CN108113976A - TH-302 preparations, preparation method and its usage - Google Patents
TH-302 preparations, preparation method and its usage Download PDFInfo
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- CN108113976A CN108113976A CN201810164476.7A CN201810164476A CN108113976A CN 108113976 A CN108113976 A CN 108113976A CN 201810164476 A CN201810164476 A CN 201810164476A CN 108113976 A CN108113976 A CN 108113976A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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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- 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
- A61L24/0015—Medicaments; Biocides
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- 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
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
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- 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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- 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
- A61L2300/60—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
- A61L2300/604—Biodegradation
-
- 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
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
- A61L2300/622—Microcapsules
Abstract
Microball preparation, Its Preparation Method And Use the present invention relates to TH 302.TH 302 is contained with the carrier material polylactic acid or polylactic acid/hydroxy acetate multipolymer that catabolite is lactic acid or hydroxyacetic acid or its pharmaceutical salts is prepared into embolism microball, on the one hand the blood supply of the physical barriers obstruction tumor tissues of microballoon can be utilized, on the other hand the activated product of TH302 can be slowly released under the action of the acid that carrier material degradation generates, further enhances antitumor action.
Description
Technical field
The present invention relates to for treating the pharmaceutical preparation of liver cancer more particularly to a kind of treat late period inoperable liver
TH-301 preparations, preparation method and the purposes of cancer patient.
Background technology
Liver cancer (Hepatocellular carcinoma HCC) is one of worldwide malignant tumour, liver cancer onset
Concealment, progress is rapid, life cycle is short, seriously endangers human health.The patient for having more than 500,000 each year occurs, and is the whole world the 3rd
The relevant cause of death of position cancer.Incidence 3.6/10 ten thousand~10.6/10 ten thousand in Europe, global incidence 16.0/10 ten thousand
People.Liver cancer patient primary treatments are surgical operation at present, but it is good to be also only limitted to early liver cancer effect, for most of liver cancer
Patient has been middle and advanced stage when being diagnosed, without operative chance.
The distribution of tumor tissues medium vessels is different from normal structure, mixed and disorderly unordered, cause its microenvironment be studded with low-oxygen area and
Chang Yang areas.In Chang Yang areas, tumour cell generation is rapid and extremely sensitive to classic chemotherapy, and low-oxygen area tumour cell is then in
Dormant state has repellence to standard chemotherapeutic and radiotherapy, becomes the major obstacle of oncotherapy.
TH-302 is the prodrug of Nitroimidazole class, is the tool synthesized by Threshold drugmakers researcher design
The selective hypoxemia activated form DNA alkylating agents of high cell toxicity.Tool alkanisation can be converted into tumor hypoxia area or chance acid activation
The dibromo isophosphoramide mustard of agent activity, but it is almost inactive under the conditions of normal oxygen or normal pH.
At present, the report for being reported as peroral dosage form of domestic and international related TH-302, Publication No.：US20140072624A1,
In addition other reports on TH-302 dosage forms be there is no.Oral medication belongs to systemic administration, is only that a part of drug reaches cancer
Cell, therefore its toxic side effect is very big.
The content of the invention
In view of the above problems, the present invention is directed to propose a kind of TH-302 preparations, can be administered with relatively low metering so that
Drug reduces the toxic side effect for the person of being administered.
The TH-302 preparations of the present invention, including active medicine and carrier material；Active medicine coats shape by carrier material
As microballoon；
Wherein, active medicine is the pharmaceutical salts of TH-302 or TH-302；Carrier material is that catabolite is lactic acid or hydroxyl
The material of acetic acid.
Preferably, the carrier material for polylactic acid, Poly(D,L-lactide-co-glycolide, or both mixture.
Preferably, the polylactic acid is the polylactic acid of ester sealing end or c-terminus；The Poly(D,L-lactide-co-glycolide is
Ester blocks or the Poly(D,L-lactide-co-glycolide of c-terminus.
Preferably, lactic acid/hydroxyacetic acid percentage in the Poly(D,L-lactide-co-glycolide of the ester sealing end or c-terminus
For 75:25.
Preferably, the grain size of the microballoon is in 75 μm -300 μm.
For above-mentioned TH-302 preparations, the present invention also proposes its preparation method, including：
Active medicine and carrier material are added in organic solvent, are completely dissolved drug and carrier material by the first step
And it is uniformly mixed；
Second step, will be dissolved completely in organic solvent and uniformly mixed drug and carrier material be injected into it is dense containing first
It spends in the water phase of emulsifier and forms lotion；
The lotion is transferred in the water phase of the emulsifier containing the second concentration, stirring at low speed by the 3rd step, is vapored away organic
It centrifuged, washed after solvent, obtain the microball preparation of TH-302.
