CN112870205B - Eutectic mixture of celecoxib and milnacipran hydrochloride, pharmaceutical composition containing eutectic mixture, and preparation method and application of eutectic mixture - Google Patents
Eutectic mixture of celecoxib and milnacipran hydrochloride, pharmaceutical composition containing eutectic mixture, and preparation method and application of eutectic mixture Download PDFInfo
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Abstract
The invention provides a eutectic mixture of celecoxib and milnacipran hydrochloride, a pharmaceutical composition containing the eutectic mixture, and a preparation method and application of the eutectic mixture. The eutectic mixture comprises celecoxib and milnacipran hydrochloride in a molar ratio of (0.1-9): 1, and is prepared by a solvent-assisted grinding or solvent dissolving method and is melted at 126 +/-3 ℃. Compared with the milnacipran hydrochloride or the celecoxib hydrochloride, the melting point of the eutectic mixture is obviously reduced, and the dissolution rate and the solubility of the celecoxib with extremely poor water solubility are obviously improved. The pharmaceutical composition provided by the invention inherits the antidepressant activity of the medicine, enhances the efficacy of the pharmaceutical composition, is easy for industrial production and application, and has good application prospect.
Description
Technical Field
The invention relates to the technical field of solid pharmaceutical chemistry, in particular to a eutectic mixture of celecoxib and milnacipran hydrochloride, a pharmaceutical composition containing the eutectic mixture, and a preparation method and application of the eutectic mixture.
Background
Depression is a serious mood disorder with a lifetime prevalence of about 17% and is currently affected by at least 3.5 million people worldwide. Depression may be associated with a specific pattern of inflammation that interacts with the brain circuit through complex direct and indirect pathways, suggesting a strong association between the inflammatory process and recurrent major depressive disorder. Research suggests that inflammatory responses are an important component of the pathological mechanism of depression, and inflammatory levels can be reflected by serum hypersensitive C-reactive protein (hs-CRP) levels, which may indicate the severity of depression to some extent.
Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) are recommended as first-line treatment for depression, and are most widely used clinically. However, due to the "delayed action" effect of SSRIs antidepressant, patients with depression often suffer from disappointment of treatment due to insufficient curative effect and tolerance of side effects of the drug, which may aggravate the disease and reduce patient compliance. The anti-inflammatory drug and the SSRIs antidepressant drug are combined to play a synergistic role in treating depression.
Milnacipran hydrochloride (Milnacipran hydrochloride), CAS number: 101152-94-7, chemical name: 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride, which has the following structure:
milnacipran hydrochloride (Milnacipran hydrochloride) was developed by Forest laboratories (Forest Lab) and was approved by the FDA for marketing in 2013 for the treatment of adult major depressive disorder.
Preclinical studies have shown that milnacipran is a potent inhibitor of neuronal norepinephrine and 5-hydroxytryptamine reuptake. Milnacipran inhibits norepinephrine uptake about 3 times more strongly than 5-hydroxytryptamine in vitro, is the only antidepressant drug with NET inhibition stronger than SERT inhibition, and has no direct effect on the uptake of dopamine or other neurotransmitters.
Celecoxib (Celecoxib), CAS number 169590-42-5, chemical name 4- [5- (4-tolyl) -3- (trifluoromethyl) -1 h-1-pyrazol-1-yl ] benzenesulfonamide, having the structure shown below:
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 traditional non-steroidal anti-inflammatory drugs (NSAIDs), celecoxib solves the centurie problem of gastrointestinal safety. Recent studies have shown that celecoxib has a potential antidepressant effect. Santiago R M, Janainaina Barbiero, Martynhak B J, et al.Antidepressant-like effect of celecoxib piroxicam in rat models of depression [ J ]. Journal of Neural Transmission 2014,121(6) report that celecoxib can play an antidepressant effect in animal models such as sucrose preference experiments and forced swimming experiments. Celecoxib as an add in the treatment of compressed or mixed antibiotics of bipolar disorders a double-blind, randomised, placebo-controlled stuck. [ J ]. Human Psychopharmacology Clinical & Experimental,2010,23(2):87-94. Celecoxib is reported to have an improving effect on the symptoms of bipolar disorder patients.
The pharmaceutical composition is characterized in that the antidepressant C, the antidepressant administration with anti-inflammatory agents [ J ]. the Journal of Clinical antidepressant, 2014,75(9):975-7, reports that celecoxib is used as a reinforcing agent, can improve the effect of the traditional SERT antidepressant, thereby improving the problems of low effect taking efficiency, slow effect taking and the like of the traditional antidepressant.
However, celecoxib belongs to the BCS class ii drug and is poorly water soluble, resulting in its clinical use being considerably limited. By the eutectic mixture preparation technology, the dissolution rate and solubility of the celecoxib can be improved, so that the bioavailability of the celecoxib is improved.
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-.
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 on a microscopic level and is ordered in 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 view of the above, there is a need to design an improved eutectic mixture of celecoxib and milnacipran hydrochloride to solve the above problems.
Disclosure of Invention
The invention aims to provide a eutectic mixture of celecoxib and milnacipran hydrochloride, a pharmaceutical composition containing the eutectic mixture, and a preparation method and application of the eutectic mixture. The anti-depression effect of the milnacipran hydrochloride is remarkably improved by preparing the celecoxib and the milnacipran hydrochloride into a eutectic mixture with the melting point of about 126 ℃.
In order to achieve the aim, the invention provides a eutectic mixture of celecoxib and milnacipran hydrochloride, which comprises the celecoxib and the milnacipran hydrochloride in a molar ratio of (0.1-9): 1.
As a further improvement of the invention, the eutectic mixture melts at 126 + -3 ℃.
As a further improvement of the invention, the eutectic mixture comprises celecoxib and milnacipran hydrochloride in a molar ratio of (0.9-1.1): 1.
The invention also provides a preparation method of the eutectic mixture of the celecoxib and the milnacipran 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 milnacipran hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture;
the solvent dissolution method comprises: and stirring and dissolving celecoxib and milnacipran hydrochloride in a solvent, removing the solvent, and drying to obtain the eutectic mixture.
In the solvent-assisted grinding method, the solid-to-liquid ratio of the sum of the masses of the celecoxib and the milnacipran 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 milnacipran hydrochloride to the solvent is (1-5) mg:1 mL.
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.
In order to realize the aim, the invention also provides a pharmaceutical composition which comprises the eutectic mixture of the celecoxib and the milnacipran hydrochloride 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.
In order to achieve the aim, the invention also provides the application of the eutectic mixture of the celecoxib and the milnacipran hydrochloride or the pharmaceutical composition, and the eutectic mixture or the pharmaceutical composition is used for treating or relieving depression.
The invention has the beneficial effects that:
1. the eutectic mixture of the celecoxib and the milnacipran hydrochloride is prepared by a solvent-assisted grinding or solvent dissolving method, the eutectic mixture with the eutectic temperature of 126 +/-3 ℃ is obtained, and compared with the single milnacipran hydrochloride or the 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 milnacipran hydrochloride, the dissolution rate and the saturation solubility are both obviously improved. Therefore, under the condition of inheriting the effect of the antidepressant effect of the medicinal composition, the antidepressant effect of the eutectic is obviously improved.
2. The eutectic mixture of celecoxib and milnacipran hydrochloride 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 milnacipran hydrochloride, the dissolution rate of the pharmaceutical composition prepared from the celecoxib is obviously improved, and the antidepressant effect of the pharmaceutical composition is further improved.
Drawings
Figure 1 is a DSC heat flow versus temperature plot of varying molar ratios of celecoxib and milnacipran hydrochloride eutectic, milnacipran hydrochloride alone, and celecoxib alone.
Figure 2 is a solid-liquid binary phase diagram of celecoxib and milnacipran hydrochloride plotted against the heat flow-temperature curve of the sample of figure 1.
FIG. 3 is a bar graph showing the results of forced swimming experiments on mice obtained in example 4 of the present invention.
FIG. 4 is a graph of the amount of celecoxib dissolved versus solvent time in an in vitro dissolution experiment of celecoxib, a celecoxib-milnacipran hydrochloride physical mixture and a celecoxib-milnacipran hydrochloride eutectic mixture obtained according to example 5.
Fig. 5 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 described 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 eutectic mixture of celecoxib and milnacipran hydrochloride provided by the invention comprises the celecoxib and the milnacipran hydrochloride with a molar ratio of (0.1-9): 1. The molar ratio of the celecoxib to the milnacipran hydrochloride is preferably (0.2-8): 1, (0.4-6): 1, (0.5-2): 1 or (0.8-1.2): 1, and more preferably 1: 1.
The eutectic mixture melts at 126 +/-3 ℃, and the obtained eutectic mixture has characteristic endothermic peaks at 126 +/-3 ℃ under the condition that the celecoxib and the milnacipran hydrochloride are mixed in different proportions.
The invention also provides a preparation method of the eutectic mixture of the celecoxib and the milnacipran hydrochloride, which comprises but is not limited to a solvent auxiliary grinding method or a solvent dissolving method.
Wherein the solvent-assisted milling process comprises: grinding celecoxib and milnacipran hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture; in the solvent-assisted grinding method, the solid-to-liquid ratio of the mass sum of the celecoxib and the milnacipran 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 milnacipran 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 milnacipran 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 milnacipran hydrochloride eutectic mixture and pharmaceutically acceptable auxiliary materials, such as excipient, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material 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 eutectic mixture of the celecoxib and the milnacipran hydrochloride or the pharmaceutical composition, and the eutectic mixture or the pharmaceutical composition is used for treating or relieving depression. Compared with a simple physical mixture of celecoxib and milnacipran hydrochloride, the anti-depression effect of the eutectic mixture has remarkable advantages.
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 molar ratio of the celecoxib to the milnacipran hydrochloride, namely X (1-X) (X is 0.1-0.9), respectively weighing the celecoxib and the milnacipran hydrochloride, putting the celecoxib and the milnacipran hydrochloride into an agate mortar, dropwise adding acetonitrile with the total volume of 0.3ml in 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 milnacipran hydrochloride.
TABLE 2 composition ratio of celecoxib and milnacipran hydrochloride
Differential Scanning Calorimetry (DSC) analysis was performed on the obtained eutectic mixtures of celecoxib and milnacipran hydrochloride in the respective groups of the samples in Table 2, and the DSC test results are shown in FIG. 1. It can be seen that the melting point of the eutectic mixture of celecoxib and milnacipran hydrochloride is significantly reduced compared to either milnacipran hydrochloride (0:1) or celecoxib hydrochloride (1:0) alone. Wherein, the low molar ratio of the celecoxib to the milnacipran hydrochloride is within the range of 0.1: 0.9-0.9: 0.1, characteristic absorption peaks appear at about 126 ℃, but three curves within the range of 0.1: 0.9-0.3: 0.7 and two curves within the range of 0.8: 0.2-0.9: 0.1 also appear second characteristic absorption peaks, which indicates that the mixing effect of the eutectic mixture is slightly poor. According to a heat flow-temperature curve of a eutectic mixture obtained by grinding celecoxib and milnacipran hydrochloride with different molar ratios, a solid line is obtained by connecting first endothermic peak sites under each ratio with the temperature as a vertical coordinate and the molar ratio content (X) of the celecoxib as a horizontal coordinate, a liquid line is obtained by connecting second endothermic peak sites appearing under each ratio, and a binary phase diagram is drawn. Referring to fig. 2, a binary phase diagram shows that the ratio of celecoxib to milnacipran hydrochloride is 5:5 (i.e. 0.5:0.5 or 1:1) at which the eutectic temperature is about 126 ℃ and there is only one melting peak, where the arrows in fig. 2 indicate the eutectic point, which is the optimum eutectic ratio for the system. It can be seen that the eutectic temperature is much lower than the melting point of milnacipran hydrochloride (0:1) or celecoxib hydrochloride (1:0) alone. The method successfully prepares the celecoxib and the milnacipran 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
Milnacipran hydrochloride 1414mg (5mmol) and celecoxib 1905mg (5mmol) were weighed into a 250ml flask, 100ml ethanol was added, and magnetic stirring was carried out at 50 ℃ for 15 minutes. After the solution is clarified, the solvent is removed by reduced pressure rotary evaporation, and then the obtained product is dried in a vacuum drying oven at 50 ℃ for 3 hours to obtain a eutectic mixture of celecoxib and milnacipran hydrochloride. The DSC curve of the eutectic obtained in example 2 is shown in fig. 1 where X is 0.5, indicating that a eutectic mixture of celecoxib and milnacipran hydrochloride having a eutectic temperature of about 126 c was successfully prepared.
Example 3
A eutectic mixture of celecoxib and milnacipran hydrochloride was prepared by weighing 209.65mg (0.55mmol) of celecoxib and 127.27mg (0.45mmol) of milnacipran hydrochloride, according to the method described in example 1. 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 0.5, indicating that a eutectic mixture of celecoxib and milnacipran hydrochloride having a eutectic temperature of about 126 ℃ was successfully prepared.
Example 4
Celecoxib-milnacipran hydrochloride eutectic mixtures were prepared by weighing 171.45mg (0.45mmol) of celecoxib, 155.55mg (0.55mmol) of milnacipran hydrochloride according to the method described in example 2. The results of the tests show that the DSC curve of the eutectic mixture is substantially identical to that of fig. 1 when X is 0.5, indicating that this example successfully produced a eutectic mixture of celecoxib and milnacipran hydrochloride having a eutectic temperature of about 126 ℃.
Example 5
Forced swimming experiment of mouse
30 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 milnacipran hydrochloride, the physical mixture of the celecoxib and the milnacipran hydrochloride and the eutectic mixture of the celecoxib and the milnacipran hydrochloride 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 3.
In the following examples, the method for obtaining the celecoxib-milnacipran hydrochloride physical mixture is as follows: respectively weighing celecoxib and milnacipran hydrochloride, placing the celecoxib and the milnacipran hydrochloride into a mortar, and stirring the mixture by using a glass rod to fully and uniformly mix the mixture to obtain a celecoxib-milnacipran hydrochloride physical mixture.
TABLE 3 dosage for forced swimming test of mice
After 60 minutes of administration in accordance with the dose amounts shown in Table 3, the mice were placed in a circular transparent plastic container having a diameter of 10cm and a water depth of 20cm, and the water temperature was controlled to 25. + -. 1 ℃. The mice struggle to struggle in this environment in an attempt to escape and fail to escape, thus providing a non-avoidable stress environment, and after a period of time the animals will exhibit a typical "immobility" reflecting a condition known as "behavioral despair". The state can be used for evaluating the pharmacological action of antidepressant drugs, and the drugs with antidepressant effect can obviously shorten the immobility time of mice. Behaviors in forced swimming are classified into 4 categories: swimming (animals move around in water), climbing (animals ' forepaws move on the water surface and touch the cylinder wall), diving (animals ' whole body sinks under water) and immobile (animals ' limbs float on the water surface without movement, and only the head is exposed out of the water surface for breathing). The immobility time was recorded within 2 to 6 minutes after the mice were placed in water.
Referring to fig. 3, the coordinates in fig. 3 represent the mice immobility time (seconds) ± standard deviation, and the median was compared by one-way anova, Tukey test, with p <0.05 and p < 0.01. It can be seen that celecoxib alone administered at 11.49mg/kg has no significant antidepressant effect. Milnacipran hydrochloride 8.51mg/kg, and a physical mixture of celecoxib and milnacipran hydrochloride of 20mg/kg (containing milnacipran hydrochloride 8.51mg/kg, and celecoxib 11.49mg/kg) significantly reduced the immobility time of the mice (p <0.05), the milnacipran hydrochloride group was reduced from the average 134 times of the solvent group to 68 times, and the physical mixture of celecoxib hydrochloride was reduced to 56 times. The immobility time (p <0.01) of the mice in the eutectic group of celecoxib hydrochloride is reduced to 29 times, and the antidepressant effect of the eutectic group of celecoxib hydrochloride is the best. Therefore, the celecoxib milnacipran hydrochloride eutectic prepared by the method can obviously improve the depression effect of milnacipran hydrochloride.
Example 5
Celecoxib-milnacipran 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, 174.22mg of a celecoxib-milnacipran hydrochloride physical mixture (containing 100mg of celecoxib) and 174.22mg of a celecoxib-milnacipran hydrochloride eutectic mixture (containing 100mg of celecoxib) are respectively weighed and sieved by a standard sieve of 40 meshes. The samples were divided into 3 groups of 3 portions each, and each was added to a dissolution cup containing 500ml of phosphate buffer solution having a pH of 6.8, and stirred at 37 ℃. + -. 0.5 ℃ at 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 saturated solubility of the celecoxib-milnacipran hydrochloride physical mixture and the celecoxib-milnacipran hydrochloride eutectic mixture are both significantly improved compared with the single celecoxib, and the dissolution rate and the saturated solubility of the celecoxib-milnacipran hydrochloride eutectic mixture are higher than those of the celecoxib-milnacipran hydrochloride physical mixture. The mixture of the celecoxib and the milnacipran 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 milnacipran hydrochloride, so that the dissolution rate and the saturation solubility of the eutectic mixture can be further improved, and the antidepressant effect of the milnacipran hydrochloride is remarkably improved.
Example 6
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 4 table of the formulation of the novel celecoxib-milnacipran hydrochloride eutectic mixture pharmaceutical composition tablet for the treatment of depression
The preparation method of the pharmaceutical composition comprises the following steps: weighing the celecoxib-milnacipran hydrochloride eutectic mixture, mannitol and microcrystalline cellulose according to the prescription amount, and sequentially sieving the mixture through 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. The acceptable dosage form of the pharmaceutical composition of the present invention may be powder, tablet, granule, capsule, pill, film, ointment, suppository or paste, but is not limited thereto.
In conclusion, the eutectic mixture of the celecoxib and the milnacipran hydrochloride provided by the invention is prepared by a solvent-assisted grinding or solvent dissolving method to obtain the eutectic mixture with the eutectic temperature of 126 +/-3 ℃, and compared with the single milnacipran hydrochloride or the celecoxib hydrochloride, the eutectic mixture has the advantages that the melting point is remarkably reduced, and the dissolution rate and the saturation solubility are remarkably improved. Therefore, the invention remarkably enhances the efficacy of the medicament besides inheriting the original antidepressant activity of the medicament, is easy for industrial production and application and has good application prospect.
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 (4)
1. A eutectic mixture of celecoxib and milnacipran hydrochloride, which is characterized by comprising the celecoxib and the milnacipran hydrochloride in a molar ratio of (0.9-1.1): 1; the eutectic mixture melts at 126 +/-3 ℃; the preparation method of the eutectic mixture comprises a solvent auxiliary grinding method or a solvent dissolving method;
the solvent-assisted milling method comprises: grinding celecoxib and milnacipran hydrochloride under the assistance of a solvent, and then drying to obtain the eutectic mixture;
the solvent dissolution method comprises: stirring and dissolving celecoxib and milnacipran hydrochloride in a solvent, then removing the solvent and 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 milnacipran hydrochloride to the solvent is (0.9-1.2) g:1 mL; in the solvent dissolution method, the solid-to-liquid ratio of the total mass of the celecoxib and the milnacipran hydrochloride to the solvent is (1-5) mg:1 mL.
2. The method for preparing the eutectic mixture of celecoxib and milnacipran hydrochloride in claim 1, wherein the solvent comprises 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.
3. A pharmaceutical composition comprising a eutectic mixture of celecoxib and milnacipran hydrochloride according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is in the form of powder, tablet, granule, capsule, pill, film, ointment, suppository, or paste.
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| CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
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| CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
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