CN111035617A - A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application - Google Patents

A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application Download PDF

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CN111035617A
CN111035617A CN201811181734.9A CN201811181734A CN111035617A CN 111035617 A CN111035617 A CN 111035617A CN 201811181734 A CN201811181734 A CN 201811181734A CN 111035617 A CN111035617 A CN 111035617A
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artemisinin
micro
drugs
cancer
ethanol
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唐麟
夏庆杰
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Sichuan University
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Sichuan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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Abstract

In order to effectively utilize the artemisinin drugs, improve the solubility of the artemisinin drugs or improve the drug concentration of the artemisinin drugs in target organs so as to better exert curative effect, the invention provides a new dosage form of the multi-molecule micro-inclusion compound loaded with the artemisinin drugs, so as to improve the current clinical application situation of the artemisinin drugs. In the preparation method of the micro-encapsulation compound preparation, the artemisinin medicament is prepared into particles, so that the water solubility of the artemisinin medicament is increased, the preparation process is simple and easy to operate, and the preparation can be stored for a long time and has good stability. The preparation can be used in combination with chemotherapeutic drugs, and has synergistic effect with chemotherapeutic drugs.

Description

A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application
Technical Field
The invention belongs to the technical field of medicament dosage forms and medicament preparation, and particularly relates to an oral liquid and an emulsion preparation loaded with artemisinin medicaments by a multi-molecular micro-encapsulation technology, and a preparation method and application thereof.
Background
The artemisinin compound is a large class of natural products obtained from plants, and is a sesquiterpene lactone drug with a peroxy group. It is extracted from the traditional medicinal plant Artemisia annua L. Artemisia annua, Artemaceae, which was recorded for disease treatment more than 2000 years ago. Chinese scientist yoyo in 1972 for extracting artemisinin for malaria for the first timeThe treatment of diseases. Since the discovery of artemisinin, it has been shown to be effective in a variety of diseases, such as cancer, diabetes, autoimmune diseases, and the like. In the 90 s of the 20 th century, researches show that artemisinin and derivatives thereof (DHA, ART, ARM and ARE) show an anti-tumor effect, and more in vitro and in vivo researches show that the artemisinin and the derivatives thereof can obviously inhibit the growth of tumor cells and have obvious curative effect when entering tumor clinical treatment in livestock and human bodies. Simultaneously, the artemisinin and the chemotherapeutic drugs are used together, so that the curative effect of the chemotherapeutic drugs can be enhanced. Clinical treatment of metastatic breast cancer, colorectal cancer, and the like is currently being seen in clinical trials. Artemisinin (Artemisinin, C)15H22O5) Is insoluble in water, soluble in chloroform, acetone, ethyl acetate and benzene, and soluble in ethanol and diethyl ether. It is unstable to heat and is susceptible to decomposition by moisture, heat and reducing substances. Its low solubility and instability limit the bioavailability of artemisinin. At present, the market has no other effective dosage forms except oral dry powder preparations, and the clinical application of artemisinin drugs such as artemisinin to treat cancers is greatly limited.
Disclosure of Invention
In order to effectively utilize artemisinin drugs, the inventors have made various attempts to improve the solubility or the drug concentration in target organs in order to better exert the therapeutic effect, and finally the inventors of the present invention have made an attempt to provide a new dosage form of loading artemisinin drugs with multi-molecule micro-inclusion complex to improve the current clinical application of artemisinin drugs.
The invention solves the first technical problem of providing the micelle loaded with artemisinin drugs, and tumor cell experiments show that the preparation can inhibit the proliferation of various tumor cells. The new dosage form for loading artemisinin drugs is a micro-inclusion complex which is a micro-inclusion complex prepared by ethanol-polidocanol-urea-glycine-glucose-water and the like and artemisinin drugs. Wherein, the polyhexodiol is a biodegradable high molecular material, and ethanol, urea, glycine, glucose and the like belong to organic reagents. The preparation system can effectively control the effective concentration of the medicine, wherein the biodegradable high molecular material can be automatically degraded. The proportion of the artemisinin drugs and the ethanol-polyhexamethylene glycol-urea-glycine-glucose-water is 10 parts of the artemisinin drugs and 90 parts of the ethanol-polyhexamethylene glycol-urea-glycine-glucose-water.
The micro-inclusion complex can be prepared by the following method:
a, mixing ethanol, polyethylene glycol, urea, glycine, glucose and water according to a certain proportion, dissolving artemisinin drugs in an organic solvent, and uniformly mixing to obtain a clear solution A;
b, removing the organic solvent of the clear solution A to obtain gel B;
and C, injecting the gel B into water (preferably water for injection) to enable the gel B to be in a clear and transparent state, and filtering to obtain the micro-inclusion compound C. D, in the method, the used organic solvent is one or a mixture of more of tert-butyl alcohol, ethyl acetate, acetone, dichloromethane, trifluoroethanol or hexafluoroisopropanol
The micro inclusion complex can be prepared by the following method according to production or laboratory equipment:
a, dissolving artemisinin in an organic solvent, and stirring to obtain a clear liquid A;
removing organic solvents such as ethyl acetate and ethanol, and performing rotary evaporation to obtain transparent micro-inclusion compound;
c, dissolving the micro-inclusion compound by using water for injection and 10% ethanol
The micro-inclusion compound of the artemisinin medicine can be used for treating cancers such as breast cancer, breast cancer metastasis, kidney cancer, colon cancer, liver cancer, stomach cancer, lung cancer, pancreatic cancer, bladder cancer, skin cancer and the like. In the preparation method of the micro-inclusion preparation, the artemisinin medicament is prepared into particles, so that the water solubility of the artemisinin medicament is increased, the preparation process is simple and easy to operate, and the preparation can be stored for a long time and has good stability. The preparation can be used in combination with chemotherapeutic drugs, and has synergistic effect with chemotherapeutic drugs.
Drawings
FIG. 1 is a graph of artemisinin microencapsulation inhibiting the growth of various tumor cells
Figure 2, IC50 values for artemisinin inhibition of tumor cells.
Detailed Description
The reagents used in this experiment were: ethanol, polyethylene glycol, urea, glycine, glucose, polycaprolactone, ethanol and ethyl acetate
The crude drug artemisinin is selected from Artemisinin (ARN), Artesunate (ART), Artemether (ARM), Dihydroartemisinin (DHA) or derivatives thereof. Can be used in one way or in combination. The following functional tests prove that the multi-molecule micro-encapsulated artemisinin-loaded medicine and the preparation method thereof have the beneficial effects. The key point of the invention is that the inventor uses the multi-molecule reagent to improve the drug loading of the micro-capsule core.
Examples
(1) Dissolving 6g of PEG and polycaprolactone powder, and 100 mg of artemisinin in 5ml of ethanol and ethyl acetate organic reagent to obtain a clear solution A;
(2) removing organic reagent from the clear solution A by rotary evaporation to obtain transparent gel
(3) Water for injection containing 10% ethanol was added to the gel, and the gel was made clear and transparent with stirring.
Treating dozens of cancer cells including human lung adenocarcinoma cells (PC-9, NCI-H441), glioma cells (U87, U251), ovarian cancer cells (SKOV 3), liver cancer cells (HepG 2), pancreatic cancer cells (MIAPACA-2), breast cancer cells (mcf-7), lymph cancer cells (Raji), leukemia cells (MOP-13), cervical cancer cells (Hela), colorectal cancer cells (HT 29, CT 26) and human normal liver cells (LO 2), human kidney epithelial cells (HEK 293) by using multi-molecule micro-nuclear loading artemisinin drugs according to different drug concentration gradients (0, 6.25ug/ml,12.5ug/ml, 25ug/ml, 50ug/ml, 0.1mg/ml, 0.2 mg/ml), and finding that the concentration of 40-100ug/ml can obviously inhibit the growth of most tumor cells, for example, 40ug/ml artemisinin can significantly inhibit the growth of pancreatic cancer cells. FIG. 2 shows the IC50 values of artemisinin for inhibition of tumor cells in ug/ml
To our knowledge, the invention discloses the first artemisinin oral preparation for treating various cancers, and promotes the development of combined dosage forms of artemisinin and other drugs for treating cancers.

Claims (2)

1. A multi-molecule micro-inclusion complex loading artemisinin drugs and a preparation method thereof, wherein the micro-inclusion complex is a micro-inclusion complex prepared from ethanol-polidocanol-urea-glycine-glucose-water and the like and artemisinin drugs, the polidocanol is a biodegradable high polymer material, the ethanol, the urea, the glycine, the glucose and the like belong to organic reagents, and the ratio of the artemisinin drugs to the ethanol-polidocanol-urea-glycine-glucose-water is 10 parts of artemisinin drugs and 90 parts of ethanol-polidocanol-urea-glycine-glucose-water; the invention is characterized in that the artemisinin drugs in the market at present have no other effective dosage forms except oral dry powder preparations, which greatly limits the clinical application of the artemisinin drugs such as artemisinin for treating cancers, but the invention is a new dosage form of a multi-molecule micro inclusion compound loaded artemisinin drugs.
2. The microencapsulation composite of claim 1 and the process for preparing the same, wherein the process comprises:
a, mixing ethanol, polyethylene glycol, urea, glycine, glucose and water according to a certain proportion, dissolving artemisinin drugs in an organic solvent, and uniformly mixing to obtain a clear solution A;
b, removing the organic solvent of the clear solution A to obtain gel B;
c, injecting the gel B into water (preferably water for injection) to enable the gel B to be in a clear and transparent state, and filtering to obtain a micro-inclusion compound C;
d, in the method, the used organic solvent is one or a mixture of more of tert-butyl alcohol, ethyl acetate, acetone, dichloromethane, trifluoroethanol or hexafluoroisopropanol
The micro inclusion complex can be prepared by the following method according to production or laboratory equipment:
a, dissolving artemisinin in an organic solvent, and stirring to obtain a clear liquid A;
removing organic solvents such as ethyl acetate and ethanol, and performing rotary evaporation to obtain transparent micro-inclusion compound;
c, dissolving the micro-inclusion compound by using water for injection and 10% ethanol
The micro-encapsulation core of the artemisinin medicine can be used for treating cancers such as breast cancer, breast cancer metastasis, kidney cancer, colon cancer, liver cancer, stomach cancer, lung cancer, pancreatic cancer, bladder cancer, skin cancer and the like.
CN201811181734.9A 2018-10-11 2018-10-11 A method for preparing multi-molecule micro-core-loaded artemisinin (DHA, ARM, ARS) for treating cancer and its application Pending CN111035617A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111978395A (en) * 2020-07-20 2020-11-24 四川大学 Monoclonal antibody against novel coronavirus RBD domain antigen

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101138550A (en) * 2007-09-18 2008-03-12 沈阳药科大学 Mixed glue bundle pharmaceutical preparations produced in combination use of multiple surfactant and processes for their preparation
CN101642448A (en) * 2009-06-29 2010-02-10 中南民族大学 Nano-Artesunate capsule and preparation process thereof
CN102198083A (en) * 2010-05-27 2011-09-28 四川大学 Micelles and freeze-dried preparations of diblock polymer-supported taxane medicines and preparation and use thereof
CN102258467A (en) * 2011-07-06 2011-11-30 西安力邦制药有限公司 Formula and preparation of intravenous injection sustained-release fat emulsion of arteannuin and derivative thereof
CN105367804A (en) * 2015-10-16 2016-03-02 姚俊华 Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer
CN108498485A (en) * 2018-06-14 2018-09-07 沈阳药科大学 The drug carrier system of dihydroartemisinine modification and its application in pharmacy

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101138550A (en) * 2007-09-18 2008-03-12 沈阳药科大学 Mixed glue bundle pharmaceutical preparations produced in combination use of multiple surfactant and processes for their preparation
CN101642448A (en) * 2009-06-29 2010-02-10 中南民族大学 Nano-Artesunate capsule and preparation process thereof
CN102198083A (en) * 2010-05-27 2011-09-28 四川大学 Micelles and freeze-dried preparations of diblock polymer-supported taxane medicines and preparation and use thereof
CN102258467A (en) * 2011-07-06 2011-11-30 西安力邦制药有限公司 Formula and preparation of intravenous injection sustained-release fat emulsion of arteannuin and derivative thereof
CN105367804A (en) * 2015-10-16 2016-03-02 姚俊华 Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer
CN108498485A (en) * 2018-06-14 2018-09-07 沈阳药科大学 The drug carrier system of dihydroartemisinine modification and its application in pharmacy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAMID REZA KHEIRI MANJILI等: "Preparation and Physicochemical Characterization of Biodegradable mPEG-PCL Core-Shell Micelles for Delivery of Artemisinin", 《PHARMACEUTICAL SCIENCES》 *
陆婷等: "高生物利用度的青蒿素类化合物给药***及制剂技术研究进展 ", 《中成药》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111978395A (en) * 2020-07-20 2020-11-24 四川大学 Monoclonal antibody against novel coronavirus RBD domain antigen

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Application publication date: 20200421