An anti-inflammatory composition and a method of preparing the same

Abstract

The present application relates to an anti-inflammatory composition and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The composition comprises a pharmaceutically active ingredient, a surfactant, a crystallization inhibitor and optionally other pharmaceutically acceptable excipients. The present application also discloses a preparation method of the composition. The composition of the present application has the advantages of high solubility, fast dissolution rate, high dissolution plateau, high bioavailability, good stability, fast disintegration rate, and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more particularly to an anti-inflammatory composition and its preparation method. Background Technology

[0002] Celecoxib is a commonly used specific nonsteroidal anti-inflammatory drug (NSAID) in clinical practice. Compared with traditional NSAIDs, celecoxib exerts its anti-inflammatory effect by specifically inhibiting cyclooxygenase-2 (COX-2) to block the synthesis of prostaglandins from arachidonic acid. It does not act on COX-1 and does not affect the synthesis of PGI2, which has a protective effect on the gastrointestinal tract and kidneys, thus effectively reducing gastrointestinal side effects. Clinically, it is often used to treat acute pain in adults and relieve symptoms and signs of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. It was launched in the United States in 1999. In my country, celecoxib formulations are approved for sale in strengths of 50 / 100 / 200 / 400 mg. However, its dosage is high, its onset of action is slow, its bioavailability is low, and patient compliance is poor.

[0003] Patent CN102188365A discloses a poorly soluble drug cocrystal solid dispersion, which is prepared from a poorly soluble drug (including celecoxib), a cocrystal ligand, and a polymeric carrier material. The molar ratio of the poorly soluble drug to the cocrystal ligand is 1–2:1, and the polymeric carrier material accounts for 10%–90% of the mass percentage of the solid dispersion. However, studies have shown that while this solid dispersion has a high drug loading and a low carrier content, its solubility is not significantly improved, and its bioavailability remains low.

[0004] Patent US20150004237A1 discloses a family of polymers that can improve the solubility or stability of poorly soluble drugs (including celecoxib) and prevent crystallization. However, this solution uses a relatively large amount of carrier and cannot achieve the technical effect of improving solubility while reducing the amount of carrier, i.e., improving the solubility of poorly soluble drugs, increasing drug loading, and reducing the amount of carrier.

[0005] Existing technologies for celecoxib formulations suffer from problems such as large particle size, low solubility, low bioavailability, slow onset of action, low drug loading in solid dispersions, and large carrier usage. In solid dispersion technology, the drug loading has a significant impact on the final formulation. If the carrier ratio is too high, i.e., the drug loading is low, the resulting solid dispersion particles constitute a large proportion of the final formulation by weight, leading to excessively heavy tablets or capsules that cannot be filled. Furthermore, excessively heavy tablets are difficult for patients to swallow, affecting patient compliance.

[0006] Therefore, in order to solve the technical problems of the above-mentioned celecoxib formulations at the same time, it is necessary to study a better celecoxib composition formulation and preparation process. Summary of the Invention

[0007] This invention provides a celecoxib composition and its preparation process.

[0008] In a first aspect, the present invention provides a composition.

[0009] A composition comprising celecoxib, a surfactant, and a crystallization inhibitor.

[0010] The crystallization inhibitors are at least two types.

[0011] The crystallization inhibitor comprises copovidone or hydroxypropyl methylcellulose acetate succinate. In some embodiments, the crystallization inhibitor comprises copovidone and hydroxypropyl methylcellulose acetate succinate, which is beneficial for obtaining a stable pharmaceutical formulation with good dissolution and an appropriate single-dose weight. In some embodiments, the crystallization inhibitor may further comprise at least one of hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the crystallization inhibitor is copovidone and hydroxypropyl methylcellulose acetate succinate, which is beneficial for obtaining a stable pharmaceutical formulation with good dissolution and an appropriate single-dose weight.

[0012] The weight ratio of the copovidone to hydroxypropyl methylcellulose acetate succinate can be 1:10-10:1. In some embodiments, the weight ratio of the copovidone to hydroxypropyl methylcellulose acetate succinate is 1:5-5:1. In some embodiments, the weight ratio of the copovidone to hydroxypropyl methylcellulose acetate succinate is 1:3-3:1. In some embodiments, the weight ratio of the copovidone to hydroxypropyl methylcellulose acetate succinate is 1:2-2:1. In some embodiments, the weight ratio of the copovidone to hydroxypropyl methylcellulose acetate succinate is 1:1-2:1.

[0013] The surfactant may include at least one selected from vitamin E polyethylene glycol succinate, poloxamer, Tween 80, sodium lauryl sulfate, and polyoxyethylene castor oil. In some embodiments, the surfactant is vitamin E polyethylene glycol succinate, which is more conducive to obtaining a stable pharmaceutical formulation with good dissolution and an appropriate single-dose weight.

