CN1682693A - An in situ gel drug delivery system for sclerotherapy of hemangiomas and vascular malformations - Google Patents
An in situ gel drug delivery system for sclerotherapy of hemangiomas and vascular malformations Download PDFInfo
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- CN1682693A CN1682693A CNA2005100460222A CN200510046022A CN1682693A CN 1682693 A CN1682693 A CN 1682693A CN A2005100460222 A CNA2005100460222 A CN A2005100460222A CN 200510046022 A CN200510046022 A CN 200510046022A CN 1682693 A CN1682693 A CN 1682693A
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- angioma
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- 208000009443 Vascular Malformations Diseases 0.000 title claims description 26
- 201000011066 hemangioma Diseases 0.000 title claims description 18
- 238000012377 drug delivery Methods 0.000 title claims description 14
- 238000011065 in-situ storage Methods 0.000 title description 2
- 238000007632 sclerotherapy Methods 0.000 title description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The medicine transfer system for hardening treatment of angioma and vascular deformation has in-site gel as medicine transfer system for injection to tumor cavity. The medicine transfer system may contain no any medicine; the angioma may be angioma or lymphangioma; the vascular deformation includes venule deformation, vein deformation, arteriovenous deformation, lymphatic vessel deformation and mixed deformation; and the medicine includes various kinds of medicine injected into tumor to cause angioma atrophy and elimination, such as sodium morrhuate, alum, Pingyangmycin, etc. The delayed releasing in-site gel can prolong the action time of medicine, reduce medicine amount, raised hardening effect and medicine bioavailability and reduced medicine toxicity.
Description
Technical field: the situ-gel drug delivery system that the present invention relates to a kind of hardening treating angioma and vascular malformation.
Background technology: hemangioma and vascular malformation are common optimum vascular pathological changes, and prevalence is up to 3%～8%.According to 1996 international vascular pathological changes research association (ISSVA) classification, can be divided into: true property hemangioma and vascular malformation.Vascular malformation is divided into blood capillary deformity, venous malformation, lymphatic vessel deformity, arteriovenous malformotion and Combination deformity again.
Hemangioma is a benign tumor common among the child.Morbidity is obviously more than Black people and yellow among the white children, and sickness rate will exceed one times of normal infant among the premature infant, and the ill ratio of men and women is about 1: 6.The hemangioma overwhelming majority finds soon that after birth about 30% pathological changes is found when being born.Incidence is angiomatous position occurred frequently, has 60～70% pathological changes to betide this zone approximately.Most of hemangioma betide skin or subcutaneous tissue.Divide proliferative phase, paracmasis, disappear the phase of finishing according to the process of pathological development.
Most of vascular malformations promptly exist at birth, but do not have tangible clinical symptoms.Vascular malformation does not have tangible proliferative phase and paracmasis, increases with age growth.The change of wound, infection, hormonal readiness, the increase of blood or lymph fluid pressure can promote the growth of pathological changes.The gradual increase of vascular malformation is not because due to the increasing of the endotheli ocytosis in the pathological changes or blood vessel, lymphatic vessel quantity, but because original blood vessel or the carrying out property expansion of lymphatic vessel tube chamber and cause in the pathological changes.Vascular endothelial cell in the vascular malformation has normal proliferating cycle.
At dissimilar vascular malformations and hemangioma numerous alternative Therapeutic Method are arranged at present, as the angiomatous hormone of infant, interferon therapy; Capillary hemangioma local freezing, isotope is applied ointment or plaster, laser therapy; Hemangioma racemosum or angiomatous thromboembolism of jawbone central authorities property or operative treatment; The angiocavernous microwave coagulation treatment heat of mucosa etc.But to cavernous hemangioma or venous malformation, blood capillary and the venous mixed hemangioma of seeing at most, and strawberry hemangioma, owing to have obvious tumor entity and blood vessel hole chamber to inject, then be prefered method with the injection of sclerosing agent for medicine.
But the hemangioma blood flow is abundant, is easy to run off after medicine injects, if strengthen the consumption or the multiple injection of sclerosing agent, the probability that drug side effect is taken place is increased greatly.Scientific seminar is consistent thinks for the treatment of 2002 national oromaxillo-facial region hemangioma and research: prolonging sclerosing agent in the holdup time of tumor intracavity, is one of key of raising sclerosing agent therapeutic effect.Have report to adopt tumor week seam to prick the back injection of sclerosing agent and can improve curative effect, but its operation is more loaded down with trivial details, patient's local response is heavier, and abundant to reach the higher hemangioma effect of blood flow rate not good enough to refluxing.
Present research mainly concentrates on the more suitable dosage form of discovery, prolongs the holdup time of Bleomycin A5 at the tumor intracavity.Existing research comprises the development and the Bleomycin A5 iodized oil Emulsion of Bleomycin A5 magnetic microsphere.Though both may improve the holdup time of Bleomycin A5 at the tumor intracavity to a certain extent, but still can not tackle the problem at its root.Wherein the Bleomycin A5 magnetic microsphere remains the feasibility problem on some concrete uses, as the anatomical position of blood vessel this technology is had no usage.Therefore, be badly in need of a kind of new dosage form of research now, not only practical but also can fundamentally solve the difficult problem of prolongation Bleomycin A5 in the tumor intracavity holdup time.
