CN111744014B - Photodynamic combination medicine composition and preparation method and application thereof - Google Patents

Photodynamic combination medicine composition and preparation method and application thereof Download PDF

Info

Publication number
CN111744014B
CN111744014B CN202010479494.1A CN202010479494A CN111744014B CN 111744014 B CN111744014 B CN 111744014B CN 202010479494 A CN202010479494 A CN 202010479494A CN 111744014 B CN111744014 B CN 111744014B
Authority
CN
China
Prior art keywords
bag
photodynamic
preparation
albendazole
echinococcosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010479494.1A
Other languages
Chinese (zh)
Other versions
CN111744014A (en
Inventor
姜虎林
巩月红
周天娇
温浩
王建华
赵军
黄张建
李飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
First Affiliated Hospital of Xinjiang Medical University
Xinjiang Medical University
Original Assignee
First Affiliated Hospital of Xinjiang Medical University
Xinjiang Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University filed Critical First Affiliated Hospital of Xinjiang Medical University
Priority to CN202010479494.1A priority Critical patent/CN111744014B/en
Publication of CN111744014A publication Critical patent/CN111744014A/en
Application granted granted Critical
Publication of CN111744014B publication Critical patent/CN111744014B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K31/33—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K47/6921—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • 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
    • A61K47/6951—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 using cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to the technical field of preparation of medicines for treating echinococcosis, and discloses a photodynamic combined medicine composition, a preparation method and application thereof, wherein the photodynamic combined medicine composition comprises a photosensitizer or/and a chemical medicine, the photosensitizer is one or more of chlorin e6, verteporfin, indocyanine green, porphin sodium, 5-aminoketone valeric acid, temoporfin and talaporfin, and the chemical medicine is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole, oxfendazole, artesunate, peganum harmala, tetrandrine and sophora japonica. The invention increases the permeability of the bag worm and the bag worm wall through photodynamic therapy, enables the chemotherapeutic drugs to accumulate in the bag worm and the bag wall, achieves the synergistic treatment effect, reduces the resistance of the bag worm and the bag to the external drugs, improves the curative effect of the anti-bag worm drugs, can greatly reduce the administration dosage and the drug toxic and side effects, and has excellent prospect in the preparation of the drugs for treating the echinococcosis.