[0014] The weight ratio of celecoxib to the crystallization inhibitor can be 2:1 to 1:10. In some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 2:1 to 1:5. In some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 1:1; in some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 2:1; in some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 1:2. In some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 1:3. In some embodiments, the weight ratio of celecoxib to the crystallization inhibitor is 1:4.

[0015] The surfactant content, based on the total weight of the composition, can be 5 wt%-30 wt%. In some embodiments, the surfactant content is 5 wt%-20 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 10 wt%-20 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 5 wt%-15 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 5 wt%-10 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 15 wt%-30 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 15 wt%-20 wt% based on the total weight of the composition. In some embodiments, the surfactant content is 20 wt%-25 wt% based on the total weight of the composition.

[0016] The content of celecoxib, based on the total weight of the composition, can be 5 wt%-85 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 15 wt%-80 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 15 wt%-70 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 15 wt%-60 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 20 wt%-60 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 20 wt%-50 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 20 wt%-40 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 20 wt%-30 wt%. In some embodiments, the content of celecoxib, based on the total weight of the composition, is 45 wt%-70 wt%. In some embodiments, the content of celecoxib is 45 wt%-55 wt%. In some embodiments, the content of descelecoxib is 55wt%-65wt%. In some embodiments, the content of descelecoxib is 65wt%-70wt%.

[0017] The content of the crystallization inhibitor, based on the total weight of the composition, can be 10 wt%-90 wt%. In some embodiments, the content of the crystallization inhibitor is 10 wt%-80 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 25 wt%-80 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 15 wt%-80 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 15 wt%-70 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 20 wt%-60 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 20 wt%-50 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 20 wt%-40 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 20 wt%-30 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 10 wt%-40 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 15 wt%-40 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 10 wt%-30 wt% based on the total weight of the composition. In some embodiments, the content of the crystallization inhibitor is 10 wt%-20 wt% based on the total weight of the composition.

[0018] The composition is prepared by a method including hot melt extrusion or spray drying. In some embodiments, the composition is prepared by hot melt extrusion. In some embodiments, the composition is prepared by spray drying.

[0019] The composition may be a solid dispersion.

[0020] The composition may also include other pharmaceutically acceptable excipients. These pharmaceutically acceptable excipients may include inorganic salts. The inorganic salts are selected from at least one of sodium chloride, potassium chloride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium phosphate, and anhydrous calcium hydrogen phosphate.

[0021] The content of the inorganic salt can be 5wt%-20wt% based on the total weight of the composition.

[0022] In some embodiments of the invention, a composition comprising celecoxib, a surfactant, a crystallization inhibitor, and optionally other pharmaceutically acceptable excipients; wherein the weight ratio of celecoxib to crystallization inhibitor is 2:1 to 1:10, and the surfactant content is 5 wt% to 30 wt%, the crystallization inhibitor content is 10 wt% to 90 wt%, and the celecoxib content is 5 wt% to 85 wt% based on the total weight of the composition; this is beneficial for improving the dissolution rate of the composition.

[0023] In some embodiments of the invention, a composition comprising celecoxib, a surfactant, a crystallization inhibitor, and optionally other pharmaceutically acceptable excipients; wherein the weight ratio of celecoxib to the crystallization inhibitor is 2:1 to 1:10, and the surfactant content is 10wt% to 20wt%, the crystallization inhibitor content is 25wt% to 80wt%, and the celecoxib content is 5wt% to 85wt% based on the total weight of the composition; this is beneficial for improving the dissolution rate of the composition.

[0024] In some embodiments of the present invention, a composition comprising: celecoxib, vitamin E polyethylene glycol succinate, copovidone, and hydroxypropyl methylcellulose acetate succinate; is beneficial for improving the dissolution and stability of the composition.

[0025] In some embodiments of the present invention, a composition comprises: celecoxib, vitamin E polyethylene glycol succinate, copovidone, and hydroxypropyl methylcellulose acetate succinate; wherein, based on the total weight of the composition, the content of celecoxib is 45wt%-70wt%, the content of vitamin E polyethylene glycol succinate is 15wt%-30wt%, the total content of hydroxypropyl methylcellulose acetate succinate and copovidone is 10wt%-40wt%, and the weight ratio of hydroxypropyl methylcellulose acetate succinate to copovidone is 1:10-10:1; this composition is beneficial for improving the dissolution rate of the composition, while also improving the drug loading and stability of the composition and reducing the amount of carrier used.

[0026] In some embodiments of the present invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methylcellulose acetate succinate, and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of celecoxib is 45wt%-55wt%, the content of vitamin E polyethylene glycol succinate is 15wt%-30wt%, the total content of hydroxypropyl methylcellulose acetate succinate and copovidone is 15wt%-40wt%, and the weight ratio of hydroxypropyl methylcellulose acetate succinate to copovidone is 1:10-10:1; this composition is beneficial for improving the dissolution rate of the composition, while also improving the drug loading and stability of the composition and reducing the amount of carrier used.

