CN-121987639-A - Pharmaceutical composition containing atractylenolide, preparation method and application

CN121987639ACN 121987639 ACN121987639 ACN 121987639ACN-121987639-A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and discloses a pharmaceutical composition containing atractylenolide, a preparation method and application thereof, the pharmaceutical composition takes liposome as a carrier and comprises atractylenolide, oxaliplatin, liposome carrier components such as phospholipid, cholesterol and the like and specific auxiliary components. The preparation adopts a film dispersion-ultrasonic homogenization method, the medicine composition of the invention effectively improves the water solubility of the atractylenolide, improves the bioavailability and the preparation stability of the medicine, enhances the anti-tumor curative effect and simultaneously reduces the toxic and side effects related to chemotherapy through the synergistic effect of the atractylenolide and oxaliplatin, can be used for preparing anti-tumor medicines, and provides a novel medicine scheme with high efficiency and low toxicity for tumor treatment.

Inventors

DING HUIQIN
ZHOU LIFEI
Ye Chengcong
LI YANG
CHEN MENGJING

Assignees

浙江中医药大学附属第二医院(浙江省新华医院)

Dates

Publication Date: 20260508
Application Date: 20260224

Claims (10)

1. The medicine composition containing the atractylenolide is characterized by being prepared into a liposome from 1-4 parts of atractylenolide, 0.5-5 parts of oxaliplatin, 60-100 parts of phospholipid, 10-50 parts of cholesterol, 1-5 parts of xylitol-based glucoside and 0.2-0.6 part of 4-guanidylbutyric acid according to the mass ratio.
2. The pharmaceutical composition containing atractylenolide according to claim 1, wherein the atractylenolide is atractylenolide II and atractylenolide III in a mass ratio of 1:1.
3. The atractylenolide-containing pharmaceutical composition according to claim 1, wherein the phospholipid is soybean phospholipid and/or egg yolk lecithin.
4. The pharmaceutical composition containing atractylenolide according to claim 3, wherein the phospholipid is soybean phospholipid and egg yolk lecithin in a mass ratio of 1:1.
5. The atractylenolide-containing pharmaceutical composition according to claim 1, wherein the atractylenolide-containing pharmaceutical composition is formulated into a liposome from 1.5 parts of atractylenolide II, 1.5 parts of atractylenolide III, 3 parts of oxaliplatin, 40 parts of soybean phospholipid, 40 parts of egg yolk lecithin, 30 parts of cholesterol, 2 parts of xylitol-based glucoside, and 0.4 part of 4-guanidinobutyric acid according to a mass ratio.
6. A method for preparing the pharmaceutical composition containing atractylenolide according to claim 1, wherein the preparation method is a film dispersion-ultrasonic homogenization method.
7. The preparation method according to claim 6, characterized in that the preparation method comprises the steps of: pretreatment of raw materials (1) Vacuum drying phospholipid at 60deg.C for 2 hr, weighing the prescription amount of atractylenolide, dissolving in organic solvent to obtain liposoluble medicinal solution, weighing oxaliplatin, xylitol-based glucoside, and 4-guanylbutyric acid, dissolving in pH buffer solution, and ultrasound for 5min to obtain water-soluble medicinal buffer solution, and refrigerating at 4deg.C for use; (2) Lipid film preparation, namely adding phospholipid and cholesterol into the fat-soluble medicine solution, placing the solution into a round bottom flask, stirring until the solution is completely dissolved, and performing reduced pressure rotary evaporation for 30-40min at 40-45 ℃ under 60r/min by using a rotary evaporator to form a uniform transparent lipid film; (3) Hydrating to form primary liposome, namely adding water-soluble medicine buffer solution into a flask containing a lipid film, oscillating and hydrating in a constant-temperature water bath at 37 ℃ and 120r/min for 60min, and shaking once every 15min to form milky primary liposome suspension; (4) Ultrasonic homogenizing to refine particle size, namely transferring the primary liposome suspension into an ultrasonic cell pulverizer, performing ultrasonic treatment for 3s and 5s intermittently under 300W power, performing total ultrasonic treatment for 10-15min, and controlling the total program temperature to be less than or equal to 15 ℃ to obtain liposome suspension with uniform particle size; (5) Filtering, sterilizing and packaging, namely sequentially sterilizing the liposome suspension by using a 0.45 mu m polyether sulfone filter membrane and a 0.22 mu m polyether sulfone filter membrane, and aseptically packaging.
8. The method according to claim 7, wherein the organic solvent is absolute ethanol.
9. The method of claim 7, wherein the pH buffer is PBS buffer having ph=6.0-7.0.
10. The use of the pharmaceutical composition containing atractylenolide according to claim 1, in the preparation of antitumor drugs.

