CN1547469A - Paclitaxel mixed composition and water-in-oil type emulsion formulation for chemoembolization and preparation method thereof - Google Patents
Paclitaxel mixed composition and water-in-oil type emulsion formulation for chemoembolization and preparation method thereof Download PDFInfo
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- CN1547469A CN1547469A CNA018236316A CN01823631A CN1547469A CN 1547469 A CN1547469 A CN 1547469A CN A018236316 A CNA018236316 A CN A018236316A CN 01823631 A CN01823631 A CN 01823631A CN 1547469 A CN1547469 A CN 1547469A
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- oil
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- paclitaxel
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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Abstract
The present invention relates to the paclitaxel mixed composition and water-in-oil type emulsion formulation for chemoembolization and preparation method thereof. The combinatory formulation of anticancer drugs can be easily prepared since the emulsion formulation of the present invention can include other hydrophilic or lipophilic drugs.
Description
Technical field
The present invention relates to be used for arterial chemotherapy Embolization (transcatheter arterial chemoembolization by what paclitaxel can be dissolved obtain; TACE) butyrous paclitaxel compositions and preparation and their manufacture method.Arterial chemotherapy Embolization (TACE) is a kind of treatment method for cancer, and it by anticarcinogen and embolization material are injected in the nutrient artery of tumor, supplies with nutrition thereby block to cancerous tissue when using contrast agent to make the operation process video picture.
Background technology
Most widely used arterial chemotherapy Embolization is the hepatic arterial chemoembolization art that is used for liver cancer treatment.Contrast agent uses at intra-operative or operation back as visualization tools, and brings out thromboembolism in tumor.Doxorubicin (adriamycin, amycin), cisplatin, the such anticarcinogen of carboplatin are dissolved or are dispersed in the oil contrast media and use.
In the arterial chemotherapy Embolization one of contrast agent of the most frequent use be for example super liquefaction iodized oil
Iodized oil such as (Lipiodol).But, contain the physical instability of the dispersion of super liquefaction iodized oil and above-mentioned anticarcinogen, a lot of restrictions are arranged during operation.In the past, diagnostic roentgenology was extensive use of anticarcinogen such as amycin, epirubicin and treated hepatocarcinoma.But these anticarcinogen major parts are water miscible, thus use in the TACE operation always outstanding turbid type preparation rather than oily solution (YoshihiroKatagiri etc., Cancer Chemother.Pharmacol 1989,23,238-242).But As time goes on, the granule of so outstanding turbid type preparation is assembled gradually and is formed precipitation, so can not long preservation.In order to overcome such stability problem, adopted anticarcinogen is dissolved in aqueous contrast after, this water is distributed to the super liquefaction of picture iodized oil
Method in such oil contrast media.That is to say, before to patient's administration, just anticarcinogen is dissolved in the aqueous contrast, by the pumping method it is mixed with oil contrast media again.
In order to make the stability maximization of emulsion, use proportion and the close aqueous contrast of super liquefaction iodized oil proportion (1.275 to 1.290), as cardiografin (Urografin, 1.328-1.332) or B-15000 (Iopamiro, 1.17-1.41) (Takashi Kanematsu etc., Journal of surgical oncology1984,25,218-226 and Takafumi Ichida etc., Cancer Chemother.Pharmacol1994,33,74-78).But, can only form temporary emulsion by described method, this emulsion is made the back and just is separated once more in a few minutes.And unsettled emulsion system can not provide sufficient effect of embolization.In fact, just observe at intra-operative and taken place in the conduit to be separated.When using this instability emulsion, amycin is organized immediately and absorbs, and the effect that continues to discharge anticarcinogen can not be provided.
One of ideal liver cancer treatment method is to use the synthetic high polymer anticarcinogen, just uses zinostatin (poly-(styrene-maleic acid) neocarzinostain NCS) (SMANCS).SMANCS has hydrophilic and lipophile concurrently, can directly be dissolved in (Konno, T. and Maeda, H. in the super liquefaction iodized oil, Targetting chemotherapy of hepatocellular carcinoma.Neoplasma of the liver, Eds.Okuda, K., and Ishak, K.G., Springger-Verlag, Berlin, P343-352).But, though the super liquefaction of SMANCS/ iodized oil preparation has solved the stability problem that exists in amycin/super liquefaction iodized oil preparation, because its price height, and have serious toxic and side effects, so be not commonly used.
