CN112807315A

CN112807315A - Celecoxib and tapentadol hydrochloride eutectic mixture, pharmaceutical composition containing same, and preparation method and application thereof

Info

Publication number: CN112807315A
Application number: CN202110062171.7A
Authority: CN
Inventors: 郝超; 杨正格; 陈寅; 金牮; 张桂森
Original assignee: Jiangsu Tieqi Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Tieqi Pharmaceutical Technology Co ltd
Priority date: 2021-01-18
Filing date: 2021-01-18
Publication date: 2021-05-18

Abstract

The invention provides a celecoxib and tapentadol hydrochloride eutectic mixture, a pharmaceutical composition containing the same, and a preparation method and application of the pharmaceutical composition. The eutectic mixture comprises celecoxib and tapentadol hydrochloride in a molar ratio of (0.1-9): 1, and is prepared by a solvent-assisted grinding or solvent dissolution method and melts at 143 +/-3 ℃. Compared with the single tapentadol hydrochloride or celecoxib hydrochloride, the melting point of the eutectic mixture is obviously reduced, and the dissolution rate and the solubility of the original celecoxib with extremely poor water solubility are obviously improved. The pharmaceutical composition provided by the invention inherits the original pharmacological activities of analgesia, anti-inflammation and the like of the medicine, and also enhances the efficacy of the pharmaceutical composition. Meanwhile, the flowability of the powder is improved, and the compressibility of the medicine is improved.

Description

Celecoxib and tapentadol hydrochloride eutectic mixture, pharmaceutical composition containing same, and preparation method and application thereof

Technical Field

The invention relates to the technical field of solid pharmaceutical chemistry, in particular to a celecoxib and tapentadol hydrochloride eutectic mixture, a pharmaceutical composition containing the same, and a preparation method and application of the pharmaceutical composition.

Background

Eutectic mixtures are generally defined most commonly as a combination of substances that melt at a single temperature, below the melting point of the separating compounds. Another definition is an isothermal reversible reaction between two (or more) solid phases during system heating, resulting in a single phase system. Cherukuvada, S., Nangia, A. (2014.) Eutechnical as improved pharmaceutical materials design, properties and characteristics, chem. Commun, 50(8),906-923 reports differences between eutectic mixtures, co-crystals, solid solutions, etc., as shown in FIG. 6.

When the two substances are mixed, under certain conditions, the mixture may form eutectic, eutectic mixture or solid solution according to different dominant intermolecular forces. The formation of eutectic mixture requires the simultaneous participation of the same intermolecular force (Cohesive force) and different intermolecular forces (Adhesive force), wherein the same intermolecular force is dominant.

The compound in the eutectic mixture still retains its original crystalline state in a short distance range, but the crystallization process is inhibited at a specific ratio due to the presence of other substances. The eutectic mixture keeps the original crystal form at a microscopic level and shows order within a short distance; on a macroscopic level, the long range appears disordered. The disorder is manifested by reduced melting point, improved solubility and dissolution rate.

Eutectic mixtures have been in the medical field for a long time. However, as a system to increase the solubility and solubility of poorly soluble drugs, his potential has not yet been fully exploited. In recent years, serial studies have shown that the solubility, dissolution rate and oral bioavailability of poorly soluble drugs can be improved by preparing eutectic mixtures.

In 1995, the american society for pain led to the first James Cambel suggesting that pain was the fifth vital sign. Today, the world health organization has established that pain is the "fifth vital sign" following blood pressure, respiration, pulse and body temperature. Pain research is becoming increasingly more appreciated, and the most common analgesics currently used are non-steroidal anti-inflammatory drugs (NSAIDs) and opioid receptor agonists. Although good clinical effects are achieved, their clinical use is limited due to side effects. Typical side effects of non-steroidal anti-inflammatory drugs are gastrointestinal reactions such as gastric ulcers, gastric bleeding. Selective COX-2 inhibitors, as second generation non-steroidal anti-inflammatory drugs, may affect the cardiovascular system while reducing gastrointestinal side effects; despite significant analgesic effects, opioid agonists have limited clinical use due to their potential abuse liability, poor tolerability and withdrawal response.

