CN109663145A - A kind of lipiodol targeted drug compound - Google Patents
A kind of lipiodol targeted drug compound Download PDFInfo
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- CN109663145A CN109663145A CN201811575943.1A CN201811575943A CN109663145A CN 109663145 A CN109663145 A CN 109663145A CN 201811575943 A CN201811575943 A CN 201811575943A CN 109663145 A CN109663145 A CN 109663145A
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- Prior art keywords
- lipiodol
- targeted drug
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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
- A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
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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
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Abstract
The invention discloses a kind of lipiodol targeted drug compound, including lipiodol and targeted drug, targeted drug is gathered in in-vivo tumour region by lipiodol targeting.Lipiodol brings targeted drug into tumor region as a kind of suppository or a kind of region targeting agent in the present invention, and targeted drug targeting gathers tumor region, rather than is applied to the organ-tissue of other non-tumours, to alleviate the side effect of targeted drug；Some targeted drugs with angiogenesis inhibiting effect can also inhibit angiogenesis caused by the release of transcatheter arterial embolization bring inflammatory factor, to inhibit the hyperplasia of the not exclusively caused residual tumor tissue of transcatheter arterial embolization.
Description
Technical field
The invention belongs to technical field of bioengineering, and in particular to a kind of lipiodol targeted drug compound.
Background technique
Transcaheter cloure (TACE) is the main means for treating rich blood supply tumour especially mid and late liver cancer
One of, because its effective and safe is widely recognized.The suppository that traditional TACE treatment uses is lipiodol or lipiodol and its
The mixed emulsion of its chemotherapeutics.Lipiodol and lipiodol carry chemotherapeutics and are trapped within performance killing tumor cell in tumour cell
Effect.Under normal conditions, lipiodol is retained in hepatocellular carcinoma (HCC) lesion 8-12 months, and can within 4 weeks from normal or
It is washed out in cirrhosis, liver parenchyma.But simple TACE treatment is difficult to block tumor tissues blood supply completely and kill all swollen
Oncocyte.Embolism is not exclusively after some patientss TACE or deposition is not good enough, and biggish tumour peripheral part is difficult to thorough embolism,
Often there is tumour cell residual.And postoperative cause tumor by local anoxic, the vascular endothelial growth factor of remaining tumor cells
(vascular endothelial growth factor, VEGF) expression is higher, generates residual tumor tissue new vessels
Also increase, and form offshoot circulation.
Summary of the invention
It is an object of the invention to overcome prior art defect, a kind of lipiodol targeted drug compound is provided.
Technical scheme is as follows:
A kind of lipiodol targeted drug compound, including
Lipiodol, as suppository and/or region targeting agent；
Targeted drug, to inhibit neonate tumour blood vessel and/or directly inhibition tumour cell；
Targeted drug is gathered in in-vivo tumour region by lipiodol targeting.
In a preferred embodiment of the invention, the targeted drug is dissolved in lipiodol by solvent.
In a preferred embodiment of the invention, be water-in-oil emulsion, the lipiodol be oil mutually and continuous phase,
The targeted drug is in water phase, and water phase is dispersed phase.
It is further preferred that the partial size of the dispersed phase is 1nm-50 μm.
It in a preferred embodiment of the invention, is water-in-oil-in water multiple emulsion, at the targeted drug
In the water phase of innermost layer, lipiodol is intermediate oily phase.
It is further preferred that the partial size of its dispersed phase is 1nm-50 μm.
In a preferred embodiment of the invention, the tumour is malignant entity tumor.
The beneficial effects of the present invention are:
1, effect of the invention is relatively lasting: because there is the lipiodol in the present invention selectivity to enter and be stranded in tumor tissues
Characteristic, so the targeted drug in the present invention is as lipiodol deposition is in tumor locus, as lipiodol is removed by body, target
It is also removed to drug, but as long as lipiodol exists in lesions position, targeted drug is also always existed.
2, side effect of the invention reduces: lipiodol, will as a kind of suppository or a kind of region targeting agent in the present invention
Targeted drug brings tumor region into, and targeted drug targeting gathers tumor region, rather than is applied to the device of other non-tumours
Official's tissue, to alleviate the side effect of targeted drug；Some targeted drugs with angiogenesis inhibiting effect, can also press down
Angiogenesis caused by transcatheter arterial embolization bring inflammatory factor release processed, to inhibit the not exclusively caused remaining of transcatheter arterial embolization
The hyperplasia of tumor tissues.
3, present invention synergistic effect improves curative effect: the embolism hindrance blocks blood of tumor tissues of the lipiodol in the present invention
For inhibiting tumour growth；Targeted drug in the present invention directly inhibits tumor cell proliferation or by inhibiting neonate tumour blood vessel
Inhibit tumor tissues hyperplasia indirectly；Targeted drug of the present invention and lipiodol improve curative effect with using.
4, the radiography function of the lipiodol in the present invention checks and evaluates curative effect convenient for postoperative CT.
5, the safety in utilization that lipiodol is improved after W/O/W multiple emulsion is made in the present invention, can be infused by vein
It penetrates, carries out systemic therapy.
Detailed description of the invention
Fig. 1 is the comparison diagram of each group mouse tumor volume after being administered in the embodiment of the present invention 4.
Fig. 2 is the comparison diagram of each group mouse knurl weight after being administered in the embodiment of the present invention 4.
Specific embodiment
Technical solution of the present invention is further explained and described below by way of specific embodiment combination attached drawing.
Embodiment 1
A kind of lipiodol targeted drug compound, including
Lipiodol, as suppository and/or region targeting agent；
Targeted drug, to inhibit neonate tumour blood vessel and/or directly inhibition tumour cell；
Targeted drug is gathered in in-vivo tumour region by lipiodol targeting, as lipiodol is removed by body, targeted drug
It is removed, but as long as lipiodol exists in lesions position, targeted drug is also always existed.
Wherein, the targeted drug is dissolved in lipiodol by can dissolve the solvent of targeted drug.
Lipiodol is to meet all lipiodines required under Pharmacopoeia of the People's Republic of China iodized oil item.Targeted drug
It has been listed and in the small molecule targeted drug ground, include but are not limited to following drug: Gefitinib, Lip river in distress are replaced including all
Buddhist nun, Conmana, gram azoles replace Buddhist nun, Lapatinib, everolimus, pa for Buddhist nun, Afatinib, Ceritinib, Ai Le for Buddhist nun, difficult to understand wish
Bo Xini, Imatinib, Sutent, Rui Gefeini, Ah pa win for Buddhist nun, Sorafenib, Vande Thani, card and replace for Buddhist nun, happy cut down
Buddhist nun, tesirolimus, pazopanib, pazopanib, olaparib, Wei Luofeini, darafinib, Trimetinib, examine than for Buddhist nun,
Vismodegib, Sonidegib etc..
By taking targeted drug is toluenesulfonic acid Sorafenib as an example, it is prepared as follows:
Toluenesulfonic acid Sorafenib 50mg is added in 4mL lipiodol after adding 1mL dmso solution, mixes well, i.e.,
?.
Embodiment 2
A kind of lipiodol targeted drug compound, including
Lipiodol, as suppository and/or region targeting agent；
Targeted drug, to inhibit neonate tumour blood vessel and/or directly inhibition tumour cell；
Targeted drug is gathered in in-vivo tumour region by lipiodol targeting, as lipiodol is removed by body, targeted drug
It is removed, but as long as lipiodol exists in lesions position, targeted drug is also always existed.
It is water-in-oil emulsion, and the lipiodol is that oil is mutually in water phase with continuous phase, the targeted drug, and water phase is
Dispersed phase.The partial size of the dispersed phase is 1nm-50 μm.
Lipiodol is to meet all lipiodines required under Pharmacopoeia of the People's Republic of China iodized oil item.Targeted drug
It has been listed and in the small molecule targeted drug ground, include but are not limited to following drug: Gefitinib, Lip river in distress are replaced including all
Buddhist nun, Conmana, gram azoles replace Buddhist nun, Lapatinib, everolimus, pa for Buddhist nun, Afatinib, Ceritinib, Ai Le for Buddhist nun, difficult to understand wish
Bo Xini, Imatinib, Sutent, Rui Gefeini, Ah pa win for Buddhist nun, Sorafenib, Vande Thani, card and replace for Buddhist nun, happy cut down
Buddhist nun, tesirolimus, pazopanib, pazopanib, olaparib, Wei Luofeini, darafinib, Trimetinib, examine than for Buddhist nun,
Vismodegib, Sonidegib etc..
By taking targeted drug is Sorafenib as an example, it is prepared as follows:
Formula: water phase is Sorafenib acetum (2mg/mL), and oil is mutually lipiodol and isopropyl myristate, emulsifier
For isopropyl myristate, cosolvent is dimethyl sulfoxide (DMSO).Above-mentioned acetic acid may be replaced by other it is ionizable go out H from
The acid solution (for example, concentrated hydrochloric acid) of son, emulsifier can also be Arlacel-80.