Description

Photodynamic combination medicine composition and preparation method and application thereof
Technical Field
The invention relates to the technical field of preparation of medicines for treating echinococcosis, and relates to a photodynamic combined medicine composition, a preparation method and application thereof.
Background
Echinococcosis (Hydatid disease), also known as Echinococcosis, is a parasitic infection of people and livestock caused by the fact that larvae of Echinococcosis are parasitic to human bodies, and is an important public safety problem worldwide. The disease is common in North China, north America, europe, russia and the like. Among them, china mainly prevails in regions such as five northwest provinces, inner Mongolia, tibet and Sichuan, and Xinjiang is a high-frequency region. Echinococcosis seriously endangers human health and hinders the development of animal husbandry, so how to inhibit the echinococcosis and ensure the physical health of people and promote the economic development of animal husbandry has become an important concern in the current society.
The preferred treatment for cystic and follicular echinococcosis is surgical treatment. But medication is the best approach for patients who cannot tolerate surgery or who have lost the opportunity for surgery. The clinical first-line drug for treating echinococcosis is benzimidazole drug. The main components include albendazole and mebendazole. Albendazole is known worldwide to be the best therapeutic drug for treating echinococcosis, and the dosage form of albendazole is an oral tablet. However, the benzimidazole medicine has the problems of single preparation, poor bioavailability, low liver distribution, frequent administration and the like, so that the clinical treatment effect of the echinococcosis is poor. Because the artemia are usually parasitic to the liver, the burden of the liver is increased, the detoxification is reduced, and the toxic and side effects of the medicine are greatly increased by high-dose and frequent administration. Therefore, the bioavailability of benzimidazole drugs is improved, the ability of the drugs to permeate the wall of the bag worm is enhanced, and the increase of the effective concentration in the bag is the primary problem for treating the echinococcosis.
Disclosure of Invention
The invention provides a photodynamic combined drug composition, a preparation method and application thereof, overcomes the defects of the prior art, and can effectively solve the problems of poor clinical medication effect and large toxic and side effects of drugs existing in the prior art.
One of the technical schemes of the invention is realized by the following measures: a photodynamic combination medicine composition comprises a photosensitizer and/or a chemical medicine, wherein the photosensitizer is one or more of chlorin e6, verteporfin, indocyanine green, porphin sodium, 5-aminolevulinic acid, temoporfin and talaporfin, and the chemical medicine is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole, oxfendazole, artesunate, peganum harmala, tetrandrine and sophora moorcroflumilast.
The following are further optimizations and/or improvements to one of the above-described inventive solutions:
the photosensitizer is one or more of chlorin e6 and verteporfin.
The chemical medicine is one or more of albendazole and albendazole sulfoxide.
The second technical scheme of the invention is realized by the following measures: the preparation method of the photodynamic combination medicine composition comprises the following steps: and (3) respectively carrying out cyclodextrin inclusion and solubilization on the photosensitizer or/and the chemical medicine, forming nanoparticles through encapsulation, adsorption and coordination, and then loading by using gel to obtain the photodynamic combined medicine composition.
The following is a further optimization and/or improvement of the second technical scheme of the invention:
the photosensitizer and/or chemical is solubilized by using one or more of polysorbate, tween, polyoxyethylene, and polyoxyethylene-polyoxypropylene copolymer.
The photosensitizer and/or the chemical drug is coated by one or more polymer materials selected from PLGA-PEG, PLA-PLGA, PEG-PCL, PLGA-PEG-PLGA and F127.
The photosensitizer and/or the chemical medicine is loaded by one or more than one of PLGA-PEG-PLGA, poloxamer, sodium alginate, hyaluronic acid, chitosan, agarose, gelatin, carrageenan, carboxymethyl cellulose, fibrin gel and polyacrylamide gel to obtain the composition of the photodynamic combined medicine.
The third technical scheme of the invention is realized by the following measures: application of a photodynamic combination medicine composition in preparing medicines for treating echinococcosis is provided.
The following is a further optimization and/or improvement of the third aspect of the present invention:
the illumination used for the photodynamic therapy is visible light with tissue penetrability of 600nm to 850 nm.
The invention increases the permeability of the bag worm and the bag worm wall and the target accumulation of the chemotherapy medicine in the bag worm and the bag wall through the photodynamic, achieves the synergistic treatment effect, reduces the resistance of the bag worm and the bag to the external medicine, improves the curative effect of the anti-bag worm medicine, can greatly reduce the administration dosage and the toxic and side effect of the medicine, and has excellent prospect in the application of preparing the medicine for treating the bag worm disease.
Drawings
FIG. 1 is a graph showing the fluorescence intensity of the case of the example 11 of the present invention, in which the uptake of the photosensitizer Ce6 is increased with time.
FIG. 2 is a graph showing the survival of the metacercaria treated by photodynamic therapy with photosensitizers of different concentrations alone in example 12 of the present invention.
FIG. 3 is a graph showing the survival of the original cercaria treated with the albendazole nanoparticles alone and the photodynamic therapy of the original cercaria with 10. Mu.g/mL Ce6 followed by the administration of albendazole nanoparticles in example 13 of the present invention.