Preferably, further include：4th step, the microball preparation of the TH-302 to obtaining freeze, and obtain microballoon lyophilized powder.
Preferably, the organic solvent be selected from dichloromethane, ethyl acetate, acetone, ethyl alcohol, methanol, benzyl alcohol and its
In two or more mixture；
The emulsifier be selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium polymethacrylate,
Polypropylene, gelatin, tragacanth and two or more mixture therein.
Preferably, the first concentration, the emulsifier of the second concentration refer to the proportion of emulsifier in water and account for 0.2%-10%, more excellent
Selection of land, the second concentration are less than the first concentration.
The present invention also proposes the purposes of TH-302 preparations, individually or with other radiotherapy and chemotherapy medicines is combined, for treating
Liver cancer.
The present invention is based on the characteristics of TH-302, by it with the carrier material polylactic acid that catabolite is lactic acid or hydroxyacetic acid
Or polylactic acid/hydroxy acetate multipolymer contains and is prepared into embolism microball, the physical barriers obstruction that on the one hand can utilize microballoon is swollen
On the other hand the blood supply of tumor tissue can slowly release TH302's under the action of the acid that carrier material degradation generates
Activated product further enhances antitumor action.
Description of the drawings
The TH-302 preparations that Fig. 1 is the present invention are formed as In-vitro release curves during the microballoon of different grain sizes.
Specific embodiment
The present invention provides TH-302 in the form of being sustained embolism microball, including TH-302, PLGA or PLA.It provides
Using PLGA/PLA as host material, prepare the smooth rounding in surface, regular particles without adhesion, grain size 75 μm -100 μm, 100 μm -
(table 1), drugloading rate and envelop rate higher (table 2), the TH- of sustained release two weeks (Fig. 1) within the scope of 200 μm, 200 μm -300 μm three
302 Microspheres For Embolization of Hepatic Artery and preparation method thereof.
The invention further relates to the preparation methods of TH-302 Microspheres For Embolization of Hepatic Artery, it is using single emulsification-evaporation method system
It is standby, active medicine and biodegradable pharmaceutical polymers are dissolved in one or more kinds of organic solvents and form oil
Phase, the organic solvent be selected from dichloromethane, ethyl acetate, acetone, ethyl alcohol, methanol, benzyl alcohol or more than one be mixed with
Solvent.In addition continuous aqueous phase is prepared, nonionic surface active agent is soluble in water, their weight percent in water are
2%-5%.The nonionic surface active agent is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, poly-
Sodium methacrylate, polypropylene, gelatin and tragacanth.The step of single emulsification-evaporation method prepares microballoon be：Macromolecule is auxiliary
Material and active medicine TH-302 are added to dichloromethane or in the mixed solvent, until completely dissolved and after mixing, with injection
Meter above-mentioned mixed solution is injected under 250-500rpm stirring conditions in the water phase of suitable concentration, under conditions of 4 DEG C after
Continue after stirring into lotion, above-mentioned emulsion is transferred in the water phase of low concentration, stirring at low speed 4-5h, volatile organic solvent；So
Afterwards, 4000-9000rpm is centrifuged, and microballoon is collected in washing, carries out vacuum freeze drying up to microballoon lyophilized powder.
Microspherical carrier material of the present invention is selected from PLGA, and molecular weight is 9800 dalton, LA in PLGA：GA mass percents
For 75：25.Microspherical carrier material of the present invention or selected from PLA.Microspherical carrier material of the present invention can also be the mixing of PLGA and PLA
Object.
The present invention is using common electromagnetic force blender or mechanical agitation its device, mixing speed 250rpm-500rpm.
The weight percent that nonionic emulsifier accounts for more in water phase is 2%-5%.
The microsphere features smooth surface rounding prepared using the method for the present invention, regular particles without adhesion, particle diameter distribution 75 μm-
Within the scope of 100 μm, 100 μm -200 μm, 200 μm -300 μm three (table 1).Envelop rate is higher (table 2), and the sustained release phase is two weeks
The microballoon of (Fig. 1).
In the following, with reference to attached drawing, to the TH-302 preparations of the present invention, and its preparation method and application be described in detail.
The TH-302 preparations of the present invention, are formed as embolism microball.
Embolism microball carrier can be divided into natural, synthesis, semi-synthetic high molecular material.Natural macromolecular material mainly has：
Gelatin, alginate, chitosan, protide；Semi-synthetic natural macromolecular material has：Cellulose derivative；The high score of synthesis
Sub- material has：Polylactic acid (PLA) and polylactide glycolic acid copolymer (PLGA).High molecular material is synthesized because of its biocompatibility
Good, degradable in vivo, stability is preferable, is a kind of preferably microsphere supported.Wherein polylactide glycolic acid copolymer,
Its catabolite in vivo is the metabolite that human body generates under normal circumstances, is widely used in microball preparation.
1 ester of example blocks influences of the PLGA to microsphere encapsulation rate
It weighs 0.6g esters sealing end PLGA to be dissolved in organic solvent oil phase is made, organic solvent is dichloromethane or dichloromethane
With the mixture of methanol.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, after ultrasonic mixing is uniform, obtains
Drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, mistake is supplied after dissolving by heating PVA repeatedly in micro-wave oven
After weight, the aqueous phase solution that concentration is 3% had both been obtained.By above-mentioned oil phase, 15ml, 3% PVA are injected into certain speed with syringe pump
In solution, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4- by 4 DEG C
5h, volatile organic solvent, centrifugation, washing, the dry PLGA microballoons to get ester sealing end, and microsphere encapsulation rate measure is carried out, as a result
As shown in table 1.
Influences of the 2 c-terminus PLGA of example to microsphere encapsulation rate
It weighs 0.6g c-terminuses PLGA and is dissolved in organic solvent and oil phase is made, organic solvent is dichloromethane or dichloromethane
With the mixture of methanol.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, after ultrasonic mixing is uniform, obtains
Drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, mistake is supplied after dissolving by heating PVA repeatedly in micro-wave oven
After weight, the aqueous phase solution that concentration is 3% had both been obtained.By above-mentioned oil phase, 15ml, 3% PVA are injected into certain speed with syringe pump
In solution, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4- by 4 DEG C
5h, volatile organic solvent, centrifugation, washing, the dry PLGA microballoons to get c-terminus, and microsphere encapsulation rate measure is carried out, as a result
As shown in table 1.
Influences of the 3 hydroxyl terminal PLGA of example to microsphere encapsulation rate
It weighs 0.6g hydroxyl terminals PLGA and is dissolved in organic solvent and oil phase is made, organic solvent is dichloromethane or dichloromethane
With the mixture of methanol.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, after ultrasonic mixing is uniform, obtains
Drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, mistake is supplied after dissolving by heating PVA repeatedly in micro-wave oven
After weight, the aqueous phase solution that concentration is 3% had both been obtained.By above-mentioned oil phase, 15ml, 3% PVA are injected into certain speed with syringe pump
In solution, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4- by 4 DEG C
5h, volatile organic solvent, centrifugation, washing, the dry PLGA microballoons to get hydroxyl terminal, and microsphere encapsulation rate measure is carried out, as a result
As shown in table 1.
Influence of the PLGA carrier materials of the different sealing ends of table 1 to microsphere encapsulation rate
4 ester of example blocks influences of the PLA to microsphere encapsulation rate
It weighs 0.6g esters sealing end PLA to be dissolved in organic solvent oil phase is made, organic solvent is dichloromethane or dichloromethane
With the mixture of methanol.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, after ultrasonic mixing is uniform, obtains
Drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, mistake is supplied after dissolving by heating PVA repeatedly in micro-wave oven
After weight, the aqueous phase solution that concentration is 3% had both been obtained.By above-mentioned oil phase, 15ml, 3% PVA are injected into certain speed with syringe pump
In solution, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4- by 4 DEG C
5h, volatile organic solvent, centrifugation, washing, the dry PLA microballoons to get ester sealing end, and microsphere encapsulation rate measure is carried out, as a result
As shown in table 2.
Influences of the 5 c-terminus PLA of example to microsphere encapsulation rate
It weighs 0.6g c-terminuses PLA and is dissolved in organic solvent and oil phase is made, organic solvent is dichloromethane or dichloromethane
With the mixture of methanol.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, after ultrasonic mixing is uniform, obtains
Drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, mistake is supplied after dissolving by heating PVA repeatedly in micro-wave oven
After weight, the aqueous phase solution that concentration is 3% had both been obtained.By above-mentioned oil phase, 15ml, 3% PVA are injected into certain speed with syringe pump
In solution, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4- by 4 DEG C
5h, volatile organic solvent, centrifugation, washing, the dry PLA microballoons to get c-terminus, and microsphere encapsulation rate measure is carried out, as a result
As shown in table 2.
Influences of the 6 hydroxyl terminal PLA of example to microsphere encapsulation rate
It weighs 0.6g hydroxyl terminals PLA and is dissolved in organic solvent and oil phase is made, organic solvent is mixed for dichloromethane and methanol
Close object.Precision weighs a certain amount of TH-302 active medicines and is dissolved in above-mentioned oil phase, and after ultrasonic mixing is uniform, it is organic to obtain drug containing
Phase.Appropriate PVA is weighed in the distilled water of certain volume, is dissolved by heating repeatedly in micro-wave oven after supplying weightlessness after PVA, both
Concentration is 3% aqueous phase solution.By above-mentioned oil phase, it is injected into syringe pump with certain speed in 15ml, 3% PVA solution,
After 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution, 250rpm, stirs 4-5h, volatilization by 4 DEG C
Organic solvent, centrifugation, washing, the dry PLA microballoons to get hydroxyl terminal, and microsphere encapsulation rate measure is carried out, as a result such as 2 institute of table
Show.
Influence of the PLA carrier materials of the different sealing ends of table 2 to microsphere encapsulation rate
The preparation of the TH-302-PLGA Microspheres For Embolization of Hepatic Artery of 7 different-grain diameter of example
Weigh ester sealing end PLGA 0.6g (molecular weight 9800LA:GA is 75:25) it is dissolved in organic solvent and oil phase is made,
Organic solvent is dichloromethane and the mixture of methanol.The TH-302 active medicines that precision weighs recipe quantity are dissolved in above-mentioned oil phase
In, after ultrasonic mixing is uniform, obtain drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, in micro-wave oven repeatedly
Weightlessness is supplied after dissolving by heating PVA, has both obtained the PVA aqueous phase solutions that concentration is 5%.By above-mentioned oil phase syringe pump with certain speed
It is injected into 15mlPVA aqueous phase solutions, after 350rpm stirrings 7min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution,
250rpm, stirs 4-5h by 4 DEG C, and volatile organic solvent, centrifugation, washing, drying measure microballoon with Malvern particle size determinations instrument
Grain size.
The preparation of the TH-302-PLGA Microspheres For Embolization of Hepatic Artery of 8 different-grain diameter of example
Weigh ester sealing end PLGA 0.6g (molecular weight 9800LA:GA is 75:25) it is dissolved in organic solvent and oil phase is made,
Organic solvent is dichloromethane and the mixture of methanol.The TH-302 active medicines that precision weighs recipe quantity are dissolved in above-mentioned oil phase
In, after ultrasonic mixing is uniform, obtain drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, in micro-wave oven repeatedly
Weightlessness is supplied after dissolving by heating PVA, has both obtained the PVA aqueous phase solutions that concentration is 5%.By above-mentioned oil phase, with syringe pump with a constant speed
Degree is injected into 15mlPVA aqueous phase solutions, after 350rpm stirrings 5min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution
In, 250rpm, stirs 4-5h by 4 DEG C, and volatile organic solvent, centrifugation, washing, drying are measured micro- with Malvern particle size determinations instrument
The grain size of ball.
The preparation of the TH-302-PLGA Microspheres For Embolization of Hepatic Artery of 9 different-grain diameter of example
Weigh ester sealing end PLGA 0.6g (molecular weight 9800LA:GA is 75:25) it is dissolved in organic solvent and oil phase is made,
Organic solvent is dichloromethane and the mixture of methanol.The TH-302 active medicines that precision weighs recipe quantity are dissolved in above-mentioned oil phase
In, after ultrasonic mixing is uniform, obtain drug containing organic phase.Appropriate PVA is weighed in the distilled water of certain volume, in micro-wave oven repeatedly
Weightlessness is supplied to get the PVA aqueous phase solutions that concentration is 5% after dissolving by heating PVA.By above-mentioned oil phase, with syringe pump with a constant speed
Degree is injected into 15mlPVA aqueous phase solutions, after 250rpm stirrings 5min, by above-mentioned emulsion transferase 12 50ml, 2% PVA solution
In, 250rpm, stirs 4-5h by 4 DEG C, and volatile organic solvent, centrifugation, washing, drying are measured micro- with Malvern particle size determinations instrument
The grain size of ball.
The TH-302-PLGA Microspheres For Embolization of Hepatic Artery of 3 different-grain diameter of table
TH-302-PLGA Microspheres For Embolization of Hepatic Artery Particle Size Determination Methods
This experiment measures the grain size of microballoon using Malvern particle size determinations instrument.Weigh a certain amount of microballoon prepared extremely
700mL contains in the distilled water of 5% suspending agent sodium carboxymethylcellulose, and compound concentration is 5% microsphere suspension, until
Malvern particle size determinations instrument measures microspherulite diameter.Mainly microspherulite diameter effect is evaluated by two parameters of span and D50.It is real
The results are shown in Table 3 for the particle size determination of example 7,8,9.
