阅读说明：本技术 一种抗炎组合物及其制备方法 (Anti-inflammatory composition and preparation method thereof ) 是由 于丽萍 汪志辉 黄心 石添香 游劲松 黄芳芳 于 2021-05-14 设计创作，主要内容包括：本发明涉及一种抗炎组合物及其制备方法,属于药物制剂领域。所述组合物包括药物活性成分,表面活性剂,结晶抑制剂和任选的其他药学上可接受的辅料。本发明还公开了所述组合物的制备方法。本发明的组合物,具有溶解度高、溶出速度快、溶出平台高、生物利用度高、稳定性好、崩解速度快,以及在保持高生物利用度的同时还能提高载药量等优点。(The invention relates to an anti-inflammatory composition and a preparation method thereof, belonging to the field of pharmaceutical preparations. The composition comprises a pharmaceutical active ingredient, a surfactant, a crystallization inhibitor and optionally other pharmaceutically acceptable auxiliary materials. The invention also discloses a preparation method of the composition. The composition has the advantages of high solubility, high dissolution speed, high dissolution platform, high bioavailability, good stability, high disintegration speed, high drug loading rate while keeping high bioavailability, and the like.)

1. A composition comprising celecoxib, a surfactant and at least two crystallization inhibitors comprising copovidone or hydroxypropylmethylcellulose acetate succinate.

2. The composition of claim 1, the crystallization inhibitor comprising copovidone and hydroxypropylmethylcellulose acetate succinate.

3. The composition of claim 1, wherein the surfactant comprises at least one member selected from the group consisting of vitamin E polyethylene glycol succinate, poloxamer, tween 80, sodium lauryl sulfate, and cremophor.

4. The composition according to any one of claims 1 to 3, wherein the weight ratio of celecoxib to crystallization inhibitor is from 2:1 to 1: 10; and/or the content of the crystallization inhibitor is 10 wt% -90 wt% based on the total weight of the composition; and/or the content of the celecoxib is 5 wt% -85 wt% based on the total weight of the composition.

5. The composition according to any one of claims 1 to 4, wherein the surfactant is present in an amount of from 5% to 30% by weight, based on the total weight of the composition.

6. The composition according to any one of claims 1 to 5, which is a solid dispersion.

7. The composition of any one of claims 1-6, wherein the composition is in the form of a tablet, capsule, granule, or dry suspension.

8. The composition according to claim 6, wherein the method for preparing the solid dispersion comprises the following steps: mixing celecoxib, a surfactant and a crystallization inhibitor, adding the mixture into a hot-melt extruder, carrying out melt mixing extrusion, cooling and crushing.

9. The composition of claim 8, wherein the hot melt extruder is set to an extrusion temperature of 140 ℃ to 180 ℃; or the extrusion temperature set by the hot-melt extruder is 150-170 ℃; or the extrusion temperature set by the hot-melt extruder is 160-165 ℃.

10. A composition characterized in that it comprises: celecoxib, vitamin E polyethylene glycol succinate, copovidone and hydroxypropylmethylcellulose acetate succinate; wherein, based on the total weight of the composition, the content of the celecoxib is 45 wt% -70 wt%, and the content of the vitamin E polyethylene glycol succinate is 15 wt% -30 wt%; the total content of the hydroxypropyl methyl cellulose acetate succinate and the copovidone is 10 wt% -40 wt%, and the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the copovidone is 1:10-10: 1.

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to an anti-inflammatory composition and a preparation method thereof.

Background

Celecoxib (Celecoxib) is a specific nonsteroidal anti-inflammatory analgesic commonly used in clinic, and compared with the traditional nonsteroidal anti-inflammatory drug, the Celecoxib has an anti-inflammatory effect by specifically inhibiting cyclooxygenase-2 (COX-2) to block synthesis of prostaglandin from arachidonic acid, does not act on COX-1, does not influence synthesis of PGI2 with a protection effect on gastrointestinal tract and kidney, and can effectively reduce side effects of the gastrointestinal tract. Clinically, the traditional Chinese medicine composition is usually used for treating adult acute pain, relieving osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and other symptoms and signs; the celecoxib preparation product which is sold in the United states in 1999 and approved to be sold in China has the specification of 50/100/200/400mg, and has the advantages of large administration dosage, slow effect, low bioavailability and low patient compliance.

The patent CN102188365A discloses an insoluble drug eutectic solid dispersion, which is prepared from an insoluble drug (including celecoxib), a eutectic ligand and a high polymer carrier material, wherein the molar ratio of the insoluble drug to the eutectic ligand is 1-2:1, and the high polymer carrier material accounts for 10-90% of the solid dispersion by mass. However, through research, the solid dispersion has high drug-loading rate and low dosage of the carrier, but the solubility is not obviously improved, and the bioavailability is still low.

