CN110833623A - Niclosamide ethanolamine-hydroxypropyl- β -cyclodextrin inclusion compound and preparation thereof - Google Patents
Niclosamide ethanolamine-hydroxypropyl- β -cyclodextrin inclusion compound and preparation thereof Download PDFInfo
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Abstract
The invention provides a niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound and a preparation method thereof, wherein niclosamide ethanolamine salt and hydroxypropyl- β -cyclodextrin are used as raw materials, and the niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound belongs to the field of pharmacy.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and relates to niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin and a preparation method thereof.
Background
Niclosamide (NHC), chemically known as N- (2 '-chloro-4' -nitrobenzene) -5-chlorosalicylamide, is a pale yellow powder, insoluble in water, soluble in hot alcohol, chloroform, and ether, and has been used as a drug for treating human intestinal parasitic diseases for over 50 years due to its high potency and low toxicity. In recent years, in the research and development process of antitumor drugs, a large number of drug screening experiments show that niclosamide also has a potential antitumor effect, and compared with the newly researched and synthesized antitumor drug, niclosamide has the advantages of strong drug cytotoxicity and small toxic and side effects on human bodies. However, niclosamide has poor solubility and low bioavailability, and clinical antitumor effect is limited.
Hydroxypropyl- β -cyclodextrin (HP- β -CD) is a hydrophilic derivative formed by condensing β -cyclodextrin and 1, 2-propylene oxide, and HP- β -CD has the advantages of good water solubility, strong solubilization, small local irritation, low hemolysis and the like, so the HP- β -CD is considered to be a medicinal solubilization auxiliary material with great development potential.
Niclosamide is the only molluscicide recommended by the world health organization and is also a high-efficiency and low-toxicity molluscicide commonly used in China at present. In order to improve the solubility of niclosamide, the research on the dosage form mainly aims at improving the molluscacidal effect field of niclosamide, such as paste, wettable powder, sustained release agent, controlled release agent and the like; however, niclosamide has been studied less as an oral preparation and an injection preparation for clinical use. At present, the research on the preparation of niclosamide mostly uses the synthesized product Niclosamide Ethanolamine Salt (NES), and the structural formula is shown as follows:
the latter has better solubility in ethanol.
Disclosure of Invention
In view of the above, the invention aims to provide a niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound (NHC inclusion compound) and a preparation method thereof through an inclusion preparation process.
In order to achieve the purpose, the technical scheme of the invention is as follows:
niclosamide ethanolamine-hydroxypropyl- β -cyclodextrin comprises niclosamide ethanolamine and hydroxypropyl- β -cyclodextrin, wherein the molar ratio of hydroxypropyl- β -cyclodextrin to niclosamide ethanolamine is 7:1-16:1, and preferably 8:1-15: 1.
The niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound is prepared by the following method:
dissolving HP- β -CD in distilled water to prepare an HP- β -CD solution with a certain concentration, weighing NES according to a certain substance proportion of HP- β -CD and NES, adding the weighed niclosamide ethanolamine salt into the HP- β -CD solution to mix to prepare a mixed solution A, placing the mixed solution A in a conical flask, oscillating for a certain time in a water bath to obtain a clear solution B, and freeze-drying the solution B to obtain a yellow powdery solid, namely the NHC inclusion compound.
The concentration of the HP- β -CD solution is 200-500g/L, and preferably 300 g/L.
The water bath temperature is 30-60 ℃, and the oscillation time is as follows: 1-4 h.
The invention has the advantages that:
firstly, HP- β -CD has the advantages of good water solubility, strong solubilization, small local irritation, low hemolysis and the like, an NHC inclusion compound is prepared by adopting a freeze-drying method, after NES and HP- β -CD are included, the phase of NES is changed, NES exists in the inclusion compound in an amorphous state and is completely dispersed in HP- β -CD, and the water solubility of the NES is greatly improved;
secondly, the NHC inclusion compound preparation method provided by the invention is low in cost, simple to operate and high in inclusion compound yield. Provides a new technical idea for inclusion of other medicines.
Drawings
FIG. 1: the preparation process flow chart of the invention;
FIG. 2X-ray powder diffraction (PXRD) patterns of NES, HP- β -CD, physical mixture of NES and HP- β -CD, and NHC inclusion compound obtained according to the preparation method;
FIG. 3 is an infrared spectrum of NES, HP- β -CD, a physical mixture of NES and HP- β -CD and NHC inclusion compound obtained according to the preparation method;
FIG. 4 dissolution profiles of NES, physical mixture of NES and HP- β -CD and NHC inclusion compound obtained according to the preparation method.
Detailed Description
Preparation method of inclusion compound
The invention provides a preparation method of niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound, which comprises the following steps, wherein all the steps are completed under the condition of keeping out of the sun.