Description

Pharmaceutical composition containing atractylenolide, preparation method and application Technical Field The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing atractylenolide, a preparation method and application thereof. Background Oxaliplatin is used as a clinical common chemotherapeutic medicament for intestinal cancer, belongs to a platinum anti-tumor preparation, plays a remarkable anti-tumor role by inhibiting synthesis and replication of tumor cell DNA, and is widely applied to auxiliary chemotherapy, palliative chemotherapy and novel auxiliary chemotherapy for intestinal cancer. On the one hand, oxaliplatin has strong toxic and side effects, is easy to cause adverse reactions such as peripheral neuropathy, gastrointestinal tract reaction, bone marrow suppression and the like, seriously affects the tolerance of patients, and part of patients are forced to interrupt treatment because of intolerance of the toxic and side effects, on the other hand, the oxaliplatin is easy to cause drug resistance of tumor cells after long-term use, so that the therapeutic effect of chemotherapy is gradually reduced, and the ideal therapeutic effect is difficult to achieve, therefore, a combined administration scheme capable of reducing the toxic and side effects of oxaliplatin and enhancing the anti-tumor therapeutic effect of the oxaliplatin is sought, and the oxaliplatin becomes a research hot spot in the field of intestinal cancer chemotherapy. The atractylenolide is an active ingredient extracted from the traditional Chinese medicinal material atractylenolide, and modern pharmacological research proves that the atractylenolide has certain anti-tumor activity, can play an anti-tumor role by inhibiting tumor cell proliferation, inducing tumor cell apoptosis, inhibiting tumor angiogenesis and other ways, and has good application potential in the treatment of intestinal cancer. However, the atractylenolide has a key technical problem of extremely poor water solubility, so that the atractylenolide has low dissolution speed in vivo and low bioavailability, is difficult to reach effective blood concentration, and greatly limits the clinical application, and meanwhile, when the atractylenolide is singly used, the anti-tumor curative effect is limited, the treatment requirement of middle and late intestinal cancer cannot be met, and the atractylenolide is required to be used in combination with other chemotherapeutics to improve the curative effect. Zhu Zhiguo et al reported that atractylenolide III regulates the effects of interleukin 6/signal transduction and transcriptional activator 3 signaling pathways on oxaliplatin resistance in colorectal cancer cells and explored whether atractylenolide III might have an effect on CRC oxaliplatin resistance by inhibiting IL-6/STAT3 signaling pathways. At present, although clinical attempts are made to combine the active ingredients of the traditional Chinese medicine with chemotherapeutics for treating intestinal cancer, the research on the combined medication of the atractylenolide and oxaliplatin is less, and a mature preparation technology is not formed to solve the problem of poor water solubility of the atractylenolide. The conventional combined administration mode is mainly that two medicaments are independently administered, so that the synergistic anti-tumor effect of the two medicaments cannot be fully exerted, the curative effect is poor due to low bioavailability of the atractylenolide, and the toxic and side effects of oxaliplatin cannot be effectively reduced. The liposome technology is used as a novel drug delivery system, has the advantages of strong targeting, capability of improving the water solubility of the drug, improving the bioavailability of the drug, reducing the toxic and side effects of the drug and the like, and has been widely applied to the research and development of the preparation of the anti-tumor drug. The liposome can wrap the medicine with poor water solubility in the liposome, improve the solubility and stability of the medicine, realize the targeted enrichment of the medicine at the tumor part and reduce the damage of the medicine to normal tissues. However, to date, no technology has been disclosed for combining atractylenolide with oxaliplatin, preparing a pharmaceutical composition by adopting a liposome technology, and applying the pharmaceutical composition to intestinal cancer treatment so as to solve the technical problems of poor water solubility of atractylenolide, strong toxic and side effects of oxaliplatin and insufficient synergistic curative effects of atractylenolide and oxaliplatin. In summary, in the current intestinal cancer treatment, the single administration of oxaliplatin has the defects of strong toxic and side effects and easy generation of drug resistance, and the clinical application of the atractylenolide is limited due to po