Patent US20150004237a1 discloses a family of polymers that enhance the solubility or stability of poorly soluble drugs, including celecoxib, and prevent crystallization. However, the technical effects of improving the solubility of the insoluble drug, increasing the drug loading rate and reducing the dosage of the carrier, namely the technical effects of improving the solubility of the insoluble drug, increasing the dosage of the carrier and reducing the dosage of the carrier, cannot be achieved due to the fact that the dosage of the carrier is large in the scheme.

The problems of large specification, low solubility, low bioavailability, slow effect, low drug-loading rate in solid dispersion, large dosage of a carrier and the like exist in the prior art of celecoxib preparations. In the solid dispersion technology, the preparation of a final preparation is greatly influenced by the level of drug loading, and when the proportion of a carrier is too high, namely the drug loading is low, the weight of prepared solid dispersion particles in the final preparation is relatively high, so that the problems that single-dose tablets are too heavy or capsules cannot be filled and the like are caused; and if the prepared tablet is too heavy, the tablet is not easy to swallow by patients and the compliance of the patients is influenced.

Therefore, in order to solve the technical problems of the celecoxib preparation, a better celecoxib composition formula and a better celecoxib composition preparation process need to be researched.

Disclosure of Invention

The invention provides a celecoxib composition and a preparation process thereof.

In a first aspect, the present invention provides a composition.

A composition comprising celecoxib, a surfactant, and a crystallization inhibitor.

The crystallization inhibitors are at least two.

The crystallization inhibitor comprises copovidone or hydroxypropyl methylcellulose acetate succinate. In some embodiments, the crystallization inhibitor comprises copovidone and hydroxypropyl methylcellulose acetate succinate, which facilitates a stable, well-dissolved pharmaceutical formulation with a suitable single dose weight. In some embodiments, the crystallization inhibitor may further include at least one of hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, polyethylene glycol, hypromellose, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the crystallization inhibitor is copovidone and hydroxypropyl methylcellulose acetate succinate, which facilitates obtaining a stable, well-dissolved pharmaceutical formulation with a suitable single dose weight.

The weight ratio of the copovidone to the hydroxypropyl methyl cellulose acetate succinate can be 1:10-10: 1. In some embodiments, the weight ratio of copovidone to hydroxypropylmethylcellulose acetate succinate is from 1:5 to 5: 1. In some embodiments, the weight ratio of copovidone to hydroxypropylmethylcellulose acetate succinate is from 1:3 to 3: 1. In some embodiments, the weight ratio of copovidone to hydroxypropylmethylcellulose acetate succinate is from 1:2 to 2: 1. In some embodiments, the weight ratio of copovidone to hydroxypropylmethylcellulose acetate succinate is from 1:1 to 2: 1.

The surfactant may include at least one selected from the group consisting of 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 advantageous for obtaining a stable, better-dissolving pharmaceutical formulation with a suitable single dose weight.

The weight ratio of the celecoxib to the crystallization inhibitor can be 2:1-1: 10. In some embodiments, the weight ratio of celecoxib to crystallization inhibitor is from 2:1 to 1: 5. In some embodiments, the weight ratio of celecoxib to crystallization inhibitor is 1:1, in some embodiments, the weight ratio of celecoxib to crystallization inhibitor is 2:1, and in some embodiments, the weight ratio of celecoxib to crystallization inhibitor is 1: 2. In some embodiments, the weight ratio of celecoxib to crystallization inhibitor is 1: 3. In some embodiments, the weight ratio of celecoxib to crystallization inhibitor is 1: 4.

The surfactant may be present in an amount of 5 wt% to 30 wt%, based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 5 wt% to 20 wt% based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 10 wt% to 20 wt% based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 5 wt% to 15 wt% based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 5 wt% to 10 wt% based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 15 wt% to 30 wt%, based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 15 wt% to 20 wt% based on the total weight of the composition. In some embodiments, the surfactant is present in an amount of 20 wt% to 25 wt% based on the total weight of the composition.

The celecoxib can be present in an amount of 5 wt% to 85 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 15 wt% to 80 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 15 wt% to 70 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 15 wt% to 60 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 20 wt% to 60 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 20 wt% to 50 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 20 wt% to 40 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 20 wt% to 30 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 45 wt% to 70 wt% based on the total weight of the composition. In some embodiments, the celecoxib is present in an amount of 45 wt% to 55 wt%. In some embodiments, the celecoxib is present in an amount of 55 wt% to 65 wt%. In some embodiments, the celecoxib is present in an amount of 65 wt.% to 70 wt.%.