Celecoxib (Celecoxib), CAS number 169590-42-5, chemical name 4- [5- (4-tolyl) -3- (trifluoromethyl) -1 h-1-pyrazol-1-yl ] benzenesulfonamide, structure shown in the following figure:

celecoxib (Celecoxib) was developed by Pfizer, a worldwide pioneer selective cyclooxygenase 2(COX-2) inhibitor, approved by the FDA for marketing in 1999 (trade name: Celebrex). Compared with the traditional non-steroidal anti-inflammatory drugs (NSAID), the celecoxib solves the hundred-year problem of gastrointestinal safety, and can effectively relieve symptoms such as toothache, acute sprain, acute attack of low back pain, postoperative pain and the like.

Tapentadol Hydrochloride (tapntadol Hydrochloride), CAS number: 175591-09-0, chemical name: 3- [ (1R,2R) -3- (dimethylamino) -1-ethyl-2-methylpropyl ] phenol hydrochloride having the following structure:

tapentadol Hydrochloride (Tapendadol Hydrochloride) is a novel analgesic drug developed jointly by the United states intensive pharmaceutical (Johnson & Johnson.) and Gruenenthal GmbH, Germany. It was approved by FDA to be marketed (trade name: NUCNTA) in 2008. Tapentadol is a novel central analgesic with a dual mode of action, and achieves a more potent analgesic effect through two complementary mechanisms of action. It is a mu opioid receptor agonist and a norepinephrine reuptake inhibitor, has analgesic effects on various animal models of acute, inflammatory and chronic neuropathic pain, and has efficacy between that of morphine and tramadol. However, compared with other opioid analgesics such as morphine and tramadol, the tapentadol is less likely to cause analgesic tolerance and dependence, and has less adverse reaction (such as nausea and vomiting) and less side effect.

Celecoxib belongs to the BCS II class of drugs, and has extremely poor water solubility, so that the clinical application of the celecoxib is limited to a considerable extent. The dissolution rate and solubility of celecoxib can be improved through a eutectic mixture preparation technology, so that the bioavailability of celecoxib is improved.

Patent CN 1042769660 discloses a preparation method of a tapentadol hydrochloride and celecoxib eutectic crystal and a composition thereof. However, the patent does not relate to the properties of the composition in terms of pharmacology, dissolution, powder chemistry, and the like. From the heat flow-temperature curve combined with thermogravimetric analysis, the melting point of the eutectic is higher than the decomposition temperature of the compound, and it is presumed that the crystal lattice energy of the crystal is higher and the dissolution of celecoxib may not be improved.

The tapentadol hydrochloride belongs to a central analgesic drug, and has quick response and rapid metabolism. Celecoxib belongs to a non-steroidal anti-inflammatory drug and has a mild and lasting analgesic effect. The two medicines are used together to achieve synergistic effect and improve curative effect of the medicines.

The patent US20050277687 "Combination of selected anagesics and COXII inhibitors" discloses a series of pharmaceutical combinations of tapentadol hydrochloride and selective COX-2 inhibitors. Experiments of examples in the patent show that the tapentadol hydrochloride and the celecoxib have synergistic effect, and the combined administration can improve the analgesic effect of the medicament. The disclosed combination belongs to a physical mixture of medicines, and has no effect of improving the dissolution of celecoxib and improving the powder characteristics of celecoxib.

In view of the above, there is a need to design an improved eutectic mixture of celecoxib and tapentadol hydrochloride to solve the above problems.

Disclosure of Invention

The invention aims to provide a eutectic mixture of celecoxib and tapentadol hydrochloride, a pharmaceutical composition containing the eutectic mixture, and a preparation method and application of the eutectic mixture.

In order to achieve the aim, the invention provides a eutectic mixture of celecoxib and tapentadol hydrochloride, which comprises the celecoxib and the tapentadol hydrochloride in a molar ratio of (0.1-9): 1.

As a further improvement of the invention, the eutectic mixture melts at 143 + -3 ℃.

As a further improvement of the invention, the eutectic mixture comprises celecoxib and tapentadol hydrochloride in a molar ratio of (1.20-1.85): 1.

The invention also provides a preparation method of the eutectic mixture of the celecoxib and the tapentadol hydrochloride, which comprises but is not limited to a solvent-assisted grinding method or a solvent dissolving method.

As a further improvement of the present invention, the solvent-assisted milling method comprises: grinding celecoxib and tapentadol hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture;

the solvent dissolution method comprises: and stirring and dissolving the celecoxib and the tapentadol hydrochloride in a solvent, removing the solvent, and drying to obtain the eutectic mixture.

As a further improvement of the present invention, the solvent includes but is not limited to: one or more of methanol, ethanol, isopropanol, n-propanol, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and dichloromethane.

As a further improvement of the invention, in the solvent-assisted grinding method, the solid-to-liquid ratio of the mass sum of the celecoxib and the tapentadol hydrochloride to the solvent is (0.9-1.2) g:1 mL; in the solvent dissolution method, the solid-to-liquid ratio of the mass sum of the celecoxib and the tapentadol hydrochloride to the solvent is (1-5) mg:1 mL.

The invention also provides a pharmaceutical composition which comprises the celecoxib and tapentadol hydrochloride eutectic mixture and pharmaceutically acceptable auxiliary materials.

As a further improvement of the invention, the dosage form of the pharmaceutical composition is powder, tablets, granules, capsules, pills, films, ointments, suppositories or pastes.

The invention also provides application of the celecoxib and tapentadol hydrochloride eutectic mixture or the pharmaceutical composition, and application of the eutectic mixture or the pharmaceutical composition in medicines for treating or relieving pain.

The invention has the beneficial effects that:

1. the eutectic mixture of the celecoxib and the tapentadol hydrochloride provided by the invention is prepared by a solvent-assisted grinding or solvent dissolving method, wherein the eutectic mixture has the eutectic temperature of 143 +/-3 ℃, and compared with the single tapentadol hydrochloride or celecoxib hydrochloride, the melting point of the eutectic mixture is obviously reduced. Compared with the single celecoxib or the physical mixture of the celecoxib and the tapentadol hydrochloride, the dissolution rate and the saturation solubility are both obviously improved. Therefore, the invention not only inherits the original pharmacological activities of the drug such as analgesia, anti-inflammation and the like, but also obviously enhances the drug effect of the drug, especially the analgesic effect.

2. Compared with a single celecoxib and medicinal physical mixture, the celecoxib and tapentadol hydrochloride eutectic mixture provided by the invention has the advantages that the natural angle of repose is smaller, the Carr index is smaller, the Haosner ratio is lower, the flowability of the medicament is improved to a certain extent, the compressibility of the medicament is improved, and the celecoxib and medicinal physical mixture is more suitable for application of various types of solid preparations.

3. The celecoxib and tapentadol hydrochloride eutectic mixture provided by the invention has good reproducibility, is easy for industrial production and application, and has good application prospect. Compared with the single celecoxib or the physical mixture of the celecoxib and the tapentadol hydrochloride, the dissolution rate and the saturation solubility of the pharmaceutical composition prepared from the compound are also obviously improved, so that the analgesic efficacy of the pharmaceutical composition is improved.

Drawings

Figure 1 is a DSC heat flow-temperature curve for eutectic mixtures of celecoxib and tapentadol hydrochloride, tapentadol hydrochloride alone, celecoxib alone, and physical mixtures of celecoxib and tapentadol hydrochloride in a molar ratio of 0.6:0.4, at different molar ratios.

Figure 2 is a solid-liquid binary phase diagram of celecoxib and tapentadol hydrochloride plotted against the heat flow-temperature curve of the sample in figure 1.

FIG. 3 is a bar graph of the results of the mouse acetic acid writhing experiment obtained in example 6 of the present invention.

Fig. 4 is a graph showing the relationship between the amount of celecoxib dissolved and the solvent time in an in vitro dissolution experiment of celecoxib, a celecoxib-tapentadol hydrochloride physical mixture and a celecoxib-tapentadol hydrochloride eutectic mixture obtained according to example 7.

Fig. 5 is a graph showing the relationship between the amount of celecoxib dissolved and the solvent time in an in vitro dissolution test of the celecoxib tablets, the celecoxib-tapentadol hydrochloride physical mixture tablets and the celecoxib-tapentadol hydrochloride eutectic mixture tablets according to example 9.

Fig. 6 is a schematic structural view of eutectic mixtures, eutectics and solid solutions.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in detail below with reference to specific embodiments.

It should be noted that, in order to avoid obscuring the present invention with unnecessary details, only the structures and/or processing steps closely related to the scheme of the present invention are shown in the specific embodiments, and other details not closely related to the present invention are omitted.

In addition, it is also to be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

In the examples below, unless otherwise indicated, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.

The invention provides a celecoxib and tapentadol hydrochloride eutectic mixture which comprises celecoxib and tapentadol hydrochloride in a molar ratio of (0.1-9): 1. The molar ratio of the celecoxib to the tapentadol hydrochloride is preferably (0.5-8): 1, (0.5-6): 1, (1-4): 1 or (1.20-1.85): 1, and more preferably 1.5: 1.

The eutectic mixture melts at 143 +/-3 ℃, and celecoxib and tapentadol hydrochloride have characteristic endothermic peaks at 143 +/-3 ℃ under the mixing of the celecoxib and the tapentadol hydrochloride in different proportions.

Wherein the solvent-assisted milling process comprises: grinding celecoxib and tapentadol hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture; in the solvent auxiliary grinding method, the solid-to-liquid ratio of the mass sum of the celecoxib and the tapentadol hydrochloride to the solvent is (0.9-1.2) g:1 mL. The solvent is preferably added in multiple portions and repeatedly ground.

The solvent dissolution method comprises: and stirring and dissolving the celecoxib and the tapentadol hydrochloride in a solvent, removing the solvent, and drying to obtain the eutectic mixture. The solvent removal method is preferably rotary evaporation solvent removal. In the solvent dissolution method, the solid-to-liquid ratio of the mass sum of the celecoxib and the tapentadol hydrochloride to the solvent is (1-5) mg:1 mL.

The solvent includes, but is not limited to: one or more of methanol, ethanol, isopropanol, n-propanol, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and dichloromethane.

The invention also provides a pharmaceutical composition, which comprises the celecoxib and tapentadol hydrochloride eutectic mixture and pharmaceutically acceptable auxiliary materials, such as excipients, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials and other additives.

The acceptable dosage form of the pharmaceutical composition provided by the invention is powder, tablets, granules, capsules, pills, films, ointments, suppositories or pastes, but not limited thereto.

The invention also provides application of the celecoxib and tapentadol hydrochloride eutectic mixture or the pharmaceutical composition, and application of the eutectic mixture or the pharmaceutical composition in medicines for treating or relieving pain. Compared with a simple physical mixture of celecoxib and tapentadol hydrochloride, the eutectic mixture has a remarkable advantage in analgesic effect.

The Differential Scanning Calorimetry (DSC) analysis chart is detected by German relaxation-resistant DSC200F3, and the heating rate is 10K/min; sealing the pricking hole by adopting an aluminum crucible; the purge gas was nitrogen (60ml/min) and the shielding gas was nitrogen (40 ml/min).

The conditions of the high performance liquid chromatography according to the present invention are shown in table 1.

TABLE 1 test conditions for high performance liquid chromatography

Example 1

According to the table, according to the molar ratio of celecoxib to tapentadol hydrochloride (X is 0.1-0.9), respectively weighing celecoxib and tapentadol hydrochloride, placing the weighed celecoxib and tapentadol hydrochloride into an agate mortar, dropwise adding acetonitrile with the total volume of 0.3ml for 3 times, and grinding for 30 minutes; and then, drying the obtained product at 50 ℃ for 3 hours in vacuum to obtain the eutectic mixture of the celecoxib and the tapentadol hydrochloride.

TABLE 2 composition ratio of celecoxib and tapentadol hydrochloride

Sample number	Celecoxib (mg)	Tapentadol hydrochloride (mg)	Molar ratio of
				1	38.1	232.2	0.1:0.9
2	76.2	206.4	0.2:0.8
				3	114.3	180.6	0.3:0.7
4	152.4	151.8	0.4:0.6
				5	190.5	129	0.5:0.5
6	228.6	103.2	0.6:0.4
				7	266.7	77.4	0.7:0.3
8	304.8	51.6	0.8:0.2
				9	342.9	25.8	0.9:0.1

The eutectic mixtures obtained from the respective groups of samples in table 2 were subjected to Differential Scanning Calorimetry (DSC) analysis, and the results of the DSC measurement are shown in fig. 1. It can be seen that the melting point of the eutectic mixture is significantly reduced compared to tapentadol hydrochloride or celecoxib alone. According to a heat flow-temperature curve of a eutectic mixture obtained by grinding celecoxib and tapentadol hydrochloride with different molar ratios, taking the temperature as a vertical coordinate and the molar ratio content (X) of the celecoxib as a horizontal coordinate, connecting first endothermic peak sites under each ratio to obtain a solid line, and connecting second endothermic peak sites appearing under each ratio to obtain a liquid line, and drawing a binary phase diagram. The binary phase diagram shows that the optimal eutectic ratio of the system is obtained when the mole ratio of the celecoxib to the tapentadol hydrochloride is 6:4 (i.e. 0.6:0.4 or 1.5:1), the eutectic temperature is about 143 ℃, and the arrows in the diagram 2 show the eutectic points. It can be seen that the eutectic temperature is much lower than the melting point of celecoxib or tapentadol hydrochloride alone. The method successfully prepares the celecoxib and the tapentadol hydrochloride into the eutectic mixture by a solvent auxiliary grinding method, and can obviously improve the dissolution rate and the solubility of the celecoxib.

Example 2

In a 250ml flask, 1289mg (5mmol) of tapentadol hydrochloride and 2857.5mg (7.5mmol) of celecoxib were weighed, 100ml of ethanol was added, and magnetic stirring was carried out at 50 ℃ for 15 minutes. And after the solution is clarified, carrying out reduced pressure rotary evaporation to remove the solvent, and drying the obtained product in a vacuum drying oven at 50 ℃ for 3 hours to obtain a eutectic mixture of celecoxib and tapentadol hydrochloride. The DSC curve of the eutectic obtained in example 2 is shown in fig. 1, where X is 0.6, indicating that a eutectic mixture of celecoxib and tapentadol hydrochloride having a eutectic temperature of about 143 c was successfully prepared.

Example 3

A eutectic mixture of celecoxib and tapentadol hydrochloride was prepared by weighing 247.65mg (0.65mmol) of celecoxib and 90.23mg (0.35mmol) of tapentadol hydrochloride, according to the method described in example 1. The test results show that the DSC curve of the eutectic mixture is basically consistent with that of X0.6 in figure 1, and the eutectic mixture of celecoxib and tapentadol hydrochloride with the eutectic temperature of about 143 ℃ is successfully prepared.

Example 4

Celecoxib-tapentadol hydrochloride eutectic mixtures were prepared by weighing 209.55mg (0.55mmol) of celecoxib and 116.01mg (0.45mmol) of tapentadol hydrochloride according to the procedure described in example 2. The results of the tests show that the DSC curve of the eutectic mixture is substantially consistent with that of fig. 1 when X is 0.6, which indicates that this example successfully produces a eutectic mixture of celecoxib and tapentadol hydrochloride having a eutectic temperature of about 143 ℃.

Example 5

And (3) testing the powdery properties of the celecoxib-tapentadol hydrochloride eutectic mixture.

The instrument model is as follows: BT-1000 powder comprehensive property tester.

The test method comprises the following steps: refer to GB/T31057 physical Property test of particulate materials.

In the following examples, the method for obtaining the physical mixture of celecoxib-tapentadol hydrochloride was: 22.86g of celecoxib and 10.31g of tapentadol hydrochloride are respectively weighed and placed in a mortar, and a glass rod is used for stirring to fully and uniformly mix the celecoxib and the tapentadol hydrochloride to obtain a celecoxib-tapentadol hydrochloride physical mixture.

TABLE 3 measurement results of the powder properties of celecoxib-tapentadol hydrochloride eutectic mixture

As can be seen from table 3, the celecoxib-tapentadol hydrochloride eutectic mixture has a smaller natural angle of repose, a lower karl index and hausner ratio, indicating that the flowability is significantly improved compared to celecoxib and the celecoxib-tapentadol hydrochloride physical mixture.

Example 6

Acetic acid writhing experiment in mice

40 female ICR mice were divided into 5 groups on average, and were given free food and water. All animals were kept in the laboratory for 3 days before the start of the experiment to acclimate the animals to the laboratory environment.

The celecoxib, the tapentadol hydrochloride, the celecoxib-tapentadol hydrochloride physical mixture and the celecoxib-tapentadol hydrochloride eutectic mixture are respectively suspended in soybean oil, and each group of mice orally take corresponding medicines according to 0.1ml/10g of body weight, and the specific dosage is shown in table 4.

TABLE 4 mouse acetic acid writhing experiment dosing amount

After administration of the doses shown in Table 4 for 20 minutes, the mice were administered with 1% acetic acid (v/v) intraperitoneally to induce writhing reaction. Writhing is defined as abdominal muscle contraction accompanied by elongation of the body and hind limbs. The number of writhing times was recorded for mice between 30-45 min, 50-65 min and 70-85 min after administration, respectively, and the results are shown in fig. 3.

The experimental result shows that after the celecoxib is administrated at 6.65mg/kg, the average writhing frequency of the mice at 50-65 minutes is reduced compared with that of a solvent control group, but the difference of the celecoxib is not obvious compared with that of the solvent control group, and the celecoxib exerts a certain analgesic effect. At the dose of 3mg/kg, the average writhing frequency of the mice is also reduced, but the average writhing frequency of the mice is not significantly different from that of a solvent control group. Compared with a solvent control group, the celecoxib-tapentadol hydrochloride physical mixture and the celecoxib-tapentadol hydrochloride eutectic mixture can obviously reduce the writhing frequency of a mouse in 50-65 minutes and 70-85 minutes. And in 50-65 minutes, the times of writhing of mice in the celecoxib-tapentadol hydrochloride eutectic mixture group are obviously reduced compared with the times of writhing of mice in the celecoxib-tapentadol hydrochloride physical mixture group. The method obviously improves the dissolution rate and solubility of the original celecoxib with extremely poor water solubility by preparing the celecoxib and the tapentadol hydrochloride into a eutectic mixture, and further obviously enhances the drug effects of the celecoxib and the tapentadol hydrochloride besides inheriting the original pharmacological activities of analgesia, anti-inflammation and the like of the drug.

Example 7

Celecoxib-tapentadol hydrochloride eutectic mixture in-vitro dissolution experiment

The test method comprises the following steps: refer to the Chinese pharmacopoeia 2015 edition

The instrument model is as follows: FADT-1202 Shanghai Fucisco

100mg of celecoxib, 145.1mg of a celecoxib-tapentadol hydrochloride physical mixture (containing 100mg of celecoxib) and 145.1mg of a celecoxib-tapentadol hydrochloride eutectic mixture (containing 100mg of celecoxib) are respectively weighed and sieved by a standard sieve with 40 meshes. The samples were divided into 3 groups of 3 portions and added to each dissolution cup containing 500ml of phosphate buffer solution with pH 6.8. Stirring at 37 +/-0.5 deg.C for 50 r/min. At 5, 10, 15, 20, 30, 45, 60 minutes, respectively, 1ml of the liquid to be tested was removed and 1ml of the buffer was added. The samples taken out are filtered by a filter membrane of 0.24 mu m, and then the content of the celecoxib in each sample is determined by adopting high performance liquid chromatography.

The test results are shown in fig. 4, and it can be seen that the dissolution rate and the saturation solubility of the celecoxib-tapentadol hydrochloride eutectic mixture are significantly improved compared with the single celecoxib, and the dissolution rate and the saturation solubility of the celecoxib-tapentadol hydrochloride eutectic mixture are higher than those of the celecoxib-tapentadol hydrochloride eutectic mixture. The mixture of the celecoxib and the tapentadol hydrochloride is helpful to improve the dissolution rate and the saturation solubility of the celecoxib. The eutectic mixture is prepared from the celecoxib and the tapentadol hydrochloride, so that the dissolution rate and the saturation solubility of the eutectic mixture can be further improved, and the drug effect is remarkably improved.

Example 8

A pharmaceutical composition is prepared into 1000 tablets in batches, the weight of the tablet is 300mg, and the specific formula composition is shown in the following table:

TABLE 5 formulation Table of novel celecoxib-tapentadol hydrochloride eutectic mixture pharmaceutical composition tablets for treating pain

Composition (I)	Proportioning
		Celecoxib-tapentadol hydrochloride eutectic mixture	48％
Mannitol	10％
		Microcrystalline cellulose	42％
Magnesium stearate	2％

The preparation method of the pharmaceutical composition comprises the following steps: weighing the celecoxib-tapentadol hydrochloride eutectic mixture, mannitol and microcrystalline cellulose according to the prescription amount, and sequentially sieving the mixture by a 40-mesh sieve; then adding the raw and auxiliary materials and magnesium stearate in a prescription amount into a three-dimensional mixer for mixing; then a rotary tablet press is used for tabletting, the weight of the tablet is controlled to be 290 mg and 310mg, and the hardness of the tablet is controlled to be 40-80N.

Example 9

Celecoxib-tapentadol hydrochloride tablet in-vitro dissolution test

Celecoxib tablets (containing 100mg of celecoxib), and celecoxib-tapentadol hydrochloride physical mixture tablets (containing 100mg of celecoxib and 45.1mg of tapentadol hydrochloride) were prepared as controls using the formulation of example 8 and using the same method. The in vitro dissolution of the celecoxib-tapentadol hydrochloride pharmaceutical composition tablets was determined by reference to the method of example 7.

The experimental results are shown in fig. 5, and it can be seen that, in the formula of the pharmaceutical composition tablet, the dissolution rate of the celecoxib tablet is significantly reduced compared with that of the pharmaceutical composition tablet in a powder state, and the dissolution results of the celecoxib-tapentadol hydrochloride physical mixture tablet and the celecoxib-tapentadol hydrochloride eutectic mixture tablet are substantially consistent with that of the pharmaceutical composition tablet. Under the formula, compared with the single celecoxib and the celecoxib-tapentadol hydrochloride physical mixture, the celecoxib-tapentadol hydrochloride eutectic mixture has remarkable advantages in the aspect of dissolution rate, and the saturation solubility is improved to a certain degree.

In conclusion, the eutectic mixture of the celecoxib and the tapentadol hydrochloride provided by the invention is prepared by a solvent-assisted grinding or solvent dissolving method, wherein the eutectic mixture has the eutectic temperature of 143 +/-3 ℃, and compared with the single tapentadol hydrochloride or celecoxib, the melting point of the eutectic mixture is obviously reduced. Compared with the single celecoxib or the physical mixture of the celecoxib and the tapentadol hydrochloride, the dissolution rate and the saturation solubility are both obviously improved. Therefore, the invention not only inherits the original pharmacological activities of the drug such as analgesia, anti-inflammation and the like, but also obviously enhances the drug effect of the drug, especially the analgesic effect. Meanwhile, the flowability of the powder is improved, the compressibility of the medicine is improved, and the preparation method is more suitable for application of various solid preparations.

Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the spirit and scope of the present invention.

Claims

1. The eutectic mixture of celecoxib and tapentadol hydrochloride is characterized by comprising the celecoxib and the tapentadol hydrochloride in a molar ratio of (0.1-9) to 1.

2. The celecoxib and tapentadol hydrochloride eutectic mixture according to claim 1, wherein the eutectic mixture melts at 143 ± 3 ℃.

3. The celecoxib and tapentadol hydrochloride eutectic mixture according to claim 1, characterized in that the eutectic mixture comprises celecoxib and tapentadol hydrochloride in a molar ratio of (1.20-1.85): 1.

4. A process for the preparation of a eutectic mixture of celecoxib and tapentadol hydrochloride according to any one of claims 1 to 3, comprising but not limited to solvent-assisted milling or solvent dissolution.

5. The process for the preparation of a eutectic mixture of celecoxib and tapentadol hydrochloride according to claim 4, wherein the solvent-assisted milling process comprises: grinding celecoxib and tapentadol hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture;

6. The process for the preparation of a eutectic mixture of celecoxib and tapentadol hydrochloride according to claim 4 or 5, wherein said solvents comprise, but are not limited to: one or more of methanol, ethanol, isopropanol, n-propanol, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and dichloromethane.

7. The method for preparing a eutectic mixture of celecoxib and tapentadol hydrochloride according to claim 5 or 6, wherein in the solvent-assisted milling method, the solid-to-liquid ratio of the mass sum of celecoxib and tapentadol hydrochloride to the solvent is (0.9-1.2) g:1 mL; in the solvent dissolution method, the solid-to-liquid ratio of the mass sum of the celecoxib and the tapentadol hydrochloride to the solvent is (1-5) mg:1 mL.

8. A pharmaceutical composition comprising a eutectic mixture of celecoxib and tapentadol hydrochloride according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in the form of powder, tablet, granule, capsule, pill, film, ointment, suppository, or paste.

10. Use of a celecoxib and tapentadol hydrochloride eutectic mixture according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 8 to 9 in a medicament for the treatment or alleviation of pain.