[0027] In some embodiments of the present invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methylcellulose acetate succinate, and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of celecoxib is 55wt%-65wt%, the content of vitamin E polyethylene glycol succinate is 15wt%-30wt%, the total content of hydroxypropyl methylcellulose acetate succinate and copovidone is 10wt%-30wt%, and the weight ratio of hydroxypropyl methylcellulose acetate succinate to copovidone is 1:10-10:1; this composition is beneficial for improving the dissolution rate of the composition, while also improving the drug loading and stability of the composition and reducing the amount of carrier used.

[0028] In some embodiments of the present invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methylcellulose acetate succinate, and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of celecoxib is 65wt%-70wt%, the content of vitamin E polyethylene glycol succinate is 15wt%-30wt%, the total content of hydroxypropyl methylcellulose acetate succinate and copovidone is 10wt%-20wt%, and the weight ratio of hydroxypropyl methylcellulose acetate succinate to copovidone is 1:10-10:1; this composition is beneficial for improving the dissolution rate of the composition, while also improving the drug loading and stability of the composition and reducing the amount of carrier used.

[0029] The aforementioned composition can be prepared into tablets, capsules, granules or dry suspensions.

[0030] In a second aspect, the present invention provides the use of the composition described in the first aspect in the preparation of pharmaceutical formulations.

[0031] The use of the composition of the first aspect in the preparation of a pharmaceutical formulation, the pharmaceutical formulation being used for anti-inflammatory or analgesic purposes, such as for relieving symptoms of osteoarthritis, symptoms of rheumatoid arthritis in adults, or for treating acute pain in adults.

[0032] The dosage form of the preparation includes tablets, capsules, granules, or dry suspensions.

[0033] Thirdly, the present invention also provides a method for preparing the composition or solid dispersion described in the first aspect.

[0034] A method for preparing the composition or solid dispersion of the first aspect comprises the following steps: taking celecoxib, a surfactant, a crystallization inhibitor and optional pharmaceutically acceptable excipients, mixing them, adding them to a twin-screw hot melt extruder, performing melt-mixing extrusion, and then cooling and pulverizing to obtain the composition or solid dispersion.

[0035] The hot melt extruder is set to an extrusion temperature of 140℃-180℃. In some embodiments, the hot melt extruder is set to an extrusion temperature of 150℃-170℃. In some embodiments, the hot melt extruder is set to an extrusion temperature of 160℃-165℃.

[0036] Beneficial effects

[0037] Compared with the prior art, the present invention has at least one of the following technical effects:

[0038] (1) High solubility, fast dissolution rate, high dissolution plateau, and high bioavailability.

[0039] (2) The composition exhibits good stability of dissolution plateau under long-term, intermediate, and accelerated stability conditions.

[0040] (3) While achieving high bioavailability, it can also increase drug loading and reduce carrier usage.

[0041] (4) The added crystallization inhibitor can inhibit celecoxib from changing from amorphous to crystalline form, thereby improving the stability of the dissolution platform.

[0042] (5) The present invention uses a surfactant, which can significantly enhance the dissolution of celecoxib and thus improve its bioavailability.

[0043] (6) The composition of the present invention uses celecoxib, two crystallization inhibitors and a surfactant, and its dissolution is significantly better than that of compositions containing celecoxib, a single crystallization inhibitor and a surfactant, and has unexpected technical effects.

[0044] (7) By comparing different crystallization inhibitors and surfactants, the optimal crystallization inhibitors were HPMCAS and PPVVA64, and the optimal surfactant was TPGS. These can effectively improve the dissolution and bioavailability of the celecoxib composition, increase the drug loading, reduce the carrier usage, and improve the stability of the dissolution plateau of the celecoxib composition. Attached Figure Description

[0045] Figure 1 The results of the bioavailability test in animals are shown for the original research capsules in Example 9 and the celecoxib tablets described in Example 6.

[0046] Figure 2 The results of the bioavailability test in animals are shown for the original research capsules in Example 13 and the celecoxib tablets described in Examples 11 and 12.

[0047] Figure 3 The XRD pattern of the solid dispersion of formulation 26 is shown.

[0048] Figure 4 The XRD pattern of the solid dispersion of formulation 46 is shown.

[0049] Figure 5 The XRD pattern of the solid dispersion of formulation 50 is shown.

[0050] Terminology Explanation:

[0051] In this invention, "drug loading ratio" refers to the ratio of drug to carrier. The carrier in this invention is a crystallization inhibitor. The higher the drug loading ratio, the higher the drug content compared to the carrier.

[0052] In this invention, "optional" means that the events or situations described below may, but are not necessarily, occur. For example, "optional pharmaceutically acceptable excipients" means that pharmaceutically acceptable excipients may or may not be present.