TH-302-PLGA Microspheres For Embolization of Hepatic Artery release in vitro methods
The release in vitro that microballoon is carried out using cultivation is investigated, the phosphorus that it is 7.4 added with surfactant pH that dissolution medium, which is,
Phthalate buffer.Specific method is：Suitable microballoon is weighed, until 250ml conical flasks, add in 100ml dissolution mediums, be placed into 37
DEG C, in the constant temperature water bath shaking table of 100rpm frequencies shaking, the sample of certain volume is taken in different time points, centrifugation takes
Clear liquid, while the blank dissolution medium of same volume is supplemented, lower floor's microballoon liquid, which is poured into conical flask, to be continued to discharge, this experiment is made
Standby microballoon can be sustained two weeks (Fig. 1).By releasing curve diagram it can be seen that the smaller example 7 of grain size, rate of release compared with
Example 8 and 9 is fast, and the releasing trend of example 8 and 9 is suitable.
The TH-302 preparations of the present invention can be used as arterial embolism microballoon, by contrast agent by way of intubation intervention,
The feeding artery of Embolization for Hepatic Carcinoma patient tumors.First aspect has blocked the blood supply of tumour, and tumour is made to be in one for a long time
The state of " starvation "；What second aspect made the drug long period rests on tumor locus, slowly discharges drug and improves medicine
Object blood concentration；The third aspect is stronger to the Execution of tumor microenvironment low-oxygen area, to the side effect of body normal structure compared with
It is small.
By the way that TH-302 is made as microballoon, drug is introduced directly into tumour and carries out local application, is extended with sustained release forms
The action time of drug, while treatment of the guarantee drug to tumour, it is secondary to the poison of subject farthest to reduce drug
Effect.
Claims (10)
1. a kind of TH-302 preparations, including active medicine and carrier material；Active medicine is formed as micro- by carrier material cladding
Ball；
Wherein, active medicine is the pharmaceutical salts of TH-302 or TH-302；Carrier material is that catabolite is lactic acid or hydroxyacetic acid
Material.
2. TH-302 preparations as described in claim 1, it is characterised in that：The carrier material is polylactic acid, polylactic acid-glycolic base
Acetate multipolymer, or both mixture.
3. TH-302 preparations as described in claim 1, it is characterised in that：The polylactic acid is blocked for ester or the poly- breast of c-terminus
Acid；The Poly(D,L-lactide-co-glycolide is blocked for ester or the Poly(D,L-lactide-co-glycolide of c-terminus.
4. TH-302 preparations as claimed in claim 3, it is characterised in that：The polylactic acid-glycolic base of the ester sealing end or c-terminus
Lactic acid/hydroxyacetic acid percentage is 75 in acetate multipolymer:25.
5. TH-302 preparations as described in claim 1, it is characterised in that：The grain size of the microballoon is in 75 μm -300 μm.
6. the preparation method of the TH-302 preparations any one of claim 1-5, including：
Active medicine and carrier material are added in organic solvent, drug and carrier material are made to be completely dissolved and mix by the first step
It closes uniform；
Second step, will be dissolved completely in organic solvent and uniformly mixed drug and carrier material are injected into containing the first concentration breast
Lotion is formed in the water phase of agent；
3rd step, the lotion is transferred in the water phase of the emulsifier containing the second concentration, and stirring at low speed vapors away organic solvent
After centrifuged, washed, obtain the microball preparation of TH-302.
7. method as claimed in claim 6, it is characterised in that further comprise：
4th step, the microball preparation of the TH-302 to obtaining freeze, and obtain microballoon lyophilized powder.
8. method as claimed in claim 6, it is characterised in that：
The organic solvent is selected from dichloromethane, ethyl acetate, acetone, ethyl alcohol, methanol, benzyl alcohol and two kinds or two therein
Kind or more mixture；
The emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium polymethacrylate, poly- third
Alkene, gelatin, tragacanth and two or more mixture therein.
9. method as claimed in claim 6, it is characterised in that：
First concentration, the emulsifier of the second concentration refer to the proportion of emulsifier in water and account for 0.2%-10%.
10. the purposes of the TH-302 preparations any one of claim 1-5 individually or with other radiotherapy and chemotherapy medicines joins
With for treating liver cancer.
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