FIG. 4 is an optical image of the metacercaria after photodynamic therapy according to example 14 of the present invention.
FIG. 5 is a diagram showing the generation of active oxygen in the body of a subject treated with different concentrations of photodynamic therapy using the metacercaria of example 15 of the present invention.
FIG. 6 is an optical image of the bag worm vesicle of example 16 of the present invention after receiving various treatments.
Detailed Description
The present invention is not limited by the following examples, and specific embodiments can be determined according to the technical scheme and practical situations of the present invention. The various chemical reagents and chemicals mentioned in the present invention are all commonly known in the art unless specifically stated otherwise.
The invention is further described below with reference to examples:
example 1: the photodynamic combined medicine composition comprises a photosensitizer and/or a chemical medicine, wherein the photosensitizer is one or more of chlorin e6, verteporfin, indocyanine green, porphin sodium, 5-aminolevulinic acid, temoporfin and talaporfin, and the chemical medicine is one or more of albendazole, albendazole sulfoxide, mebendazole, flubendazole, oxfendazole, artesunate, peganum harmala, hanfangchin A and sophora japonica.
When the composition of the photodynamic combined medicine is used, the combined photodynamic therapy and the echinococcosis-resistant chemical medicine can be adopted, so that the effect of killing the echinococcosis efficiently is achieved.
Photodynamic therapy (Photodynamic therapy, PDT) is a new method for treating diseases with photosensitizers and lasers. The target is irradiated with a specific wavelength to activate the photosensitizing drug accumulated in the target tissue, which initiates a photochemical reaction to destroy the target. Photosensitizers in photodynamic therapy transfer energy to surrounding oxygen to generate active oxygen with killing properties, which reacts with nearby biological macromolecules to produce cytotoxicity which in turn kills the target tissue. Photodynamic therapy has the advantage of enabling accurate and effective treatment with minimal side effects compared to conventional therapies.
Aiming at the problem that the medicine is difficult to enter the bag wall of the bag to reduce the curative effect in the echinococcosis treatment, the invention can realize the combination of the photodynamic and chemical medicines, provides the composition of the photodynamic and chemical medicines for the echinococcosis treatment, can strengthen the capability of the anti-echinococcosis medicine to penetrate through the bag wall of the bag, increase the effective medicine concentration in the bag, damage the bag wall of the bag by using the photodynamic treatment, and increase the accumulation of the chemical medicines in the bag wall of the bag, thereby improving the echinococcosis treatment effect.
In the invention, chlorin e6 is Chlorin e6, ce6 for short, verteporfin is Verteporfin, indocyanine green is ICG, porphin sodium is Porpher sodium, temoporfin is Temoporf, and Talaporfin is Talaporf.
Example 2: as an optimization of the above embodiment, the photosensitizer is one or more of chlorin e6 and verteporfin.
Example 3: as the optimization of the embodiment, the chemical medicine is one or more than one of albendazole and albendazole sulfoxide.
Example 4: the preparation method of the photodynamic combination drug composition comprises the following steps: and (3) respectively carrying out cyclodextrin inclusion and solubilization on the photosensitizer or/and the chemical medicine, forming nanoparticles through wrapping, adsorption and coordination, and then loading by using gel to obtain a photodynamic combined medicine composition, thus obtaining the photodynamic combined medicine composition.
Example 5: as an optimization of the above embodiment, the photosensitizing agent and/or the chemical drug is solubilized by using one or more of polysorbate, tween, polyoxyethylene-polyoxypropylene copolymer.
Example 6: as optimization of the embodiment, the photosensitizer and/or the chemical drug are coated by using one or more polymer materials of PLGA-PEG, PLA-PLGA, PEG-PCL, PLGA-PEG-PLGA and F127.
Example 7: as an optimization of the above embodiments, photosensitizers and/or chemicals were encapsulated by using one or more of phospholipids, cholesterol, DSPE-PEG2000 in DMPC, DOPC, DSPC and DPPC.
Example 8: as an optimization of the above embodiments, the photosensitizer and/or the chemical drug is 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 photodynamic combination medicine composition in preparing medicines for treating echinococcosis is provided.
Example 10: as an optimization of the above embodiment, the illumination used for photodynamic therapy is visible light of 600nm to 850nm with tissue penetrability.
Example 11: a PBS solution of 1 mg/mL chlorin e6 (Ce 6) was prepared. 10 mg of Ce6 solid powder is weighed into a penicillin bottle, 5 mL of PBS solution is added, naOH solution (1M) is dropwise added under magnetic stirring until the Ce6 solid is completely dissolved, then HCl solution (1M) is used for adjusting the pH value of the solution to 7.4, the solution is transferred into a 10 mL volumetric flask, the medicament on the wall of the penicillin bottle is washed by PBS, the washing liquid is transferred into the volumetric flask, and the PBS solution is supplemented to the scale mark of the volumetric flask.
The cercaria were cultured in 24-well plates at a concentration of 2000 per well, and 20. Mu.g/mL Ce6 broth was added per well. After co-treatment of the larvae with Ce6 broth for 2, 4, 8 and 24, h, the broth was removed, the larvae were washed 3 times with PBS, 600 μl of 0.1M NaOH solution was added to each well, and transferred to a 2 mL centrifuge tube, and the larvae were ground 45 s using a grinder. The grinding fluid is centrifuged for 5 min by 10000 r/min, 200 mu L of supernatant is added into a 96-well plate, and the fluorescence intensity of 660 nm under 405 nm excitation light is measured by a multifunctional enzyme-labeled instrument, wherein the fluorescence intensity is the fluorescence intensity of Ce6 ingested by the metacercaria. Each group is provided with 3 parallel holes. As shown in FIG. 1, the results show that the metacercaria can be taken in a large amount of photosensitizers and has time dependence.