Method: the lipiodol of 1.6mL is uniformly mixed with 2.4mL isopropyl myristate, addition 200 μ L of DMSO, then with
1mL Sorafenib acetum (2mg/mL) mixing, ultrasonic 6min make the bubble for being sufficiently mixed and excluding to be likely to form, homogenizer
It is gradually adjusted to 15000r/min, homogeneous 10min, that is, emulsion A (water-in-oil emulsion) is made.
Embodiment 3
A kind of lipiodol targeted drug compound, including
Lipiodol, as suppository and/or region targeting agent；
Targeted drug, to inhibit neonate tumour blood vessel and/or directly inhibition tumour cell；
Targeted drug is gathered in in-vivo tumour region by lipiodol targeting, as lipiodol is removed by body, targeted drug
It is removed, but as long as lipiodol exists in lesions position, targeted drug is also always existed.
It is water-in-oil-in water multiple emulsion, and the targeted drug is in the water phase of innermost layer, and lipiodol is intermediate oil
Phase.The partial size of its dispersed phase is 1nm-50 μm.
Lipiodol is to meet all lipiodines required under Pharmacopoeia of the People's Republic of China iodized oil item.Targeted drug
It has been listed and in the small molecule targeted drug ground, include but are not limited to following drug: Gefitinib, Lip river in distress are replaced including all
Buddhist nun, Conmana, gram azoles replace Buddhist nun, Lapatinib, everolimus, pa for Buddhist nun, Afatinib, Ceritinib, Ai Le for Buddhist nun, difficult to understand wish
Bo Xini, Imatinib, Sutent, Rui Gefeini, Ah pa win for Buddhist nun, Sorafenib, Vande Thani, card and replace for Buddhist nun, happy cut down
Buddhist nun, tesirolimus, pazopanib, pazopanib, olaparib, Wei Luofeini, darafinib, Trimetinib, examine than for Buddhist nun,
Vismodegib, Sonidegib etc..
By taking targeted drug is Sorafenib as an example, it is prepared as follows:
Formula: inner aqueous phase is Sorafenib acetum (2mg/mL), and oil is mutually lipiodol and isopropyl myristate, outer water
It is mutually sodium bicarbonate aqueous solution (5%, w/v) that emulsifier is isopropyl myristate, Pluronic F-88, Arlacel-80, spits
Temperature -80 etc., cosolvent is dimethyl sulfoxide.Outer aqueous phase: oily phase: inner aqueous phase volume ratio is 5: 4: 1, and emulsifier is in outer aqueous phase
Concentration is 5% (w/v), and cosolvent dimethyl sulfoxide concentration in oily phase is 5% (v/v).Above-mentioned acetic acid may be replaced by it
The acid solution (for example, concentrated hydrochloric acid) of his ionizable H ion out, above-mentioned outer aqueous phase can also be sodium chloride solution.
Method: water-in-oil emulsion first is prepared as colostrum, 5mL sodium bicarbonate aqueous solution (5%w/ by 2 method of embodiment
V) it is mixed with Pluronic F-88 (5%w/v) as outer aqueous phase.Outer aqueous phase is slowly stirred with magnetic stirring apparatus, revolving speed
Colostrum is pressed into outer aqueous phase by SPG film (0.1-19.6 μm of aperture), i.e., then under the constant pressure of 50kPa by 200r/min
Emulsion B (water-in-oil-in water multiple emulsion) is made.
4 lipiodol of embodiment-therapeutic effect of the Sorafenib combination drug to nude mice by subcutaneous liver cancer model
Nude mice by subcutaneous liver cancer model is established:
Male BALB/c-nu nude mouse, 4-5 week old, weight 12-14g.The human hepatoma cell strain MHCC-97H of culture exists
When cell is in growth logarithmic phase, cell is collected, is diluted to 1 × 107 living cells/mL with PBS buffer solution, 75% alcohol disinfecting is naked
Mouse back takes 0.2mL to inject nude mice by subcutaneous.Tumor formation nude mice 25 are chosen after being inoculated with 2 weeks, are used for following experiment.Experimental group and
Dosage:
Tumor-bearing mice is grouped at random: control group, oral administration group, knurl administration group, intravenously administrable group (n=5).Knurl is given
Medicine group: it according to the weight of animals, is calculated according to 2mg/kg Sorafenib, emulsion A is injected in subcutaneous knurl, once daily；It is quiet
Arteries and veins administration group: it according to the weight of animals, is calculated according to 2mg/kg Sorafenib, emulsion B is injected in mouse tail vein, is disposably given
Medicine；Oral administration group: according to the weight of animals, according to 2mg/kg Sorafenib+0.2mL physiological saline, stomach-filling, once a day；It is right
According to group: not giving any treatment.Surrounding is raised after administration, all experimental animal diet and rearing conditions are all the same.During raising
Subcutaneous tumors line of apsides of vernier caliper measurement is used weekly, and knurl product is calculated by formula: (wherein L is most for V=L × W2 × 0.52
Major diameter, W are shortest diameter).The 4th week measurement same day put to death mouse, and took tumour, weighed.