Experimental example 1 quality evaluation of NHC clathrate preparation Using different preparation methods
Grinding method (connecting method)
Weighing 0.25g of NES powder and 10g of HP- β -CD, placing the NES powder and the HP- β -CD in a mortar, uniformly mixing, adding a proper amount of distilled water, grinding to be thick paste (about 2h), drying at 40 ℃, crushing, and sieving by a 80-mesh sieve to obtain a yellow powder product.
Freeze-drying method (Co-lyophilized)
Weighing 0.25g of NES powder, weighing 25mL of HP- β -CD solution with the mass concentration of about 400g/L, heating the obtained product to 60 ℃ under magnetic stirring, slowly adding the NES into the HP- β -CD aqueous solution, continuously stirring for 2h at constant temperature to obtain a clear solution, pre-freezing the clear solution in a refrigerator at the temperature of-80 ℃ for 18h, freeze-drying the clear solution in a vacuum freeze-drying machine for 24h, crushing the dried product, and sieving the crushed product with a 80-mesh sieve to obtain a yellow powdery product.
Ultrasonic method (Ultrasonic method)
Weighing 0.25g of NES powder, weighing 25mL of HP- β -CD solution with the mass concentration of about 400g/L, immediately carrying out ultrasonic treatment for 2h at the intensity of 200W and the temperature of 60 ℃ by using an ultrasonic instrument after mixing to obtain a clear solution, carrying out vacuum drying (40 ℃), crushing the dried product, and sieving by using a sieve of 80 meshes to obtain a yellow powdery product.
Respectively preparing the inclusion compound according to a grinding method, a freeze drying method and an ultrasonic method, and calculating the inclusion rate according to the following formula: the inclusion rate (content of NES in the inclusion compound/charge of NES) × 100%, and the results are shown in table 1.
Table 1 quality evaluation of NHC inclusion complex prepared by different preparation methods
The experimental results are as follows: the NHC inclusion compound prepared by the freeze-drying method of the preparation method has high inclusion rate and good inclusion effect. The results show that only NHC inclusion compounds prepared by the freeze-drying method using the preparation method of the present invention have the best quality.
Experimental example 2 quality evaluation of NHC clathrate preparation Using HP- β -CD solutions of different concentrations
Preparing 10mL of cyclodextrin solutions with the concentrations of 200g/L, 250g/L, 300g/L, 350g/L, 400g/L and 500g/L respectively, adding NES according to the mass ratio of 11:1 into the HP- β -CD aqueous solution slowly with stirring under the condition of water bath at 45 ℃, stirring for 2 hours at constant temperature to obtain clear solutions, and calculating the inclusion rate respectively, wherein the results are shown in Table 2.
TABLE 2 quality evaluation of NHC clathrate preparation from HP- β -CD solutions of various concentrations
The experiment result shows that the NHC inclusion compound prepared by the HP- β -CD concentration (300g/L) has high inclusion rate and good inclusion effect, and the result shows that the quality of the NHC inclusion compound prepared by the HP- β -CD concentration (300g/L) is optimal.
Experimental example 3 quality evaluation of NHC clathrate preparation Using different ratios of HP- β -CD to NES
Preparing 300g/L HP- β -CD solution, precisely measuring 10mL, respectively proportioning 9 different HP- β -CD and NES substances (6:1, 7:1, 8:1, 10:1, 11:1, 14:1, 15:1, 16:1 and 18:1) in a water bath condition at 45 ℃, slowly adding NES into the HP- β -CD aqueous solution while stirring, continuously stirring at constant temperature for 2h to obtain clear solutions, and respectively calculating the inclusion rate, wherein the results are shown in Table 3.
TABLE 3 quality evaluation of NHC inclusion complex preparation with different ratios of HP- β -CD to NES amounts
Experiment results show that the NHC inclusion compound prepared by adopting the HP- β -CD and NES substance quantitative ratio (8:1-15:1) has high inclusion rate, the inclusion rate is over 80 percent, the inclusion effect is good, the inclusion rate and the drug-loading rate are comprehensively considered, the HP- β -CD and NES substance quantitative ratio is selected to be 8:1 as the optimal preparation condition, and the prepared NHC inclusion compound has the best quality.
Experimental example 4A cyclodextrin solution of 300g/L was prepared, 10mL of each cyclodextrin solution was taken, NES was added according to the amount ratio of NES substance (8:1), NES was slowly added to an HP- β -CD aqueous solution under stirring in water baths at 5 different inclusion temperatures (30, 40, 45, 50, 60 ℃), stirring was continued for 2 hours at constant temperature to obtain clear solutions, and inclusion rates were respectively calculated, and the results are shown in Table 4.