Situ-gel (in situ gel) is from the proposition of notion year surplus in the of 10 only so far, since its have unique solution gel property of transition make its have concurrently preparation simple, easy to use, organize advantages such as affinity is strong, the holdup time is long with agents area, purposes and good control Release Performance are subjected to abroad pharmaceutics person's great attention always widely in addition, at present existing sophisticated product is asked the city, and the research of China in this field still is in the starting stage.Situ-gel can freely load the medicine of various character and molecular weight with liquid condition, is the incomparable advantage of other drug transmission system.Particularly biodegradable situ-gel is showing the potentiality that attract people's attention aspect the long-acting implant system.
Summary of the invention: based on these advantages of situ-gel, the invention provides the novel form of a kind of hemangioma and vascular malformation sclerotherapy: the situ-gel drug delivery system of a kind of hardening treating angioma and vascular malformation.Situ-gel is the transmission system intracavitary injection.Situ-gel injection back is solid or semisolid drug depot by liquid system transition; The situ-gel system can not contain any medicine; Described hemangioma comprises hemangioma and lymphangioma; Described vascular malformation comprises venule deformity, venous malformation, arteriovenous malformotion, lymphatic vessel deformity, mixed type; Described medicine comprises the medicine of tumor drug disposition injection hyperamization tuberculation atresia; Described medicine comprises sodium morrhuate, Alumen, Bleomycin A5, hormone medicine, sodium tetradecyl sulfate, ethanolamine, amidotrizoic acid, quinoline, opium poppy oil, dehydrated alcohol, tetracycline, doxycycline, OKA-432 (molten chain bacterium), zein (zein), urea element, interferon; And the compositions more than both or both; The material of described situ-gel comprises polyoxyethylene polyoxypropylene block copolymer (PEO-PPO, or be called poloxamer), polyoxyethylene-polylactic acid (PEO-PLA) copolymer, pla-pcl-polyoxyethylene; And the compositions more than both or both; The material of described situ-gel comprises various fatty glycerides, as glyceryl monooleate (GMO), glycerol trioleate; And both compositionss; The material of described situ-gel comprises poly-third lactic acid (PLA), lactic acid ethanol copolymer (PLGA) or lactic acid caprolactone copolymer, and the compositions more than both or both; Poly-third lactic acid (PLA), lactic acid ethanol copolymer (PLGA) or lactic acid caprolactone copolymer comprise the polymer that contains special end group or functional group in the described situ-gel, are polylactic acid (PLA), lactic acid ethanol copolymer (PLGA) or the lactic acid caprolactone copolymer of end group as carboxyl; And the compositions more than both or both; The material of described situ-gel comprises the sucrose ester precipitate; Described sucrose ester precipitate comprise acetic acid sucrose isobutyl ester (sucrose acetate isobutyrate, SAIB), with and derivant; For regulating the rate of release of medicine, wherein can also add the above-mentioned material that forms situ-gel, or their both or both above compositions; In order to regulate drug releasing rate, can add the adjuvant or the additive that allow use on the pharmaceuticss such as cellulose derivative, polyvinylpyrrolidone, Polyethylene Glycol, and the compositions more than both or both.
Advantage of the present invention is: this slow release situ-gel can prolong drug action time, reduce the toxic and side effects of medication number of times and dosage, raising sclerosis and bioavailability of medicament, reduction medicine.
Description of drawings:
Fig. 1 is embodiment 2 vitro drug release curves.
Fig. 2 is embodiment 2 drug disposition release profiles.
Fig. 3 is embodiment 3 vitro drug release curves.
Fig. 4 is embodiment 3 drug disposition release profiles.
The specific embodiment:
Below will test the slow release effect that further specifies situ-gel drug delivery system of the present invention by embodiment and situ-gel drug delivery system inside and outside drug release.
1000 bottles prescription: SAIB 8000g, Bleomycin A5 8g, dehydrated alcohol 1000g, PLA1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 8000g, Bleomycin A5 4g, dehydrated alcohol 1000g, PLA1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 8000g, Bleomycin A5 8g, dehydrated alcohol 1000g, PLGA1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 8000g, dexamethasone 10g, dehydrated alcohol 1000g, glyceryl monooleate: glycerol trioleate mixture 1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 8000g, carbamide 40g, dehydrated alcohol 1000g, PEG100g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 4000g, doxycycline 4g, polyoxyethylene polyoxypropylene block copolymer 500g, dehydrated alcohol 1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
1000 bottles prescription: SAIB 2000g, doxycycline 4g, zein 1000g, dehydrated alcohol 1000g.Preparation technology: take by weighing each component by prescription, put in the blender, mix, stir, the sterilization packing promptly gets preparation.
The extracorporeal releasing test of situ-gel drug delivery system
Laboratory sample: according to the situ-gel of the embodiment of the invention 2,3 described method preparations
Experiment condition: temperature: 37 ± C °, rotating speed: 30rp/ minute.
Experimental technique: get buffer (50mM hydroxyethyl piperazine ethanesulfonic acid (HEPES), 5mM EDTA, the 0.01%w/vNaN of 100 μ l as for 1.5ml
3, pH8.0) in, put into constant temperature oscillator, sampling on time, HPLC detects.
Sampling time point (my god): 0,1,2,3,4,5,6,7.
Experimental result: the inside and outside release profiles of medicine is seen accompanying drawing 1 and accompanying drawing 2.
The vivo releasing test of situ-gel drug delivery system
Laboratory sample: according to the situ-gel of the embodiment of the invention 2,3 described method preparations.
Experimental technique: get 100 μ l and carry out the animal vivo releasing test, experimental subject is a rabbit, and the injection of row ear vein utilized microdialysis technology sampling and measuring in 0 to 7 day, and sample detects with HPLC.
Sampling time point (my god): 0,1,2,3,4,5,6,7.
Experimental result: the inside and outside release profiles of medicine is seen accompanying drawing 3 and accompanying drawing 4.
By the external and intravital drug release data of above situ-gel drug delivery system, as can be seen, situ-gel drug delivery system provided by the invention has the excellent drug slow release effect, has proved absolutely feasibility of the present invention.
Claims (10)
1, the situ-gel drug delivery system of a kind of hardening treating angioma and vascular malformation, it is characterized in that: the situ-gel drug delivery system is used for preparation treatment hemangioma and vascular malformation medicine, and situ-gel injection back is solid or semisolid drug depot by liquid system transition.
2, according to the situ-gel system of described a kind of hardening treating angioma of claim 1 and vascular malformation, it is characterized in that: the situ-gel drug delivery system can not contain any medicine.
3, according to the situ-gel system of described a kind of hardening treating angioma of claim 1 and vascular malformation, it is characterized in that: described hemangioma comprises hemangioma and lymphangioma;
4, according to the situ-gel system of described a kind of hardening treating angioma of claim 1 and vascular malformation, it is characterized in that: described vascular malformation comprises venule deformity, venous malformation, arteriovenous malformotion, pouring, crust pipe deformity, mixed type.
5, according to the situ-gel system of described a kind of hardening treating angioma of claim 1 and vascular malformation, it is characterized in that: described medicine comprises the medicine of tumor drug disposition injection hyperamization tuberculation atresia.
6, the situ-gel system of a kind of hardening treating angioma according to claim 5 and vascular malformation is characterized in that: described medicine comprises sodium morrhuate, Alumen, Bleomycin A5, hormone medicine, sodium tetradecyl sulfate, ethanolamine, amidotrizoic acid, quinoline, opium poppy oil, dehydrated alcohol, tetracycline, doxycycline, OKA-432 (molten chain bacterium), zein (zein), urea element, interferon; And the compositions more than both or both.
7, the situ-gel system of a kind of hardening treating angioma according to claim 1 and vascular malformation, it is characterized in that: the situ-gel material in the described situ-gel drug delivery system comprises polyoxyethylene polyoxypropylene block copolymer (PEO-PPO, or be called poloxamer), polyoxyethylene-polylactic acid (PEO-PLA) copolymer, polycaprolactone-polyoxyethylene; And the compositions more than both or both; Comprise various fatty glycerides, as glyceryl monooleate (GMO), glycerol trioleate; And both compositionss; Comprise poly-third lactic acid (PLA), lactic acid ethanol copolymer (PLGA) or lactic acid caprolactone copolymer, and the compositions more than both or both; Comprise the sucrose ester precipitate.
8, the situ-gel system of a kind of hardening treating angioma according to claim 7 and vascular malformation, it is characterized in that: described sucrose ester precipitate comprises acetic acid sucrose isobutyl ester (sucrose acetateisobutyrate, SAIB), with and derivant.
9, the situ-gel system of a kind of hardening treating angioma according to claim 8 and vascular malformation, it is characterized in that: by situ-gel described in the claim 8, for regulating the rate of release of medicine, the material that wherein can also add the formed situ-gel described in the claim 6,7, or their both or both above compositions;
10, the situ-gel system of a kind of hardening treating angioma according to claim 7 and vascular malformation, it is characterized in that: by situ-gel described in the claim 7, in order to regulate drug releasing rate, can add and comprise adjuvant or the additive that allows use on cellulose derivative, polyvinylpyrrolidone, dextran, the Polyethylene Glycol pharmaceutics, and the compositions more than both or both.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100460222A CN1682693A (en) | 2005-03-15 | 2005-03-15 | An in situ gel drug delivery system for sclerotherapy of hemangiomas and vascular malformations |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100460222A CN1682693A (en) | 2005-03-15 | 2005-03-15 | An in situ gel drug delivery system for sclerotherapy of hemangiomas and vascular malformations |
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| CN1682693A true CN1682693A (en) | 2005-10-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100460222A Pending CN1682693A (en) | 2005-03-15 | 2005-03-15 | An in situ gel drug delivery system for sclerotherapy of hemangiomas and vascular malformations |
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| CN (1) | CN1682693A (en) |
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