In addition, the anticarcinogen paclitaxel is as having remarkable Cytotoxic material to be known by people to ovarian cancer, breast carcinoma, esophageal carcinoma, melanoma, leukemia.The commercial product of paclitaxel is that the trade mark of Bristol-Myers Squibb Co. is a taxol
(Taxol) injection.
Paclitaxel is a kind of insoluble drug, thus since the development phase just simultaneously the exploitation of solubilising technology.As an example of such solubilising technology, can enumerate in order in whole body administrations such as intravenous injection, to use and the use solubilizing agent.Described taxol
Use polyoxyethylene castor oil (Cremophor EL: polyoxyethylene 35-Oleum Ricini) and ethanol as solubilizing agent.Taxol
Be a kind of Emulsion pre-concentration type preparation, said preparation will spontaneously form microemulsion (microemulsion) (with reference to No. the 5438072nd, United States Patent (USP)) when disperseing in excessive water.But, known taxol
In employed solubilizing agent meeting cause toxic and side effects.So, have high anti-cancer activity and hypotoxic novel formulation for paclitaxel in order to develop, carried out multiple research.
In the arterial chemotherapy Embolization, the hepatic arterial chemoembolization art is the most representative, and except that the hepatic arterial chemoembolization art, the arterial chemotherapy Embolization can also be used for multiple solid tumor.For example, by implementing the arterial chemotherapy Embolization, the super liquefaction of SMANCS/ iodized oil preparation has been used for targeted therapy (the K.Tsuchiya.Tumor-targeted chemotherapy with SMANCS inLipiodol for renal cell carcinoma:longer survival with larger size tumors.Urology.2000 Apr of renal carcinoma at renal artery; 55 (4): 495-500).
Summary of the invention
Up to the present, also paclitaxel is not used the example of anticarcinogen as blood vessel embolism or angiography.The objective of the invention is by making paclitaxel, thereby paclitaxel is used for the arterial chemotherapy Embolization with oil contrast media and aqueous contrast emulsifying.
The problem of amycin in the past/super liquefaction iodized oil/B-15000 Emulsion maximum is that stability is low.By just being separated in a few minutes behind the pumping method formation Emulsion, usually in conduit, just can observe this being separated.Existing preparation does not reach the effect that expection continues to carry anticarcinogen.
Therefore, need a kind of novel chemoembolization preparation of exploitation, different with amycin/super liquefaction iodized oil/B-15000 preparation in the past, described new formulation should be in arterial chemotherapy thromboembolism operation or even operation after can both keep the stability of Emulsion, and said preparation should be more cheap than the super liquefaction of SMANCS/ iodized oil preparation in the past, toxic and side effects is littler.
So, the purpose of this invention is to provide and can make the soluble novel paclitaxel compositions of paclitaxel.
More particularly, the purpose of this invention is to provide the paclitaxel emulsion that can in the arterial chemotherapy Embolization of treatment solid tumor, use.
Another object of the present invention provides the manufacture method of the blend compositions and Water-In-Oil (w/o) the type Emulsion of paclitaxel.
Description of drawings
Fig. 1 be contain the super liquefaction iodized oil of 0.8ml and 0.2ml B-15000 compositions (left side) and contain the paclitaxel of super liquefaction iodized oil, 8mg of 0.8ml and the compositions (right side) of the B-15000 of 0.2ml, before whirling motion is handled, when whirling motion finishes, the photo of whirling motion end after 3 hours.
Fig. 2 is the how gentle compositions (right side) that must star of the B-15000 of paclitaxel, 0.2ml of the compositions (left side) that the B-15000 of the super liquefaction iodized oil that contains 0.8ml, 0.2ml and 4mg how gentle must star and the super liquefaction iodized oil that contains 0.8ml, 8mg and 4mg, before whirling motion is handled, during the whirling motion end, the photo of whirling motion end after 3 hours.