As a result:
As depicted in figs. 1 and 2, after being administered 4 weeks, the gross tumor volume and knurl weight of mouse are significantly less than control group, illustrate to treat
Achieve good effect.And knurl direct administration group (emulsion A) and intravenously administrable group (emulsion B) effect and oral administration group phase
Closely, but overall dosage is reduced, and can reduce damage of the drug induced side effect of large dosage to body.Results of animal
Show to improve safety after water-in-oil-in water multiple emulsion is made in lipiodol, it can be with intravenously administrable.
The foregoing is only a preferred embodiment of the present invention, the range that the present invention that therefore, it cannot be limited according to is implemented, i.e.,
Equivalent changes and modifications made in accordance with the scope of the invention and the contents of the specification should still be within the scope of the present invention.
Claims (7)
1. a kind of lipiodol targeted drug compound, it is characterised in that: including
Lipiodol, as suppository and/or region targeting agent；
Targeted drug, to inhibit neonate tumour blood vessel and/or directly inhibition tumour cell；
Targeted drug is gathered in in-vivo tumour region by lipiodol targeting.
2. a kind of lipiodol targeted drug compound as described in claim 1, it is characterised in that: the targeted drug passes through solvent
It is dissolved in lipiodol.
3. a kind of lipiodol targeted drug compound as described in claim 1, it is characterised in that: it is water-in-oil emulsion, institute
It states lipiodol to be mutually in water phase with continuous phase, the targeted drug for oil, water phase is dispersed phase.
4. a kind of lipiodol targeted drug compound as claimed in claim 3, it is characterised in that: the partial size of the dispersed phase is
1nm-50μm。
5. a kind of lipiodol targeted drug compound as described in claim 1, it is characterised in that: it is compound for water-in-oil-in water
Emulsion, the targeted drug are in the water phase of innermost layer, and lipiodol is intermediate oily phase.
6. a kind of lipiodol targeted drug compound as claimed in claim 5, it is characterised in that: the partial size of its dispersed phase is 1nm-
50μm。
7. a kind of lipiodol targeted drug compound as described in any claim in claim 1 to 6, it is characterised in that: institute
Stating tumour is malignant entity tumor.
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| CN201811575943.1A CN109663145A (en) | 2018-12-21 | 2018-12-21 | A kind of lipiodol targeted drug compound |
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| CN201811575943.1A CN109663145A (en) | 2018-12-21 | 2018-12-21 | A kind of lipiodol targeted drug compound |
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Family
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Cited By (4)
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| CN112933250A (en) * | 2020-12-17 | 2021-06-11 | 太阳雨林（厦门）生物医药有限公司 | Iodized oil emulsion or drug-loaded iodized oil emulsion and preparation method and application thereof |
| CN112933246A (en) * | 2020-12-17 | 2021-06-11 | 太阳雨林（厦门）生物医药有限公司 | Developable oil preparation and preparation method thereof |
| CN114377192A (en) * | 2021-12-28 | 2022-04-22 | 广东粤港澳大湾区国家纳米科技创新研究院 | Preparation method of embolism material |
| CN114470304A (en) * | 2021-12-28 | 2022-05-13 | 广东粤港澳大湾区国家纳米科技创新研究院 | Chemoembolization composition and application thereof |
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Cited By (4)
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| CN112933250A (en) * | 2020-12-17 | 2021-06-11 | 太阳雨林（厦门）生物医药有限公司 | Iodized oil emulsion or drug-loaded iodized oil emulsion and preparation method and application thereof |
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| CN114377192A (en) * | 2021-12-28 | 2022-04-22 | 广东粤港澳大湾区国家纳米科技创新研究院 | Preparation method of embolism material |
| CN114470304A (en) * | 2021-12-28 | 2022-05-13 | 广东粤港澳大湾区国家纳米科技创新研究院 | Chemoembolization composition and application thereof |
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