CN111643670A - Energy dual-regulation medicine and preparation method and application thereof - Google Patents

Energy dual-regulation medicine and preparation method and application thereof Download PDF

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Publication number
CN111643670A
CN111643670A CN202010479412.3A CN202010479412A CN111643670A CN 111643670 A CN111643670 A CN 111643670A CN 202010479412 A CN202010479412 A CN 202010479412A CN 111643670 A CN111643670 A CN 111643670A
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energy
respiratory chain
mitochondrial respiratory
glucose uptake
dual
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姜虎林
周天娇
巩月红
温浩
王建华
赵军
李飞
黄张建
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First Affiliated Hospital of Xinjiang Medical University
Xinjiang Medical University
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Xinjiang Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the technical field of preparing medicines for treating echinococcosis, in particular to an energy dual-regulation medicine and a preparation method and application thereof. The invention combines the glucose uptake inhibitor and the mitochondrial respiratory chain blocker to prepare the anti-echinococcosis drug, realizes the energy uptake inhibition of the drug to the insect body, simultaneously realizes the energy metabolism inhibition by the mitochondrial respiratory chain blocker, completely blocks the energy uptake and the metabolic process of the insect body, performs the anti-echinococcosis function in multiple ways, and achieves the effect of improving the anti-echinococcosis treatment.

Description

Energy dual-regulation medicine and preparation method and application thereof
Technical Field
The invention relates to the technical field of preparing medicines for treating echinococcosis, in particular to an energy dual-regulation medicine and a preparation method and application thereof.
Background
Cystic echinococcosis is a serious zoonosis caused by echinococcus granulosus parasitizing in humans. Belonging to the important public health problem in the world. The economic loss of human and livestock caused by echinococcosis in China accounts for about 40 percent of the world and is the first place in the world. The prevention and treatment means of echinococcosis mainly comprise surgical treatment and drug treatment, but the drugs for efficiently treating echinococcosis are still lacked. At present, the world health organization recommends that first-line drugs for treating echinococcosis are benzimidazole drugs, mainly including albendazole and mebendazole. Albendazole inhibits the survival of insect bodies by inhibiting the uptake of glucose and the fumarase system, the generation of ATP. The principle of action of the mebendazole is basically similar to that of albendazole, glucose uptake and utilization by the polypide are inhibited, transport of nutrient substances is blocked, endogenous glycogen of the polypide is depleted, and enzymes required by energy metabolism such as phosphoenolpyruvate carboxylase and the like can be inhibited, so that the inhibition or insecticidal effect is achieved. Although benzimidazoles are the main drugs against echinococcosis, they still suffer from the following two limitations: the medicines mainly inhibit a certain link of energy metabolism, and the cure rate is low; the medicine can inhibit echinococcus granulosus, but does not have the effect of killing echinococcus granulosus, and the toxic reaction of the medicine is easily caused by increasing the dosage. Therefore, the search for new anti-echinococcosis drug targets and drug molecules has important significance for preventing and treating echinococcosis.
Mitochondria are the site where eukaryotes undergo oxidative metabolism, and are the site where sugars, fats, and amino acids are ultimately oxidized to produce energy. Meanwhile, aiming at diseases caused by infection of protozoa such as echinococcosis, mitochondria of the echinococcosis are a potential drug target. Since protozoan mitochondria are widely distinct from mammalian host mitochondria, and mitochondrial energy metabolism is critical for protozoan survival. Therefore, the mitochondrial energy-related enzyme or the compound is taken as the target point of resisting echinococcosis, so that the aims of enhancing the curative effect of resisting echinococcosis and reducing the toxic and side effects of the medicament can be achieved.
Atovaquone (Atovaquone) is an effective anti-insect drug approved by FDA to be on the market, and has low price and small side effect. It acts by inhibiting the parasite's mitochondrial cytochrome bc1 complex (cyt bc 1). And cyt bc1 is a core compound of the mitochondrial respiratory chain, and the aim of inhibiting the energy conversion of mitochondria can be achieved by inhibiting the activity of the core compound. Therefore, atovaquone and other mitochondrial respiratory chain inhibitors are expected to be novel effective therapeutic agents against hydatid.
Disclosure of Invention
The invention provides an energy dual-regulation medicament, a preparation method and application thereof, overcomes the defects of the prior art, and can effectively solve the problems of single action target, poor treatment effect on echinococcosis and large side effect of the existing medicament for treating echinococcosis.
One of the technical schemes of the invention is realized by the following measures: an energy dual-regulation medicine comprises a glucose uptake inhibitor and a mitochondrial respiratory chain blocker, wherein the glucose uptake inhibitor is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole and oxfendazole, and the mitochondrial respiratory chain blocker is one or more of atovaquone, antimycin A, rotenone, piericidin A, amobarbital, alpha-tocopherol succinate, metformin and azoxystrobin.
The following is a further optimization or/and improvement of one of the above-mentioned technical solutions of the invention:
the glucose uptake inhibitor is one or more of albendazole and albendazole sulfoxide.
The mitochondrial respiratory chain blocker is atovaquone.
The second technical scheme of the invention is realized by the following measures: a preparation method of an energy dual-regulation medicine is carried out according to the following steps: after the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are wrapped, adsorbed and coordinated to form nanoparticles, the nanoparticles are loaded to obtain the energy dual-regulation medicament.
The glucose uptake inhibitor and the mitochondrial respiratory chain blocker are coated by one or more than one high polymer materials selected from PLGA-PEG, PLA-PLGA, PEG-PCL, PLGA-PEG-PLGA and F127.
The glucose uptake inhibitor and mitochondrial respiratory chain blocker are coated by using one or more of phospholipid selected from DMPC, DOPC, DSPC and DPPC, cholesterol, and DSPE-PEG 2000.
The glucose uptake inhibitor and mitochondrial respiratory chain blocker described above were loaded by using a sustained-release gel formulation.
The glucose uptake inhibitor and mitochondrial respiratory chain blocker are loaded by using one or more of PLGA-PEG-PLGA, poloxamer, sodium alginate, hyaluronic acid, chitosan, agarose, gelatin, carrageenan, carboxymethyl cellulose, fibrin gel and polyacrylamide gel.
The third technical scheme of the invention is realized by the following measures: an application of a medicine for regulating and controlling energy in preparing the medicines for treating echinococcosis is disclosed.
The invention combines the glucose uptake inhibitor and the mitochondrial respiratory chain blocker for preparing the medicine for treating echinococcosis, can realize the energy uptake inhibition of the medicine to the polypide, simultaneously realizes the energy metabolism inhibition by using the mitochondrial respiratory chain blocker, completely blocks the energy uptake and the metabolic process of the polypide, plays the anti-echinococcosis role in multiple ways, and achieves the effect of improving the anti-echinococcosis treatment.
Drawings
FIG. 1 is a graph showing the particle size distribution of albendazole nanoparticles according to example 10 of the present invention.
FIG. 2 is a graph showing the particle size distribution of the atovaquone nanoparticles of example 11.
FIG. 3 is a graph showing the particle size distribution of the nanoparticle of albendazole-atovaquone in example 12.
FIG. 4 is a graph showing the survival rate of metacercaria of the albendazole nanoparticles of example 13 after treatment of metacercaria.
FIG. 5 is a graph showing the survival rate of metacercaria of example 14 after treatment of metacresol nanoparticles with metacercaria.
FIG. 6 is a graph showing the oxygen consumption inhibition of the metacercaria in example 15, after the metacercaria is treated with the atovaquone nanoparticles.
FIG. 7 is a graph showing the survival rate of metacercaria after the abendazole nanoparticles and the atovaquone nanoparticles of example 16 were mixed in different ratios to treat metacercaria.
Detailed Description
The present invention is not limited by the following examples, and specific embodiments may be determined according to the technical solutions and practical situations of the present invention. The various chemical reagents and chemicals mentioned in the present invention are all well known and commonly used in the art, unless otherwise specified.
The invention is further described below with reference to the following examples:
example 1: the energy dual-regulation medicine comprises a glucose uptake inhibitor and a mitochondrial respiratory chain blocker, wherein the glucose uptake inhibitor is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole and oxfendazole, and the mitochondrial respiratory chain blocker is one or more of atovaquone, antimycin A, rotenone, pulverycin A, amobarbital, alpha-tocopherol succinate, metformin and azoxystrobin.
