CN108283728A - A kind of pH responsive types self-regulated drug release tumor embolism microballoon and preparation method thereof - Google Patents

A kind of pH responsive types self-regulated drug release tumor embolism microballoon and preparation method thereof Download PDF

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CN108283728A
CN108283728A CN201810109478.6A CN201810109478A CN108283728A CN 108283728 A CN108283728 A CN 108283728A CN 201810109478 A CN201810109478 A CN 201810109478A CN 108283728 A CN108283728 A CN 108283728A
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microballoon
tumor
drug
parts
embolism
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CN108283728B (en
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陶秀梅
冷鸿飞
陈鹏
徐小雨
刘培岩
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BEIJING NUOKANGDA PHARMACEUTICAL Co Ltd
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BEIJING NUOKANGDA PHARMACEUTICAL Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • 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
    • A61K9/1611—Inorganic compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/1635—Organic macromolecular compounds 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
    • A61K9/14—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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Abstract

The present invention provides a kind of pH sensitivities self-regulated drug release tumor embolism microballoons and preparation method thereof, which includes pH sensitive compounds and tumor microenvironment conditioning agent.PH sensitive compounds are prepared into prepolymer by the present invention, after being mixed with tumor microenvironment conditioning agent, sodium alginate and drug, are added in atoleine, are sufficiently stirred and are prepared into interpenetrating net polymer microballoon.Tumor embolism microballoon provided by the invention can realize that pH sensitivity self-regulateds release the drug, and adjust the acidic environment on cancerous tissue cell periphery to inhibit the reproduction and transfer of cancer cell, be conducive to oncotherapy, the application prospect with wide antitumor embolism chemical therapeutic.

Description

A kind of pH responsive types self-regulated drug release tumor embolism microballoon and preparation method thereof
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of tumor embolism microballoon and preparation method thereof, and in particular to a kind of The tumor embolism microballoon and preparation method thereof of pH responsive type self-regulateds drug release.
Background technology
According to the newest commentary of the World Health Organization, tumour is the second-biggest-in-the-world cause of the death, annual at present to increase 1000 newly Ten thousand cancer patients, have seriously threatened human health.Modern medicine is often with modes such as tumor eradication operation, chemotherapy, radiotherapies to tumour Patient treats, but these traditional treatment means effects are limited, and toxic side effect is apparent.
Arterial embolization developed in recent years is a kind of important interventional therapeutic technique, has been applied at present various The Arterial embolization and palliative therapy of solid tumor, internal organs bleeding, vascular malformation, internal medicine devisceration etc..TACE is (through leading Pipe Chemoembolization art) traditional chemotherapy is compared, it is safe and effective, with obvious effects, there is apparent advantage, it has also become tumour One of most important technology of interventional treatment.
Tumour blood supply can not only be blocked by carrying medicine embolism microball so that tumour lacks necessary nutrient, moreover it is possible to reinforce drug pair The lethality of tumour and the system toxicity for reducing drug, such as DC bead, HepaSphere in the market.In addition, patent CN 105816920 A are modified sodium alginate and introduce sulfonic group as load medicine group；101536986 A of patent CN are disclosed A kind of preparation of the sodium alginate micro ball of load Sorafenib.But the sodium alginate and other polymeric acceptor drift bolts announced at present In the technology of preparing for filling in microballoon, the drug of load is mostly to load medicine by electrostatic interaction with the negatively charged group on microballoon Object or physically trapping carrying medicament.The drug of such embolism microball load is set at embolism position with the degradation or ion of microballoon It changes and gradually discharges, the release of drug is uncontrollable；In addition, in order to increase drugloading rate, these embolism materials contain carboxylic mostly The acidic-groups such as base, sulfonic group, further reduced the pH value at embolism position while embolism, and formation is easy to propagation of cancer cells Environment, be unfavorable for the recovery of human body.
PH value around human normal cell is 7.35~7.45, meta-alkalescence, and the pH value of carcinoma cells be 6.85~ 6.95 slant acidity.If human body fluid is chronically at acidic environment, it is easy to obtain cancer, the more lower more suitable cancer of the pH value of body fluid The survival and development of cell, and the lower cancer cell of body fluid pH value of histoorgan is easy for being transferred to the organ.Meanwhile cancer cell A kind of toxin of entitled L50 can be discharged, it is a kind of highly acid substance, can destroy the acid-base balance of human body fluid, and attack is internal Immunocyte.In addition, either using radiotherapy or chemotherapy means when treatment tumour, can also be killed while killing cancer cell Normal cell, while also will produce a large amount of acidic materials --- oxygen radical causes internal pH value to decline, and makes the immune of human body Function reduces, and new cancer cell is in such a case again with breeding.According to the environment of tumour subacidity, can prepare with acid-sensitive The antitumor drug of sense realizes the targeted therapy of tumour medicine.
104758945 A of patent CN disclose a kind of preparation method of the thrombolytic drug targeted nano gel of pH responses, lead to It crosses and prepares thrombolytic drug and oxidized dextran by the imine linkage of pH sensitivities is covalently attached, but system only can be used as Thrombolytic Drugs Object carrier for the conveying of protein or peptide medicament, and is only limitted to the plasminogen activator class of lysine amino residue Drug.104208704 A of patent discloses a kind of carbon nanotube-targeted preparation method for passing medicine body system of pH sensitivities, poly- by shell Drug delivery tumour cell is promoted drug in the tumour cell ring of low pH by the double action of the modification of sugar and RGD targeting guidings Release in border.But carbon nanotube cannot degrade, residual can increase the burden of patient in vivo.
Invention content
To overcome disadvantage of the existing technology, present invention introduces pH sensitive materials, realize the pH sensitivities of embolism microball certainly Drug release is adjusted, for tumour cell region intelligent medicine releasing, avoids or mitigate the damage of normal tissue；Tumor microenvironment is added simultaneously Conditioning agent is conducive to the highly acid substance for neutralizing cancerous tissue periphery and its release, adjusts the acyclic acidic on cancerous tissue cell periphery It is ruled by law in intervention to inhibit the reproduction and transfer of cancer cell and treats tumor area with bright application prospect in border.
The present invention provides a kind of pH responsive types self-regulated drug release tumor embolism microballoon, and the tumor embolism microballoon includes pH sensitive Compound and tumor microenvironment conditioning agent.
Further, the tumor embolism microballoon includes the pH sensitive compounds and 0.5-6 parts by weight of 30-50 parts by weight Tumor microenvironment conditioning agent.
Further, the pH sensitive compounds are selected from N, Phenhenzamine methacrylate or N, N- diethylamino One or both of ethylmethyl acrylate.
The tumor microenvironment conditioning agent is selected from arginine, lysine, histidine, chitosan, β-TCP, NaHCO3In It is one or more.
Further, the tumor embolism microballoon also include the sodium alginates of 35-60 parts by weight, 50-300 parts by weight it is anti- Other auxiliary agents of tumour medicine, the crosslinking agent of 8-16 parts by weight and 5.501-15.05 parts by weight.
Further, the sodium alginate viscosity is 100-600mpas.
The crosslinking agent is one or more in calcium chloride, magnesium chloride, barium chloride, preferably calcium chloride.
The antitumor drug is selected from：Adriamycin, Irinotecan, topotecan, hydroxycamptothecin, epirubicin, cis-platinum, Carboplatin, oxalic acid platinum, oxaliplatin, mustargen, Chlorambucil, cyclophosphamide, ifosfamide, melphalan, phosphinothioylidynetrisaziridine, Ka Mosi Spit of fland, Semustine, busulfan, mitomycin, methotrexate (MTX), pemetrexed, 5-FU, FT-207, capecitabine, 6- sulfydryls are fast Purine, 6-TG, hydroxycarbamide, cytarabine, gemcitabine, actinomycin D, daunorubicin, Epi-ADM, aclacinomycin, radiance Mycin, taxol, docetaxel, vinblastine, navelbine, Podophyllum emodi var chinense bases, homoharringtonine, L-Asparaginasum, Tamoxifen, Toremifene, Exemestane, Aminoglutethimide, Formestane, Letrozole, Anastrozole, medroxyprogesterone acetate, first Progesterone, Methyltestosterone, testosterone propionate, diethylstilbestrol, fluorine its ammonia, Goserelin, one kind in leuprorelin acetate or more Kind.
Further, the antitumor drug in doxorubicin, cyclophosphamide, cyclophosphamide, Exemestane one Kind is a variety of.
Further, other described auxiliary agents include：5-10 parts of degree of polymerization conditioning agents, 0.5-5 parts of acrylic crosslinking agents and 0.001-0.05 parts of catalyst.
Further, the one kind or two of the degree of polymerization conditioning agent in hydroxyethyl methacrylate and acrylamide Kind.
The acrylic crosslinking agent is selected from：N, N '-methylene-bisacrylamide, diacrylate -1,4- butanediol esters, diformazan One or more of base acrylic acid glycol ester, triallyl cyanurate, preferably N, N '-methylene-bisacrylamides.
The catalyst is selected from least one of ammonium persulfate-sodium bisulfite, potassium peroxydisulfate-tetramethylethylenediamine, Preferably ammonium sulfate-sodium hydrogensulfite.
Further, the preparation method of pH responsive type self-regulateds drug release tumor embolism microballoon is prepared using following step It obtains：
(1) in deionized water by sodium alginate dissolving, sodium alginate soln is obtained；
(2) pH sensitive compounds, degree of polymerization conditioning agent and acrylic crosslinking agent are dissolved in water, are caused with catalyst, Prepare prepolymer；
(3) prepolymer and the dissolving of tumor microenvironment conditioning agent form solution in deionized water, and it is molten that sodium alginate is added Liquid and antitumor drug are uniformly mixed；
(4) W/O systems (water-in-oil system) are prepared with emulsion process, sodium alginate cross-linking agent is added, freeze-drying prepares pH Responsive type self-regulated drug release embolism microball.
Beneficial effects of the present invention are：
1. the present invention introduces pH sensitive materials when preparing embolism microball, make the microballoon in high ph-values, polymer gel Amino does not dissociate, and gel is relatively compact non-swelling, and drug is wrapped in wherein.With the reduction of pH, amino group dissociation, charge is close Degree increases, and polymer swelling realizes pH value-sensitivity self-regulated of embolism microball to be wrapped in the drug release inside microballoon Drug release.
2. present invention introduces tumor microenvironment conditioning agent, the highly acid object of cancerous tissue periphery and its release can be neutralized Matter, in addition under the double action of embolism and drug therapy, can also by adjust the acidic environment on cancerous tissue cell periphery to The reproduction and transfer for inhibiting cancer cell, effectively improve influence of the acidic-group of embolism materials to embolism position pH value, favorably In Rehabilitation.
3. the structure of the interpenetrating network system of acrylate and sodium alginate, improves the intensity of embolism microball, increases The elasticity of microballoon avoids and the disadvantages such as intensity is low that sodium alginate prepares microballoon is used alone.
Description of the drawings
Fig. 1 is the liver after the tumor embolism microspheres in treating lotus knurl rabbit 7d prepared using embodiment 3 under an optical microscope Tumor tissues
Fig. 2 is the liver after the tumor embolism microspheres in treating lotus knurl rabbit 7d prepared using comparative example 2 under an optical microscope Tumor tissues
Specific implementation mode
Tumor embolism microballoon is released in embodiment 1pH sensitivity self-regulateds
It includes following components that tumor embolism microballoon is released in pH sensitivity self-regulateds：N, 30 parts of Phenhenzamine methacrylate, 5 parts of hydroxyethyl methacrylate, N, 1 part of N '-methylene-bisacrylamides, 0.05 part of ammonium persulfate-sodium bisulfite, alginic acid 60 parts, 12 parts 50 parts of sodium, 1 part of lysine, azithromycin calcium chloride.
The specific preparation method of tumor embolism microballoon is released in the pH sensitivities self-regulated：
(1) preparation of pH sensitivities prepolymer
By N, 30 parts of Phenhenzamine methacrylate, 5 parts of hydroxyethyl methacrylate are dissolved in 300ml deionizations In water, 1 part of N is added, N '-methylene-bisacrylamides add 0.05 part of ammonium persulfate-sodium bisulfite as cross-linking reagent, Stirring and dissolving is simultaneously uniformly mixed, and heating water bath is warming up to 40 DEG C, is reacted 5 hours, and viscosity flow shape prepolymer is formed, and the prepolymer is molten Liquid is added dropwise in the tertiary ethereal solution of first and precipitates, and by dissolving-reprecipitation repeatedly, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate (SA) solution
The sodium alginate that 50 parts of viscosity are 400mpas is dissolved in 1L deionized waters, mechanical agitation is uniform to being formed Solution.
(3) polymer blend solution is prepared
The Solutions Solution that acrylic ester prepolymer and 1 part of lysine dissolving are formed to 1.5wt% in deionized water, will be pre- Copolymer solution, SA solution and 60 parts of Doxorubicin solution mixing, stir 3 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier that 1wt%span-80 is added in 2000 parts of atoleines, and high-speed stirred 500r/min stirs 10min, Then the blend solution of acrylate prepolymer body and SA are added in atoleine, 50r/min is stirred 1 hour and formed stabilization Calcium chloride solution (12 parts of calcium chloride are dissolved in 35 parts of water) is then slowly dropped in W/O systems by W/O systems, and stirring crosslinking is anti- 2h is answered to prepare microballoon, 1000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release embolism microball processed.
Tumor embolism microballoon is released in 2 pH sensitivity self-regulateds of embodiment
It includes following components that tumor embolism microballoon is released in pH sensitivity self-regulateds：N, 50 parts of Phenhenzamine methacrylate, 7 parts of hydroxyethyl methacrylate, N, 0.5 part of N '-methylene-bisacrylamides, 0.001 part of ammonium persulfate-sodium bisulfite, sea 200 parts, 16 parts 60 parts of mosanom, 6 parts of chitosan, Carmustine calcium chloride.
The specific preparation method of tumor embolism microballoon is released in the pH sensitivities self-regulated：
(1) preparation of pH sensitivities prepolymer
By N, 50 parts of Phenhenzamine methacrylate, 7 parts of hydroxyethyl methacrylate are dissolved in 350ml deionizations In water, 0.5 part of N is added, N '-methylene-bisacrylamides add 0.001 part of ammonium persulfate-bisulfite as cross-linking reagent Sodium, stirring and dissolving are simultaneously uniformly mixed, and heating water bath is warming up to 40 DEG C, are reacted 4 hours, viscosity flow shape prepolymer are formed, by the pre-polymerization Object solution is added dropwise in the tertiary ethereal solution of first and precipitates, and by dissolving-reprecipitation repeatedly, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate (SA) solution
The sodium alginate that 60 parts of viscosity are 200mpas is dissolved in 1L deionized waters, mechanical agitation is uniform to being formed Solution.
(3) polymer blend solution is prepared
The Solutions Solution that acrylic ester prepolymer and 6 parts of chitosan dissolvings are formed to 3wt% in deionized water, by pre-polymerization Object solution, SA solution and 200 parts of Carmustine mixing, stir 3 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier, high-speed stirred 2000r/min stirrings that 2wt%span-80 is added in 3000 parts of atoleines Then the blend solution of acrylate prepolymer body and SA are added in atoleine by 10min, 100r/min stirs 2 hours shapes At stable W/O systems, then calcium chloride solution (16 parts of calcium chloride are dissolved in 50 parts of water) is slowly dropped in W/O systems, is stirred It mixes cross-linking reaction 0.5h and prepares microballoon, 2000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release processed Embolism microball.
Tumor embolism microballoon is released in 3 pH sensitivity self-regulateds of embodiment
It includes following components that tumor embolism microballoon is released in pH sensitivity self-regulateds：N, 45 parts of Phenhenzamine methacrylate, 10 parts of hydroxyethyl methacrylate, N, 5 parts of N '-methylene-bisacrylamides, 0.008 part of ammonium persulfate-sodium bisulfite, seaweed 35 parts of sour sodium, NaHCO350 parts, 8 parts 0.5 part, cyclophosphamide calcium chloride.
The specific preparation method of tumor embolism microballoon is released in the pH sensitivities self-regulated：
(1) preparation of pH sensitivities prepolymer:
By N, 45 parts of Phenhenzamine methacrylate, 10 parts of hydroxyethyl methacrylate are dissolved in 500ml deionizations In water, 5 parts of N are added, N '-methylene-bisacrylamides add 0.008 part of ammonium persulfate-sodium bisulfite as cross-linking reagent, Stirring and dissolving is simultaneously uniformly mixed, and heating water bath is warming up to 40 DEG C, is reacted 5 hours, and viscosity flow shape prepolymer is formed, and the prepolymer is molten Liquid is added dropwise in the tertiary ethereal solution of first and precipitates, and by dissolving-reprecipitation repeatedly, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate soln
The sodium alginate that 35 parts of viscosity are 600mpas is dissolved in 700ml deionized waters, mechanical agitation is equal to being formed Even solution.
(3) polymer blend solution is prepared
By acrylic ester prepolymer and 0.5 part of NaHCO3Dissolving forms the Solutions Solution of 3wt% in deionized water, will be pre- Copolymer solution, SA solution and 50 parts of cyclophosphamide mixing, stir 5 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier, high-speed stirred 1000r/min stirrings that 1wt%span-80 is added in 3600 parts of atoleines Then the blend solution of acrylate prepolymer body and SA are added in atoleine by 10min, 300r/min stirs 2 hours shapes At stable W/O systems, then calcium chloride solution (8 parts of calcium chloride are dissolved in 25 parts of water) is slowly dropped in W/O systems, is stirred Microballoon is prepared after cross-linking reaction 1h, 1000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release bolt processed Fill in microballoon.
Tumor embolism microballoon is released in 4 pH sensitivity self-regulateds of embodiment
It includes following components that tumor embolism microballoon is released in pH sensitivity self-regulateds：40 parts of N, N- diethyl amino ethyl group methacrylate, 8 parts of acrylamide, 2 parts of diacrylate -1,4- butanediol esters, 0.01 part of ammonium persulfate-sodium bisulfite, 50 parts of sodium alginate, 300 parts, 13 parts-TCP3 parts of β, Exemestane barium chlorides.
The specific preparation method of tumor embolism microballoon is released in the pH sensitivities self-regulated：
(1) preparation of pH sensitivities prepolymer:
By N, 40 parts of N- diethyl amino ethyl groups methacrylate, 8 parts of acrylamide are dissolved in 500ml deionized waters, addition 2 parts of diacrylates -1,4-butanediol ester adds 0.01 part of ammonium persulfate-sodium bisulfite, stirring and dissolving is simultaneously as cross-linking reagent It is uniformly mixed, heating water bath is warming up to 40 DEG C, reacts 5 hours, forms viscosity flow shape prepolymer, which is added dropwise to first It is precipitated in tertiary ethereal solution, by dissolving-reprecipitation repeatedly, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate soln
The sodium alginate that 50 parts of viscosity are 100mpas is dissolved in 700ml deionized waters, mechanical agitation is equal to being formed Even solution.
(3) polymer blend solution is prepared
The Solutions Solution that acrylic ester prepolymer and 3 parts of β-TCP dissolvings are formed to 3wt% in deionized water, by pre-polymerization Object solution, SA solution and 300 parts of Exemestane mixing, stir 5 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier, high-speed stirred 1500r/min stirrings that 2wt%span-80 is added in 4800 parts of atoleines Then the blend solution of acrylate prepolymer body and SA are added in atoleine by 10min, 300r/min stirs 2 hours shapes At stable W/O systems, then barium chloride solution (13 parts of barium chlorides are dissolved in 80 parts of water) is slowly dropped in W/O systems, is stirred Microballoon is prepared after mixing cross-linking reaction 1h, 1000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release processed Embolism microball.
Comparative example 1
5 parts of hydroxyethyl methacrylate, N, 1 part of N '-methylene-bisacrylamides, ammonium persulfate-sodium bisulfite 0.05 60 parts, 13 parts part, 50 parts of sodium alginate, 1 part of lysine, azithromycin calcium chloride.
Specifically preparation method includes：
(1) preparation of pH sensitivities prepolymer
It is dissolved in 5 parts of hydroxyethyl methacrylate in 300ml deionized waters, adds 1 part of N, N '-methylene bisacrylamide acyls Amine adds 0.05 part of ammonium persulfate-sodium bisulfite as cross-linking reagent, and stirring and dissolving is simultaneously uniformly mixed, heating water bath heating It to 40 DEG C, reacts 5 hours, forms viscosity flow shape prepolymer, which is added dropwise in the tertiary ethereal solution of first and is precipitated, by anti- Solution-reprecipitation is redissolved, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate (SA) solution
The sodium alginate that 50 parts of viscosity are 400mpas is dissolved in 1L deionized waters, mechanical agitation is uniform to being formed Solution.
(3) polymer blend solution is prepared
The Solutions Solution that acrylic ester prepolymer and 1 part of lysine dissolving are formed to 1.5wt% in deionized water, will be pre- Copolymer solution, SA solution and 60 parts of adriamycin mixing, stir 3 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier that 1wt%span-80 is added in 2000 parts of atoleines, and high-speed stirred 500r/min stirs 10min, Then the blend solution of acrylate prepolymer body and SA are added in atoleine, 50r/min is stirred 1 hour and formed stabilization Calcium chloride solution (13 parts of calcium chloride are dissolved in 40 parts of water) is then slowly dropped in W/O systems by W/O systems, and stirring crosslinking is anti- 2h is answered to prepare microballoon, 1000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release embolism microball processed.
Comparative example 2
10 parts of hydroxyethyl methacrylate, N, 5 parts of N '-methylene-bisacrylamides, ammonium persulfate-sodium bisulfite 0.008 part, 35 parts of sodium alginate, 50 parts, 8 parts calcium chloride of cyclophosphamide.
Specifically preparation method includes：
(1) preparation of pH sensitivities prepolymer
It is dissolved in 10 parts of hydroxyethyl methacrylate in 500ml deionized waters, adds 5 parts of N, N '-methylene bisacrylamide acyls Amine adds 0.008 part of ammonium persulfate-sodium bisulfite as cross-linking reagent, and stirring and dissolving is simultaneously uniformly mixed, heating water bath heating It to 40 DEG C, reacts 5 hours, forms viscosity flow shape prepolymer, which is added dropwise in the tertiary ethereal solution of first and is precipitated, by anti- Solution-reprecipitation is redissolved, finally vacuum drying obtains pure polymer.
(2) preparation of sodium alginate soln
The sodium alginate that 35 parts of viscosity are 600mpas is dissolved in 700ml deionized waters, mechanical agitation is equal to being formed Even solution.
(3) polymer blend solution is prepared
Acrylic ester prepolymer dissolving is formed to the Solutions Solution of 3wt% in deionized water, pre-polymer solution, SA is molten Liquid and 50 parts of cyclophosphamide mixing, stir 5 hours, component are made to be sufficiently mixed uniformly.
(4) interpenetrating net polymer microballoon is prepared
It is emulsifier, high-speed stirred 1000r/min stirrings that 1wt%span-80 is added in 3600 parts of atoleines Then the blend solution of acrylate prepolymer body and SA are added in atoleine by 10min, 300r/min stirs 2 hours shapes At stable W/O systems, then calcium chloride solution (8 parts of calcium chloride are dissolved in 25 parts of water) is slowly dropped in W/O systems, is stirred Microballoon is prepared after cross-linking reaction 1h, 1000r/min is washed for several times after centrifuging, and is freeze-dried pH responsive types self-regulated drug release bolt processed Fill in microballoon.
The pH response releasing research of tumor embolism microballoon is released in 5 pH sensitivity self-regulateds of embodiment
The drug bearing microsphere 10mg that precision weighs embodiment 1-4, prepared by comparative example 1 and 2 is respectively placed in the PBS of 1mL pH6.85 In the PBS buffer solution of buffer solution and pH 7.35,37 DEG C carry out antitumor drugs release test, and when 72h samples lmL, using efficient Liquid chromatogram (HPLC) tests the antitumor drug release rate of microballoon 72h.
The pH response releasing results of microballoon are referring to table 1, when being as a result shown in pH 6.85, pH value-sensitivity provided by the invention Self-regulated releases the drug release rate of tumor embolism microballoon up to 4% or more, and the drug release of the common micro-ball without pH sensitive materials Rate is significantly lower than microballoon provided by the invention, illustrates that microballoon provided by the invention is higher in tumor vicinity release rate.In pH 7.35 When, the drug release rate maximum that tumor embolism microballoon is released in pH sensitivities self-regulated provided by the invention is only 0.05%, and quick without pH The drug release rate for feeling the common micro-ball of material is apparently higher than microballoon provided by the invention, illustrates microballoon provided by the invention just Drug is seldom discharged under the conditions of the higher pH of ordinary person's body, pH value-sensitivity self-regulated drug release may be implemented.
The pH of 1 microballoon of table responds releasing result
The clinical therapeutic efficacy of tumor embolism microballoon is released in 6 pH sensitivity self-regulateds of embodiment
The foundation of 6.1VX-2 liver cancer animal models
(1) leg is carried into the kind rabbits of VX-2 tumours with the yellow Jackets of 30mg/kg after auricular vein general anesthesia, by lotus Tumor rabbit aseptically removes tumour, cuts the vigorous flesh of fish sample tissue block of mass marginal growth, repeatedly clear in physiological saline It washes, is cut into 1 × 1 × 1mm3Tumor tissue be placed in be added 50mL containing gentamicin physiological saline (contain gentamicin 20,000 IU spare in).
(2) passage of lotus knurl rabbit：For new zealand rabbit with the yellow Jackets of 30mg/kg after auricular vein general anesthesia, back leg is standby Inside skin sterilizes, and respectively does one and is about 1.5cm notch, by 1mm32 pieces of merging intramuscular of tumor mass, hemostatic suture, penicillin powder are spread Apply incision.400,000 IU of postoperative continuous 4 days intramuscular injection penicillin.
(3) plantation in VX-2 tumor mass liver：Fasting can't help drinking in preoperative 12 hours of plantation new zealand rabbit.With 30mg/kg's Yellow Jackets are after auricular vein general anesthesia, under normal sterile surgical condition, the notch at about 1cm under xiphoid-process, successively detach to Exposure liver, the left centre leaf of liver is gently hauled out outside abdominal cavity, is taken in spare tumor tissue's 1-2 blocks implantation liver, hemostasis, by liver It is included in abdominal cavity dirty time.After replace another set of aseptic apparatus, by peritonaeum, muscle, skin layer-by-layer suture.Iodophor disinfection is used after suture, Penicillin powder is smeared, is wrapped up by the waist, 400,000 IU penicillin of postoperative intramuscular injection, continuous four days.
6.2 tumor embolism microspheres in treating VX-2 liver cancer rabbits
The successful experimental rabbit of modeling is divided into 2 groups, and every group 5, carried out with tumor embolism microballoon prepared by embodiment 3 respectively The experimental group of interventional treatment and the control group that interventional treatment is carried out with comparative example 2.
After each group lotus knurl rabbit is with 3% yellow Jackets auricular vein anesthesia, iliac region routine disinfection drape.It is dynamic along stock Arteries and veins longitudinal incision skin, separation subcutaneous tissue, musculature, exposure femoral artery sheath cut off femoral artery sheath, it is long to isolate femoral artery It is spare that sutures are worn in about 1.5~2cm, proximal end and distal end respectively.Lift proximal suture, temporary interruption blood flow, after puncturing successfully, Short-length guidewires are introduced, puncture needle outer sheath is exited, 3F catheter sheaths are inserted into along seal wire to proximal femoral.Tumor formation is confirmed through B ultrasound Experimental rabbit introduces 4F Cobra conduits after searching out arteria coeliaca through sheath, and row celiac arteriogram confirms proper hepatic artery, It is coaxial to introduce 3F conduits, surpass selection to proper hepatic artery, contrasted confirmation tumor imaging.Experimental rabbit presses different groups, notes successively Enter medicament.0.5ml heparin saline irrigating catheters are used after interventional procedure.Art ligatures femoral artery while finishing Lumen catheter and sheath Proximal end and distal end, layer-by-layer suture, painting spread penicillin powder and wrap up notch, and green vegetables and special rabbit feed are fed.
(1) tumor growth rate
Before treatment, after treatment 7 days using B ultrasound monitor tumor volume change, measure tumour major diameter (a) and with shortest diameter (b), Utilize formula V=ab2/ 2 calculate gross tumor volume.According to pretherapy and post-treatment gross tumor volume ratio, tumor growth rate is calculated, it is flat with each group Mean value indicates, as a result referring to table 2.
2 lotus knurl rabbit liver tumor growth rate of table
Experimental group Control group
Growth rate (%) 1.12 3.38
After 7 treatment, experimental group treats lotus knurl rabbit, and liver neoplasm growth rate is minimum, significant with control group Difference illustrates that pH sensitivities self-regulated provided by the invention releases tumor embolism microballoon and has good tumor inhibition effect.
(2) pathological examination
After treatment 7 days, by each group tumor tissues through optical microphotograph sem observation, as a result referring to attached drawing 1~2.
The general pathology performance of each group experimental rabbit institute embolism hepatic segments is wedge shaped, with the distinct between normal tissue.Light Mirror row sections observe the necrosis of each group experimental rabbit visible different range and degree, the visible different journeys of experimental group (Fig. 1) The blood vessel endothelium of degree destroys, and vascular wall continuity disappears, surrounding tissue cells pyknosis necrosis, and visible a large amount of inflammatory cell leachings Profit.Control group (Fig. 2) organizes also visible big sheet necrosis and surrounding inflammatory cell infiltration, but the tube wall of vascular embolization is still complete, and Continuity exists, the slight oedema of surrounding hepatic tissue.It is swollen to illustrate that tumor embolism microballoon provided by the present invention can be destroyed more effectively The vascular wall of tumor tissue, and then lead to the necrosis of tumour cell.
(3) pH value measures at tumor tissues
After treatment 7 days, pH value at tumor tissues is measured, as a result referring to table 3
Tumor tissues pH value after 3 lotus knurl rabbit of table is treated 7 days
PH value at tumor tissues after 7 days embolotherapies
Experimental group 7.23
Control group 6.75
As shown in Table 3, pH is apparently higher than control group at experimental group tumor tissues, illustrates pH sensitivities self-regulated provided by the invention Tumor embolism microballoon is released, due to containing tumor microenvironment conditioning agent, the acid environment that can significantly adjust around tumor tissues is advantageous In the treatment of tumour.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to The scope of the claims of the present invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention In the range of scheme.

Claims (10)

  1. The tumor embolism microballoon 1. a kind of pH responsive types self-regulated releases the drug, which is characterized in that the tumor embolism microballoon includes pH sensitive Compound and tumor microenvironment conditioning agent.
  2. The tumor embolism microballoon 2. pH responsive types self-regulated according to claim 1 releases the drug, which is characterized in that the pH sensitizations It is 30-50 that object and tumor microenvironment conditioning agent, which are closed, according to weight ratio：0.5-6.
  3. The tumor embolism microballoon 3. pH responsive types self-regulated according to claim 1 releases the drug, which is characterized in that the pH sensitizations It closes object and is selected from N, one or both of Phenhenzamine methacrylate or N, N- diethyl amino ethyl group methacrylate.
  4. The tumor embolism microballoon 4. pH responsive types self-regulated according to claim 1 releases the drug, which is characterized in that the tumour micro-loop Border conditioning agent is selected from arginine, lysine, histidine, chitosan, β-TCP, NaHCO3In it is one or more.
  5. The tumor embolism microballoon 5. pH responsive types self-regulated according to claim 1 releases the drug, which is characterized in that the tumor embolism Microballoon also include the sodium alginate of 35-60 parts by weight, the antitumor drug of 50-300 parts by weight, 8-16 parts by weight crosslinking agent with And other auxiliary agents of 5.501-15.05 parts by weight.
  6. The tumor embolism microballoon 6. pH responsive types self-regulated according to claim 5 releases the drug, it is characterised in that the sodium alginate Viscosity is 100-600mpas；The crosslinking agent is one or more in calcium chloride, magnesium chloride, barium chloride, preferably chlorine Change calcium.
  7. The tumor embolism microballoon 7. pH responsive types self-regulated according to claim 5 releases the drug, it is characterised in that the antineoplastic Object is selected from：Adriamycin, Irinotecan, topotecan, hydroxycamptothecin, epirubicin, cis-platinum, carboplatin, oxalic acid platinum, Ao Shali Platinum, Chlorambucil, cyclophosphamide, ifosfamide, melphalan, phosphinothioylidynetrisaziridine, Carmustine, Semustine, disappears at mustargen in vain Peace, mitomycin, methotrexate (MTX), pemetrexed, 5-FU, FT-207, capecitabine, Ismipur, 6-TG, hydroxycarbamide, Ah Sugared cytidine, gemcitabine, actinomycin D, daunorubicin, Epi-ADM, aclacinomycin, mithramycin, taxol, more west he Match, vinblastine, navelbine, Podophyllum emodi var chinense bases, homoharringtonine, L-Asparaginasum, tamoxifen, Toremifene, Exemestane, Aminoglutethimide, Formestane, Letrozole, Anastrozole, medroxyprogesterone acetate, megestrol acetate, Methyltestosterone, third It is one or more in acid andrusol, diethylstilbestrol, fluorine its ammonia, Goserelin, leuprorelin acetate, preferably adriamycin, ring It is one or more in phosphamide, cyclophosphamide, Exemestane.
  8. The tumor embolism microballoon 8. pH responsive types self-regulated according to claim 5 releases the drug, which is characterized in that other described auxiliary agents Including：5-10 parts of degree of polymerization conditioning agents, 0.5-5 parts of acrylic crosslinking agents and 0.001-0.05 parts of catalyst.
  9. The tumor embolism microballoon 9. pH responsive types self-regulated according to claim 8 releases the drug, which is characterized in that the degree of polymerization tune It saves agent and is selected from one or both of hydroxyethyl methacrylate and acrylamide；
    The acrylic crosslinking agent is selected from：N, N '-methylene-bisacrylamide, diacrylate -1,4- butanediol esters, dimethyl propylene One or more of olefin(e) acid glycol ester, triallyl cyanurate, preferably N, N '-methylene-bisacrylamides；
    The catalyst is selected from least one of ammonium persulfate-sodium bisulfite, potassium peroxydisulfate-tetramethylethylenediamine, preferably For ammonium sulfate-sodium hydrogensulfite.
  10. 10. the preparation method for the tumor embolism microballoon that released the drug according to claim 1-9 any one of them pH responsive type self-regulateds, special Sign is that the pH value-sensitivity self-regulated is released tumor embolism microballoon and is prepared using following step：
    (1) in deionized water by sodium alginate dissolving, sodium alginate soln is obtained；
    (2) pH sensitive compounds, degree of polymerization conditioning agent and acrylic crosslinking agent are dissolved in water, are caused with catalyst, prepared Prepolymer；
    (3) prepolymer and tumor microenvironment conditioning agent dissolving forms solution in deionized water, and be added sodium alginate soln and Antitumor drug is uniformly mixed；
    (4) W/O systems are prepared with emulsion process, sodium alginate cross-linking agent is added, freeze-drying prepares pH responsive type self-regulateds drug release bolt Fill in microballoon.
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US20070178135A1 (en) * 2006-01-31 2007-08-02 Boston Scientific Scimed, Inc. Medical articles containing biodegradable polymers and acid-neutralizing cationic species
CN102018674A (en) * 2010-12-14 2011-04-20 同济大学 Diclofenac sodium hydrogel microballoon with pH sensitivity, preparation method and application thereof
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