diagram illustrating the anti-inflammatory effect of the piroxicam solid dispersion quaternary system in Example 8 on paw swelling caused by subacute inflammation in rats.

[0041] Figure 12 The solubility diagrams are for the quaternary systems of piroxicam solid dispersions in Examples 9-12. Detailed Implementation

[0042] The present invention will be further described below through specific embodiments and in conjunction with the accompanying drawings. These embodiments are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention. Unless otherwise specified, all percentages mentioned in the present invention are mass percentages.

[0043] Example 1: Solubility experiment of piroxicam active pharmaceutical ingredient in different media

[0044] Excess piroxicam raw material was added to 5 mL of pure water, hydrochloric acid solution (pH 1.0), and phosphate buffer solutions (pH 4.0 and pH 6.8) to prepare supersaturated solutions. These solutions were placed in a constant-temperature shaker (37℃, 150 rpm) and samples were taken after 72 h. The solutions were filtered through a 0.45 μm aqueous microporous membrane, and the initial filtrate was discarded. The subsequent filtrate was diluted with pure water and the solubility was determined by UV-Vis spectrophotometry at 356 nm. The results showed that piroxicam had a low saturated solubility in pure water (28.719 μg / mL), classifying it as almost insoluble or insoluble according to the solubility limits in the Chinese Pharmacopoeia.

[0045] Example 2: Solubility Experiment of a Binary System of Piroxicam Solid Dispersion

[0046]

[0047]

[0048]

[0049] Preparation method: The weight of piroxicam in the formulation is fixed at 400 mg, and the solvent volume is 300 mL. The first excipient component is added to the solvent and ultrasonically mixed to form a homogeneous solution. Then, piroxicam is added and ultrasonically mixed for 20 min to fully react, thus obtaining a piroxicam mixture. The piroxicam mixture is then spray-dried under the process conditions of an inlet air temperature of 80-110℃, an outlet air temperature of 50-70℃, and an atomization pressure of 4-10 kPa to remove the solvent and obtain the final product.

[0050] Excess finished powder was added to 5 mL of pure water to prepare a supersaturated solution. The solution was placed in a constant temperature shaker (37℃, 150 rpm) and sampled after 72 h. The solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured at 356 nm using UV-Vis spectrophotometry. The solubility of piroxicam was calculated, and the results are shown below. Figure 1 .

[0051] This embodiment investigated the saturated solubility of binary solid dispersions prepared from piroxicam and different carriers under different weight percentage conditions. Figure 1The results showed that when polyethylene glycol 6000 was used as a carrier, the saturated solubility of the drug was significantly improved. The highest saturated solubility (130.752 μg / mL) was achieved when the weight percentage of polyethylene glycol 6000 was 80%. Secondly, the carrier copovidone VA64 also significantly improved the saturated solubility of the drug, with the best solubilizing effect (127.541 μg / mL) achieved when the weight percentage of copovidone VA64 was 75%. When polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose were used as carriers, regardless of the weight percentage of the carrier, the saturated solubility of the drug could not be increased above 100 μg / mL, indicating a relatively poor solubilizing effect. Therefore, binary solid dispersions prepared with different carriers or with the same carrier at different weight percentages will exhibit different solubilities.

[0052] Example 3: Solubility Experiment of Piroxicam Solid Dispersion Ternary System

[0053]

[0054]

[0055] Preparation method: The weight of piroxicam in the formulation is fixed at 400 mg, and the solvent volume is 300 mL. The first excipient component and the second excipient component are added to the solvent and sonicated to form a homogeneous mixed solution. Then, piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60°C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product.

[0056] Excess finished powder was added to 5 mL of pure water to prepare a supersaturated solution. The solution was placed in a constant temperature shaker (37℃, 150 rpm) and sampled after 72 h. The solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured at 356 nm using UV-Vis spectrophotometry. The solubility of piroxicam was calculated, and the results are shown below. Figure 2 .

[0057] This embodiment describes the preparation of ternary solid dispersions by adding different second excipients to a partial binary solid dispersion formulation, and investigates the solubility of piroxicam in the formulation. Figure 2The results showed that when the carrier was polyethylene glycol 4000, the addition of sodium dodecyl sulfate resulted in the highest saturated solubility of the drug among all ternary formulations in this example, reaching 163.744 μg / mL, which was 5.8 times higher than that of the active pharmaceutical ingredient (28.617 μg / mL). However, when Tween 80 or Poloxamer 188 were added, the saturated solubility only reached 126.621 μg / mL and 129.226 μg / mL, respectively. When the carrier was copovidone VA64, the addition of Tween 80 resulted in the highest saturated solubility of the drug in this carrier system, reaching 158.705 μg / mL. Therefore, for the same carrier system, the degree of improvement in drug saturated solubility varies with the addition of different second excipients, and the solubilizing ability of different second excipients also differs for different carrier systems. Although the solubility of the ternary solid dispersion prepared in this embodiment was significantly improved compared to the active pharmaceutical ingredient, it still falls within the category of extremely low solubility according to the solubility limits defined in the Chinese Pharmacopoeia.

[0058] Example 4: Solubility Experiment of Piroxicam Solid Dispersion Quaternary System

[0059]

[0060] Preparation method: The weight of piroxicam in the formulation is fixed at 400 mg, and the solvent volume is 300 mL. The first excipient component, the second excipient component, and the third excipient component are added to the solvent and sonicated to form a homogeneous mixed solution. Then, piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60°C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product.

[0061] Excess finished powder was added to 5 mL of pure water to prepare a supersaturated solution. The solution was placed in a constant temperature shaker (37℃, 150 rpm) and sampled after 72 h. The solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured at 356 nm using UV-Vis spectrophotometry. The solubility of piroxicam was calculated, and the results are shown below. Figure 3 .

[0062] This embodiment describes the preparation of quaternary solid dispersions by adding different third excipients to a ternary solid dispersion formulation, and investigates the saturated solubility of piroxicam in the formulation. Figure 3The results showed that when N-methyl-D-glucosamine and L-arginine were added, the saturated solubility of the prepared quaternary solid dispersion reached 609.646 μg / mL and 592.537 μg / mL, respectively, representing increases of 21 times and 20 times compared to the active pharmaceutical ingredient (API). When anhydrous dipotassium hydrogen phosphate was added, the saturated solubility was 374.671 μg / mL, a 13-fold increase compared to the API. The greatest increase in saturated solubility was observed when anhydrous sodium carbonate was added, reaching 2010.767 μg / mL, approximately 70 times higher than the API. This demonstrates that adding different third excipients can produce varying solubilizing effects.

[0063] Example 5: Comparative Experiment on Solubility and Dissolution Rate of Different Component Systems of Pyroxicam Solid Dispersion

[0064]

[0065] Preparation method: The weight of piroxicam in the formulation is fixed at 400 mg, and the solvent volume is 300 mL. The first excipient component, the second excipient component, and the third excipient component are added to the solvent and sonicated to form a homogeneous mixed solution. Then, piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60°C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product.

[0066] Excess finished powder was added to 5 mL of pure water to prepare a supersaturated solution. The solution was placed in a constant temperature shaker (37℃, 150 rpm) and sampled after 72 h. The solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured at 356 nm using UV-Vis spectrophotometry. The solubility of piroxicam was calculated, and the results are shown below. Figure 4 .

[0067] A dose equivalent to 20 mg of piroxicam was added to a dissolution apparatus. Using 900 mL of pure water as the release medium, the mixture was continuously stirred at 37 ± 0.5 °C and 75 rpm. Samples of 5 mL were taken at 5, 10, 15, 30, 45, 60, 90, and 120 min, with 5 mL of pure water added at 37 ± 0.5 °C each time. The sample solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured using UV-Vis spectrophotometry at 356 nm. The in vitro dissolution rate was calculated, and the results are shown below. Figure 5 .

[0068] This embodiment compares the saturated solubility and in vitro dissolution of the binary, ternary, and quaternary systems of the carrier copovidone VA64. Figure 4The results showed that the saturated solubility of piroxicam in the quaternary system was 2010.767 μg / mL, in the ternary system it was 158.705 μg / mL, and in the binary system it was 124.313 μg / mL. Compared to the latter two, the saturated solubility of the drug in the quaternary system was significantly improved, increasing by 12 times and 16 times, respectively. Figure 5 The results showed that the quaternary system achieved 100% drug release within 5 minutes, while the ternary and binary systems both required 120 minutes to fully release the drug. Therefore, the piroxicam quaternary solid dispersion formulation provided by this invention can significantly improve the saturated solubility and dissolution rate of piroxicam, and the improvement effect is significantly better than that of the binary and ternary systems.

[0069] Example 6: Dissolution test of piroxicam solid dispersion quaternary system in different media

[0070]

[0071] Preparation method: The weight of piroxicam in the formula is fixed at 400 mg, and the solvent volume is 300 mL. Copovidone VA64, Tween 80 and anhydrous sodium carbonate are added to the solvent and sonicated to form a homogeneous mixed solution. Then piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60 °C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product.

[0072] A dose equivalent to 20 mg of piroxicam was added to the dissolution apparatus container. Release media included 900 mL of pure water, pH 1.0 hydrochloric acid, pH 4.0 phosphate buffer, and pH 6.8 phosphate buffer, respectively. The mixture was continuously stirred at 37 ± 0.5 °C and 75 rpm. Samples (5 mL) were taken at 5, 10, 15, 30, 45, 60, 90, and 120 min, with 5 mL of dissolution medium added at 37 ± 0.5 °C each time. The sample solutions were filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with the dissolution medium and measured using UV-Vis spectrophotometry at 356 nm. The in vitro dissolution rate was calculated, and the results are shown below. Figure 6 .

[0073] This embodiment investigated the dissolution rate of the piroxicam quaternary solid dispersion provided by this invention in different dissolution media. Figure 6The results showed that the piroxicam quaternary solid dispersion achieved 100% drug release within 5 minutes in pure water, pH 1.0 hydrochloric acid, and pH 6.8 phosphate buffer, and nearly 100% drug release within 45 minutes in pH 4.5 phosphate buffer. Therefore, the piroxicam quaternary solid dispersion provided by this invention exhibits good dissolution rates in four different media.

[0074] Example 7: In vitro characterization of the piroxicam solid dispersion quaternary system

[0075]

[0076] Preparation method: The weight of piroxicam in the formula is fixed at 400 mg, and the solvent volume is 300 mL. Copovidone VA64, Tween 80 and anhydrous sodium carbonate are added to the solvent and sonicated to form a homogeneous mixed solution. Then piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60 °C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product.

[0077] Operation 1: Powder X-ray diffraction test

[0078] Powder X-ray diffraction tests were performed on the active pharmaceutical ingredient, copovidone VA64, the physical mixture, and the obtained solid dispersion. The test methods are as follows:

[0079] A suitable amount of sample was placed in the sample holder for measurement. The working conditions were as follows: a Cu target, Ka as the radiation source, a voltage of 40 kV, and a current of 40 mA for sample detection and analysis. The detection conditions were as follows: scanning range of 5-30°, scanning speed of 0.05° / s, and scanning step size of 0.02°. The test results are shown in [the table below]. Figure 7 .

[0080] Depend on Figure 7The results showed that the active pharmaceutical ingredient (API) exhibited obvious type I crystallization characteristic diffraction peaks at 8.60°, 14.46°, 17.66°, 21.72°, and 27.36°, and weak type II crystallization characteristic peaks at 10.20°, 15.82°, 19.52°, 20.42°, and 25.82°. The carrier copovidone VA64 did not show obvious diffraction peaks. The characteristic diffraction peaks of the drug were clearly visible in the physical mixture, but their intensity was reduced. The characteristic diffraction peaks of the drug disappeared in the diffraction pattern of the quaternary solid dispersion. Therefore, it can be seen that the active pharmaceutical ingredient is a mixture of most type I crystals and a small amount of type II crystals, and the copovidone VA64 is an amorphous polymer. The state of the drug in the physical mixture has not changed. The decrease in diffraction peak intensity is due to the dilution of the carrier. In the piroxicam quaternary solid dispersion, the drug is in an amorphous form, indicating that the quaternary solid dispersion formulation provided by the present invention can transform the drug from a crystalline form to an amorphous form, thereby improving the drug's solubility.

[0081] Operation 2: Scanning electron microscopy imaging

[0082] Scanning electron microscopy (SEM) images were taken of the active pharmaceutical ingredient, copovidone VA64, the physical mixture, and the obtained solid dispersion. The imaging method is as follows:

[0083] Take an appropriate amount of sample and spread it evenly on a sample holder with conductive tape. Spray gold onto the sample for 80 seconds under vacuum. Remove the sample with clean tweezers and observe and photograph it under a scanning electron microscope. The photographic results are shown below. Figure 8 .

[0084] Depend on Figure 8 The results showed that the piroxicam active pharmaceutical ingredient (API) contained a large number of cubic crystals (Type I) and a small number of needle-like crystals (Type II), with varying crystal sizes. The carrier copovidone VA64 was an irregularly concave, wrinkled spherical structure. In the physical mixture, it was clearly a simple mixture of drug and carrier material. However, no obvious crystals were observed in the piroxicam quaternary solid dispersion, which appeared as irregular flake-like objects. Therefore, the API is a mixture of mostly Type I crystals and a small number of Type II crystals, consistent with the results of powder X-ray diffraction testing. In the piroxicam quaternary solid dispersion, the drug was transformed into an amorphous form.

[0085] Example 8: In vivo evaluation of the piroxicam solid dispersion quaternary system

[0086]

[0087] Preparation method: The weight of piroxicam in the formulation is fixed at 400 mg, and the solvent volume is 300 mL. Copovidone VA64, Tween 80 and anhydrous sodium carbonate are added to the solvent and sonicated to form a homogeneous mixed solution. Then piroxicam is added and sonicated for 20 min to react fully to obtain a piroxicam mixture. The piroxicam mixture is heated in a 60°C water bath and the solvent is removed by rotary evaporation under reduced pressure to obtain the final product (hereinafter referred to as the highly soluble piroxicam formulation).

[0088] Procedure 1: Determination of oral bioavailability of highly soluble piroxicam prescription

[0089] The active pharmaceutical ingredient (API), physical mixture, and commercially available formulation (Langzhi piroxicam capsules, 2104141, Langzhi Group Wanrong Pharmaceutical Co., Ltd.) were prepared as reference formulations. Twenty-four healthy, clean-grade SD rats (from the Animal Experiment Center of Chongqing Medical University), all female and weighing 200±20g, were randomly divided into four groups of six rats each: the piroxicam group, the physical mixture group, the highly soluble piroxicam formulation group, and the commercially available formulation group. Patients were kept NPO (nothing by mouth) for 12 hours prior to gavage, but were allowed free access to water. The drug was administered via gavage at a dose of 5 mg / kg (based on piroxicam). Blood samples (approximately 0.5 mL each time) were collected from the orbital venous plexus at 0.17, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-administration. The samples were placed in heparinized centrifuge tubes and centrifuged at 1000 x g for 10 min to separate the plasma. The plasma concentration was determined by high-performance liquid chromatography (HPLC), and relevant pharmacokinetic parameters were calculated using DSA 3.0 software. The results are shown in Table 1. Figure 9 .

[0090] Table 1. Pharmacokinetic Parameters

[0091]

[0092] The prescriptions listed in the table refer to highly soluble piroxicam prescriptions.

[0093] Depend on Figure 9As shown in Table 1, the mean plasma concentration of the highly soluble piroxicam formulation was higher than that of the piroxicam active pharmaceutical ingredient (API), physical mixture, and commercially available reference formulation at all time points. The areas under the curve (AUC) for the API, physical mixture, highly soluble piroxicam formulation, and commercially available formulation were 306.41±131.47, 312.31±79.49, 650.24±92.16, and 401.21±54.34 μg / mL*h, respectively. Compared with the API, the AUC of the highly soluble piroxicam formulation was 2.12 times higher. Compared with commercially available formulations, the area under the pharmacokinetic curve (AUC) of the highly soluble piroxicam formulation was increased by 1.62 times. The maximum plasma concentrations (MPCs) of the active pharmaceutical ingredient (API), the physical mixture, the highly soluble piroxicam formulation, and the commercially available formulation were 13.91±4.62, 16.39±4.99, 28.23±4.98, and 17.83±2.23 μg / mL, respectively. Compared with the API, the highly soluble piroxicam formulation increased the MPC by 2.03 times; compared with the commercially available formulation, the highly soluble piroxicam formulation increased the MPC by 1.58 times. Therefore, the piroxicam quaternary solid dispersion provided by this invention, after improving solubility and dissolution rate, can significantly improve the bioavailability of the drug, and its effect is superior to that of the physical mixture and the commercially available reference formulation.

[0094] Operation 2: Evaluation of the anti-inflammatory effects of highly soluble piroxicam formulation in rat paws with acute inflammation.

[0095] The active pharmaceutical ingredient (API), physical mixture, and commercially available formulation (Langzhi piroxicam capsules, 2104141, Langzhi Group Wanrong Pharmaceutical Co., Ltd.) were prepared as reference formulations. Thirty healthy, clean-grade SD rats (from the Animal Experiment Center of Chongqing Medical University), all female, weighing 200±20g, were randomly divided into 5 groups of 6 rats each: a model group (administered via gavage with physiological saline), a piroxicam group, a physical mixture group, a highly soluble piroxicam formulation group, and a commercially available formulation group. Rats were fasted for 12 hours prior to gavage but had free access to water. The piroxicam was administered at a dose of 5 mg / kg via gavage. One hour after administration, 0.1 mL of 1% carrageenan was injected into the right hind paw of each rat to induce acute paw inflammation. The thickness of the right toe was measured using calipers before and 1, 2, and 3 hours after inflammation. Foot swelling was calculated as (post-inflammatory toe thickness - pre-inflammatory toe thickness) / pre-inflammatory toe thickness * 100%. The measurement results are shown below. Figure 10 .

[0096] Depend on Figure 10The results showed that after carrageenan injection, the swelling in the model group increased significantly, reaching 29.81% at 3 hours, indicating that the acute inflammation model was successfully established. Over time, the swelling in all treatment groups gradually decreased. At 3 hours, the swelling in the highly soluble piroxicam group decreased to 7.03%, significantly lower than that in the raw material group (11.46%) and the commercially available formulation group (17.36%). Therefore, the highly soluble piroxicam formulation provided by this invention has a better acute anti-inflammatory effect and can significantly reduce rat paw swelling caused by acute inflammation compared to commercially available formulations.

[0097] Operation 3: Evaluation of the anti-inflammatory effects of highly soluble piroxicam formulation in subacute paw inflammation in rats

[0098] The active pharmaceutical ingredient (API), physical mixture, and commercially available formulation (Langzhi piroxicam capsules, 2104141, Langzhi Group Wanrong Pharmaceutical Co., Ltd.) were prepared as a reference formulation. Thirty healthy, clean-grade SD rats (from the Animal Experiment Center of Chongqing Medical University), all female and weighing 200±20g, were randomly divided into 5 groups of 6 rats each: a model group (administered via gavage with physiological saline), a piroxicam group, a physical mixture group, a highly soluble piroxicam group, and a commercially available formulation group. Subacute inflammation of the paw was induced by injecting 0.1mL of Freund's complete adjuvant into the right hind paw of each rat. One hour after inflammation induction, the rats were administered piroxicam at a dose of 5mg / kg via gavage for 7 consecutive days, once daily. The thickness of the right toe was measured using calipers before inflammation and on days 1, 2, 3, 4, 5, 6, and 7 after inflammation induction. Foot swelling was calculated as (post-inflammatory toe thickness - pre-inflammatory toe thickness) / pre-inflammatory toe thickness * 100%. The measurement results are shown below. Figure 11 .