Example 12: the cercaria is cultured in 24-well plates at the concentration of 2000 heads per well, and after 2 h times of co-culture with 5, 10, 15 and 20 mug/mL Ce6 culture solution, the plates are washed three times with PBS, replaced with normal culture solution, and subjected to 30 min illumination with 635 nm visible light with the light dose of 5 mW/cm2, and then cultured for 24 h. 10 mu L of the metacercaria were stained with H & E3 times per well, and survival of the metacercaria in the well plate was counted. Three parallel wells were provided for each concentration. As shown in fig. 2, the photodynamic therapy has a certain killing effect on the metacercaria, but the effect is not remarkable as shown in fig. 2.
Example 13: the albendazole nanoparticles were prepared using a thin film dispersion method. 90 mg of PLGA-PEG,10 mg albendazole, was first added to a 50 mL round bottom flask and dissolved in 10 mL acetonitrile. Then, the organic solvent was removed by rotary evaporator at 40℃to form a transparent film. A PBS solution, preheated to 40 ℃ at 2 mL, was added to the flask and sonicated at 40 ℃ for 20 min to disperse the film to form nanoparticles. The resulting solution was centrifuged at 3500 r/min for 5 min to remove unencapsulated drug. The nanoparticles were demulsified using acetonitrile to calculate albendazole drug concentration.
Culturing the original cercaria in 24-well plate at 2000 wells, co-culturing the original cercaria with 10 μg/mL Ce6 culture solution of 2 h, removing the culture solution, washing the original cercaria with PBS three times, replacing with new culture solution, and culturing with 5 mW/cm 2 The 635 nm dose of visible light was illuminated for 30 min. The photodynamic therapy treated metacercaria was then co-cultured with 0, 20, 40, 60, 80, 100 μg/mL albendazole nanoparticles 24 h. Taking 10 mu L of original cercaria for 3 times per hole&E, staining and counting the survival rate. To demonstrate that photodynamic therapy enhances the insecticidal effect of albendazole nanoparticles, in a different manner without photodynamic therapyConcentration albendazole nanoparticle treated group served as control group. Three parallel holes are provided for each group. The results are shown in fig. 3, and it can be seen from fig. 3 that the combination of photodynamic therapy and albendazole can significantly improve the ability of albendazole to kill the protocercaria.
Example 14: the 10. Mu.g/mL Ce6 treated 2H and then irradiated by light were cultured for 24H, and then H & E stained in the well plate, and observed and photographed using an optical microscope, as compared to untreated H & E stained larvae. As shown in FIG. 4, it is clear from FIG. 4 that photodynamic therapy can disrupt the wall integrity of the protocercaria, thereby increasing the drug concentration of albendazole within the protocercaria.
Example 15: the cercaria was cultured in 24-well plates at a concentration of 2000 wells per well, 1.5 h were co-cultured with the cercaria using 0, 5, 10, 15, 20. Mu.g/mL Ce6 broth, and then an active oxygen assay reagent DCFH-DA was added to give a concentration of 10. Mu.M per well. Culturing for 30 min, removing culture solution containing Ce6 and DCFH-DA, washing the original cercaria with PBS three times, and using 5 mW/cm 2 The 635 nm dose of visible light was illuminated for 30 min. Finally, blue light excitation is carried out on the metacercaria in the pore plate by using an inverted fluorescence microscope, and the generation condition of active oxygen in the metacercaria is observed. The brighter the fluorescence indicates more active oxygen is produced. As shown in FIG. 5, the photodynamic therapy can destroy the wall of the metacercaria by generating active oxygen as shown in FIG. 5.
Example 16: the primordial vesicles were incubated in 24 well plates at a concentration of 200 per well, and the vesicles were treated using different methods: 1. no treatment is performed; 2.100 μg/mL free albendazole treatment; 3.100 Treatment of mug/mL albendazole nanoparticles; 4.15 Mu g/mL Ce6 treatment of 2 h followed by 5 mW/cm 2 635 and nm light dose, visible light irradiation for 30 min (hereinafter referred to as photodynamic therapy); 5. treatment with 100 μg/mL free albendazole after photodynamic therapy; 6. after photodynamic therapy, 100. Mu.g/mL albendazole nanoparticles were used. Vesicles were photographed and compared using an optical microscope after drug treatment 24 h. As shown in FIG. 6, it is clear from FIG. 6 that the combination of photodynamic therapy and anti-artemia agent can cause shrinkage of vesicles, and has ideal effect of killing artemiaIs effective in (1).
The invention can realize the combination of photodynamic therapy and echinococcosis-resistant drug therapy in the application of preparing the echinococcosis-resistant drug, has obvious curative effect, easy control and small side effect, can increase the accumulation of the drug in the target, and can lead a small amount of chemotherapeutic drugs to be completely effective. Meanwhile, the drug administration dosage and the toxic and side effects of the drug can be reduced by increasing the bioavailability of the drug, and the compliance of patients is improved.
In conclusion, the invention increases the permeability of the bag worm and the bag wall of the bag worm through photodynamic therapy, so that the chemotherapeutic drugs are efficiently accumulated in the bag worm and the bag wall, the synergistic treatment effect is achieved, the resistance of the bag worm and the bag to external drugs is reduced, the curative effect of the anti-bag worm drugs is improved, the administration dosage and the toxic and side effects of the drugs can be greatly reduced, and the invention has excellent prospect in the application of preparing the drugs for treating the bag worm diseases.
The technical characteristics form the embodiment of the invention, have stronger adaptability and implementation effect, and can increase or decrease unnecessary technical characteristics according to actual needs so as to meet the requirements of different situations.

Claims (4)

1. The photodynamic combination drug composition is characterized by comprising a photosensitizer and a chemical drug, wherein the photosensitizer is chlorin e6, the chemical drug is albendazole nanoparticles, and the composition is used for treating echinococcosis.
2. A process for the preparation of a photodynamic combination composition according to claim 1, characterized in that it is prepared according to the following method: and coating the chemical medicine by PLGA-PEG high polymer material to obtain the photodynamic combination medicine composition.
3. Use of a composition of a photodynamic combination according to claim 1 for the preparation of a medicament for the treatment of echinococcosis.
4. Use according to claim 3, characterized in that the illumination used for photodynamic therapy is visible light with tissue penetration between 600nm and 850 nm.
CN202010479494.1A 2020-05-29 2020-05-29 Photodynamic combination medicine composition and preparation method and application thereof Active CN111744014B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010479494.1A CN111744014B (en) 2020-05-29 2020-05-29 Photodynamic combination medicine composition and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010479494.1A CN111744014B (en) 2020-05-29 2020-05-29 Photodynamic combination medicine composition and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN111744014A CN111744014A (en) 2020-10-09
CN111744014B true CN111744014B (en) 2023-06-06

Family

ID=72674080

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010479494.1A Active CN111744014B (en) 2020-05-29 2020-05-29 Photodynamic combination medicine composition and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111744014B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117295522A (en) * 2021-05-14 2023-12-26 香港大学 Compositions and methods for megalin inhibitors and photodynamic therapy for the treatment of cancer
CN114931563A (en) * 2022-03-17 2022-08-23 吉林大学 Preparation method of hyaluronic acid nanoparticle/verteporfin compound
CN117941691A (en) * 2024-03-14 2024-04-30 山东第二医科大学 Albumin composite nano-particles based on photosensitive effect and application of albumin composite nano-particles as pesticide