[0053] In this invention, wt% represents the mass fraction percentage. HPMCAS represents hydroxypropyl methylcellulose acetate succinate. HPMCAS-LF represents hydroxypropyl methylcellulose acetate succinate with model number LF. PVPVA64 represents copovidone. TPGS represents vitamin E polyethylene glycol succinate. rpm represents rotational speed (revolutions per minute). SDS represents sodium lauryl sulfate. Cermophor EI35 represents polyoxyethylene castor oil 35. LOQ represents the limit of quantitation. NaCl represents sodium chloride. PEG represents polyethylene glycol. XRD represents X-ray diffraction. AUClast represents the area under the curve from the time of administration to the last quantification point. Cmax represents the peak plasma concentration. Mean represents the average value. SD represents the standard deviation. Tmax represents the time corresponding to the peak plasma concentration. T 1 / 2 represents the half-life. h represents hours. RH represents relative humidity. RD represents relative mean deviation. nm represents nanometers. min represents minutes. g represents grams. ng represents nanograms. ml represents milliliters. pH represents acidity or alkalinity. HPMC represents hydroxypropyl methylcellulose. HPMCE3 and HPMCE15 represent hydroxypropyl methylcellulose with model numbers E3 and E15, respectively. PVP represents polyvinylpyrrolidone. PVPK29 / 32 represents polyvinylpyrrolidone with model number K29 / 32. soluplus represents a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. HPLC represents high-performance liquid chromatography. RRT represents relative retention time, which is the ratio of the retention time of this peak to the retention time of the main peak.

[0054] In this invention, the original capsule refers to the commercially available celecoxib capsule, Celebrex from Pfizer Inc., 200mg / capsule.

[0055] In the description of this invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0056] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples. Detailed Implementation

[0057] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0058] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0059] In this embodiment of the invention, the LOQ (limit of quantitation) is 0.05%.

[0060] In this embodiment of the invention, the " / " in "report single impurities" indicates that they were not detected, and a single impurity content less than the detection limit (0.02%) is considered as not detected.

[0061] The methods for detecting dissolution, content, and related substances described in this embodiment of the invention are as follows:

[0062] High-performance liquid chromatography (HPLC) conditions for dissolution testing:

[0063] Instrument: HPLC (UV);

[0064] Chromatographic column: Chrome Core 120 C18, 150*4.6mm, 5μm;

[0065] Flow rate: 1.5 mL / min; Run time: 6 min;

[0066] Injection volume: 10 μL; Column temperature: 30℃; Detection wavelength: 250 nm.

[0067] Stability of Samples and Detection of Related Substances: High Performance Liquid Chromatography (HPLC) Chromatographic Conditions:

[0068] Instrument: HPLC;

[0069] Detection wavelengths: Content - UV 265nm; Related substances - UV 265, 254nm;

[0070] Chromatographic column: Nanochrom 120 C18, 4.6*250mm, 5μm;

[0071] Protective pillars: Pillar sleeve - 4.6*10mm Analytical Cartridge, Pillar core - 4.6*10mm Xtimate C18 3μm

[0072] Column temperature: 40℃; Flow rate: 1.0 mL / min; Injection volume: 20 μL;

[0073] Run time: 25 min; Sample tray temperature: 10 ℃; Elution method: isocratic elution.

[0074] Example 1: HPMCAS Single-Carrier Formulation

[0075] Solid dispersion preparation: Solid dispersions were prepared using a hot melt extrusion process according to the formulation in the table below:

[0076]

[0077] Dissolution results: Solid dispersions of formulations 1-8 were placed in dissolution vessels containing 1000 mL of pH 6.8 buffer salt dissolution medium. The rotation speed was 50 rpm and the temperature was 37℃. 2 mL samples were taken at 10 min, 20 min, 30 min and 60 min respectively, and 2 mL of dissolution medium was added at the same time. The 2 mL samples were filtered through a 0.45 μm microporous membrane. The filtrate was subjected to high performance liquid chromatography to determine the celecoxib content and the dissolution percentage was calculated. The dissolution results are shown in the table below.

[0078]

[0079] in conclusion:

[0080] (1) In prescriptions 1-3, under the condition of a fixed drug loading ratio of 1:1, appropriately increasing the amount of TPGS can significantly improve the dissolution of celecoxib.

[0081] (2) The dissolution of HPMCAS monocarrier formulations with added TPGS (formulations 1, 4-7) was better than that of HPMCAS monocarrier formulations without added TPGS (formulation 8), indicating that TPGS can improve the solubility and dissolution plateau of celecoxib.

[0082] (3) When the amount of TPGS is 10%, the formulation of HPMCAS single carrier can only achieve good dissolution results when the drug loading ratio is below 1:5.

[0083] Example 2: PVPVA64 Single-Carrier Formulation

[0084] Solid dispersion preparation: Solid dispersions were prepared using a hot melt extrusion process according to the formulation in the table below:

[0085]

[0086] Dissolution results: The solid dispersions of the above formulations 9-18 were dissolved in a phosphate buffer solution at pH 6.8 (dissolution conditions were the same as in Example 1), and the dissolution results are shown in the table below.

[0087]

[0088] in conclusion:

[0089] (1) Only formulations with a low drug loading ratio (1:5) and TPGS (Formulation 17) can achieve good dissolution results; formulations with a high drug loading ratio (1:1-1:4), especially 1:1-1:3, have poor dissolution results.

[0090] (2) In the PPVVA64 monocarrier formulation (formulation 9-12) with a drug loading ratio of 1:1-1:2, the amount of TPGS added had no significant effect on the dissolution results of celecoxib. In the HPMCAS monocarrier formulation (formulation 13-15) with a drug loading ratio of 1:3, increasing the amount of TPGS added could improve the dissolution plateau.

[0091] Example 3: Dissolution and stability results of tablets prepared according to Formula 15

[0092] Tablet preparation: Take the solid dispersion described in Formula 15, microcrystalline cellulose, sodium chloride, croscarmellose sodium, and magnesium stearate, and compress them according to the following formula to prepare celecoxib tablets:

[0093] Tablet components Prescription rate (%) The solid dispersion described in Formula 15 62.50 microcrystalline cellulose 22.00 Sodium chloride 10.00 Cross-linked carboxymethyl cellulose sodium 5.00 magnesium stearate 0.50 total 100.00

[0094] Stability results: The tablets were placed under accelerated conditions (40°C, 75% RH) for 1, 2, 3, and 6 months, and under long-term conditions (25°C, 60% RH) for 3 and 6 months. Samples were taken for content, related substances, and dissolution tests (dissolution conditions were the same as in Example 1). The results are shown in Tables 1-4.

[0095] Table 1: Stability sampling results

[0096]

[0097] Table 2: Results of stability sampling related substances (detection wavelength 254 nm)

[0098]

[0099] Table 3: Results of stability sampling related substances (detection wavelength 265nm)

[0100]

[0101] Table 4: Stability Sample Dissolution Results

[0102]

[0103]

[0104] Conclusion: Celecoxib tablets with the addition of TPGS and PPVVA64 single carrier system showed relatively stable content, related substances, dissolution rate, and dissolution plateau over 6 months under long-term and accelerated conditions.

[0105] Example 4: Screening of vectors in a dual-vector system (HPMC, PVP, soluplus)

[0106] Preparation of solid dispersions: Celecoxib, PVPVA64, and other carriers and excipients are used to prepare solid dispersions according to the following formula using a hot-melt extrusion process:

[0107]

[0108] Dissolution results: The solid dispersions of the above formulations (formulations 19-22) were subjected to dissolution tests in phosphate buffer at pH 6.8 (dissolution conditions were the same as in Example 1), and the results are shown in the table below.

[0109]

[0110] Conclusion: In dual-carrier systems with PPVVA64 as the first carrier and HPMCE3, HPMCE15, PVPK29 / 32, or Soluplus as the second carrier and TPGS, the dissolution plateau of celecoxib was low and its bioavailability was not high.

[0111] Example 5: Screening of carriers (HPMCAS, PPVVA64), drug loading ratio, and TPGS content in a dual-carrier system

[0112] Preparation of solid dispersions: Take celecoxib, PVPVA64, HPMCAS, and TPGS, and prepare solid dispersions according to the table below using a hot melt extrusion process:

[0113]

[0114]

[0115] Dissolution results: The solid dispersions of the above formulations (formulations 23-29) were subjected to dissolution tests in phosphate buffer at pH 6.8 (dissolution conditions were the same as in Example 1), and the results are shown in the table below.

[0116]

[0117] in conclusion:

[0118] (1) In the dual-carrier system with HPMCAS and PPVVA64 as carriers, when the drug loading ratio is 1:1 (formulation 23-25), increasing TPGS can improve the dissolution plateau of celecoxib, and the optimal content of TPGS is 15%.

[0119] (2) Compared with the dual-carrier system with HPMCE3, HPMCE15, PVPK29 / 32 or Soluplus as the second carrier and TPGS added, the dual-carrier system with HPMCAS and PPVVA64 as carriers and TPGS added has a better dissolution platform and thus higher bioavailability.

[0120] (3) Compared with the single carrier system with HPMCAS or PPVVA64 as carriers and TPGS added, the dissolution platform of the dual carrier system with HPMCAS and PPVVA64 as carriers and TPGS added has been significantly improved, resulting in unexpected technical effects.

[0121] Example 6: Stability results of tablets prepared from the solid dispersion of Formulation 26 (HPMCAS and PPVVA64 in a 1:1 ratio, drug loading ratio in a 1:2 ratio).

[0122] Tablet preparation: Take the solid dispersion, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate from Formula 26, and prepare them into tablets using conventional processes according to the formula in the table below:

[0123] Tablet components Prescription rate (%) Solid dispersion of formulation 26 55.56 microcrystalline cellulose 39.14 Cross-linked carboxymethyl cellulose sodium 5.00 magnesium stearate 0.30 total 100.00

[0124] Stability results: The above tablets were placed under accelerated conditions (40°C, 75% RH) for 1, 2, 3, and 6 months, and under long-term conditions (25°C, 60% RH) for 3 and 6 months. After removal, dissolution tests (dissolution conditions as in Example 1), content and related substances were detected. The results are shown in Tables 5-8.

[0125] Table 5: Stability Sample Dissolution Results

[0126]

[0127] Table 6: Stability Sample Content Results

[0128]

[0129] Table 7: Results of stability testing related materials (254 nm)

[0130]

[0131] Table 8: Results of materials related to stability surveying (265 nm)

[0132]

[0133] in conclusion:

[0134] (1) Celecoxib tablets prepared by a dual carrier system with HPMCAS and PPVVA64 as carriers and TPGS have excellent and stable dissolution rate, dissolution plateau, content and related substances under accelerated and long-term conditions.

[0135] (2) Compared with the single carrier system with HPMCAS or PPVVA64 as carriers and TPGS added, the celecoxib tablets prepared with the dual carrier system with HPMCAS and PPVVA64 as carriers and TPGS added have a higher dissolution plateau, resulting in unexpected technical effects.

[0136] Example 7: Formulation stability with a 1:2 ratio of HPMCAS to PPVVA64 and a 1:1 drug loading ratio.

[0137] Preparation of solid dispersions: Take celecoxib, PPVVA64, and HPMCAS, and prepare solid dispersions using a hot melt extrusion process according to the table below:

[0138]

[0139]

[0140] Tablet preparation: The solid dispersion, microcrystalline cellulose, croscarmellose sodium cellulose, and magnesium stearate from Example 7 were used to prepare tablets according to the formulation in the table below using conventional formulation processes:

[0141] Tablet components Prescription rate (%) The solid dispersion described in Example 7 67.23 microcrystalline cellulose 22.27 Cross-linked carboxymethyl cellulose sodium 10.00 magnesium stearate 0.50 total 100.00

[0142] Stability results: The above tablets were placed under accelerated conditions (40°C, 75% RH) for 1, 2, and 3 months, and under long-term conditions (25°C, 60% RH) for 3 months. After removal, dissolution tests (dissolution conditions as in Example 1), content and related substances were detected. The results are shown in Tables 9-12.

[0143] Table 9: Stability Sample Dissolution Results

[0144]

[0145] Table 10: Stability sampling results

[0146]

[0147] Table 11: Results of stability sampling related substances (detection wavelength 254 nm)

[0148]

[0149] Table 12: Results of stability sampling related substances (detection wavelength 265nm)

[0150]

[0151] Conclusion: In celecoxib tablets with HPMCAS and PPVVA64 dual carriers containing TPGS, the formulation with a 1:2 ratio of HPMCAS to PPVVA64 remained stable and met acceptable standards for dissolution, dissolution plateau, content, and related substances under accelerated and long-term conditions.

[0152] Example 8: Screening of Surfactants

[0153] Preparation of solid dispersions: Take celecoxib, HPMCAS, PPVVA64, TPGS and other excipients, and prepare them according to Tables 13-14 using hot melt extrusion process.

[0154] Table 13: Screening of surfactants in single carriers

[0155]

[0156] Table 14: Screening of surfactants in dual-carrier systems

[0157]

[0158]

[0159] Dissolution results: Solid dispersions of the above formulations (formulations 30-43) were subjected to dissolution tests (dissolution conditions were the same as in Example 1). The results are shown in Table 15.

[0160] Table 15: Dissolution Results

[0161]

[0162] Conclusion: Selecting a suitable surfactant can improve the dissolution plateau of celecoxib. The preferred surfactant is TPGS, followed by poloxamer, polyoxyethylene castor oil 35, sodium dodecyl sulfate, and Tween 80.

[0163] Example 9: Comparison of in vivo bioavailability and dissolution data of the original capsules and the tablets of Example 6 in animals.

[0164] Animal bioavailability test: The original capsules (commercially available celecoxib capsules, Pfizer's Celebrex, 200mg / capsule, 1 capsule administered) and the celecoxib tablets described in Example 6 (2 tablets administered) were used to conduct bioavailability tests in beagle dogs. Ten beagle dogs were selected for a double-crossover experiment. The experimental results are shown in Table 16 (see attached graph). Figure 1 ).

[0165] Table 16: Results of Bioavailability Tests in Animals

[0166]

[0167] Dissolution: Dissolution tests were conducted on the original capsules (commercially available celecoxib capsules, Pfizer's Celebrex, 200 mg / capsule) and the celecoxib tablets described in Example 6 (dissolution conditions were the same as in Example 1). The results are shown in Table 17.

[0168] Table 17: Dissolution Results

[0169]

[0170] in conclusion:

[0171] (1) Based on the above in vivo data, the AUC of the celecoxib tablets described in Example 6 was increased by 2.9 times and the Cmax was increased by 4.5 times compared with the original capsules. This indicates that the celecoxib tablets prepared by hot melt extrusion technology using TPGS, HPMCAS and PPVVA64 as surfactants and crystallization inhibitors can significantly improve the solubility of celecoxib and thus improve the bioavailability of celecoxib in vivo.

[0172] (2) Based on the above dissolution test data, the celecoxib tablets described in Example 6 have a higher dissolution plateau compared with the original capsules.

[0173] This invention compares the dissolution results with and without surfactants, and finds that surfactants can enhance the dissolution of celecoxib, thereby improving its bioavailability.

[0174] By comparing the dissolution results of the "celecoxib + single crystallization inhibitor + surfactant" system and the "celecoxib + two crystallization inhibitors + surfactant" system, it was concluded that at a drug-to-carrier ratio of 1:1 to 1:4, the dissolution results of the "celecoxib + two crystallization inhibitors + surfactant" system were significantly better than those of the "celecoxib + single crystallization inhibitor + surfactant" system. By adding two crystallization inhibitors and a surfactant, high bioavailability can be achieved while reducing the amount of carrier required.

[0175] By comparing different crystallization inhibitors and surfactants, HPMCAS and PPVVA64 were selected as the optimal crystallization inhibitors, and TPGS was selected as the optimal surfactant.

[0176] Example 10: Screening of high drug loading compositions

[0177] Preparation of solid dispersion: Celecoxib, HPMCAS, PPVVA64, TPGS and sodium dodecyl sulfate were prepared according to Table 18 using a hot melt extrusion process.

[0178] Table 18: Formulation of Solid Dispersions

[0179]

[0180] Dissolution results: Solid dispersions of the above formulations (formulations 44-52) were subjected to dissolution tests (dissolution conditions were the same as in Example 1). The results are shown in Table 19.

[0181] Table 19: Dissolution Results

[0182]

[0183] in conclusion:

[0184] (1) Formulas 44 and 45 have 15% TPGS and PPVVA64 as the carrier material. They have poor solubilization effect for formulas with high drug loading (drug loading ratio of 1.5:1, 2:1).

[0185] (2) In formulations 46, 47, and 48, TPGS was 15% and HPMCAS was used as the carrier material. As the API ratio increased (drug loading ratio 1.125:1, 1.5:1, 2:1), the solubilization effect gradually decreased.

[0186] (3) Formulas 49, 50, and 51, with TPGS of 15% and PPVVA64 and HPMCAS as carrier materials, still showed good solubilization effects in formulas with high drug loading (drug loading ratio of 1.125:1, 1.5:1, and 2:1).

[0187] (4) Formulas 51 and 52 use 15% TPGS and 15% SDS as surfactants, respectively. Under high drug loading conditions, TPGS has a better solubilizing effect than SDS.

[0188] Example 11: Formulation stability with a 1:1 ratio of HPMCAS to PPVVA64 and a drug loading ratio of 1.5:1.

[0189] Tablet preparation: Take the solid dispersion of Formula 50, microcrystalline cellulose, crospovidone and magnesium stearate, and prepare tablets according to the formula in Table 20 using conventional processes (ingredient preparation, mixing and tableting).

[0190] Table 20: Tablet Preparation

[0191] Tablet components Prescription rate (%) Solid dispersion of formulation 50 61.28 microcrystalline cellulose 28.23 Cross-linked polyvinylpyrrolidone 10.00 magnesium stearate 0.50 total 100.00

[0192] Stability results: The above tablets were placed under accelerated conditions (40°C, 75% RH) for 1, 2, 3, and 6 months, and under long-term conditions (25°C, 60% RH) for 3 and 6 months. After removal, dissolution tests (dissolution conditions as in Example 1), content and related substances were detected. The results are shown in Tables 21-24.

[0193] Table 21: Stability Sample Dissolution Results

[0194]

[0195]

[0196] Table 22: Stability sampling results

[0197]

[0198] Table 23: Results of materials related to stability sampling (254 nm)

[0199]

[0200] Table 24: Results of materials related to stability surveying (265 nm)

[0201]

[0202] Conclusion: After tableting of a solid dispersion with 15% TPGS and high drug loading (drug loading ratio of 1.5:1, HPMCAS to PPVVA64 ratio of 1:1), the dissolution plateau, content, and related substances remained very good and stable under accelerated and long-term conditions.

[0203] Example 12: Preparation of Formula 46 solid dispersion tablets

[0204] Tablet preparation: Take the solid dispersion of Formula 46, microcrystalline cellulose, crospovidone and magnesium stearate, and prepare tablets according to the formula in Table 25 using conventional processes (ingredient preparation, mixing and tableting).

[0205] Table 25: Prescription 46 Tablet Formula

[0206] Tablet components Prescription rate (%) Formula 46 Solid Dispersion 69.44 microcrystalline cellulose 20.06 Cross-linked polyvinylpyrrolidone 10.00 magnesium stearate 0.50 total 100.00

[0207] Example 13: Animal bioavailability test and dissolution comparison of the original capsules and the tablets of Examples 11 and 12.

[0208] Animal bioavailability study: Original capsules (commercially available celecoxib capsules, Pfizer's Celebrex, 100mg specification), and tablets (100mg specification) from Examples 11 and 12 were used to conduct bioavailability studies in beagle dogs. Twelve beagle dogs were selected for a three-way crossover experiment. The results are shown in Table 26 and the drug-time curve. Figure 2 ).

[0209] Table 26: Pharmacokinetic Results in Beagle Dogs

[0210]

[0211] Dissolution: Dissolution tests were conducted on the original capsules (commercially available celecoxib capsules, Pfizer's Celebrex, 100mg), and tablets from Examples 11 and 12 (dissolution conditions were the same as in Example 1). The results are shown in Table 27.

[0212] Table 27: Dissolution rates of the original capsules, tablets from Example 11 and Example 12

[0213]

[0214] in conclusion:

[0215] (1) Based on the above in vivo data, the AUC of the tablets described in Examples 11 and 12 was increased by 2.4 times and 1.5 times, respectively, and the Cmax was increased by 2.8 times and 1.8 times, respectively, compared with the original capsules. This indicates that with the same 15% TPGS dosage, the bioavailability of the solid dispersion of formulation 46 in Example 12 (with HPMCAS as the carrier and a drug-to-capacity ratio of 1.125:1) was less improved than that of the solid dispersion of formulation 50 in Example 11 (with HPMCAS and PPVVA64 as the carriers and a drug-to-capacity ratio of 1.5:1). HPMCAS and PPVVA64 together as carrier materials are superior to HPMCAS as a single carrier material and can achieve a higher drug loading.

[0216] (2) Based on the above dissolution test data, the tablets described in Examples 11 and 12 have a higher dissolution platform than the original capsules, and the dissolution platform of Example 11 is higher than that of Example 12.

[0217] The above prescriptions only illustrate several embodiments of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. To keep the description concise, not all possible combinations of the various technical features in the above prescriptions have been described. However, as long as the combination of these technical features does not contradict each other, it should be considered to be within the scope of the present invention.

Claims

1. A composition comprising celecoxib, a surfactant, and a crystallization inhibitor, wherein the crystallization inhibitor is a combination of copovidone and hydroxypropyl methylcellulose acetate succinate; the surfactant is vitamin E polyethylene glycol succinate; the weight ratio of celecoxib to the crystallization inhibitor is 2:1 to 1:5; the content of the surfactant is 5wt% to 15wt%; the weight ratio of hydroxypropyl methylcellulose acetate succinate to copovidone is 1:1 to 1:2; and the composition is a solid dispersion.

2. The composition according to claim 1, wherein the weight ratio of celecoxib to the crystallization inhibitor is 2:1-1:2; and / or the content of the crystallization inhibitor is 25wt%-80wt% based on the total weight of the composition; and / or the content of celecoxib is 15wt%-60wt% based on the total weight of the composition.

3. The composition according to claim 1 or 2, wherein the content of the surfactant is 10wt%-15wt% based on the total weight of the composition.

4. The composition according to claim 1 or 2, characterized in that, The composition is further prepared into tablets, capsules, granules or dry suspensions.

5. The composition according to claim 1 or 2, characterized in that, The method for preparing the solid dispersion includes the following steps: taking celecoxib, surfactant and crystallization inhibitor, mixing them, adding them to a hot melt extruder, performing melt mixing and extrusion, and then cooling and pulverizing.

6. The composition according to claim 5, characterized in that, The extrusion temperature of the hot melt extruder is set to 140℃-180℃; or the extrusion temperature of the hot melt extruder is set to 150℃-170℃; or the extrusion temperature of the hot melt extruder is set to 160℃-165℃.

7. The composition according to claim 1 or 2, characterized in that, Based on the total weight of the composition, the content of celecoxib is 30wt%-55wt%, the content of the surfactant is 10wt%-15wt%, and the content of the crystallization inhibitor is 30wt%-70wt%; the weight ratio of hydroxypropyl methylcellulose acetate succinate and copovidone is 1:1 or 1:2.

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