[0099] Depend on Figure 11 The results showed that after injection of Freund's complete adjuvant, the swelling in all groups initially increased and then decreased, reaching its peak on day 2, indicating the successful establishment of a chronic paw inflammation model in rats. On day 4, the swelling in the highly soluble piroxicam group decreased to 10.61%, significantly lower than the commercially available formulation. At this point, the swelling in the model group, piroxicam group, physical mixture group, and commercially available formulation group were 23.05%, 16.01%, 15.08%, and 15.26%, respectively. On day 7, the swelling in the piroxicam group, physical mixture group, and commercially available formulation group decreased to 15.35%, 11.49%, and 12.26%, respectively. However, the therapeutic effect in these three groups at this point was still less than that in the highly soluble piroxicam group on day 4. Therefore, the highly soluble piroxicam formulation provided by the present invention has a good chronic anti-inflammatory effect and can reduce toe swelling induced by chronic inflammation to a low level in a short period of time.

[0100] The inventors prepared the piroxicam quaternary solid dispersions of Examples 9-12 according to Example 7.

[0101] Example 9

[0102]

[0103] Example 10

[0104]

[0105] Example 11

[0106]

[0107] Example 12

[0108]

[0109]

[0110] An excess of the finished powder from Examples 9-12 was added to 5 mL of pure water to prepare a supersaturated solution. This solution was placed in a constant-temperature shaker (37°C, 150 rpm) and sampled after 72 hours. The solution was filtered through a 0.45 μm aqueous microporous membrane. The initial filtrate was discarded, and the subsequent filtrate was diluted with pure water and measured at 356 nm using UV-Vis spectrophotometry. The solubility of piroxicam was calculated, and the results are shown below. Figure 12 .

[0111] Depend on Figure 12 The results show that the saturated solubility of the four quaternary solid dispersions in Examples 9-12 increased to 521.944 μg / mL, 1077.564 μg / mL, 402.425 μg / mL, and 1523.721 μg / mL, respectively, which are significantly improved compared to the active pharmaceutical ingredient. Therefore, the piroxicam quaternary solid dispersion formulation provided by this invention can effectively solve the problem of poor solubility of the drug piroxicam.

[0112] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention.

Claims

1. A solid dispersion containing piroxicam, characterized in that, The product comprises the following components: piroxicam 20-35%, a first excipient component 50-65%, a second excipient component 10-20%, and a third excipient component 1-5%, by mass percentage; the first excipient component is selected from one or more combinations of copovidone VA64, polyethylene glycol 6000, polyethylene glycol 4000, hydroxypropyl methylcellulose, and polyvinylpyrrolidone K30; the second excipient component is selected from one or more combinations of sodium dodecyl sulfate, poloxamer 188, Tween 20, Tween 60, and Tween 80; and the third excipient component is selected from one or more combinations of anhydrous dipotassium hydrogen phosphate, anhydrous sodium carbonate, L-arginine, and N-methyl-D-glucosamine.

2. The method for preparing the piroxicam-containing solid dispersion as described in claim 1, comprising the following steps: S1. Vacuum dry the piroxicam, the first excipient component, the second excipient component, and the third excipient component to remove moisture; S2. Weigh out piroxicam, the first excipient component, the second excipient component, and the third excipient component in proportion, and add them in equal amounts and mix them evenly. S3. Dissolve the well-mixed prescription components in a solvent; S4. Ensure all components are completely dissolved and reacted, then remove the solvent to obtain a dried finished product.

3. The method as described in claim 2, characterized in that, The solvent mentioned in step S3 is selected from one or a combination of several of water, acetone, ethanol, and ethylene glycol.

4. The method as described in claim 2, characterized in that, The solvent removal method described in step S4 is selected from one or a combination of spray drying, freeze drying, rotary evaporation and fluidized bed drying.

5. The method as described in claim 2, characterized in that, The solvent mentioned in step S3 is ethanol or an aqueous solution containing ethanol.

6. The method as described in claim 2, characterized in that, The solvent removal method described in step S4 is rotary evaporation, with the temperature set at 55-65℃.

7. The method as described in claim 2, characterized in that, The solvent removal method described in step S4 is spray drying, with an inlet air temperature of 80-110℃, an outlet air temperature of 50-70℃, and an atomization pressure of 4-10kPa.

8. The method as described in claim 2, characterized in that, The solvent removal method described in step S4 is a fluidized bed drying method, with an inlet air temperature of 40-60℃ and an atomization pressure of 10-20 kPa.

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