Levo-gossypol for treating tumors or cyclodextrin clathrate compound of acetate thereof

A technology of inclusion compound of L-gossypol acetate and cyclodextrin, which is applied in the field of anti-tumor drug composition, and can solve problems such as unsatisfactory stabilization effect, low stabilization effect, and slow drug release.

Active Publication Date: 2011-08-03
山东肽莱生物制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Literature reports show (Wang Qifang, Xiu Rui, Zhao Zhe, Guo Jing, Su Desen. Effects of povidone and polyethylene glycol on inclusion complex of piroxicam-β-cyclodextrin. Journal of Shenyang Pharmaceutical University. 2000, 17(4 ): 240-312.), povidone and polyethylene glycol 4000 can improve the stability and inclusion rate of piroxicam-β-cyclodextrin inclusion compound, but the adopted piroxicam-β-cyclodextrin The preparation method of inclusion complex is grinding method and shaking mixing, and the temperature is room temperature. Studies have shown that its stabilizing effect is low in processes such as freeze-drying or spray-drying of cyclodextrin inclusion compound, and povidone and polyethylene glycol 4000 If the concentration is outside the range of 3-5g / L, there will be problems such as unsatisfactory stability or slow drug release.

Method used

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  • Levo-gossypol for treating tumors or cyclodextrin clathrate compound of acetate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 prepares the cyclodextrin inclusion compound of L-gossypol

[0032] The formula is:

[0033] L-Gossypol 5g

[0034] Macrogol 2000 3.5g

[0035] Hydroxypropyl-β-cyclodextrin (average degree of substitution 5.4) 40.5g

[0036] Proceed as follows:

[0037]1) Add hydroxypropyl-β-cyclodextrin, polyethylene glycol 2000 and L-gossypol to a small amount of absolute ethanol in a prescribed proportion, the amount of absolute ethanol per 1g of L-gossypol is 4ml, then add water to volume , prepared into a solution containing 1g L-gossypol or L-gossypol acetate per 140ml, magnetically stirred at 40°C for 5 hours, divided into vials, and half-tightened;

[0038] 2) freeze-drying:

[0039] a. Pre-freezing: quickly freeze the solution in the vials to -32°C, and keep freezing for 5 hours;

[0040] b. Primary drying: evacuate to 20Pa, then raise the temperature to -8°C at a rate of 8°C / hour, and dry at constant temperature for 6 hours;

[0041] c. Secondary drying: Af...

Embodiment 2

[0043] Embodiment 2 prepares the cyclodextrin inclusion complex of L-gossypol acetate

[0044] The formula is:

[0045] L-Gossypol Acetate 5g

[0046] Macrogol 1500 3.0g

[0047] Hydroxypropyl-β-cyclodextrin (average degree of substitution 5.7) 50g

[0048] Proceed as follows:

[0049] 1) Add hydroxypropyl-β-cyclodextrin, polyethylene glycol 1500 and L-gossypol acetate to a small amount of absolute ethanol in a prescribed proportion, and the amount of absolute ethanol per 1g of L-gossypol acetate is 3ml , then add water to constant volume, prepare a solution containing 1g of gossypol or gossypol acetate per 160ml, magnetically stir at 40°C for 5 hours, pack in vials, and half stopper;

[0050] 2) freeze-drying:

[0051] a. Pre-freezing: quickly freeze the solution in the vials to -40°C, and keep freezing for 5 hours;

[0052] b. Primary drying: evacuate to 40Pa, then raise the temperature to -12°C at a rate of 8°C / hour, and dry at constant temperature for 6 hours;

[00...

Embodiment 3

[0055] Example 3 Preparation of cyclodextrin inclusion compound of L-gossypol acetate

[0056] The formula is:

[0057] L-Gossypol Acetate 5g

[0058] Macrogol 2000 3.0g

[0059] Hydroxypropyl-β-cyclodextrin (average degree of substitution 5.5) 45g

[0060] Proceed as follows:

[0061] 1) Add hydroxypropyl-β-cyclodextrin, polyethylene glycol 2000 and gossypol acetate to a small amount of absolute ethanol in a prescribed proportion, and the amount of absolute ethanol per 1g of gossypol acetate is 4ml , then add water to constant volume, prepare a solution containing 1g L-gossypol or L-gossypol acetate per 180ml, magnetically stir at 40°C for 5 hours, pack in vials, and half stopper;

[0062] 2) freeze-drying:

[0063] a. Pre-freezing: quickly freeze the solution in the vials to -32°C, and keep freezing for 5 hours;

[0064] b. Primary drying: evacuate to 30Pa, then raise the temperature to -12°C at a rate of 8°C / hour, and dry at constant temperature for 6 hours;

[0065]...

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Abstract

The invention discloses levo-gossypol for treating tumors or a cyclodextrin clathrate compound of an acetate thereof, which consists of levo-gossypol or a levo-gossypol acetate, polyethylene glycol and hydroxypropyl-beta-cyclodextrin, wherein the polyethylene glycol is one of polyethylene glycol 1500 or polyethylene glycol 2000; a mass ratio of the levo-gossypol or the levo-gossypol acetate to the polyethylene glycol is 1:(0.3-1.2); the average substitution degree of the hydroxypropyl-beta-cyclodextrin is between 4.6 and 6.5; and a mass ratio of the levo-gossypol or the levo-gossypol acetate to the hydroxypropyl-beta-cyclodextrin is 1:(7.0-12.0). The levo-gossypol for treating the tumors or the cyclodextrin clathrate compound of the acetate thereof has the advantages of high bioavailability and stability, large medicine carrying amount and the like.

Description

technical field [0001] The invention relates to an antitumor pharmaceutical composition, in particular to a cyclodextrin inclusion compound of L-gossypol and acetate. Background technique [0002] Gossypol, CAS No. 303-45-7, is a yellow phenolic compound consisting of two optical isomers, L-gossypol and D-gossypol. Natural gossypol exists in the seeds, leaves, stems and roots of the Malvaceae cotton plant. [0003] Gossypol is known for its spermicidal properties and can be used as a male birth control. At present, gossypol acetate oral preparations have been marketed as male contraceptives or for the treatment of gynecological diseases, including endometriosis, menorrhagia or disorders. Chinese patent 200510022777.9 (applicant: Shenyang Pharmaceutical University, publication number CN1827117, date of authorization announcement: December 16, 2009) discloses a gossypol acetate slow-release tablet for treating gynecological diseases. Release materials to form sustained-rele...

Claims

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Application Information

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IPC IPC(8): A61K31/11A61K47/34A61K47/40A61K9/48A61K9/19A61P35/00A61K47/10
Inventor 厉保秋
Owner 山东肽莱生物制药有限公司
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