The crystallization inhibitor may be present in an amount of 10 wt% to 90 wt% based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 10 wt% to 80 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 25 wt% to 80 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 15 wt% to 80 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 15 wt% to 70 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 20 wt% to 60 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 20 wt% to 50 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 20 wt% to 40 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 20 wt% to 30 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 10 wt% to 40 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 15 wt% to 40 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 10 wt% to 30 wt%, based on the total weight of the composition. In some embodiments, the crystallization inhibitor is present in an amount from 10 wt% to 20 wt%, based on the total weight of the composition.

The preparation method of the composition comprises a hot-melt extrusion method or a spray drying method. In some embodiments, the composition is prepared by a hot melt extrusion process. In some embodiments, the composition is prepared by a spray drying process.

The composition may be a solid dispersion.

The composition may also include other pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include inorganic salts. The inorganic salt is 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.

The inorganic salt may be present in an amount of 5 wt% to 20 wt% based on the total weight of the composition.

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

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

In some embodiments of the invention, a composition comprises: celecoxib, vitamin E polyethylene glycol succinate, copovidone and hydroxypropylmethylcellulose acetate succinate; is favorable for improving the dissolution rate and the stability of the composition.

In some embodiments of the invention, a composition comprises: celecoxib, vitamin E polyethylene glycol succinate, copovidone and hydroxypropylmethylcellulose acetate succinate; wherein, based on the total weight of the composition, the content of the celecoxib is 45 wt% -70 wt%, and the content of the vitamin E polyethylene glycol succinate is 15 wt% -30 wt%; the total content of the hydroxypropyl methyl cellulose acetate succinate and the copovidone is 10 wt% -40 wt%, and the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the copovidone is 1:10-10: 1; is favorable for improving the dissolution rate of the composition, simultaneously is favorable for improving the drug loading rate and stability of the composition and reducing the dosage of the carrier.

In some embodiments of the invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methyl cellulose acetate succinate and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of the celecoxib is 45 wt% -55 wt%, and the content of the vitamin E polyethylene glycol succinate is 15 wt% -30 wt%; the total content of the hydroxypropyl methyl cellulose acetate succinate and the copovidone is 15 to 40 weight percent; the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the copovidone is 1:10-10: 1; is favorable for improving the dissolution rate of the composition, simultaneously is favorable for improving the drug loading rate and stability of the composition and reducing the dosage of the carrier.

In some embodiments of the invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methyl cellulose acetate succinate and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of the celecoxib is 55 wt% -65 wt%, and the content of the vitamin E polyethylene glycol succinate is 15 wt% -30 wt%; the total content of the hydroxypropyl methyl cellulose acetate succinate and the copovidone is 10 to 30 weight percent; the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the copovidone is 1:10-10: 1; is favorable for improving the dissolution rate of the composition, simultaneously is favorable for improving the drug loading rate and stability of the composition and reducing the dosage of the carrier.

In some embodiments of the invention, a composition comprises: celecoxib, copovidone, hydroxypropyl methyl cellulose acetate succinate and vitamin E polyethylene glycol succinate; wherein, based on the total weight of the composition, the content of the celecoxib is 65-70 wt%, and the content of the vitamin E polyethylene glycol succinate is 15-30 wt%; the total content of the hydroxypropyl methyl cellulose acetate succinate and the copovidone is 10 to 20 weight percent; the weight ratio of the hydroxypropyl methyl cellulose acetate succinate to the copovidone is 1:10-10: 1; is favorable for improving the dissolution rate of the composition, simultaneously is favorable for improving the drug loading rate and stability of the composition and reducing the dosage of the carrier.

The composition can be prepared into tablets, capsules, granules or dry suspensions.

In a second aspect, the present invention provides the use of a composition according to the first aspect in the preparation of a pharmaceutical formulation.

Use of a composition according to the first aspect in the manufacture of a pharmaceutical formulation for anti-inflammatory or analgesic use, such as for alleviating symptoms of osteoarthritis, adult rheumatoid arthritis, or treating acute adult pain.

The preparation formulation comprises tablets, capsules, granules or dry suspension.

In a third aspect, the present invention also provides a process for preparing the composition or solid dispersion of the first aspect.

A method of preparing a composition or solid dispersion of the first aspect, comprising the steps of: mixing celecoxib, a surfactant, a crystallization inhibitor and optional pharmaceutically acceptable auxiliary materials, adding the mixture into a double-screw hot-melt extruder, carrying out melt mixing extrusion, cooling and crushing to obtain the composition or the solid dispersion.