The glucose uptake inhibitor and the mitochondrial respiratory chain blocker are combined to cooperatively inhibit glucose uptake and energy metabolism transport of the polypide, and the multi-target full-coverage property completely blocks the energy uptake and metabolism process of the polypide, so that the high-efficiency anti-hydatid effect is achieved, the polypide is induced to die, and the high-efficiency anti-hydatid effect is achieved.
Example 2: in the optimization of the above embodiment, the glucose uptake inhibitor is one or more of albendazole and albendazole sulfoxide.
Example 3: as an optimization of the above example, the mitochondrial respiratory chain blocker is atovaquone.
Example 4: the preparation method of the energy dual-regulation medicine is carried out according to the following steps: after the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are wrapped, adsorbed and coordinated to form nanoparticles, the nanoparticles are loaded to obtain the energy dual-regulation medicament.
Example 5: as the optimization of the above example 4, the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are encapsulated by using one or more than one polymer materials of PLGA-PEG, PLA-PLGA, PEG-PCL, PLGA-PEG-PLGA and F127.
Example 6: as optimization of examples 4 and 5 above, the glucose uptake inhibitor and mitochondrial respiratory chain blocker were encapsulated by using one or more phospholipids of DMPC, DOPC, DSPC and DPPC, cholesterol, DSPE-PEG 2000.
Example 7: as an optimization of the above examples 4 and 5 and 6, the glucose uptake inhibitor and mitochondrial respiratory chain blocker were loaded by using a sustained-release gel formulation.
Example 8: as optimization of the above examples 4 and 5 and 6 and 7, the glucose uptake inhibitor and mitochondrial respiratory chain blocker were loaded by using one or more of PLGA-PEG-PLGA, poloxamer, sodium alginate, hyaluronic acid, chitosan, agarose, gelatin, carrageenan, carboxymethyl cellulose, fibrin gel, and polyacrylamide gel.
Example 9: the application of the energy dual-regulation medicine in preparing a medicine for treating echinococcosis.
Example 10: the albendazole nanoparticles are prepared by a reverse titration method. 100 mg of polymer materials PLGA-PEG and 10 mg of albendazole were precisely weighed, dissolved in 1 mL of DMSO, and after the polymer materials were dissolved sufficiently by sonication, the solution was slowly added dropwise to a 5-fold volume of phosphate buffer solution (PBS, 10 mM, pH = 7.4) under stirring using a pipette gun, and after the dropwise addition, the mixture was stirred at room temperature for 20 min. Then, the mixture was centrifuged at 3500 r/min for 5min to remove the unencapsulated drug. The organic phase in PBS was removed using an ultrafiltration tube (molecular weight cut-off 10 KDa) and the albendazole nanoparticles were concentrated. And detecting the particle size distribution of the prepared nanoparticles. The results are shown in fig. 1, and it can be seen from fig. 1 that albendazole can be successfully coated with the polymer material PLGA-PEG to form nanoparticles with uniform particle size.
Example 11: the atovaquone nanoparticles were prepared by reverse titration. 100 mg of polymer materials PLGA-PEG and 10 mg of atovaquone are accurately weighed, dissolved in 1 mL of DMSO, and after being sufficiently dissolved by ultrasonic waves, the solution is slowly dripped into 5-fold volume of phosphate buffer solution (PBS, 10 mM, pH = 7.4) in a stirring state by using a pipette gun, and after the dripping is finished, the solution is stirred at room temperature for 20 min. Then, the mixture was centrifuged at 3500 r/min for 5min to remove the unencapsulated drug. The organic phase in PBS was removed using an ultrafiltration tube (molecular weight cut-off 10 KDa) and the atovaquone nanoparticles were concentrated. And detecting the particle size distribution of the prepared nanoparticles. The result is shown in fig. 2, and it can be known from fig. 2 that atovaquone can be successfully coated by the polymer material PLGA-PEG to form nanoparticles with uniform particle size.
Example 12: the albendazole-atovaquone nano particle is prepared by a reverse titration method. 150 mg of polymer materials PLGA-PEG, 5 mg of albendazole and 10 mg of atovaquone are accurately weighed, dissolved in 1.5 mL of DMSO, and after the polymer materials are fully dissolved by ultrasonic treatment, the solution is slowly dripped into 5-fold volume of phosphate buffer solution (PBS, 10 mM, pH = 7.4) in a stirring state by using a pipette gun, and after the dripping is finished, the solution is stirred for 20 min at room temperature. Then, the mixture was centrifuged at 3500 r/min for 5min to remove the unencapsulated drug. The organic phase in PBS was removed using an ultrafiltration tube (molecular weight cut-off 10 KDa) and the atovaquone nanoparticles were concentrated. And detecting the particle size distribution of the prepared nanoparticles. The results are shown in fig. 3, and it can be seen from fig. 3 that albendazole and atovaquone can be successfully coated with the polymer material PLGA-PEG to form nanoparticles with uniform particle size.
Example 13: the metacercaria was cultured in 24-well plates at a concentration of 2000 per well, and coculture was performed for 5 days using 0, 20, 40, 60, 80, 100. mu.g/mL albendazole nanoparticle culture medium. The new albendazole nanoparticle culture solution was replaced on the third day. On days 1, 2, 3 and 5, 10. mu.L of metacercaria was stained with H & E3 times per well to calculate the survival rate. Three parallel groups are provided for each group. The results are shown in fig. 4, and it can be seen from fig. 4 that the albendazole nanoparticles can inhibit the growth of the metacercaria, and have time dependence and concentration dependence, but the killing effect on the metacercaria is not obvious.
Example 14: the metacercaria was cultured in 24-well plates at a concentration of 2000 per well, and coculture was performed for 5 days using 0, 10, 20, 40, 80, 160. mu.g/mL of atovaquone nanoparticle culture medium. And on the third day, the culture solution containing atovaquone nanoparticles is replaced. On days 1, 2, 3 and 5, 10. mu.L of metacercaria was stained with H & E3 times per well to calculate the survival rate. Three parallel groups are provided for each group. The results are shown in fig. 5, and it can be seen from fig. 5 that the albendazole nanoparticles can significantly inhibit the growth of metacercaria, and have time dependence and concentration dependence.
Example 15: culturing the metacercaria in a penicillin bottle with the diameter of 3 cm at the concentration of 2000 heads per hole, adding culture solution or culture solution containing 50 mu g/mL atovaquone nanoparticles, inserting a probe of an oxygen dissolving instrument below the liquid level, and fixing the device under the condition of mild magnetic stirring at the same speed. And liquid paraffin is used for liquid sealing, so that gas exchange between gas in the culture solution and the atmosphere is avoided, and a completely closed environment is constructed. And recording the change condition of the dissolved oxygen (Dissolvetoxygen) of the culture solution within 360 min after the reading is stable, and calculating the oxygen consumption condition of the metacercaria. The results are shown in FIG. 6, and it can be seen from FIG. 6 that the atovaquone nanoparticles can completely inhibit the consumption of oxygen by the metacercaria, which indicates that the atovaquone has an inhibitory effect on the mitochondrial respiratory chain of the metacercaria.
Example 16: culturing the metacercaria in a 24-well plate at the concentration of 2000 heads per well, fixing the concentration of albendazole nanoparticles to be 25 mu g/mL, and setting the molar ratio of atovaquone to albendazole to be 1: 2; 1: 1; 2: 1; 3: 1; 4: 1; 5: 1, adding atovaquone nanoparticles, and co-culturing the metacercaria for 3 days. On days 1, 2 and 3, 10. mu.L of metacercaria was stained with H & E from each well 3 times to calculate the survival rate. Three parallel holes are provided for each group. The results are shown in fig. 7, and it can be seen from fig. 7 that the albendazole nanoparticle and the atovaquone nanoparticle can show the growth inhibition of the metacercaria under the condition of low concentration, which indicates the feasibility of the combination of the two drugs.
The albendazole serving as the echinococcus resisting drug is preferred clinically at present, however, the albendazole has large toxic and side effects, the atovaquone has low toxic and side effects, and the bioavailability of the two drugs can be improved through the co-inhibition effect of energy metabolism by the combined use of the two drugs, so that the administration dosage is reduced, the toxic and side effects of the drugs are reduced, and the clinical medication compliance of patients is improved. The invention can simultaneously amplify the insecticidal capacities of two medicines, achieves the effect of '1 +1> 2' and can provide a new idea for the clinical treatment of cystic echinococcosis.
In conclusion, the invention combines the glucose uptake inhibitor and the mitochondrial respiratory chain blocker to prepare the medicine for treating echinococcosis, realizes the energy uptake inhibition of the medicine on the polypide, simultaneously realizes the energy metabolism inhibition by the mitochondrial respiratory chain blocker, completely blocks the energy uptake and the metabolic process of the polypide, performs the anti-echinococcosis function in multiple ways, and achieves the effect of improving the anti-echinococcosis treatment. The technical characteristics form an embodiment of the invention, which has strong adaptability and implementation effect, and unnecessary technical characteristics can be increased or decreased according to actual needs to meet the requirements of different situations.

Claims (9)

1. The drug for regulating energy comprises a glucose uptake inhibitor and a mitochondrial respiratory chain blocker, wherein the glucose uptake inhibitor is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole and oxfendazole, and the mitochondrial respiratory chain blocker is one or more of atovaquone, antimycin A, rotenone, piericidin A, amobarbital, alpha-tocopherol succinate, metformin and azoxystrobin.
2. The dual-energy regulating pharmaceutical composition according to claim 1, wherein the glucose uptake inhibitor is one or more of albendazole and albendazole sulfoxide.
3. The dual energy regulating pharmaceutical of claim 1 or 2, wherein the mitochondrial respiratory chain blocker is atovaquone.
4. A method for preparing a dual energy regulating pharmaceutical according to claim 1, 2 or 3, characterized by the following steps: after the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are wrapped, adsorbed and coordinated to form nanoparticles, the nanoparticles are loaded to obtain the energy dual-regulation medicament.
5. The method for preparing an energy dual regulation drug according to claim 4, wherein the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are encapsulated by using one or more polymer materials selected from PLGA-PEG, PLA-PLGA, PEG-PCL, PLGA-PEG-PLGA and F127.
6. The method for preparing an energy dual regulation medicament according to claim 4 or 5, wherein the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are encapsulated by using one or more phospholipids of DMPC, DOPC, DSPC and DPPC, cholesterol, DSPE-PEG 2000.
7. The method for preparing an energy dual regulation medicament according to claim 4, 5 or 6, characterized in that the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are loaded by using a sustained-release gel formulation.
8. The method for preparing a dual-energy regulating pharmaceutical according to claim 4, 5, 6 or 7, wherein the glucose uptake inhibitor and the mitochondrial respiratory chain blocker are loaded by using one or more of PLGA-PEG-PLGA, poloxamer, sodium alginate, hyaluronic acid, chitosan, agarose, gelatin, carrageenan, carboxymethyl cellulose, fibrin gel and polyacrylamide gel.
9. Use of the dual energy modulating pharmaceutical of claim 1 or 2 or 3 in the manufacture of a medicament for the treatment of echinococcosis.
CN202010479412.3A 2020-05-29 2020-05-29 Energy dual-regulation medicine and preparation method and application thereof Pending CN111643670A (en)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
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WO2012153162A1 (en) * 2011-05-12 2012-11-15 Lupin Limited Novel method for preparation of atovaquone
CN105641716A (en) * 2016-01-11 2016-06-08 王思博 Imaging model in small animal living bodies with echinococcus granulosus and construction method thereof
WO2019115511A1 (en) * 2017-12-14 2019-06-20 Basf Se Fungicidal mixture comprising substituted 3-phenyl-5-(trifluoromethyl)-1,2,4-oxadiazoles
CN110623942A (en) * 2019-09-30 2019-12-31 武汉大学 All-trans retinoic acid nano-drug preparation, and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006143A1 (en) * 1998-07-27 2000-02-10 Texas Pharmaceuticals, Inc. Chemically induced intracellular hyperthermia
WO2012153162A1 (en) * 2011-05-12 2012-11-15 Lupin Limited Novel method for preparation of atovaquone
CN105641716A (en) * 2016-01-11 2016-06-08 王思博 Imaging model in small animal living bodies with echinococcus granulosus and construction method thereof
WO2019115511A1 (en) * 2017-12-14 2019-06-20 Basf Se Fungicidal mixture comprising substituted 3-phenyl-5-(trifluoromethyl)-1,2,4-oxadiazoles
CN110623942A (en) * 2019-09-30 2019-12-31 武汉大学 All-trans retinoic acid nano-drug preparation, and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIGEHIRO ENKAI等: ""Mitochondrial complex III in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts"", 《PARASITOLOGY INTERNATIONAL》 *

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