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9-nitrocamptothecin-cyclodextrin inclusion compound, its preparation method and pharmaceutical composition containing the inclusion compound

A technology of cyclodextrin inclusion complex and nitrocamptothecin, which can be used in drug combinations, medical preparations containing active ingredients, antitumor drugs, etc., can solve problems such as low bioavailability and poor solubility of 9-NC , to achieve the effect of improving dissolution, solubility and significant sustained release.

Inactive Publication Date: 2016-02-24
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the technical problems of poor solubility and low bioavailability of 9-NC in the existing preparation technology, the present invention provides 9-nitrocamptothecin-cyclodextrin inclusion compound, the purpose of which is to improve the water solubility of 9-NC, It can be developed into a liquid preparation to meet different clinical needs; at the same time, it can also improve the in vivo absorption of 9-NC solid preparation and increase its bioavailability

Method used

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  • 9-nitrocamptothecin-cyclodextrin inclusion compound, its preparation method and pharmaceutical composition containing the inclusion compound
  • 9-nitrocamptothecin-cyclodextrin inclusion compound, its preparation method and pharmaceutical composition containing the inclusion compound
  • 9-nitrocamptothecin-cyclodextrin inclusion compound, its preparation method and pharmaceutical composition containing the inclusion compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19-N

[0032] Phase solubility curve experiment of embodiment 19-NC and hydroxypropyl-β-cyclodextrin (HP-β-CD)

[0033] Different amounts of HP-β-CD were dissolved in 3mL PBS (pH 5.0), prepared into a series of HP-β-CD solutions with a concentration, placed in stoppered test tubes, and excess 9-NC was added to each tube, respectively at 25 ℃, 37℃, 60℃ constant temperature water bath shake for 48h, take the suspension, centrifuge at 12000rpm for 10min, take the supernatant, measure the absorbance value, and calculate the concentration. Taking the concentration of 9-NC (mmol / L) as the ordinate and the concentration of HP-β-CD (mmol / L) as the abscissa, draw the equilibrium phase solubility curves at 25°C, 37°C, and 60°C, and the results are shown in the table 1.

[0034] Table 1 Phase solubility curves at different temperatures

[0035] Table 1Phasesolubilitycurveunderdifferenttemperature

[0036]

[0037] It can be seen from Table 1 that the phase solubility curves are all linear...

Embodiment 2

[0038] Example 2 Primary screening of 9-NC: HP-β-CD molecular molar ratio: preparation of 9-nitrocamptothecin-cyclodextrin inclusion compound, the steps are as follows:

[0039] 1) 9-NC was made into 10ml of saturated acetone solution, and 13 parts were prepared, that is, 14.9mg of 9-NC in each part was dissolved in 10ml of acetone solution, and the amount of 9-NC was 0.03788mmol;

[0040] 2) According to the 9-NC:HP-β-CD molecular molar ratio of 1:30, 50, 60, 80, 100, 110, 120, 130, 140, 150, 160, 180, 200, weigh the cyclodextrin amount, and were dissolved in 5ml of water to make a cyclodextrin solution;

[0041] 3) Slowly add 13 parts of 9-NC saturated acetone solution dropwise to 13 parts of cyclodextrin solutions with different cyclodextrin concentrations, and magnetically stir at 60°C until the acetone is completely volatilized to obtain a suspension;

[0042] 4) Centrifuge the prepared suspension at 2000 r.p.m for 10 min, take the supernatant and freeze-dry to obtain 9-...

Embodiment 3

[0048] Embodiment 3 Orthogonal experiments optimize the best preparation process parameters

[0049] By the results obtained in Example 2, further use the orthogonal experiment design to optimize the inclusion process, to influence factors: inclusion ratio (A) of medicine and HP-β-CD, inclusion time (B) and HP-β-CD The aqueous solution concentration (C) was investigated. With L9(3 4 ) Orthogonal table arrangement experiment, the inclusion process is optimized with the drug content of 9-NC in the finished inclusion compound as the investigation index. See Table 2 for the level table of each factor, and Table 3 for the results.

[0050] Table 2 Factors and levels of orthogonal experiment

[0051] Table 2 Factors and levels so for thogonal test

[0052]

[0053] Table 3 Orthogonal test results

[0054] Table 3 The programs and results so for thogonal test

[0055]

[0056] Orthogonal test results show that the best inclusion process is A 1 B 2 C 3 , ie drug: HP-β-C...

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Abstract

The invention provides a 9-nitrocamptothecin (NC)-cyclodextrin inclusion compound aiming at the technical problems of poor solubility and low bioavailability of 9-nitrocamptothecin in the prior art. The 9-NC-cyclodextrin inclusion compound comprises an active ingredient 9-NC of which the molecular mole ratio is 1:(30-200), an inclusion agent beta-CD or a derivant thereof. A concrete preparation method comprises the following steps: dropwise adding a 9-NC-acetone saturated solution to a CD solution; magnetically stirring at 25-60 DEG C until acetone completely volatilizes; taking supernate to carry out freeze drying after centrifuging the obtained suspension, so as to obtain 9-NC-CD inclusion compound powder. Meanwhile, the invention provides a pharmaceutical composition containing the 9-NC-CD inclusion compound and a pharmaceutically acceptable excipient. Compared with a 9-NC free drug, the solubility of the inclusion compound provided by the invention is increased by over 300 times; meanwhile, the inclusion compound displays higher lactone stability and in-vitro slow-release effect. An X-ray diffraction analysis method and a thermal analysis method indicate that 9-NC in the inclusion compound is completely included, and the reliability of the technology is further verified. Therefore, the inclusion compound can be developed into a liquid preparation, also can improve in vivo absorption of a 9-NC solid preparation, and the bioavailability is improved.

Description

technical field [0001] The invention belongs to the field of western medicines, and in particular relates to a 9-nitrocamptothecin-cyclodextrin inclusion compound, a preparation method thereof and a pharmaceutical composition containing the inclusion compound. Background technique [0002] 9-nitrocamptothecin (9-NC), also known as rubitecan, is a new type of camptothecin derivative developed by Supergen Corporation of the United States. The drug is an ideal antitumor drug. Camptothecin drugs have a balance between the two forms of lactone and carboxylate in both humans and animals (such as figure 1 ), while the lactone type is recognized as the main active form with antitumor effects, and the carboxylate type is the inactive form [1]. [0003] However, the poor solubility, instability and low bioavailability of 9-NC limit the development of its liquid preparations such as injections, and are also the main reasons for hindering its effect; Degrades rapidly in the blood. I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/4745A61P35/00
Inventor 顾薇陈军杨希雄陆姗姗严旭
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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