Fig. 3 be the B-15000 of the super liquefaction iodized oil that contains 0.8ml, 0.2ml and 4mg carboplatin compositions (left side) and contain the B-15000 of paclitaxel, 0.2ml of super liquefaction iodized oil, the 8mg of 0.8ml and the compositions (right side) of the carboplatin of 4mg, before whirling motion is handled, when whirling motion finishes, the photo of whirling motion end after 3 hours.
Fig. 4 be the B-15000 of the super liquefaction iodized oil that contains 0.8ml, 0.2ml and 4mg cisplatin compositions (left side) and contain the B-15000 of paclitaxel, 0.2ml of super liquefaction iodized oil, the 8mg of 0.8ml and the compositions (right side) of the cisplatin of 4mg, before whirling motion is handled, when whirling motion finishes, the photo of whirling motion end after 3 hours.
Fig. 5 be the granularity of water-in-oil emulsion of the B-15000 of the super liquefaction iodized oil that contains 0.8ml, 0.2ml and various anticarcinogen when whirling motion finishes, whirling motion finishes the figure after 3 hours, wherein will not have the situation (left side) of paclitaxel and will have the situation (right side) of paclitaxel to compare.
Fig. 6 is that the expression doxorubicin is from compositions that contains super liquefaction iodized oil/B-15000/doxorubicin (0.8ml/0.2ml/4mg) and the curve chart that contains external stripping result the compositions that surpasses liquefaction iodized oil/B-15000/doxorubicin/paclitaxel (0.8ml/0.2ml/4mg/8mg).
The specific embodiment
For achieving the above object, the inventor is surprised to find that under study for action the water-in-oil emulsion of oil contrast media/aqueous contrast/paclitaxel is stable more than the super liquefaction iodized oil/B-15000/doxorubicin Emulsion that was used for the arterial chemotherapy Embolization in the past.That is to say that when finding to use the doxorubicin in paclitaxel replacement super liquefaction iodized oil/B-15000/doxorubicin preparation in the past, paclitaxel can be dissolved, the physical property of its Emulsion system is extremely stable, the present invention is accomplished thus.
The present invention has just increased the stability of described Emulsion greatly only by add paclitaxel in the super liquefaction iodized oil/B-15000/doxorubicin Emulsion as existing preparation.
More particularly, the invention provides and comprise 50%～98.9% (V/V; Volume ratio) be dissolved with 0.01%～1% (W/V; W/v) blend compositions of the aqueous contrast of the oil contrast media of paclitaxel and 0.1%～50% (V/V).
The present invention also provides by physical force and makes the described stable water-in-oil emulsion that oil contrast media and aqueous contrast mix homogeneously obtain in the soluble blend compositions of paclitaxel that makes.
As above-mentioned, though super liquefaction iodized oil/B-15000/doxorubicin preparation is to inhale through the pump more than 100 times to make, will be separated in a few minutes after making, be extremely unsettled emulsion system.
Relative with it, the water-in-oil emulsion of paclitaxel/oil contrast media of the present invention/aqueous contrast can not be separated more than 1 month yet.So, can think that paclitaxel itself plays an important role to the stability that improves oil contrast media/aqueous contrast system.Therefore, even before the several hrs of implementing the arterial chemotherapy Embolization, by physical mixed blend compositions of the present invention in advance, it is stable that the Emulsion of formation also can keep.In case formation Emulsion, water and oil phase just can mix fully and stably.Therefore, blend compositions of the present invention has solved the stability problem of Emulsion in the past.
The rerum natura of oil contrast media/aqueous contrast of the present invention/paclitaxel emulsion is greatly improved than the existing super liquefaction iodized oil preparation that contains the such water-soluble anticancer agent of doxorubicin, and oil contrast media/aqueous contrast of the present invention/paclitaxel emulsion has the characteristic that is similar to the super liquefaction of SMANCS/ iodized oil preparation.But, too high with the cost of the super liquefaction of SMANCS/ iodized oil preparation, and have serious toxic and side effects difference, blend compositions of the present invention uses cheap raw material and makes easily, so can reduce manufacturing cost.
The example of the oil contrast media that uses when making the blend compositions of paclitaxel/oil contrast media/aqueous contrast as the present invention has iodized oil.Iodized oil comprises super liquefaction iodized oil (Lipiodol; Laboratoire Guerbet, France), ethiodized Oil (Ethiodol; Savage Laboratories, Melville, NY) iodate poppy seed oil of Denging (iodized poppy seed oil) or iodate soybean oil (iodized soybean oil).Ma Tai has made detailed description (The effect oforal iodized oil on prevention and treatment of endemic goiter.Chinese Med.J.61 (9): 533,1981) to the iodate soybean oil.