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

Advantageous effects

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

(1) high solubility, high dissolution speed, high dissolution platform and high bioavailability.

(2) The composition has good dissolution platform stability under the stability lofting conditions of long term, intermediate, acceleration and the like.

(3) The bioavailability is high, the drug loading rate can be improved, and the dosage of the carrier can be reduced.

(4) The added crystallization inhibitor can inhibit the celecoxib from being converted from an amorphous form into a crystal form, and further improve the stability of a dissolution platform.

(5) The invention adopts the surfactant, can obviously enhance the dissolution rate of the celecoxib, and further improves the bioavailability.

(6) The composition provided by the invention adopts celecoxib, two crystallization inhibitors and a surfactant, the dissolution of the composition is obviously superior to that of a composition containing celecoxib, a single crystallization inhibitor and a surfactant, and the composition has an unexpected technical effect.

(7) By comparing different crystallization inhibitors and surfactants, the optimal crystallization inhibitors selected from HPMCAS and PVPVA64 and the optimal surfactant selected from TPGS can effectively improve the dissolution rate and bioavailability of the celecoxib composition, improve the drug loading rate, reduce the carrier consumption and improve the stability of a dissolution platform of the celecoxib composition.

Drawings

Figure 1 shows the results of the bioavailability test in animals of the primary capsules of example 9 and celecoxib tablets described in example 6.

Figure 2 shows the results of bioavailability test in animals of the primary capsules of example 13 and celecoxib tablets of examples 11 and 12.

Figure 3 shows the XRD pattern of formula 26 solid dispersion.

Figure 4 shows the XRD pattern of formula 46 solid dispersion.

Figure 5 shows an XRD pattern of the formula 50 solid dispersion.

Description of terms:

in the invention, the 'drug loading ratio' represents the ratio of a drug to a carrier, the carrier is a crystallization inhibitor, and the higher the drug loading ratio is, the higher the drug content is compared with the carrier.

In the present invention, "optional" means that the subsequently described event or circumstance may, but need not, occur. For example, "optional pharmaceutically acceptable adjuvant" means that a pharmaceutically acceptable adjuvant may or may not be present.

In the present invention, wt% means mass fraction percentage. HPMCAS represents hydroxypropylmethylcellulose acetate succinate. HPMCAS-LF denotes hydroxypropylmethylcellulose acetate succinate of type LF. PVPVA64 represents copovidone. TPGS represents vitamin E polyethylene glycol succinate. rpm represents the rotational speed (rpm). SDS represents sodium dodecyl sulfate. Cermophor EI35 represents polyoxyethylated castor oil 35. LOQ denotes the limit of quantitation. NaCl means sodium chloride. PEG represents polyethylene glycol. XRD represents X-ray diffraction. AUClast represents the area under the time curve from the time of administration to the last point of quantitation. Cmax represents the highest blood concentration. Mean represents the Mean value. SD represents the standard deviation. T max represents the time corresponding to the highest blood concentration. T1/2 denotes half life. h represents an hour. RH means relative humidity. RD denotes the relative mean deviation. nm denotes nanometer. min represents minutes. g represents g. ng represents nanogram. ml means ml. pH means pH value. HPMC refers to hydroxypropyl methylcellulose. HPMCE3 and HPMCE15 represent hydroxypropyl methylcellulose types E3 and E15, respectively. PVP stands for polyvinylpyrrolidone. PVPK29/32 represents polyvinylpyrrolidone of type K29/32. soluplus denotes a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. HPLC means high performance liquid chromatography. RRT represents the relative retention time, i.e. the ratio of the retention time of the peak to the retention time of the main peak.

In the invention, the original grinding capsule refers to a commercially available celecoxib capsule, celecoxib from Perey company in America, and 200 mg/capsule.

In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the examples of the present invention, LOQ (limit of quantitation) was 0.05%.

In the example of the present invention, "/" in "report single impurity" indicates no detection, and a single impurity content less than the detection limit (0.02%) is regarded as no detection.

The detection method of dissolution, content and related substances in the embodiment of the invention is as follows:

dissolution rate detection high performance liquid chromatography conditions:

the instrument comprises the following steps: hplc (uv);

a chromatographic column: chrome Core 120C 18,150 × 4.6mm, 5 μm;

flow rate: 1.5 mL/min; operating time: 6 min;

sample introduction amount: 10 mu L of the solution; column temperature: 30 ℃; detection wavelength: 250 nm.

The content of the stable sample and the chromatographic conditions of the high performance liquid chromatography for detecting related substances are as follows:

the instrument comprises the following steps: HPLC;

detection wavelength: content-UV 265 nm; related substances-UV 265, 254 nm;

a chromatographic column: nanochrom 120C 18,4.6 x 250mm, 5 μm;

protection of the column: column jacket-4.6X 10mm Analytical Cartridge, column core-4.6X 10mm Xtimate C183 μm

Column temperature: 40 ℃; flow rate: 1.0 mL/min; sample introduction amount: 20 mu L of the solution;

operating time: 25 min; temperature of a sample injection tray: 10 ℃; and (3) an elution mode: isocratic elution.

Example 1: HPMCAS single vector prescription

Preparing a solid dispersion: a solid dispersion was prepared using a hot melt extrusion process according to the following formula:

dissolution rate results: taking the solid dispersions of the formulas 1-8, respectively placing the solid dispersions in dissolution cups containing 1000mL of pH6.8 buffer salt dissolution medium, sampling 2mL at the rotation speed of 50rpm and the temperature of 37 ℃ for 10min, 20min, 30min and 60min, respectively, simultaneously respectively supplementing 2mL of dissolution medium, filtering the sampled 2mL through a 0.45 mu m microporous membrane, measuring the content of celecoxib in subsequent filtrate by using a high performance liquid chromatography, calculating the dissolution percentage, and the dissolution results are shown in the following table.

And (4) conclusion:

(1) the formula is 1-3, and under the condition that the fixed drug loading ratio is 1:1, the dosage of TPGS is properly increased, so that the dissolution rate of celecoxib can be remarkably improved.

(2) The dissolution rate of the formula (formula 1, formula 4-7) of the HPMCAS single carrier added with TPGS is better than the dissolution rate of the formula (formula 8) of the HPMCAS single carrier without TPGS, which indicates that TPGS can improve the solubility and dissolution platform of celecoxib.

(3) Under the condition that the TPGS dosage is 10 percent, the HPMCAS single carrier prescription can achieve better dissolution result only when the drug loading ratio is less than 1: 5.

Example 2: PVPVA64 single carrier formula

Preparing a solid dispersion: a solid dispersion was prepared using a hot melt extrusion process according to the following formula:

dissolution rate results: the solid dispersions of formulas 9 to 18 were dissolved in a phosphate buffer solution having a pH of 6.8 (under the same dissolution conditions as in example 1), and the dissolution results are shown in the following table.

And (4) conclusion:

(1) the single carrier formulation of PVPVA64 can achieve better dissolution results only with the formulation (formulation 17) with TPGS added and the drug loading ratio is lower than 1: 5; formulations with high drug loading ratios (1:1-1:4), especially 1:1-1:3, have poor dissolution results.

(2) In the PVPVA64 single carrier prescription (prescription 9-12) with the drug loading ratio of 1:1-1:2, the adding amount of TPGS has no obvious influence on the dissolution result of celecoxib, and in the HPMCAS single carrier prescription (prescription 13-15) with the drug loading ratio of 1:3, the adding amount of TPGS can be increased to improve the dissolution platform.

Example 3: dissolution and stability results for tablets prepared according to formulation 15

Preparation of tablets: taking the solid dispersion, microcrystalline cellulose, sodium chloride, croscarmellose sodium and magnesium stearate in the formula 15, and tabletting according to the following formula to prepare the celecoxib tablets:

tabletting components	Prescription ratio (%)
		Formulation 15 the solid dispersion	62.50
Microcrystalline cellulose	22.00
		Sodium chloride	10.00
Croscarmellose sodium	5.00
		Magnesium stearate	0.50
Total up to	100.00

Stability results: the tablets were allowed to stand under accelerated conditions (40 ℃ C., 75% RH) for 1,2, 3, and 6 months, and under prolonged conditions (25 ℃ C., 60% RH) for 3 and 6 months, respectively, and then sampled to examine the contents, substances and dissolution rates (the dissolution conditions were the same as in example 1), and the results are shown in tables 1 to 4.

Table 1: stability loft content results

Table 2: stability lofting related substance results (254nm detection wavelength)

Table 3: stability lofting of the relevant Material results (265nm detection wavelength)

Table 4: stability lofting dissolution results

And (4) conclusion: the celecoxib tablet added with TPGS and PVPVA64 single carrier system has stable content, related substances, dissolution rate, dissolution platform and the like within 6 months under long-term conditions and accelerated conditions.

Example 4: screening of vectors in Dual vector System (HPMC, PVP, soluplus)

Preparation of solid dispersion: taking celecoxib, PVPVA64 and other carriers and other auxiliary materials, adopting a hot-melt extrusion process, and preparing a solid dispersion according to the following formula:

dissolution rate results: the solid dispersion of the above formulation (formulation 19-22) was subjected to dissolution test in a phosphate buffer solution of pH6.8 (dissolution conditions were the same as in example 1), and the results are shown in the following table.

And (4) conclusion: the dissolution platform of celecoxib is low and the bioavailability is not high in a double-carrier system which is prepared by adding TPGS and takes PVPVA64 as a first carrier and a second carrier selected from HPMCE3, HPMCE15, PVPK29/32 or Soluplus.

Example 5: screening of vector (HPMCAS, PVPVA64), drug loading ratio and TPGS content in double-vector system

Preparation of solid dispersion: taking celecoxib, PVPVA64, HPMCAS and TPGS, adopting a hot-melt extrusion process, and preparing a solid dispersion according to the following table:

dissolution rate results: the solid dispersion of the above formulation (formulation 23-29) was subjected to dissolution test in a phosphate buffer solution of pH6.8 (dissolution conditions were the same as in example 1), and the results are shown in the following table.

And (4) conclusion:

(1) in a double-carrier system taking HPMCAS and PVPVA64 as carriers, when the drug loading ratio is 1:1 (formula 23-25), the dissolution platform of celecoxib can be improved by adding TPGS, and the optimal content of TPGS is 15%.

(2) Compared with a double-carrier system which takes the PVPVA64 as the first carrier and is selected from HPMCE3, HPMCE15, PVPK29/32 or Soluplus and added with TPGS, the double-carrier system which takes the HPMCAS and the PVPVA64 as the carriers and is added with TPGS has a better dissolution platform and higher bioavailability.

(3) Compared with a single carrier system which takes HPMCAS or PVPVA64 as a carrier and is added with TPGS, the dissolution platform of a double carrier system which takes HPMCAS and PVPVA64 as carriers and is added with TPGS is obviously improved, and unexpected technical effects are generated.

Example 6: tablet stability results prepared from solid dispersions of formulation 26 (1:1 HPMCAS and PVPVA64, 1:2 loading ratio)

Preparation of tablets: taking the solid dispersion, microcrystalline cellulose, croscarmellose sodium and magnesium stearate in the formula 26, preparing tablets according to the following formula by adopting a conventional process:

tabletting components	Prescription ratio (%)
		Solid dispersion of formula 26	55.56
Microcrystalline cellulose	39.14
		Croscarmellose sodium	5.00
Magnesium stearate	0.30
		Total up to	100.00

Stability results: the tablets were allowed to stand under accelerated conditions (40 ℃ C., 75% RH) for 1,2, 3 and 6 months and under prolonged conditions (25 ℃ C., 60% RH) for 3 and 6 months, respectively, and then subjected to dissolution test (dissolution conditions were the same as in example 1), content and related substance test, and the results are shown in tables 5 to 8.

Table 5: stability lofting dissolution results

Table 6: stability loft content results

Table 7: stability lofting related substance results (254nm)

Table 8: stability lofting of relevant materials results (265nm)

And (4) conclusion:

(1) the celecoxib tablet prepared by a double-carrier system with HPMCAS and PVPVA64 as carriers and TPGS is very good and stable in dissolution rate, dissolution platform, content and related substances under accelerated and long-term conditions.

(2) Compared with the celecoxib tablet prepared by a single carrier system which takes HPMCAS or PVPVA64 as a carrier and is added with TPGS, the celecoxib tablet prepared by a double carrier system which takes HPMCAS and PVPVA64 as a carrier and is added with TPGS has a higher dissolution platform, and unexpected technical effects are generated.

Example 7: prescription stability with 1:2 HPMCAS to PVPVA64 ratio and 1:1 drug load ratio

Preparation of solid dispersion: taking celecoxib, PVPVA64 and HPMCAS, adopting a hot-melt extrusion process, and preparing a solid dispersion according to the following table:

preparation of tablets: tablets were prepared from the solid dispersion of example 7, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, using conventional formulation techniques, according to the following formula:

tabletting components	Prescription ratio (%)
		Solid Dispersion described in example 7	67.23
Microcrystalline cellulose	22.27
		Crosslinked carboxymethylSodium cellulose	10.00
Magnesium stearate	0.50
		Total up to	100.00

Stability results: the tablets were allowed to stand under accelerated conditions (40 ℃ C., 75% RH) for 1,2 and 3 months and under prolonged conditions (25 ℃ C., 60% RH) for 3 months, and then subjected to dissolution test (dissolution conditions were the same as in example 1), contents and related substance test, and the results are shown in tables 9 to 12.