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0215534D0 (en) * 2002-07-04 2002-08-14 Ecole Polytech Selective photochemotherapy using oligonucleotide targeting agents
WO2007038201A1 (en) * 2005-09-23 2007-04-05 Bioenvision, Inc. Methylene blue therapy of parasitic infections
US10925963B2 (en) * 2015-06-22 2021-02-23 Washington University Combination artemisinin and chemiluminescent photodynamic therapy and uses therefor
CN107417706B (en) * 2017-08-04 2019-07-16 大连理工大学 With light, the quick active chlorin Artesunate conjugate of sound and the preparation method and application thereof
CN108452303A (en) * 2018-03-06 2018-08-28 中国药科大学 It is a kind of to carry double medicine nanometer formulations and preparation method thereof
CN108635581A (en) * 2018-05-23 2018-10-12 昆药集团股份有限公司 A kind of composition and its application in the drug for preparing treatment tumour

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Breaking-then-curing strategy for efficient cystic echinococcosis therapy;Tianjiao Zhou等;Chinese Chemical Letters;第33卷;2949-2953 *

Also Published As

Publication number Publication date
CN111744014A (en) 2020-10-09

Similar Documents

Publication Publication Date Title
CN111744014B (en) Photodynamic combination medicine composition and preparation method and application thereof
US11331387B2 (en) Self-assembled drug-loading system and preparation method therefor
EP2464384B1 (en) Salt of a photosensitizing agent for use in photochemical internalization
CN108452303A (en) It is a kind of to carry double medicine nanometer formulations and preparation method thereof
Zeng et al. Ultra-thin metal–organic framework nanosheets for chemo-photodynamic synergistic therapy
WO2022077830A1 (en) Use of artemisinin and derivative thereof in preparation of sensitizer for thermodynamic therapy
Yu et al. Near-infrared photoactivatable semiconducting polymer nanocomplexes with bispecific metabolism interventions for enhanced cancer immunotherapy
CN113350503B (en) Carrier-free hybrid nano assembly and preparation method and application thereof
CN113559064B (en) Novel self-oxygen-supply liposome nanoparticle and preparation method and application thereof
CN112933045A (en) Co-loaded dihydroartemisinin/chloroquine phosphate double-sensitive nano preparation and preparation method thereof
CN114191550A (en) Oxygen-carrying nano photosensitive preparation and preparation method and application thereof
CN110448699A (en) The neoplastic cell nuclei targeted medicament carrying nano particle and preparation method of seven methine Hua Jingsu class dyestuffs are modified comprising functional polypeptide
CN113648401A (en) Hybrid nano assembly for protease inhibition sensitization photodynamic therapy and preparation and application thereof
US11021496B2 (en) Mesoporous organosilica nanoparticles, production method thereof and uses of same
CN110882218B (en) Liposome composition and preparation and application thereof
CN113633784B (en) Hybrid nano-assembly for heat shock protein inhibition sensitization photothermal therapy and preparation and application thereof
CN106606783A (en) Drug delivery system for targeting co-delivery of photosensitizer and chemotherapeutic drug
CN113384698B (en) Self-assembled nano-medicament for synergetic chemotherapy/acousto-photodynamic therapy and application thereof
CN108578697A (en) A kind of preparation method of chlorin e 6 and ferroso-ferric oxide composite nanoparticle
CN113827553A (en) Zinc phthalocyanine in-situ gel for intratumoral injection administration for tumor photodynamic therapy and preparation method thereof
CN113797336A (en) Arginine-small peptide compound and photosensitizer co-assembled nanoparticle and preparation method and application thereof
CN107970226B (en) Nano-carrier medicine and preparation method and application thereof
CN115381940A (en) Target tumor radiotherapy sensitizer and preparation method thereof
CN109806394B (en) Mesoporous silica drug delivery system and application thereof
CN110124033B (en) Liposome with photodynamic action and preparation and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant