CN107281502A - The compound development thermo-sensitive gel suppository of one kind, preparation method and applications - Google Patents
The compound development thermo-sensitive gel suppository of one kind, preparation method and applications Download PDFInfo
- Publication number
- CN107281502A CN107281502A CN201610207908.9A CN201610207908A CN107281502A CN 107281502 A CN107281502 A CN 107281502A CN 201610207908 A CN201610207908 A CN 201610207908A CN 107281502 A CN107281502 A CN 107281502A
- Authority
- CN
- China
- Prior art keywords
- sensitive gel
- thermo
- compound development
- compound
- solution
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/36—Arsenic; Compounds thereof
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to the compound development thermo-sensitive gel suppository of one kind, preparation method and applications.Anti-tumor active substance, temperature sensing material and developer mixed aqueous solution are first prepared into compound development thermo-sensitive gel, compound development thermo-sensitive gel embolism is then formed with flocculating agent at the scene.Described temperature sensing material is the alkylcelluloses of hydroxyl C1 4, Pluronic, alginate or their mixture；Anti-tumor active substance medicine is arsenic trioxide, Docetaxel, cis-platinum, carboplatin, Nedaplatin, oxaliplatin, lobaplatin, Miboplatin, siRNA or their mixture；Developer is the water-soluble developer such as Iodixanol, Ioversol or Iohexol.Preparation method of the present invention is easy, suitable for industrialization large-scale production, it is particularly adapted to prepare biodegradable, good biocompatibility for hemorrhagic disease plug formulations, the compound development thermo-sensitive gel suppository of preparation treatment liver cancer, kidney, lung cancer, prostate cancer, fibroid or the splenic tumor etc. of being particularly suitable for use in.
Description
Technical field
The invention belongs to compound temperature-sensitive gel-type vehicle, application of the development thermo-sensitive gel suppository in liver tumour embolotherapy is more particularly to combined.
Background technology
Classical Emden equation (transcatheter arterial chemoembolization, TACE it is) by intervening the guidance quality that arterial duct is intubated, chemotherapeutics and suppository are injected to lesion vesselses, on the one hand occurs occlusion and middle clinopodium polycephalum, so that pathological tissues ischemic necrosis, reducing to reach control bleeding；On the other hand, local drug concentration, extension medicine and contact tumor tissue time are improved, so as to reach treatment tumour and vascular lesionses and eliminate the purpose of affected organ's function.Therefore suppository plays critical effect in arterial perfusion embolism.The suppository clinically used at present has liquid suppository and embolism agent of granule.Although these suppositories are continued to develop and improved, but still there are problems that, therefore in the urgent need to a kind of embolism materials, meet claimed below：1. nontoxic, no antigen, with good Bc；2. rapid occluded blood vessel, can the different bores of occlusion, the blood vessel of different flow on demand；3. The book of Changes conduit is transmitted, not collophore, is easily obtained, easily sterilization；4. without teratogenesis and carcinogenicity.
Temperature sensing material is that a class changes with ambient temperature, and the material of solution-gel transformation can occur for its aqueous solution.It can form situ-gel in vivo to reach the slow release effect in medicine-feeding part, or solidification increase preparation stability etc. in vitro using this property in pharmacy.Pluronic is a class good biocompatibility, and wide variety of temperature sensing material, and FDA approveds are used for people's intravascular administration.When temperature is raised, its aqueous solution can be transformed into hydrogel, play a part of slow-release depot by degraded and corrosion come the speed of Drug controlled release in vivo.Polyacrylamide and its be also the relatively broad temperature sensitive polymer of research with the copolymer of esters of acrylic acid, when temperature raise, its aqueous solution forms network gel structure, passes through temperature change and the rate of release of intraskeletal osmotic controlled drug.Single thermo-sensitive gel haves the shortcomings that unstable, obvious corrosion can occur in the solution until cause structure to dissociate, it is impossible to persistently play embolism function, cause embolization effect incomplete.Sodium alginate is a kind of natural polysaccharide, with the stability needed for pharmaceutical preparation auxiliary material, dissolubility, stickiness and security.Alginate can be dissolved in water, and negatively charged, meet Ca2+、Ba2+、Mg2+During Deng divalent metal, gel state can be transformed into by liquid.And alginate is that a kind of natural material, nontoxic, immunogenicity be low, bio-compatibility is good.When carcinoma intervention is performed the operation, phase change transition is realized by its Thermo-sensitive by In-situ reaction gel and polymer, alginate crosslinks gelation in the blood vessels with bivalent cation, strengthen the intensity of single gel, embolism peripheral vessel, and by the biodegradability of its own, slow degraded is the next rebasing basis of embolism again.Li et al. is prepared for carragheen pluronic compound temperature-sensitive hydrogel, improves the stability of gel, with preferable gel strength, reaches suitable degradation time.【Chenxi Li, Chunyan Li, Zheshuo Liu, Qiuhong Li, Xueying Yan, Yu Liu, Weiyue Lu.International Journal of Pharmaceutics, 2014,474:123-133】.Kojarunchitt et al. is prepared into compound temperature-sensitive gel toward with the addition of glucan in pluronic gel, strengthens the intensity of gel, reduces the erosion rate of gel.【Kojarunchitt.T, Hook.S, Rade.T, Baldursdottir.S.International Journal of Pharmaceutics, 2011,408,20-6】.
The content of the invention
The purpose of the present invention is, for of the prior art not enough there is provided a kind of compound development thermo-sensitive gel suppository, to also provide compound development thermo-sensitive gel agent necessary to a kind of above-mentioned compound development thermo-sensitive gel suppository.
The purpose of the present invention also provides the preparation method of a kind of above-mentioned compound development thermo-sensitive gel agent and compound development thermo-sensitive gel suppository respectively.Can in the intensity of blood vessel, there is provided a kind for the treatment of means of embolism with stable gel.
Another object of the present invention is to provide a kind of above-mentioned compound development thermo-sensitive gel agent and is used to prepare purposes of the purposes for being combined development thermo-sensitive gel suppository with compound development thermo-sensitive gel embolism for preparing anti-tumor agent, is particularly used as the application in the solid tumor drugs such as treatment liver cancer, lung cancer, kidney, prostate cancer, fibroid or splenic tumor in preparation.
To achieve the above object, the present invention is adopted the technical scheme that：Temperature sensing material, anti-tumor activity medicine and developer are mixed into compound development thermo-sensitive gel agent, compound development thermo-sensitive gel embolism is then mixed to form at the scene with flocculating agent (divalent metal saline solution).
Above-mentioned compound development thermo-sensitive gel agent is made up of temperature sensing material, anti-tumor active substance, developer and water, described temperature sensing material is Pluronic (Pluronic, also known as poloxamer Poloxamer), hydroxyl C1-4 alkylcelluloses, alginate；Wherein Pluronic and/or the content of hydroxyl C1-4 alkylcelluloses are that 5-30g/100ml, the content of alginate are 0.001-5g/100ml, the mass concentration of anti-tumor active substance is 0.001-10%, and the content of described developer is 20mg I/ml-200mg I/ml；Remaining is water.
Described flocculating agent is the aqueous solution of divalent metal salt, and the content of divalent metal salt is 0.00lmol/L-5.0mol/L；
Described compound development thermo-sensitive gel agent and the volume ratio of flocculating agent are 1: 0.01-1: 3.
Above-mentioned anti-tumor activity medicine is arsenic trioxide, Docetaxel, cis-platinum, carboplatin, Nedaplatin, oxaliplatin, lobaplatin, Miboplatin, siRNA or their mixture.
Above-mentioned developer is the water-soluble developer such as Iodixanol, Ioversol, Iohexol.
Above-mentioned Pluronic is F127, P105 or their mixture, hydroxyl C1-4 alkylcelluloses or their mixture, such as hydroxymethyl cellulose, hydroxypropyl methyl cellulose or their mixture.
Above-mentioned alginate is sodium alginate, potassium alginate or their mixture.
In described divalent metal salt, cation be calcium, barium, magnesium, zinc or or their mixed-cation, anion be chlorion, acetate ion, phosphate anion, nitrate ion in a kind of or their hybrid ionic.
The preparation method of compound development thermo-sensitive gel suppository of the present invention is as follows, compound development thermo-sensitive gel agent is initially formed after aforementioned temperature sensitive material, anti-tumor active substance, developer are mixed at room temperature according to foregoing amount of substance, then gel is condensed by flocculating agent again and forms suppository, described Thermo-sensitive material, anti-tumor active substance, the definition of developer and flocculating agent and the weight that uses are for example foregoing.
In the present invention, described temperature sensing material is mainly more than the one or two kinds of of Pluronic F127, P105, more than the one or two kinds of in hydroxyl C1-4 alkylcelluloses, alginate such as sodium alginate, potassium alginate；Described anti-tumor active substance is the one or two kinds of in arsenic trioxide, Docetaxel, cis-platinum, carboplatin, Nedaplatin, oxaliplatin, lobaplatin, Miboplatin, siRNA or their mixture；Described pluronic, hydroxyl C1-4 alkylcelluloses, the mass percent of alginate are 5%-30%, 0.001%-5%, 0.001%-5%, anti-tumor activity medicine be arsenic trioxide, Docetaxel, cis-platinum, carboplatin, Nedaplatin, oxaliplatin, lobaplatin, Miboplatin, siRNA or their mixture in one or two kinds of more than, the weight percentage of anti-tumor active substance is 0.001-10%, the water solubility developer such as developer Iodixanol, Ioversol, Iohexol, concentration is 20mg I/ml-200mg I/ml.
The compound development thermo-sensitive gel suppository of the present invention can develop under DSA, be easy to observation, and embolism is carried out to target vessel, reduce the probability of dystopy embolism, improve the success rate of embolism.
The compound development thermo-sensitive gel agent of the present invention and compound development thermo-sensitive gel suppository preparation method can be further described below：
(1) preparation of the load medicine alginate aqueous solution containing developer
In the reagent solution that 1mg-5000mg hydroxyl C1-4 alkylcelluloses are added to the 100ml that concentration is 20mg I/ml-200mg I/ml, lucifuge is stirred at room temperature；1mg-5000mg alginate and 1mg-10000mg anti-tumor activity medicines is added, 10-24h is stirred at room temperature in lucifuge, stand 4 DEG C of preservations；
(2) preparation of the compound development thermo-sensitive gel suppository of medicine is carried
At room temperature, adding in the alginate solution containing developer that temperature sensing material is prepared to (1) makes Thermo-sensitive material weight concentration be 5%-30%, and lucifuge is uniformly mixing to obtain the load medicine compound temperature-sensitive gel embolism containing developer under 0 DEG C of ice bath；
(3) prepare containing the divalent metal aqueous solution, the flocculating agent that concentration is 0.00lmol/L-5.0mol/L；
(4) scene will (2) load medicine compound temperature-sensitive gel containing developer and the divalent metal solution mixing of (3).Mixed volume ratio is 1:0.01-1:3.
In the preparation process in accordance with the present invention, described compound development thermo-sensitive gel suppository is the gel that water is matrix, the mass content of described temperature sensing material is 5-30g/100ml, 0.001-5g/100ml, described alginate mass percent is 0.001-5g/100ml, the weight percentage of anti-tumor active substance is 0.001-10%, and described concentration of developer is 20mg I/ml-200mg I/ml；Described Thermo-sensitive material is that hydroxyl C1-4 alkylcelluloses, poloxamer F127, P105 isogel quality of materials content are 5-30g/100ml, 0.001-5g/100ml, described divalent metal salt 0.00lmol/L-5.0mol/L.
The compound development thermo-sensitive gel suppository of the present invention can be used for preparing the antineoplastic preparation for the treatment of, or for preparing treatment hemorrhagic disease plug formulations.Described tumour is liver cancer, lung cancer, kidney, prostate cancer, fibroid or splenic tumor.
The compound development thermo-sensitive gel suppository of the present invention can adjust the temperature-sensitive and gel stability of gel and compound development thermo-sensitive gel suppository by adjusting the species and composition of temperature sensing material, it can be uniformly distributed, so that gel rubber material is uniformly dispersed in gel vascular occlusive agent, can be with the intensity of stable gel in the blood vessel, the stability of gel is improved, the embolism function of gel is persistently played.It is liquid at room temperature that this, which is combined development thermo-sensitive gel agent and flocculating agent, the embolism or tumor vascular embolism for blood vessel can be injected by separately or concurrently conduit, block target vessel, so that on the other hand the blood supply of target tissue is reduced, suppository can improve local drug concentration, extend medicine and contact tumor tissue time, reach the purpose for the treatment of.The suppository has embolism, transports the functions such as active material, oncotherapy.It can apply to prepare the pharmaceutical preparations such as treatment liver cancer, lung cancer, kidney, prostate cancer, fibroid, splenic tumor；It can be used for preparing the pharmaceutical preparation of the hemorrhagic disease such as arterial hamorrhage caused by gastric ulcer massive haemorrhage, vascular malformation.
Beneficial effect
Not only preparation method is easy by the present invention, suitable for large-scale production, is particularly adapted to prepare compound development thermo-sensitive gel suppository, and compound development thermo-sensitive gel suppository prepared by the present invention, it can develop in DSA, be easy to operator to observe, and overcome single thermo-sensitive gel unstability in the blood vessel, strengthen gel in embolism intensity, lasting embolism function is played, and improves medicine local concentration, delays Slow release, treatment is more accurate, with good industrial applications prospect.
Brief description of the drawings
Accompanying drawing 1 is " PSHI-Ca in the corrosion characteristics of compound temperature-sensitive gel, figure2+" for can be combined development plus calcium thermo-sensitive gel solution; " PSHI " for compound development thermo-sensitive gel solution; " Gel Corrosion Concentration (%) " is gel erosion percentage (%), and Time (min) represents erosion time (minute).
" PluronicF127 micelle ", " Hydroxymethyl cellulose ", " Sodium Alginate ", " Pluronic F127 ", " Composite gels ", " Drug " represent pluronic F127 micellas, hydroxyl C1-4 alkylcelluloses, sodium alginate, pluronic F127, plural gel, active anticancer medicine respectively during accompanying drawing 2 is compound development thermo-sensitive gel mechanism of action, figure.
Accompanying drawing 3 is the DSA images after the normal rabbit side arteria renalis injects compound development thermo-sensitive gel suppository through transcatheter arterial, in figure A, B, C, D represent respectively before embolism, the DSA images of 30 minutes, " Control ", " PSHI-Ca 5 minutes after embolism, 15 minutes after embolism, after embolism2+" it is expressed as single temperature sensing material F127, compound development thermo-sensitive gel.
Accompanying drawing 4 is the histopathologic analysis after the CT images and embolism of compound development thermo-sensitive gel embolism normal rabbit arteria renalis one week after, wherein, A1 is the kidney CT after F127 embolisms, A2 is the kidney CT images after compound development thermo-sensitive gel embolism, B1 is the image of 7 days after F127 embolisms, the image of 7 days after the compound development thermo-sensitive gel embolisms of B2, and C1 is F127 embolisms Pathological after 7 days, C2 is " Control ", " PSHI-Ca in the kidney after compound development thermo-sensitive gel embolism, figure2+" single temperature sensitive suppository F127, compound development thermo-sensitive gel suppository are represented respectively.
Accompanying drawing 5 is to be combined development thermo-sensitive gel into rabbit VX2 liver cancer animal models through transcatheter arterial injection, wherein, A1, A2 are the tumor vessel development figures after the development figure of the supply artery of the tumor before embolism, B1 physiological saline embolisms, and B2 is the development figure after compound development thermo-sensitive gel embolism." Control " " PSHI-Ca in figure2+" it is expressed as normal saline solution, compound temperature-sensitive gel.
Accompanying drawing 6 is the CT graphical analyses of compound development thermo-sensitive gel via hepatic artery embolization on VX 2 rabbit hepatocarcinoma animal model, wherein, A1, B1 are the liver cancer CT images before embolism, and A2 is rabbit liver cancer image after physiological saline embolism, B2 is " Control ", " PSHI-Ca in the CT images after compound development thermo-sensitive gel embolism, figure2+" normal saline solution, compound development thermo-sensitive gel suppository are represented respectively.
Accompanying drawing 7 is to be combined development thermo-sensitive gel into rabbit VX2 kidney animal models through transcatheter arterial injection, wherein, A1, A2 are the tumor vessel development figures after the development figure of the supply artery of the tumor before embolism, B1 physiological saline embolisms, and B2 is the development figure after compound development thermo-sensitive gel embolism." Saline " " PSHI-Ca in figure2+" it is expressed as normal saline solution, compound temperature-sensitive gel.
Accompanying drawing 8 is the CT graphical analyses of compound development thermo-sensitive gel embolism rabbit VX2 kidney animal models, wherein, A1, A2 are the kidney CT images after 1 week after embolism, B1, B2 are the kidney CT images after 2 weeks after embolism, C1, C2 are the kidney CT images after 3 weeks after embolism, D1, D2 are " Saline ", " PSHI-Ca in the kidney CT images after 4 weeks, figure after embolism2+" normal saline solution, compound development thermo-sensitive gel suppository are represented respectively.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only illustrative of the invention and is not intended to limit the scope of the invention.In addition, it is to be understood that after the content of the invention lectured has been read, those skilled in the art can make various changes or modifications to the present invention, these equivalent form of values equally fall within the application appended claims limited range.
Embodiment 1
The preparation of the compound development thermo-sensitive gel of different component and sign
Take 5000mg hydroxymethyl cellulose to add 100ml concentration in 20mg I/L Iodixanol solution, lucifuge stirs 24h at room temperature, 5000mg sodium alginate and 1mg arsenic trioxides are added after stirring, room temperature continues to stir 24h, stirred.In above-mentioned solution, adding F127 makes F127 concentration be 5%, and lucifuge dissolves under 0 DEG C of ice bath, obtains the compound temperature-sensitive gel solution of Iodixanol, sodium alginate, hydroxyl C1-4 alkylcelluloses, F127 and arsenic trioxide, standby.
Prepare the CaCl that concentration is 5mol/L2Solution, it is standby.
At room temperature, compound development thermo-sensitive gel is divided into two parts, portion is compound development thermo-sensitive gel, another adds calcium group for compound development thermo-sensitive gel.With compound development thermo-sensitive gel and CaCl2Volume ratio 1: 0.5 is mixed.
The compound development thermo-sensitive gel of preparation is determined into its corrosion characteristics with method with plastic film, its corrosion characteristics determines its erosion time to pluronic F127 as single determination of aqueous solution, and the biodegradability of observation compound temperature-sensitive gel is shown in Fig. 1.Mechanism of action is shown in Fig. 2, alginate, F127, hydroxyl C1-4 alkylcelluloses, cancer therapy drug formation network structure, short texture, erosion time is very fast, but adds after calcium ion, alginate and calcium binding, close network structure is formed, erosion rate substantially lowers, and degradation speed substantially slows down.
Embodiment 2
The preparation and thrombosis of renal artery application of the compound development thermo-sensitive gel of arsenic trioxide
500mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 200mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 1mg sodium alginate and 1mg arsenic trioxides, and lucifuge is stirred at room temperature 24h, stirred.In above-mentioned solution, adding P105 makes P105 concentration be 30%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the Ca (CH that concentration is 0.001mol/L3COO)2Solution, it is standby.
The normal rabbit arteria renalis, observation period embolization effect are expelled to the compound development thermo-sensitive gel of preparation.Normal rabbit right common femoral artery is intubated to left renal artery opening, by microtubular, and to the compound development thermo-sensitive gel solution of arteria renalis porch injection 1ml, 0.01ml Ca (CH are injected after 1min3COO)2Solution, row angiogram finds that thrombosis of renal artery is complete.CT observation periods long-term embolization effect is used after embolism, experimental group normal rabbit arteria renalis vascular occlusion is found completely, embolism after 5 minutes, 15 minutes, 30 minutes normal rabbit arteria renalis blood vessel do not lead to, illustrate embolism successfully, and Fig. 3 is clearly seen at embolism position.It can be seen experimental group nephrolithotomy after one week with CT observation embolization effects and still suffered from contrast agent, and control group contrast agent has disappeared, and illustrate that the compound development thermo-sensitive gel suppository embolism arteria renalis is complete, can be for a long time in the presence of seeing Fig. 5.The nephridial tissue of 7 days after embolism is done into frozen section, the nephridial tissue section mesonephric glomerulus atrophy necrosis after as a result visible compound development thermo-sensitive gel embolism, and the section of the renal tissue of control group is shown in accompanying drawing 4 without significant change.
Embodiment 3
The preparation and left gastric artery embolism application of the compound development thermo-sensitive gel of Docetaxel
1000mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 20mg I/L Iohexol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 50mg sodium alginate and 10mg Docetaxels, and lucifuge is stirred at room temperature 24h, stirred.In above-mentioned solution, adding F127 makes F127 concentration be 25%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the CaCl that concentration is 0.001mol/L2Solution, it is standby.
Normal rabbit left gastric artery, observation period embolization effect are expelled to the compound development thermo-sensitive gel of preparation.Normal rabbit right common femoral artery is intubated to left gastric artery opening, to the compound development thermo-sensitive gel solution of left gastric artery porch injection 1ml, and 0.5mlCaCl is injected again after 1min2Solution, angiogram at once, and with CT observation periods long-term embolization effect.As a result the blood flow occlusion of experimental group rabbit stomach left artery side is found, illustrates that embolism position is clearly seen.Anatomic observation finds that gastrointestinal tissue's necrosis of embolism illustrates left gastric artery occlusion necrosis, so as to illustrate that embolization effect is clear and definite.
Embodiment 4
The preparation and liver cancer embolism application of the compound development thermo-sensitive gels of siRNA
500mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 100mg I/L Ioversol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 500mg sodium alginate, and 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 20%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Taking siRNA to be added to the water makes siRNA concentration for 0.25nM, adds CaCl2, prepare the CaCl that respective concentration is 2.0mol/L2Solution, it is standby.
Rabbit liver cancer model 12 is set up, random packet, every group 6.Rabbit liver cancer artery, observation period embolization effect are expelled to the compound development thermo-sensitive gel of preparation.One group is intubated to arteria hepatica through rabbit liver cancer model right common femoral artery, and the CaCl that 2ml is injected after the compound development thermo-sensitive gel solution of the 1ml prepared, 1min is injected to blood supply of tumor2Solution, another group of injecting normal saline solution, angiogram at once after embolism terminates, and observe long-term embolization effect with CT, as a result the injection thermo-sensitive gel group vascular occlusion of experimental group rabbit liver cancer is found, do not lead to again, and control group vascular flow is unobstructed, illustrates that Fig. 5, Fig. 6 are clearly seen in compound development thermo-sensitive gel embolism position.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, illustrates that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 5
The preparation and kidney embolism application of the compound development thermo-sensitive gel of cis-platinum
1mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 150mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 5000mg potassium alginate and 1000mg cis-platinums, and lucifuge is stirred at room temperature 24h, stirred.In above-mentioned solution, adding P105 makes P105 concentration be 30%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the Ca (CH that concentration is 0.001mol/L3COO)2Solution, it is standby.
Rabbit renal carcinoma model is set up, is intubated through right common femoral artery to right renal arteries, to the compound development thermo-sensitive gel solution of blood supply of tumor injection 1ml, 3ml Ca (CH are injected after 1min3COO)2Solution, angiogram at once after embolism terminates, and long-term embolization effect is observed with CT, the injection thermo-sensitive gel group vascular occlusion of experimental group rabbit kidney is found, is not led to again, and control group vascular flow is unobstructed, illustrates that Fig. 7 is clearly seen at compound temperature-sensitive gel embolism position.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it can be seen that tumor regression after embolism, while contrast agent is still suffered from after 4 weeks in CT displays kidney, and control group contrast-agent-free, it is seen that compound development thermo-sensitive gel embolization effect is clearly shown in Fig. 8.
Embodiment 6
The preparation and cerebral arteriovenous malformation embolism application of the compound development thermo-sensitive gel of arsenic trioxide
100mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 20mg I/L Ioversol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 200mg sodium alginate and 20mg arsenic trioxides, and lucifuge is stirred at room temperature 24h, stirred.In above-mentioned solution, adding F127 makes F127 concentration be 18%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the BaCl that concentration is 0.001mol/L2Solution, it is standby.
Pig brain deformation knurl model is set up, is expelled to compound development thermo-sensitive gel is prepared at pig brain aneurysm blood supply, observes embolization effect.It is intubated through pig right common femoral artery to tumor feeding, the thermo-sensitive gel solution that the 1ml prepared to intravascular injection can develop, 0.5ml BaCl is injected after 1min2Solution, angiogram at once after embolism terminates, and long-term embolization effect is observed with CT, vascular occlusion after the compound development thermo-sensitive gel of pig brain deformation knurl injection is found, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 7
The preparation and prostate cancer embolism application of the compound development thermo-sensitive gel of cis-platinum
200mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 50mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 500mg potassium alginate and 500mg cis-platinums, and lucifuge is stirred at room temperature 24h, stirred.In above-mentioned solution, adding F127 makes F127 concentration be 25%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the CaCl that concentration is 0.001mol/L2Solution, it is standby.
Nude rat prostatitis cancer model is set up, is intubated through right common femoral artery to prostatic artery, the CaCl that 2ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, nude rat prostate cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 8
The preparation and liver cancer embolism application of the compound development thermo-sensitive gel of carboplatin
1000mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 73.6mg I/L iodine sea sand alcoholic solution, 24h is stirred at room temperature in lucifuge, stirs, and adds 5000mg sodium alginate and 10000mg carboplatins in above-mentioned solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding P105 makes P105 concentration be 18%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the ZnCl that respective concentration is 1.25mol/L2Solution, it is standby.
Rabbit liver cancer model is set up, is intubated through right common femoral artery to arteria hepatica, the ZnCl that 0.5ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit liver cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 9
The preparation and lung cancer embolism application of the compound development thermo-sensitive gel of Nedaplatin
1mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 80mg I/L Ioversol solution, 24h is stirred at room temperature in lucifuge, stirs, and the sodium alginate and 10mg Nedaplatins for adding 800mg enter above-mentioned solution, and 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 20%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the Mg (NO that respective concentration is 1.25mol/L3)2Solution, it is standby.
Nude rat lung cancer model is set up, is intubated through right common femoral artery to pulmonary artery, the Mg (NO that 0.01ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min are injected to blood supply of tumor3)2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, nude rat lung cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 10
The preparation and fibroid embolism application of the compound development thermo-sensitive gel of oxaliplatin
10mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 90mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs, and the potassium alginate and 100mg oxaliplatins for adding 1000mg enter above-mentioned solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 22%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the Ca that respective concentration is 2.5mol/L3(PO4)2Solution, it is standby.
Nude rat hysteromyoma model is set up, is intubated through right common femoral artery to uterine artery, the Ca that 0.01ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor3(PO4)2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, nude rat fibroid injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 11
The preparation and liver cancer embolism application of the compound development thermo-sensitive gel of lobaplatin
50mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 40mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs, and the potassium alginate and 500mg lobaplatins for adding 2000mg enter above-mentioned solution, and 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 27%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the CaCl that respective concentration is 0.25mol/L2Solution, it is standby.
Rabbit liver cancer model is set up, is intubated through right common femoral artery to arteria hepatica, the CaCl that 3ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit liver cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 12
The preparation and kidney embolism application of the compound development thermo-sensitive gel of Miboplatin
900mg hydroxyl C1-4 alkylcelluloses are taken to add 100ml concentration in 150mg I/L Iohexol solution, 24h is stirred at room temperature in lucifuge, stirs, and the sodium alginate and 1000mg Miboplatins for adding 3000mg enter above-mentioned solution, and 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 24%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.
Prepare the CaCl that respective concentration is 1.25mol/L2Solution, it is standby.Rabbit renal carcinoma model is set up, is intubated through right common femoral artery to the arteria renalis, the CaCl that 3ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit kidney injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 13
The preparation and liver cancer embolism application of the compound development thermo-sensitive gel of Miboplatin
800mg sodium alginate and 10000mg Miboplatins is taken to add 100ml concentration in 168mg I/L Ioversol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 23%, and lucifuge dissolves under 0 DEG C of ice bath, obtains thermo-sensitive gel solution, standby.Prepare the MgCl that respective concentration is 0.75mol/L2Solution, it is standby.
Rabbit liver cancer model is set up, is intubated through right common femoral artery to arteria hepatica, the MgCl that 1ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit liver cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 14
The preparation and kidney embolism application of the compound development thermo-sensitive gel of arsenic trioxide
5000mg sodium alginate and 5000mg arsenic trioxides is taken to add 100ml concentration in 200mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 18%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the ZnCl that respective concentration is 1.5mol/L2Solution, it is standby.
Rabbit renal carcinoma model is set up, is intubated through right common femoral artery to the arteria renalis, the ZnCl that 0.5ml is injected after the thermo-sensitive gel solution that 1ml can develop, 1min is injected to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit kidney injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 15
The preparation and liver cancer embolism application of the compound development thermo-sensitive gel of Docetaxel
2000mg potassium alginate and 500mg Docetaxels is taken to add 100ml concentration in 180mg I/L Iohexol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 21%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the ZnCl that respective concentration is 0.125mol/L2Solution, it is standby.
Rabbit liver cancer model is set up, is intubated through right common femoral artery to arteria hepatica, to the compound development thermo-sensitive gel solution of blood supply of tumor injection 1ml, 1.5ml ZnCl is injected after 1min2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit liver cancer injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 16
The preparation and kidney embolism application of the compound development thermo-sensitive gel of arsenic trioxide-Docetaxel
600mg sodium alginate, 10mg arsenic trioxides and 500mg Docetaxels is taken to add 100ml concentration in 200mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 20%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the Ca that respective concentration is 1.0mol/L3(PO4)2Solution, it is standby.
Rabbit renal carcinoma model is set up, is intubated through right common femoral artery to arteria hepatica, to the compound development thermo-sensitive gel solution of blood supply of tumor injection 1ml, 1ml Ca is injected after 1min3(PO4)2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit kidney injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 17
The preparation and kidney embolism application of the compound development thermo-sensitive gels of arsenic trioxide-siRNA
1mg sodium alginate, 1mg arsenic trioxides is taken to add 100ml concentration in 100mg I/L Ioversol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 20%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Taking siRNA to be added to the water makes siRNA concentration for 0.25nM, adds MgCl2, prepare the MgCl that respective concentration is 2.0mol/L2Solution, it is standby.
Rabbit renal carcinoma model is set up, is intubated through right common femoral artery to arteria hepatica, the compound development thermo-sensitive gel solution of 1ml and 1.5ml MgCl is injected simultaneously to blood supply of tumor2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit kidney injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Embodiment 18
The preparation and splenic tumor embolism application of the compound development thermo-sensitive gel of arsenic trioxide
1000mg sodium alginate and 1000mg arsenic trioxides is taken to add 100ml concentration in 200mg I/L Iodixanol solution, 24h is stirred at room temperature in lucifuge, stirs.In above-mentioned solution, adding F127 makes F127 concentration be 20%, and lucifuge dissolves under 0 DEG C of ice bath, obtains compound development thermo-sensitive gel solution, standby.Prepare the Zn (NO that respective concentration is 1.5mol/L3)2Solution, it is standby.
Rabbit splenic tumor model is set up, is intubated through right common femoral artery to arteria linenalis, to the blood supply of tumor thermo-sensitive gel solution that injection 1ml can develop simultaneously and 2.5ml Zn (NO3)2Vascular occlusion after solution, angiogram at once after embolism terminates, regular CT observations, rabbit splenic tumor injection thermo-sensitive gel, and control group vascular flow is unobstructed, illustrates that compound development thermo-sensitive gel embolism position is clear and definite.CT observes the change of Tumor size, as a result shows that lump is obviously reduced, and control group lump gradually increases, it is seen that tumor regression after embolism, it is seen that compound development thermo-sensitive gel embolization effect is clear and definite.
Claims (12)
1. the compound development thermo-sensitive gel suppository of one kind, it is characterised in that：By temperature sensing material, anti-tumor activity medicine
Compound development thermo-sensitive gel agent is mixed into developer, then with flocculating agent divalent metal saline solution existing
Field is mixed to form compound development thermo-sensitive gel suppository；
In above-mentioned compound development thermo-sensitive gel agent, described temperature sensing material is Pluronic, hydroxyl C1-4 alkane
Base cellulose, wherein Pluronic, the content of hydroxyl C1-4 alkyl base celluloses are 5-30g/100ml, sea
The content of alginates is 0.001-5g/100ml；The mass concentration of anti-tumor active substance is 0.001-10%；
Described development agent content is 20mg I/ml-200mg I/ml；Remaining is water；
Described flocculating agent is the aqueous solution of divalent metal salt, and the content of divalent metal salt is
0.00lmol/L-5.0mol/L；
Described compound development thermo-sensitive gel agent and the volume ratio of flocculating agent are 1:0.01-1:3.
2. the compound development thermo-sensitive gel agent of one kind, it is characterised in that：Its by temperature sensing material, anti-tumor activity medicine and
Developer is constituted：Described temperature sensing material is Pluronic, wherein hydroxyl C1-4 alkylcelluloses, Pulan Buddhist nun
Gram, the contents of hydroxyl C1-4 alkyl base celluloses be 5-30g/100ml, the content of alginate is
0.001-5g/100ml；The mass concentration of anti-tumor active substance is 0.001-10%；Described developer
Content is 20mg I/ml-200mg I/ml；Remaining is water.
3. compound development thermo-sensitive gel suppository according to claim 1, it is characterised in that described is antitumor
Active medicine is arsenic trioxide, Docetaxel, cis-platinum, carboplatin, Nedaplatin, oxaliplatin, Lip river
Platinum, Miboplatin, siRNA or their mixture.
4. compound development thermo-sensitive gel suppository according to claim 1, it is characterised in that described developer
For Iodixanol, iodine fluorine alcohol, the water-soluble developer of Iohexol.
5. compound development thermo-sensitive gel suppository according to claim 1, it is characterised in that described Pulan Buddhist nun
Gram it is F127, P105 or their mixture, hydroxyl C1-4 alkylcelluloses are hydroxypropyl methyl fibers
Element, hydroxymethyl cellulose or their mixture.
6. compound development thermo-sensitive gel suppository according to claim 1, it is characterised in that described alginic acid
Salt is sodium alginate, potassium alginate or their mixture.
7. compound development thermo-sensitive gel agent suppository according to claim 1, it is characterised in that described divalence
In metal salt, cation be calcium, barium, magnesium, zinc or their mixed-cation, anion be chlorion,
A kind of or their hybrid ionic in acetate ion, phosphate anion, nitrate ion.
8. a kind of preparation method of compound development thermo-sensitive gel suppository according to claim 1, its feature exists
In：Gel is formed after described alginate, Thermo-sensitive material, anti-tumor active substance are mixed,
Gel is condensed by flocculating agent again and forms suppository.
9. the preparation method of compound development thermo-sensitive gel suppository according to claim 8, it is characterised in that by
Following methods are obtained：
(1) preparation of the load medicine alginate aqueous solution containing developer
1mg-5000mg hydroxyl C1-4 alkylcelluloses are added to concentration for 20mg I/ml-200mg I/ml
100ml reagent solution in, lucifuge is stirred at room temperature；Add 1mg-5000mg marine alga
10-24h is stirred at room temperature in hydrochlorate and 1mg-10000mg anti-tumor activity medicines, lucifuge, stands 4 DEG C of preservations；
(2) it is combined the preparation of development thermo-sensitive gel agent
At room temperature, adding in the alginate solution containing developer that temperature sensing material is prepared to (1) makes temperature
Sensitive materials weight concentration is 5%-30%, and lucifuge is uniformly mixing to obtain the load containing developer under 0 DEG C of ice bath
Medicine compound temperature-sensitive gel；
(3) prepare containing the divalent metal aqueous solution, the cohesion that concentration is 0.00lmol/L-5.0mol/L
Agent；
(4) the live load medicine compound temperature-sensitive gel and the divalent metal of (3) containing developer by (2)
Solution is mixed, and it is 1 to carry medicine compound temperature-sensitive gel and divalent metal liquor capacity ratio:0.01-1：3；
In preparation method, described in the definition claim 1 or 2 of the material, development thermo-sensitive gel is combined
In agent, the content of Pluronic and hydroxyl C1-4 alkyl base celluloses is 5-30g/100ml, alginate
Content is 0.001-5g/100ml, and the mass concentration of anti-tumor active substance is 0.001-10%, described
Development agent content is 20mg I/ml-200mg I/ml；Remaining is water；
Described divalent metal salinity is 0.00lmol/L-5.0mol/L.
10. preparation method as claimed in claim 9, it is characterised in that described Pluronic and alginate
Mass ratio is 1-30000:1.
11. a kind of compound development thermo-sensitive gel suppository as claimed in claim 1 is used to prepare antineoplastic embolism system
Agent, or for preparing treatment hemorrhagic disease plug formulations.
12. the application of the compound development thermo-sensitive gel suppository described in claim 11 as claimed in claim, it is special
Levy is that described tumour is liver cancer, lung cancer, kidney, prostate cancer, fibroid or splenic tumor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610207908.9A CN107281502B (en) | 2016-04-05 | 2016-04-05 | Composite developing temperature-sensitive gel suppository, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610207908.9A CN107281502B (en) | 2016-04-05 | 2016-04-05 | Composite developing temperature-sensitive gel suppository, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107281502A true CN107281502A (en) | 2017-10-24 |
| CN107281502B CN107281502B (en) | 2021-05-04 |
Family
ID=60092718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610207908.9A Active CN107281502B (en) | 2016-04-05 | 2016-04-05 | Composite developing temperature-sensitive gel suppository, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107281502B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019231498A1 (en) * | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Treatment of kidney tumors by intratumoral injection of taxane particles |
| US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
| US10507181B2 (en) | 2017-06-14 | 2019-12-17 | Crititech, Inc. | Methods for treating lung disorders |
| US10874660B2 (en) | 2016-04-04 | 2020-12-29 | CritlTech, Inc. | Methods for solid tumor treatment |
| CN112812223A (en) * | 2021-01-21 | 2021-05-18 | 杨杨 | Drug-loaded temperature-sensitive polymer, embolic material and preparation method thereof |
| US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
| US11523983B2 (en) | 2017-06-09 | 2022-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
| CN115645635A (en) * | 2022-10-24 | 2023-01-31 | 杭州旸顺医疗科技有限公司 | Liquid-phase embolic agent, preparation method and application thereof |
| CN116115819A (en) * | 2023-02-21 | 2023-05-16 | 北京冠合医疗科技有限公司 | Developable in-situ crosslinking embolic composition and method of use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020102298A1 (en) * | 1998-06-18 | 2002-08-01 | David Needham | Temperature-sensitive liposomal formulation |
| CN102525882A (en) * | 2012-02-28 | 2012-07-04 | 上海市肿瘤研究所 | Nanocomposite temperature-sensitive gel and preparation method and application thereof |
| CN102988274A (en) * | 2010-09-08 | 2013-03-27 | 上海市肿瘤研究所 | Sustained-release blood vessel embolic gel used for treating tumor, and preparation method thereof |
| CN103622902A (en) * | 2012-08-24 | 2014-03-12 | 上海现代药物制剂工程研究中心有限公司 | A temperature-sensitive gel medicine preparation and a preparation method thereof |
-
2016
- 2016-04-05 CN CN201610207908.9A patent/CN107281502B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020102298A1 (en) * | 1998-06-18 | 2002-08-01 | David Needham | Temperature-sensitive liposomal formulation |
| CN102988274A (en) * | 2010-09-08 | 2013-03-27 | 上海市肿瘤研究所 | Sustained-release blood vessel embolic gel used for treating tumor, and preparation method thereof |
| CN102525882A (en) * | 2012-02-28 | 2012-07-04 | 上海市肿瘤研究所 | Nanocomposite temperature-sensitive gel and preparation method and application thereof |
| CN103622902A (en) * | 2012-08-24 | 2014-03-12 | 上海现代药物制剂工程研究中心有限公司 | A temperature-sensitive gel medicine preparation and a preparation method thereof |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10993927B2 (en) | 2015-06-04 | 2021-05-04 | Crititech, Inc. | Taxane particles and their use |
| US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
| US11123322B2 (en) | 2015-06-04 | 2021-09-21 | Crititech, Inc. | Taxane particles and their use |
| US10729673B2 (en) | 2015-06-04 | 2020-08-04 | Crititech, Inc. | Taxane particles and their use |
| US10894045B2 (en) | 2016-04-04 | 2021-01-19 | Crititech, Inc. | Methods for solid tumor treatment |
| US11458133B2 (en) | 2016-04-04 | 2022-10-04 | Crititech, Inc. | Methods for solid tumor treatment |
| US10874660B2 (en) | 2016-04-04 | 2020-12-29 | CritlTech, Inc. | Methods for solid tumor treatment |
| US11033542B2 (en) | 2016-04-04 | 2021-06-15 | Crititech, Inc. | Methods for solid tumor treatment |
| US11737972B2 (en) | 2017-06-09 | 2023-08-29 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
| US11523983B2 (en) | 2017-06-09 | 2022-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
| US11160754B2 (en) | 2017-06-14 | 2021-11-02 | Crititech, Inc. | Methods for treating lung disorders |
| US10507181B2 (en) | 2017-06-14 | 2019-12-17 | Crititech, Inc. | Methods for treating lung disorders |
| US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
| US11583499B2 (en) | 2017-10-03 | 2023-02-21 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
| US11918691B2 (en) | 2017-10-03 | 2024-03-05 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
| WO2019231498A1 (en) * | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Treatment of kidney tumors by intratumoral injection of taxane particles |
| CN112812223A (en) * | 2021-01-21 | 2021-05-18 | 杨杨 | Drug-loaded temperature-sensitive polymer, embolic material and preparation method thereof |
| CN115645635A (en) * | 2022-10-24 | 2023-01-31 | 杭州旸顺医疗科技有限公司 | Liquid-phase embolic agent, preparation method and application thereof |
| CN116115819A (en) * | 2023-02-21 | 2023-05-16 | 北京冠合医疗科技有限公司 | Developable in-situ crosslinking embolic composition and method of use thereof |
| CN116115819B (en) * | 2023-02-21 | 2023-11-10 | 北京冠合医疗科技有限公司 | Developable in-situ crosslinking embolic composition and method of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107281502B (en) | 2021-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107281502A (en) | The compound development thermo-sensitive gel suppository of one kind, preparation method and applications | |
| Kempe et al. | In situ forming implants—an attractive formulation principle for parenteral depot formulations | |
| JP5248492B2 (en) | Hydrogels containing low molecular weight alginate and biostructures made therefrom | |
| RU2393867C2 (en) | Self-gelatinised alginate systems and application thereof | |
| CN102657869B (en) | Alginate hard capsule disintegrable at different positions in gastrointestinal tract | |
| US9844597B2 (en) | Biocompatible in situ hydrogel | |
| JP7312822B2 (en) | Injectable hydrogel system and lesion labeling method | |
| CN106334213B (en) | A kind of vascular suppository material, preparation method and the purposes in medicine preparation | |
| Lord et al. | Advancements in the development on new liquid embolic agents for use in therapeutic embolisation | |
| Huang et al. | Thermo-sensitive composite hydrogels based on poloxamer 407 and alginate and their therapeutic effect in embolization in rabbit VX2 liver tumors | |
| Caballero et al. | Characterization of alginate beads loaded with ibuprofen lysine salt and optimization of the preparation method | |
| CN105462142A (en) | Thermo-sensitive type interpenetrating polymer network hydrogel material and preparation method and application thereof | |
| KR20140097424A (en) | Pharmaceutical composition useful for adhesion prevention or hemostasis | |
| Ko et al. | Recent progress in liquid embolic agents | |
| JPS6363534B2 (en) | ||
| Zhang et al. | Investigation on ionical cross-linking of alginate by monovalent cations to fabrication alginate gel for biomedical application | |
| Jiang et al. | Liquid embolic agents for interventional embolization | |
| US9655842B1 (en) | Injectable non-aqueous compositions and methods of treating vascular disease | |
| WO2001024775A9 (en) | Gel-forming compositions | |
| CN111557898B (en) | Embolism agent and preparation method thereof | |
| JP2842647B2 (en) | Drug sustained release granules and method for producing the same | |
| CN107875436B (en) | Sodium bicarbonate powder-loaded liquid embolic agent composition and application thereof | |
| CN101283978A (en) | Anticancer sustained-release gel injection containing platinum compound | |
| Xie et al. | A thermosensitive Pickering gel emulsion with a high oil–water ratio for long-term X-ray imaging and permanent embolization of arteries | |
| Hu et al. | Temperature-responsive hydrogel for tumor embolization therapy |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220105 Address after: 215500 No.8 Shengyu Avenue, Haiyu Town, Changshu City, Suzhou City, Jiangsu Province Patentee after: Suzhou Shenrun Medical Technology Co.,Ltd. Address before: 200032 Shanghai city Xuhui District Xietu Road 2200 Lane 25 Patentee before: SHANGHAI CANCER INSTITUTE |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220119 Address after: 215500 No.8 Shengyu Avenue, Haiyu Town, Changshu City, Suzhou City, Jiangsu Province Patentee after: Suzhou Shenrun Medical Technology Co.,Ltd. Patentee after: Jiangsu Shenming Medical Technology Co., Ltd Address before: 215500 No.8 Shengyu Avenue, Haiyu Town, Changshu City, Suzhou City, Jiangsu Province Patentee before: Suzhou Shenrun Medical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |