CN113336874B - Inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium and preparation method thereof - Google Patents
Inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium, which is an inclusion compound of celecoxib and 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium, wherein the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium has the following structural formula:
wherein
Description
Technical Field
The invention relates to a celecoxib-cyclodextrin inclusion compound, in particular to a celecoxib and lactone modified sulfobutyl betacyclodextrin sodium inclusion compound and a preparation method thereof.
Background
Celecoxib (Celecoxib) is a specific Cox-2 inhibitor, has the effects of resisting inflammation, relieving pain and reducing fever due to the generation of inflammatory prostaglandins. Compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs), celecoxib can selectively inhibit COX-2 cyclooxygenase, does not inhibit the expression of COX-1 related to gastrointestinal tract protection, and causes lower adverse reactions. At present, the traditional Chinese medicine is mainly used for acute trauma and postoperative pain in clinic.
However, the solubility of celecoxib in water is only 5-7 mug/mL, and the celecoxib is in Class II low-solubility high-permeability medicine in biological pharmaceutics classification; in addition, the celecoxib also has the characteristics of easy adhesion and low compression rate, so that the preparation performance is poor. After oral administration, the drug cannot be completely wetted and dissolved in gastrointestinal tract, and further absorption of the drug is inhibited. At present, the clinical dosage form of celecoxib in China is mainly capsules, but the capsules have the defects of low bioavailability, large administration dosage and slow absorption. In order to better alleviate the pain of the patient, it is desirable that the drug can be rapidly absorbed by the patient, resulting in an analgesic effect.
The cyclodextrin or the derivative thereof is adopted to carry out inclusion on the insoluble drug, which is a widely applied mode for solubilizing the insoluble drug at present. Common cyclodextrins include sulfobutylbetacyclodextrin (SBE- β -CD), hydroxypropylbetacyclodextrin (HP- β -CD). The literature reports that SBE-beta-CD has the advantages of low nephrotoxicity, low hemolytic effect and better inclusion capacity compared with HP-beta-CD. However, the stability of the inclusion compound of SBE-beta-CD and the medicament still needs to be enhanced, and the stability of long-term storage has important influence on the clinical practical use. It is closely related to the active ingredient, impurity content, bioavailability.
CN108992676A discloses a celecoxib solid dispersion using a metal-organic framework as a carrier, wherein the organic framework comprises alpha-cyclodextrin and potassium ions and sodium ions. The MOFs are used as drug carriers and can be rapidly dissolved. However, due to the characteristics of the MOFs, there may be insufficient stability when the MOFs are left in the air for a long time.
CN103405782A discloses a celecoxib-containing clathrate compound, and the clathrate compound is made of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin. CN103211825A discloses a celecoxib composition which is an inclusion compound of celecoxib and a cyclodextrin derivative.
Chen Rong Sha et al (preparation of celecoxib inclusion compound and pharmacokinetics in rat body, J. China pharmaceutical industry, 2013, 44(5), 475-. Schwanxia et al (a preparation method for improving solubility of celecoxib, Heilongjiang medical science, 2016, vol. 39, No. 1) also reported that alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin are prepared into inclusion compounds with different formulas according to cyclodextrin mixtures with different proportions and celecoxib, and data of solubility and in-vitro dissolution are researched.
In the prior art, various cyclodextrin derivatives and celecoxib are adopted to prepare the inclusion compound with improved solubility, the solubility of the celecoxib is improved, but the problem of medicament stability is not solved.
Disclosure of Invention
In order to overcome the defect of poor stability of a celecoxib inclusion compound in the prior art, the invention provides the inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium and a preparation method thereof.
The invention aims to provide an inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium, which is an inclusion compound of celecoxib and 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium, wherein the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium has the following structural formula:
wherein
Represents sulfobutyl betacyclodextrin sodium, and n is an integer of 3-15.
Cyclodextrins are a major class of pharmaceutical excipients often used to include insoluble drugs to improve the dissolution properties of pharmaceutical formulations. The inventor finds that the sulindac is included by adopting sulfobutyl-beta-CD-Na cyclodextrin sodium (SBE-beta-CD-Na), has good safety and high inclusion rate, and can be prepared into oral dosage forms such as oral freeze-dried powder, suspension and solution by compounding. The sulfobutyl betacyclodextrin sodium is an anionic high-water-solubility cyclodextrin derivative, can be well included with insoluble drugs to form a non-covalent compound, and has the advantages of improving the stability, water solubility and safety of the drugs, reducing the nephrotoxicity, relieving the hemolysis of the drugs and controlling the release rate of the drugs; however, the obtained inclusion compound is still lack of stability, particularly, the purity of the celecoxib serving as an active ingredient is reduced after the inclusion compound is placed in a high-humidity environment for a period of time, and zoological experiments of mice show that the bioavailability is reduced after the inclusion compound is placed in the high-humidity environment for a period of time and then is administrated by intragastric administration to the mice. The sulfobutyl betacyclodextrin sodium has some surface hydroxyls which are not reacted, particularly 6-site primary hydroxyls, the reactivity is higher than that of 2-site secondary hydroxyls and 3-site secondary hydroxyls, and chemical modification modes such as etherification, esterification, oxidation, crosslinking and the like are conveniently carried out. The inventor unexpectedly finds that the solubility of the inclusion compound obtained by modifying the sulfobutyl-beta-cyclodextrin sodium by using 4-methylbutyrolactone (gamma-valerolactone) and then including the celecoxib is still excellent, but the stability is obviously improved. The applicant modifies the sulfobutyl-beta-cyclodextrin sodium by using gamma-butyrolactone, beta-butyrolactone, delta-valerolactone and epsilon-caprolactone, but the stability of the sulfobutyl-beta-cyclodextrin sodium and the celecoxib inclusion compound is not obviously improved.
The prior art reports of modifying cyclodextrins by ring-opening polymerization of lactones, for example.
Document 1 J. Am. chem. Soc. 2004, 126, 42, 13588-;
document 2 Phys. chem. B2016, 120, 29, 7174-7181;
reference 3 Macromolecules 2007, 40, 9, 3154-3158;
document 4 Polymer Chemistry 2012,3, 1119-1122.
No literature is found that the sulfobutyl-beta-cyclodextrin modified by 4-methylbutyrolactone can play a role in improving the stability of the medicament except for solubilization. Although the reason is unknown, the applicant unexpectedly finds that lactone modified sulfobutyl betacyclodextrin sodium obtained after the surface hydroxyl of the sulfobutyl betacyclodextrin sodium initiates the ring opening polymerization of 4-methyl-butyrolactone is prepared into an inclusion compound together with celecoxib, the encapsulation efficiency and the solubilization multiple are slightly reduced, but the stability is obviously improved, and the inclusion compound has great advantages for the production, storage and use of actual medicaments, so that the encapsulation efficiency and the solubilization multiple are reduced, but the satisfactory degree is still achieved, and meanwhile, the stability is greatly improved, and the inclusion compound is more beneficial to the development and clinical use of the celecoxib.
The inventors have found that it is difficult to obtain a modified product of a lactone ring-opening polymer directly from β -cyclodextrin as a reaction substrate and a lactone. The reasons may be that the solubility of beta-cyclodextrin is not enough on one hand, and the hydrogen bonding force between beta-cyclodextrin hydroxyl groups is strong, so that the coordination of the catalyst and the hydroxyl groups is prevented, and the efficiency of initiating the ring-opening polymerization of lactone through the hydroxyl groups is not high on the other hand. And partial hydroxyl of the sulfobutyl betacyclodextrin is reacted, a certain amount of primary hydroxyl can be subjected to surface modification, meanwhile, the sulfobutyl betacyclodextrin has good solubility, and the sulfobutyl betacyclodextrin is used as a reaction substrate and lactone to perform ring-opening polymerization reaction under mild conditions to obtain the modified cyclodextrin.
The 4-methyl-butyrolactone modified sulfobutyl betacyclodextrin sodium is obtained by a preparation method comprising the following steps: under inert atmosphere, adding sulfobutyl betacyclodextrin sodium, 4-methyl butyrolactone and catalyst into an organic solvent, uniformly mixing, reacting under a reflux condition, cooling, pouring the reaction solution into a poor solvent, precipitating, recrystallizing, and finally obtaining the sulfobutyl betacyclodextrin sodium modified by the 4-methyl-butyrolactone, wherein the sulfobutyl betacyclodextrin sodium and the 4-methyl butyrolactone are white crystals. The inert atmosphere is preferably an argon atmosphere; the poor solvent is ethyl acetate.
The organic solvent has a boiling point higher than the reaction temperature, such as DMF, toluene, etc. The organic solvent is used as a non-aqueous treatment, such as sodium hydride, before use.
Further, the heating reflux reaction is carried out for 24-48h at the temperature of 100-120 ℃, and the recrystallization is carried out by dissolving with water and then putting into absolute ethyl alcohol and/or acetone for recrystallization.
Further, the catalyst is selected from organic tin compounds such as stannous octoate, dibutyltin dilaurate, dioctyltin dilaurate.
Further, sulfobutylbetacyclodextrin sodium, 4-methylbutyrolactone, the mass ratio of the catalyst is 1: 15-30: 0.001-0.01.
Further, the molecular weight of the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium is 2500-.
In a preferred technical scheme of the invention, the mole ratio of the celecoxib to the sodium sulfobutylbetacyclodextrin modified by the 4-methylbutyrolactone is 1: 1-2, preferably 1: 1.3-1.5. Within the proportion range, the comprehensive performances of the encapsulation rate, the solubilization property and the stability of the obtained inclusion compound are optimal.
The invention also provides a celecoxib oral solution, which comprises the following components in parts by mass: 100 parts of inclusion compound of celecoxib and 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium, 20-30 parts of solubilizer, 3-6 parts of antioxidant, 500 parts of water for injection and 700 parts of alcohol solvent, and 70-100 parts of alcohol solvent.
Further, the antioxidant comprises at least one of p-aminophenol, vitamin C, L-lysine and sodium metabisulfite; the solubilizer is selected from at least one of tween 80, tween 60, sodium dodecyl sulfate, sodium oleate and medium chain triglyceride; the alcohol solution is at least one of glycerol ethanol and propylene glycol.
The invention achieves the following beneficial effects:
the sultone graft modified sultone-beta-cyclodextrin sodium is obtained by modifying the sultone-butyl-beta-cyclodextrin sodium through 4-methyl-butyrolactone ring-opening polymerization, and the stability is obviously improved after the inclusion compound is prepared from the sultone and the celecoxib, so that the development of a new medicament form of the celecoxib is facilitated.
Detailed Description
Sulfobutylbetacyclodextrin sodium was purchased from Xian De Li Biochemical Co., Ltd, and the average degree of substitution was about 4.3;
the celecoxib bulk drug is purchased from Henan Dongtai pharmaceutical Co., Ltd, and has the purity of 99.9%;
in the examples of the present invention, "part" means part by mass unless otherwise specified, and "percent" means percent by mass unless otherwise specified.
Preparation example 1
Under the nitrogen atmosphere, adding sodium sulfobutyl-beta-cyclodextrin, 4-methylbutyrolactone and stannous octoate into a reactor containing a DMF solvent subjected to anhydrous treatment; wherein the molar ratio of sulfobutyl-beta-cyclodextrin sodium to 4-methylbutyrolactone to stannous octoate is 1: 20: 0.005, heating to 110 ℃, reacting for 24h under the condition of reflux stirring, cooling to room temperature, directly pouring the reaction liquid into glacial ethyl ether, separating out a precipitate, dissolving the precipitate with water, recrystallizing with absolute ethyl alcohol for 2 times to obtain white crystals, namely the product of the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium. The heavy molecular weight was about 3620 by GPC molecular weight test, PDI =1.31, and the average degree of polymerization n after ring-opening polymerization of the lactone was about 5.8, hereinafter referred to as modified cyclodextrin 1.
Preparation example 2
The other conditions were the same as in preparation example 1 except that the molar ratio of sulfobutylbetacyclodextrin sodium to 4-methylbutyrolactone was 1: 15. The weight average molecular weight of the obtained product was about 2850, PDI =1.28, and the average degree of polymerization n after ring-opening polymerization of lactone, hereinafter referred to as modified cyclodextrin 2, was about 2.7 by GPC molecular weight test.
Preparation example 3
The other conditions were the same as in preparation example 1 except that the molar ratio of sulfobutylbetacyclodextrin sodium to 4-methylbutyrolactone was 1: 30. The weight average molecular weight of the obtained product was about 4360, PDI =1.33, and the average degree of polymerization n after ring-opening polymerization of lactone, hereinafter referred to as modified cyclodextrin 3, was about 8.3 by GPC molecular weight test.
Example 1
Dissolving a certain amount of celecoxib in ethanol at the temperature of 40-45 ℃, keeping the temperature at 40-45 ℃, adding saturated aqueous solutions of the modified cyclodextrin 1 prepared in the preparation example 1 in different molar proportions, stirring for 1h, cooling to room temperature to obtain a white suspension, filtering by a PES filter with the size of 0.22 mu m of Jinteng, and drying in vacuum at the temperature of 70 ℃ under the pressure of 0.01MPa after filtering to obtain the celecoxib-containing polysaccharide. The resulting inclusion complex was tested for solubilization, and stability.
The solubility enhancement is that a certain amount of prepared inclusion compound is weighed and ultrasonically dispersed and dissolved for 1h at normal temperature, the obtained saturated solution is accurately diluted by 100 times in a volumetric flask after being filtered, and the HLPC is used for testing the concentration. The inclusion solubility of celecoxib without inclusion in water is only 0.94 mug/mL, which is similar to that described in the literature.
The stability is characterized in that the prepared inclusion compound is uniformly prepared into a 10 mu g/mL aqueous solution counted by celecoxib, and the stability is evaluated by the retention rate of the HPLC characteristic peak area of the celecoxib after 5 times of freeze-thaw cycle. The freeze-thaw cycle is that the sample is placed at-15 ℃ for 2 days, and then is placed at 40 ℃ and 60RH% for 2 days after being recovered to normal temperature, and the freeze-thaw test is repeated for 5 times.
Characteristic peak retention = characteristic peak area after 30 days of storage/characteristic peak area in celecoxib 10 μ g/mL aqueous solution × 100%.
The formulation is shown in table 1 below:
as can be seen from the data in Table 1, the inclusion rate tends to increase with the increase of the amount of cyclodextrin, and the solubility increase is at a maximum when the molar ratio of celecoxib to modified cyclodextrin 1 is 1:1.4, while the solubility decrease with the increase of the amount of cyclodextrin. Therefore, the optimal ratio is that the mole ratio of the celecoxib to the modified cyclodextrin is 1: 1.2-1.5.
The evaluation of the inclusion rate, the solubilization degree and the stability of celecoxib and unmodified sulfobutyl-betacyclodextrin sodium at different molar ratios were tested under the same conditions and the results are shown in the following table 2:
by comparing the data in tables 1 and 2, it can be seen that the solubility of celecoxib is also increased after inclusion of the celecoxib by the sodium sulfobutylbetacyclodextrin modified by 4-methylbutyrolactone of the invention, although the solubility is reduced compared with the unmodified sodium sulfobutylbetacyclodextrin, the stability is obviously improved. This has great advantages for the production, storage and use of practical drugs, especially for direct oral solution dosage forms. The phenomenon of improving the stability of the inclusion compound of the celecoxib is not found in other lactone modified sulfobutyl betadex sodium, but the applicant modifies the sulfobutyl betadex sodium by using gamma-butyrolactone, beta-butyrolactone and delta-valerolactone, and then prepares the inclusion compound with the celecoxib, the solubilization of the inclusion compound is improved to different degrees, but the stability of the inclusion compound is not obviously improved, and the improvement is close to that of the unmodified sulfobutyl betadex sodium. The epsilon-caprolactone modified sulfobutyl betacyclodextrin sodium has a certain improvement on the stability of the celecoxib inclusion compound, but the solubility is not ideal enough, and the maximum value can only reach 9.53 mu g/mL. Applicants speculate that the 4-methylbutyrolactone modified sodium sulfobutylbetacyclodextrin and celecoxib inclusion compounds can improve stability without significantly affecting solubility due to the special graft steric hindrance.
Modified cyclodextrins obtained in preparation examples 2 and 3 and celecoxib were prepared as inclusion compounds under the same conditions, and tested for solubility and stability, and the results are shown in tables 3 and 4 below:
as can be seen from the data of table 1, table 3, table 4, the inclusion compound prepared with the modified cyclodextrin 1 of preparation example 1 and celecoxib can achieve an optimum balance between solubility improvement and stability improvement. The influence of the obtained branch length of the ring-opening polymerization of 4-methylbutyrolactone on the performance of the clathrate compound is shown.
Example 2
100 parts of celecoxib and 1-4 parts of inclusion compound of 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium, 25 parts of tween 80 and 4.2 parts of p-aminophenol are added into a mixed alcohol aqueous solution of 500 parts of water for injection and 70 parts of ethanol, the mixture is stirred to be completely dissolved, and a PES filter with the diameter of 0.22 mu m of Jinteng is filtered to obtain a celecoxib oral solution which is colorless and transparent liquid. The stability of the celecoxib oral solution is tested, the accelerated test conditions are 40 +/-2 ℃ and the relative humidity is 55 +/-5 RH%, and the results are shown in the following table 5, which shows that the celecoxib oral solution obtained under the accelerated test conditions is very good in stability and basically does not change after being stored for 3 months.
Example 3
Celecoxib oral solution prepared by modified/unmodified cyclodextrin and celecoxib inclusion compound according to the method of the embodiment 2, wherein the inclusion compound is 1-4, 2-4, 3-4 and 0-3 respectively; and performing pharmacokinetic tests on beagle dogs (10 +/-1 kg, male and female halves) by using commercially available celecoxib capsules (celecoxib, 200 mg/capsule, fevere pharmaceutical limited), wherein the administration dose is 20mg/kg in terms of celecoxib, the beagle dogs are male and female halves and are randomly divided into experimental groups (oral solutions prepared by inclusion compound) and control groups (celecoxib), the experimental groups are respectively prepared solutions (0 day) and 5 times of freeze-thaw tests (-15 ℃, 2d/40 ℃, 2d), 8 beagle dogs each group are respectively subjected to gastric lavage after the drugs are fasted for 16h, the above solutions and capsules are respectively administered, and pharmacokinetic data are shown in the following table 6:
as can be seen from Table 6, the inclusion compound prepared by using the sulfobutyl betadex sodium modified by the 4-methylbutyrolactone and the celecoxib is slightly poorer in bioavailability than the inclusion compound prepared by using the unmodified sulfobutyl betadex sodium and the celecoxib, but the bioavailability is not reduced basically after 5 times of freeze-thaw tests, and the bioavailability of the inclusion compound prepared by using the unmodified cyclodextrin and the celecoxib is reduced obviously after 5 times of freeze-thaw tests. The inclusion compound prepared by modifying the sulfobutyl-beta-cyclodextrin sodium by adopting the 4-methylbutyrolactone and the celecoxib is successful, the stability is obviously improved, and the development of the medicament is facilitated.
The invention also tests whether the 4-methylbutyrolactone can affect the safety of the final product after modifying the sodium sulfobutylbetacyclodextrin, and tests the acute toxicity test of the inclusion compounds 1-4 with better solubility to mice proves that no obvious toxic effect is seen when the inclusion compound is orally administrated and the stomach is gavaged under the condition that the maximum dosage is 0.5 g/kg/d. The mice were dissected 15 days after administration, and no obvious abnormalities were observed in the body surface and organs. The 4-methyl butyrolactone is safe to modify the sodium sulfobutylbetacyclodextrin.
Claims (7)
1. An inclusion compound of celecoxib and lactone modified sulfobutyl betacyclodextrin sodium is an inclusion compound of celecoxib and 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium, wherein the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium has the following structural formula:
wherein
Represents sulfobutyl betacyclodextrin sodium, n is an integer of 3 to 15;
the 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium is prepared by a preparation method comprising the following steps: under inert atmosphere, adding sulfobutyl betacyclodextrin sodium, 4-methyl butyrolactone and a catalyst into an organic solvent, uniformly mixing, reacting under a reflux condition, cooling, pouring the reaction solution into a poor solvent, precipitating, recrystallizing, and finally obtaining sulfobutyl betacyclodextrin sodium modified by 4-methyl-butyrolactone, wherein the sulfobutyl betacyclodextrin sodium and the 4-methyl butyrolactone are white crystals;
sulfobutyl betacyclodextrin sodium, 4-methylbutyrolactone, the mass ratio of the catalyst is 1: 15-30: 0.001-0.01;
in the inclusion compound, the mole ratio of celecoxib to 4-methylbutyrolactone modified sulfobutyl betacyclodextrin sodium is 1: 1-2.
2. The clathrate of claim 1, wherein the inert atmosphere is preferably an argon atmosphere; the poor solvent is ethyl acetate.
3. The inclusion compound method as claimed in claim 1, wherein the heating reflux reaction is carried out at 100 ℃ and 120 ℃ for 24-48h, and the recrystallization is carried out by dissolving with water and then putting into absolute ethyl alcohol and/or acetone for recrystallization.
4. The clathrate of claim 1, wherein the catalyst is selected from organotin compounds.
5. The clathrate compound according to claim 4, wherein the organotin compound is at least one selected from stannous octoate, dibutyltin dilaurate and dioctyltin dilaurate.
6. The inclusion complex as claimed in claim 1, wherein the molecular weight of the 4-methylbutyrolactone-modified sodium sulfobutylbetacyclodextrin is 2500-.
7. The inclusion complex of claim 1, wherein the celecoxib and 4-methylbutyrolactone modified sulfobutylbetacyclodextrin sodium are present in a 1: 1.3-1.5.
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