Table 4 quality evaluation of NHC inclusion complex preparation at different temperatures
The experimental results are as follows: the NHC inclusion compound prepared at the inclusion temperature (45 ℃) has high inclusion rate and good inclusion effect. The results show that only the NHC inclusion mass prepared using the inclusion temperature (45 ℃) of the present invention is the best.
Experimental example 5A cyclodextrin solution of 300g/L was prepared, 10mL of each cyclodextrin solution was taken, NES was added according to the amount ratio of NES substance (8:1), NES was slowly added to the HP- β -CD aqueous solution under 45 ℃ water bath with stirring, the mixture was continuously stirred for 1,2, 3 and 4 hours to obtain clear solutions, and the inclusion rate was calculated, respectively, and the results are shown in Table 5.
TABLE 5 quality evaluation of NHC Inclusion preparation at different Inclusion times
The experimental results are as follows: the NHC inclusion compound prepared by adopting the inclusion time is high in inclusion rate and good in inclusion effect. The inclusion rate is improved along with the increase of the inclusion time, and the change of the inclusion rate is not obvious after the inclusion time is 3 hours. Therefore, the invention selects 3h as the inclusion time.
The preparation process of the inclusion compound comprises the steps of taking 100mg of NES powder, slowly adding the NES into 300g/L of HP- β -CD aqueous solution under the condition of 45 ℃ water bath with stirring, continuously stirring for 3h at constant temperature, standing at room temperature, filtering the solution through a 0.45 mu m microporous filter membrane, pre-freezing the filtrate in a refrigerator at-80 ℃ for 18h, and continuously freezing and drying in a vacuum freeze dryer for 24h to obtain a yellow powdery product, wherein the operations are all finished under the condition of keeping out of the sun.
Three batches of NHC inclusion compounds are prepared by adopting an optimal formula, and the inclusion rates are 89.78%, 88.85% and 90.09% respectively; the drug loading rates are 2.90%, 2.87% and 2.91%, respectively.
Characterization of clathrates
The powder X-ray diffraction method (PXRD) test method of the NHC inclusion compound comprises the following steps of taking NES, HP- β -CD, the NHC inclusion compound and physical mixture powder in a corresponding proportion, respectively detecting on an X-ray diffractometer under the detection conditions of a Cu anode and a Ka radiation source, under the wavelength of 1.54056nm, the tube voltage is 40KV, the tube current is 30 mA., and the diffraction intensity (I) and the intensity (I) of the strongest diffraction peak are measured0) Ratio (I/I)0) The result is shown in figure 2. NES (a) presents a plurality of sharp crystal diffraction peaks, HP- β -CD (b) is amorphous powder and is amorphous, physical mixture (c) is the superposition of NES diffraction peaks with weakened intensity and HP- β -CD, the NES diffraction peaks are still in the original crystal form and do not form a new crystal structure, the NES diffraction peaks and the HP- β -CD are only in the physical mixture, and inclusion compound (d) shows that the obvious diffraction peaks of the NES disappear after the NES is included by the HP- β -CD, so that a new phase is formed, and the NES and the HP- β -CD are proved to form an inclusion compound.
The infrared spectrum test method of the NHC inclusion compound comprises the step of respectively including NES, HP- β -CD and NHCPerforming infrared spectrum measurement on the substance and a physical mixture of the substance and the corresponding proportion by adopting KBr tabletting, wherein the scanning range is 4000-400 cm-1Respectively taking NES, HP- β -CD, NHC inclusion compound and physical mixture powder of the inclusion compound in corresponding proportion as samples, taking light transmittance (%) as ordinate and wave number (cm)-1) The infrared spectra of the inclusion compound and the physical mixture show that the inclusion compound of NES and HP- β -CD has been formed, because the infrared spectra have great differences in absorption peak positions and intensities and some characteristic absorption peaks disappear.
Third, determination of dissolution rate of inclusion compound
The in vitro dissolution rate test method of the NHC inclusion compound comprises the following steps: according to the dissolution determination method (the first basket method of dissolution and release determination method of 0931 in the fourth part of the 'Chinese pharmacopoeia' 2015 edition), the rotation speed is 50 revolutions per minute, distilled water is used as dissolution medium, and the temperature is 37 +/-0.5 ℃. The raw material medicine NES27mg, NHC clathrate (equivalent to 27mg raw material medicine) and physical mixture of corresponding proportion are put into dissolution medium, sampling 5mL respectively for 2, 5, 10, 15, 20, 30, 45, 60 and 90min, adding distilled water with same temperature and volume in time, and taking the subsequent filtrate as sample solution. The cumulative dissolution rate is calculated by adopting an ultraviolet spectrophotometry according to a standard curve method. The cumulative release profile of NHC inclusion in the medium is shown in figure 4.