Table 9: stability lofting dissolution results

Table 10: stability loft content results

Table 11: stability lofting related substance results (254nm detection wavelength)

Table 12: stability lofting of the relevant Material results (265nm detection wavelength)

And (4) conclusion: in the HPMCAS and PVPVA64 double-carrier celecoxib tablets added with TPGS, the dissolution rate, dissolution platform, content, related substances and the like of the formula with the proportion of 1:2 of HPMCAS and PVPVA64 still meet the acceptable standard and are stable under accelerated and long-term conditions.

Example 8: screening of surfactants

Preparation of solid dispersion: the celecoxib, HPMCAS, PVPVA64, TPGS and other auxiliary materials are taken, hot-melt extrusion process is adopted, and the preparation is carried out according to the table 13-table 14.

Table 13: screening of surfactants in Single Carrier

Table 14: screening of surfactants in Dual vectors

Dissolution rate results: the solid dispersion of the above formulation (formulations 30 to 43) was taken and subjected to dissolution test (dissolution conditions were the same as in example 1). The measurement results are shown in table 15:

table 15: dissolution results

And (4) conclusion: the proper surfactant is selected to improve the dissolution platform of the celecoxib, the surfactant is preferably TPGS, and then poloxamer, polyoxyethylene castor oil 35, sodium dodecyl sulfate and tween 80 are selected.

Example 9: in vivo bioavailability test and dissolution data comparison of original ground capsules and example 6 tablets in animals

In vivo bioavailability test in animals: the experimental results obtained by performing the double crossover experiments on celecoxib tablets (2 tablets to be administered) prepared in example 6 from the original ground capsules (commercially available celecoxib capsules, 200 mg/tablet, 1 tablet to be administered) and on beagle dogs respectively, and selecting 10 beagle dogs are shown in table 16 (the graph is shown in fig. 1).

Table 16: results of bioavailability test in animals

Dissolution rate: dissolution tests were carried out on celecoxib tablets (same dissolution conditions as in example 1) as described in example 6, using the original ground capsules (commercial celecoxib capsules, 200 mg/capsule of celecoxib, pfcs, inc., usa). The measurement results are shown in table 17:

table 17: dissolution results

And (4) conclusion:

(1) from the in vivo data, the AUC of the celecoxib tablet in example 6 is increased by 2.9 times and the Cmax is increased by 4.5 times compared with the original ground capsule, which indicates that the celecoxib tablet prepared by using TPGS, HPMCAS and PVPVA64 as surfactants and crystallization inhibitors through the hot melt extrusion technology can significantly improve the solubility of celecoxib, and further improve the bioavailability of celecoxib in vivo.

(2) As can be seen from the dissolution test data, the celecoxib tablets described in example 6 have a higher dissolution plateau than the original ground capsules.

According to the invention, the dissolution results of the added surfactant and the non-added surfactant are compared to obtain the surfactant which can enhance the dissolution rate of celecoxib, so that the technical effect of improving the bioavailability is achieved.

By comparing the dissolution results of a system of celecoxib + single crystal inhibitor + surfactant and a system of celecoxib + two crystal inhibitors + surfactant, the conclusion that the dissolution result of the system of celecoxib + two crystal inhibitors + surfactant is obviously superior to that of the system of celecoxib + single crystal inhibitor + surfactant under the condition that the drug loading ratio is 1:1-1:4 is obtained. By adding two crystallization inhibitors and a surfactant, the technical effect of reducing the dosage of the carrier while achieving high bioavailability can be achieved.

By comparing different crystallization inhibitors and surfactants, the optimal crystallization inhibitors are HPMCAS and PVPVA64, and the optimal surfactant is TPGS.

Example 10: high drug load composition screening

Preparation of solid dispersion: celecoxib, HPMCAS, PVPVA64, TPGS and sodium dodecyl sulfate are taken, hot melt extrusion process is adopted, and the preparation is carried out according to the table 18.

Table 18: preparation of solid dispersions

Dissolution rate results: the solid dispersion of the above formulation (formulation 44 to 52) was taken and subjected to dissolution test (dissolution conditions were the same as in example 1). The measurement results are shown in Table 19.

Table 19: dissolution results

And (4) conclusion:

(1) formulas 44 and 45 have 15% of TPGS and have poor solubilizing effect on the formula with high drug loading (drug loading ratio of 1.5:1 and 2:1) because PVPVA64 is used as a carrier material.

(2) Formulations 46, 47, 48, 15% TPGS and HPMCAS as carrier material, the solubilization efficiency decreased gradually with increasing API proportion (loading ratio 1.125:1,1.5:1,2: 1).

(3) Formulas 49, 50 and 51 have TPGS of 15 percent, and PVPVA64 and HPMCAS are carrier materials, so that the high-drug-loading-rate (drug loading ratio is 1.125:1,1.5:1,2:1) formula still has good solubilization effect.

(4) Formulations 51 and 52, which use 15% TPGS and 15% SDS as surfactant, respectively, have better solubilization effect of TPGS than SDS under the condition of high drug loading.

Example 11: prescription stability of 1:1 HPMCAS to PVPVA64 ratio and 1.5:1 drug load ratio

Preparation of tablets: tablets were prepared from the solid dispersion of formula 50, microcrystalline cellulose, crospovidone, and magnesium stearate, using conventional techniques (compounding, mixing, and tableting) according to the formula of table 20.

Table 20: preparation of tablets

Tabletting components	Prescription ratio (%)
		Solid dispersion of formula 50	61.28
Microcrystalline cellulose	28.23
		Cross-linked polyvidone	10.00
Magnesium stearate	0.50
		Total up to	100.00

Stability results: the tablets were allowed to stand under accelerated conditions (40 ℃ C., 75% RH) for 1,2, 3 and 6 months and under prolonged conditions (25 ℃ C., 60% RH) for 3 and 6 months, respectively, and then subjected to dissolution test (dissolution conditions were the same as in example 1), content and related substance test, and the results are shown in tables 21 to 24.

Table 21: stability lofting dissolution results

Table 22: stability loft content results

Table 23: stability lofting related substance results (254nm)

Table 24: stability lofting of relevant materials results (265nm)

And (4) conclusion: after tabletting the solid dispersion with 15% of TPGS and high drug loading (drug loading ratio of 1.5:1, ratio of HPMCAS to PVPVA64 of 1:1), the dissolution platform, content and related substances and the like under accelerated and long-term conditions were still very good and stable.

Example 12: formulation 46 solid Dispersion tablet preparation

Preparation of tablets: tablets were prepared from formula 46 solid dispersion, microcrystalline cellulose, crospovidone, and magnesium stearate using conventional techniques (compounding, mixing, and tableting) according to the formula of table 25.

Table 25: prescription 46 tabletting prescription

Tabletting components	Prescription ratio (%)
		Formula 46 solid dispersion	69.44
Microcrystalline cellulose	20.06
		Cross-linked polyvidone	10.00
Magnesium stearate	0.50
		Total up to	100.00

Example 13: animal in vivo bioavailability test and dissolution comparison of original capsule and tablets of example 11 and example 12

In vivo bioavailability test in animals: the experimental results obtained by taking the original ground capsules (commercially available celecoxib capsules, 100mg standard of celecoxib of feverre, usa), tablets of example 11 and example 12 (100mg standard) and performing in vivo bioavailability tests on beagle dogs respectively, selecting 12 beagle dogs and performing a triple cross experiment are shown in table 26 and a time curve chart (fig. 2).

Table 26: results of experimental pharmacokinetics in beagle

Dissolution rate: dissolution tests were carried out on the tablets of example 11 and example 12 (dissolution conditions the same as in example 1) using the original ground capsules (commercially available celecoxib capsules, celecoxib from pfeiffer, fevere, usa, 100m standard). The measurement results are shown in Table 27:

table 27: dissolution of original ground capsules, tablets of examples 11 and 12

And (4) conclusion:

(1) from the above in vivo data, the tablets described in examples 11 and 12 showed 2.4-fold and 1.5-fold increase in AUC and 2.8-fold and 1.8-fold increase in Cmax, respectively, compared to the original ground capsules, indicating that the same 15% TPGS dose was used, the bioavailability of the solid dispersion of formula 46 in example 12 (HPMCAS as the vehicle and the drug loading ratio of 1.125:1) was improved to a lesser extent than the bioavailability of the solid dispersion of formula 50 in example 11 (HPMCAS and PVPVA64 as the vehicles and the drug loading ratio of 1.5:1), and the HPMCAS and pv 64 were both better than the HPMCAS single vehicle material as the vehicle material and higher drug loading was achieved.

(2) As can be seen from the dissolution test data, the tablets of examples 11 and 12 have a higher dissolution plateau than the original ground capsule, and the dissolution plateau of example 11 is higher than that of example 12.

The above-mentioned embodiments of the present invention have been described in detail, but it should not be understood that the scope of the invention is limited thereto, and it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit of the invention.