The cumulative release curve chart 4 shows that the cumulative dissolution of the inclusion compound is more than 2 times of that of the physical mixture, which proves that the NHC inclusion compound is formed, the dissolution of the inclusion compound is far higher than that of the bulk drug, the dissolution in water is improved by more than 4 times, the NHC inclusion compound can release about 95% in 90min, the water solubility of the bulk drug is poor, and only about 23% is released in 90min, which shows that the water solubility is greatly improved after the NES and the HP- β -CD are included.
Claims (7)
1. The niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound is characterized by comprising niclosamide ethanolamine salt and hydroxypropyl- β -cyclodextrin, wherein the molar ratio of hydroxypropyl- β -cyclodextrin to niclosamide ethanolamine salt is 7:1-16: 1.
2. The niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound of claim 1, wherein the molar ratio of hydroxypropyl- β -cyclodextrin to niclosamide ethanolamine salt is 8:1-15: 1.
3. A method for preparing the niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound as claimed in claim 1, is characterized in that the niclosamide ethanolamine salt is added into a prepared hydroxypropyl- β -cyclodextrin solution by taking hydroxypropyl- β -cyclodextrin as a main body and niclosamide ethanolamine salt as an object, stirred in the dark to form the inclusion compound, and the niclosamide ethanolamine salt-hydroxypropyl- β -cyclodextrin inclusion compound is obtained after vacuum freeze drying.
4. The method for preparing the niclosamide ethanolamine salt hydroxypropyl- β -cyclodextrin inclusion compound as claimed in claim 3, wherein the concentration of the hydroxypropyl- β -cyclodextrin solution is 200-500 g/L.
5. The method for preparing the niclosamide ethanolamine salt hydroxypropyl- β -cyclodextrin inclusion compound of claim 3, wherein the inclusion temperature is 30-60 ℃.
6. The method for preparing the niclosamide ethanolamine salt hydroxypropyl- β -cyclodextrin inclusion compound as claimed in claim 3, wherein the stirring time is 1-4 h.
7. The method for preparing the niclosamide ethanolamine salt hydroxypropyl- β -cyclodextrin inclusion compound according to claim 3, wherein the inclusion temperature is 45 ℃, and the concentration of hydroxypropyl- β -cyclodextrin solution is 300g/L, and the stirring time is 3 h.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111808299A (en) * | 2020-07-02 | 2020-10-23 | 山东滨州智源生物科技有限公司 | Preparation method of hydroxypropyl betacyclodextrin aqueous solution |
| US11045434B1 (en) | 2020-04-01 | 2021-06-29 | UNION therapeutics A/S | Niclosamide formulations for treating disease |
| CN113303473A (en) * | 2021-06-10 | 2021-08-27 | 石河子大学 | Preparation method of apple polyphenol-hydroxypropyl-beta-cyclodextrin inclusion compound |
| WO2021198116A1 (en) * | 2020-04-01 | 2021-10-07 | UNION therapeutics A/S | Formulation |
| WO2021202928A1 (en) * | 2020-04-01 | 2021-10-07 | Board Of Regents, The University Of Texas System | Pharmaceutical compositions of niclosamide |
| WO2021198115A1 (en) * | 2020-04-01 | 2021-10-07 | UNION therapeutics A/S | Treatment |
| WO2024049167A1 (en) * | 2022-09-02 | 2024-03-07 | 주식회사 스카이테라퓨틱스 | Novel salt of niclosamide, molecular aggregate thereof, and pharmaceutical composition containing same |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11045434B1 (en) | 2020-04-01 | 2021-06-29 | UNION therapeutics A/S | Niclosamide formulations for treating disease |
| WO2021198116A1 (en) * | 2020-04-01 | 2021-10-07 | UNION therapeutics A/S | Formulation |
| WO2021202928A1 (en) * | 2020-04-01 | 2021-10-07 | Board Of Regents, The University Of Texas System | Pharmaceutical compositions of niclosamide |
| WO2021198115A1 (en) * | 2020-04-01 | 2021-10-07 | UNION therapeutics A/S | Treatment |
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| CN111808299A (en) * | 2020-07-02 | 2020-10-23 | 山东滨州智源生物科技有限公司 | Preparation method of hydroxypropyl betacyclodextrin aqueous solution |
| CN111808299B (en) * | 2020-07-02 | 2022-05-31 | 山东滨州智源生物科技有限公司 | Preparation method of hydroxypropyl betacyclodextrin aqueous solution |
| CN113303473A (en) * | 2021-06-10 | 2021-08-27 | 石河子大学 | Preparation method of apple polyphenol-hydroxypropyl-beta-cyclodextrin inclusion compound |
| WO2024049167A1 (en) * | 2022-09-02 | 2024-03-07 | 주식회사 스카이테라퓨틱스 | Novel salt of niclosamide, molecular aggregate thereof, and pharmaceutical composition containing same |
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Application publication date: 20200225 |
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