The amount of paclitaxel is set in 0.001%～1.5% (W/V) scope in the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and in the Emulsion.If the amount of paclitaxel surpasses 1.5% (W/V), excessive paclitaxel can precipitate, so be not preferred.On the other hand, if the amount less than 0.001% (W/V) of paclitaxel, active anticancer is low excessively, and the Emulsion instability, so neither be preferred.
Among the present invention, be preferably 30 weight %～50 weight % as the amount of iodine in the employed iodized oil of oil contrast media.Preferred amount of iodine is 35 weight %～45 weight %.Most preferably use super liquefaction iodized oil (Lipiodol) as oil contrast media.
In paclitaxel/oil contrast media of the present invention/aqueous contrast Emulsion, the content of oil contrast media is 50%～98.9% (V/V), is preferably 75%～80% (V/V).If the amount less than 50% (V/V) of oil contrast media or surpass 98.9% (V/V), described Emulsion instability is not so be preferred.
In the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and in the Emulsion, described aqueous contrast can be from metrizamide (Metrizamide), Diatrizoate (Diatrizoate), ioxaglic acid salt (Ioxaglate), iopentol (Iopentol), iopamidol (Iopamidol), iomeprol (Iomeprol), iotrolan (Iotrolan), iohexol (Iohexol), ioversol (Ioversol), ioxilan (Ioxilan), iopromide (Iopromide), select in the group that iodixanol (Iodixanol) and iobitridol (Iobitridol) constitute to use.Wherein, most preferably use the commercially available iopamidol of trade mark as B-15000 (Iopamiro).
The content of aqueous contrast is 0.1%～50% (V/V), is preferably 20%～25% (V/V).
Except that paclitaxel, the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and Emulsion can also additionally comprise other anticarcinogen.The anticarcinogen that allows to add comprises doxorubicin (being also referred to as amycin), 5-fluorouracil, carboplatin, cisplatin, carmustine (Carmustine), dacarbazine (Dacarbazine), etoposide (Etoposide), vinorelbine (Vinorelbine), hycamtin (Topotecan), irinotecan (Irinotecan), estramustine (Estramustine) etc.The amount of additional anticarcinogen is 0.0001%～2% (W/V) of whole blend compositions.
The blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and Emulsion can also additionally contain the emulsifying agent of 0.0001 weight %～20 weight %.Emulsifying agent can be dissolved in the aqueous contrast, and described emulsifying agent comprises phospholipid, nonionic surfactant, anionic surfactant, cationic surfactant or bile salts etc.
As the phospholipid of emulsifying agent of the present invention covalent bonding has been arranged on phosphatidylcholine (PC) and derivant, PHOSPHATIDYL ETHANOLAMINE (PE) and derivant thereof, Phosphatidylserine (PS) and derivant or the phospholipid polymer class lipid of hydrophilic polymer.
Nonionic surfactant as emulsifying agent of the present invention has poloxamer (Poloxamer, polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor seed oil (HCO), sorbitan ester (Sorbitanesters, Span), polyoxyethylene-sorbitan aliphatic ester (Tween) or polyoxyethylene ether (Brij).
As the anion surfactant of emulsifying agent of the present invention Phosphatidylserine (PS) and derivant, phosphatidic acid (PA) and derivant thereof, dodecyl sodium sulfate (SDS) are arranged.
Cationic surfactant as emulsifying agent of the present invention has 1; 2-dioleoyl-3-trimethyl ammonium-propane (DOTAP), dimethyl dioctadecyl ammonium DDA N,N-Dimethyl-N-octadecyl-1-octadecanaminium bromine (DDAB), N-[1-(1; 2-two oily acyloxy) propyl group]-N; N; N-trimethyl ammonium chlorine (DOTMA), 1; 2-dioleoyl-3-ethyl phosphatidylcholine (DOEPC), 3 β-[N-[(N ', N '-dimethylamino) ethane] carbamoyl] cholesterol (DC-Chol).
Bile salts as emulsifying agent of the present invention has cholic acid and salt and derivant, deoxycholic acid and salt thereof and derivant, chenocholic acid and salt thereof and derivant, ursodesoxycholic acid and salt thereof and derivant and lithocholic acid and salt and derivant.
The blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast can make easily by following steps: 1) in oil contrast media, described compositing range adds an amount of paclitaxel, stirs to make its dissolving, 2) aqueous contrast of adding described compositing range.At this moment, can be heated to about 35～45 ℃ or in groove type ultrasonic ripple instrument, carry out supersound process for accelerate dissolution.The blend compositions of the paclitaxel/oil contrast media of the present invention/aqueous contrast of Zhi Zaoing is preserved after sterilization like this.Also can under aseptic condition, mix sterilized raw material.In addition, paclitaxel/oil contrast media compositions is injected so that sterilize by aseptic injection filter (aperture is 200 μ m, PVDF sterilize filter membrane).In addition, can adopt gamma-radiation or EO gas sterilization, with after iodate poppy seed oil and the paclitaxel sterilization, mix again earlier, adopt gamma-radiation or EO gas sterilization again after perhaps earlier it being mixed, its compositions is sterilized.
Add under the situation of the anticarcinogen except that paclitaxel,, it is dissolved in the aqueous contrast then adds with the amount in the described compositing range if the anticarcinogen that adds is water miscible.If the anticarcinogen that adds is fat-soluble, it is dissolved in the oil contrast media then adds with the amount in the described compositing range.
Like this, when the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast of making is used for the arterial chemotherapy Embolization, undertaken using after the emulsifying by the whirling motion processing.After whirling motion is handled, described Emulsion in room temperature through not being separated and stable existence more than 30 days.
The operation of arterial chemotherapy Embolization needs 3～5 hours at most.So intra-operative, Emulsion stable existence of the present invention is even after entering in the tumor, also can discharge anticarcinogen constantly.This point and forms how gentle must the comparing by star/super iodized oil/B-15000 preparation that liquefies that just is separated in a few minutes behind the Emulsion by the pumping method in the past, the stability of Emulsion of the present invention be improved significantly.
The blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast also can be by being dissolved with paclitaxel oil phase and the form that is dissolved with the two-phase mixture that the water of additional anticarcinogen forms provide.In addition, the preparation of paclitaxel/oil contrast media of the present invention/aqueous contrast also can be used as by the blend compositions to paclitaxel/oil contrast media/aqueous contrast and applies physical force and the form of water-in-oil type (w/o) Emulsion of mix homogeneously provides.Emulsion of the present invention was not separated and stable existence after emulsifying at least in 2 months.
In addition, for the amount of application and the application process of paclitaxel/oil contrast media of the present invention/aqueous contrast Emulsion, the doctor can carry out suitable adjustment according to patients' such as patient De Elderly, sex, body weight, severity of symptom individual diversity.Usually, such according to original paclitaxel/oil contrast media/aqueous contrast, the arterial chemotherapy Embolization can carry out once in per 1～4 month, and can repeat to implement.The described preparation of 2～15ml is injected through the nutrient artery of solid tumor, for example is that trans-hepatic artery injects with regard to hepatocarcinoma.
It is following that the present invention will be described in more detail according to embodiment.But following embodiment only supplies to understand the present invention, and the present invention is not limited by condition, raw material or device among these embodiment.
Embodiment
Embodiment 1. surpasses the manufacturing of liquefaction iodized oil/B-15000/paclitaxel emulsion
The super liquefaction iodized oil (France, amount of iodine is 38 weight % for Lipiodol Ultra-fluid, Laboratoire Guerbet) that uses 800 μ l is as oil contrast media.In described super liquefaction iodized oil, add paclitaxel (Korea S three foster-Zhen Naikesi companies (Samyang Genex, Korea)), the test tube of the packing into (microtest tube that has safety cock of 8mg, polyethylene system, 1.5ml, German Eppendorf AG), dissolve in stirring at room.Be heated 40 ℃ in order to dissolve rapidly.In this oily mixture, add the B-15000 (Bracco s.p.a.Italy) of 200 μ l.Mixture in contrast uses the mixture of the B-15000 of the paclitaxel of 0.8ml and 0.2ml.Photo after these two kinds of mixture are made is shown in Fig. 1 (up).Use vortex agitator, (120V, 0.65A 60Hz) handled 10 minutes each mixture whirling motion with maximum set value.When whirling motion finished, super liquefaction iodized oil/B-15000/formulation for paclitaxel was separated and forms Emulsion, then observes be separated (middle row) in super liquefaction iodized oil/B-15000 compositions.Whirling motion finished after 3 hours, and the Emulsion of super liquefaction iodized oil/B-15000/paclitaxel compositions is stable, then almost completely was separated in super liquefaction iodized oil/B-15000 compositions (descending).Super liquefaction iodized oil/B-15000/paclitaxel compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/formulation for paclitaxel fully, and help to increase the stability of said preparation.
The super liquefaction iodized oil (France, amount of iodine is 38 weight % for Lipiodol Ultra-fluid, Laboratoire Guerbet) that uses 800 μ l is as oil contrast media.In described super liquefaction iodized oil, add paclitaxel (Korea S three foster-Zhen Naikesi companies (Samyang Genex, Korea)), the test tube of the packing into (microtest tube that has safety cock of 8mg, polyethylene system, 1.5ml, German Eppendorf AG), dissolve in stirring at room.For rapid dissolving, carry out supersound process with groove type ultrasonic ripple instrument.In this oily mixture, add the B-15000 (Bracco s.p.a.Italy) that contains 4mg doxorubicin (uncommon trellis code chemical company) of 200 μ l.Mixture in contrast uses the mixture of being made up of the B-15000 that contains the 4mg doxorubicin of the paclitaxel of 0.8ml and 0.2ml.Photo after these two kinds of mixture are made is shown in Fig. 2 (up).Use vortex agitator, (120V, 0.65A 60Hz) handled 10 minutes each mixture whirling motion with maximum set value.When whirling motion finished, super liquefaction iodized oil/B-15000/paclitaxel/doxorubicin preparation was separated and forms Emulsion, then observes be separated (middle row) in super liquefaction iodized oil/B-15000/doxorubicin compositions.Whirling motion finished after 3 hours, and the Emulsion in super liquefaction iodized oil/B-15000/paclitaxel/doxorubicin compositions is still stable, super liquefaction iodized oil/B-15000/doxorubicin compositions then almost completely be separated (descending).Super liquefaction iodized oil/B-15000/paclitaxel/doxorubicin compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/doxorubicin preparation fully, and help to increase the stability of said preparation.
Embodiment 3. surpasses the manufacturing of liquefaction iodized oil/B-15000/paclitaxel/carboplatin compositions
Except that the carboplatin that uses 4mg replaces doxorubicin, as embodiment 2, make compositions and matched group.Photo after these two kinds of mixture are made is shown in Fig. 3 (up).Use vortex agitator, (120R, 0.65A 60Hz) handled 10 minutes each mixture whirling motion with maximum set value.When whirling motion finished, super liquefaction iodized oil/B-15000/paclitaxel/carboplatin preparation was separated and forms Emulsion, then observes be separated (middle row) in super liquefaction iodized oil/B-15000/carboplatin compositions.Whirling motion finished after 3 hours, and the Emulsion of super liquefaction iodized oil/B-15000/paclitaxel/carboplatin compositions is stable, super liquefaction iodized oil/B-15000/carboplatin compositions then almost completely be separated (descending).Super liquefaction iodized oil/B-15000/paclitaxel/carboplatin compositions of making only can be observed little water droplet (400～600nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/carboplatin preparation fully, and help to increase the stability of said preparation.
Except that the cisplatin that uses 4mg replaces doxorubicin, as embodiment 2, make compositions and matched group.Photo after these two kinds of mixture are made is shown in Fig. 4 (up).Use vortex agitator, (120V, 0.65A 60Hz) handled 10 minutes each mixture whirling motion with maximum set value.When whirling motion finished, super liquefaction iodized oil/B-15000/paclitaxel/cisplatin formulations was separated and forms Emulsion, then observes be separated (middle row) in super liquefaction iodized oil/B-15000/cisplatin compositions.Whirling motion finished after 3 hours, and the Emulsion of super liquefaction iodized oil/B-15000/paclitaxel/cisplatin compositions is stable, super liquefaction iodized oil/B-15000/cisplatin compositions then almost completely be separated (descending).Super liquefaction iodized oil/B-15000/paclitaxel/cisplatin compositions of making only can be observed little water droplet (500～900nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/cisplatin formulations fully, and help to increase the stability of said preparation.
The granularity of super liquefaction iodized oil/B-15000 Emulsion when embodiment 5. paclitaxels exist
Each water-in-oil emulsion that embodiment 1～4 is made with 100 times of soybean oil dilutions after, adopt Malvem Zetasizer method (QELS method) to measure the granularity of water droplet in each Emulsion.The refractive index of medium and viscosity are decided to be the value as the glycerol trioleate of main constituent, promptly be respectively 1.84 (Handbook of Chemistry and Physics, the 23rd edition, CRC Press) and 69.3cSt/s (Chung etc., J.Cont.Rel. (2001) 71:339-350), at this moment, the refractive index of emulsion grain and viscosity are decided to be 1.84 and 0.97cSt/s respectively.When measuring whirling motion and finishing and whirling motion finish granularity after 3 hours, it the results are shown in Fig. 5.The situation that has carboplatin or cisplatin for no paclitaxel in the preparation, though Emulsion is more stable when whirling motion finishes, whirling motion finished after 3 hours, granularity increases to 5 μ m or more than the 5 μ m, is separated.Assemble owing to observe the emulsion grain of prepared no paclitaxel, so can confirm that this Emulsion is extremely unstable.On the contrary, when having paclitaxel, even after whirling motion finishes 3 hours, the Emulsion granularity does not increase yet, and hence one can see that, and this Emulsion is very stable.
Embodiment 6. uses the external stripping experiment of the doxorubicin of super liquefaction iodized oil/B-15000 Emulsion
Get super liquefaction iodized oil/B-15000/doxorubicin and the super liquefaction iodized oil/B-15000/paclitaxel/doxorubicin Emulsion made among the 200 μ l embodiment 2 respectively, in the bag filter of packing into, and with sealed at both ends.Described bag filter is immersed in the phosphate-buffered saline of 10ml.In the jolting tank, carry out the stripping experiment at 37 ℃.With ultraviolet (UV)/visible spectrophotometer, measure the doxorubicin concentration of stripping.It the results are shown in Fig. 6.Compare with the Emulsion of no paclitaxel, the dissolution rate that contains doxorubicin in the Emulsion of paclitaxel is slower.After 140 hours, the doxorubicin of observing greater than 30% still remains in the Emulsion, can confirm that therefore paclitaxel increases the stability of Emulsion, has the effect that reduces the doxorubicin dissolution rate.
Embodiment 7. surpasses the manufacturing of liquefaction iodized oil/iomeprol/paclitaxel compositions
Removing the iomeprol (lomeron300 injection, Korea S's one star new drug) that uses 0.2ml replaces making compositions and matched group outside the B-15000 as embodiment 1.Super liquefaction iodized oil/iomeprol/paclitaxel compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/iomeprol/formulation for paclitaxel fully.
Embodiment 8. surpasses the manufacturing of liquefaction iodized oil/iopromide/paclitaxel compositions
Removing the iopromide (Ultravist 370 injections, Korea S match Pedicellus et Pericarpium Trapae (セ-リ Application グ) Co., Ltd.) that uses 0.2ml replaces making compositions and matched group outside the B-15000 as embodiment 1.Super liquefaction iodized oil/iopromide/paclitaxel compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/iopromide/formulation for paclitaxel fully.
Embodiment 9. surpasses the manufacturing of liquefaction iodized oil/iodixanol/paclitaxel compositions
Removing the iodixanol (Visipaque 320mg/ml, Nycomed IrelandLtd.) that uses 0.2ml replaces making compositions and matched group outside the B-15000 as embodiment 1.Super liquefaction iodized oil/iodixanol/paclitaxel compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/iodixanol/formulation for paclitaxel fully.
The manufacturing of embodiment 10. ethiodized Oil/B-15000/paclitaxel compositions
(Savage Laboratories, Melville NY) replace making compositions and matched group outside the super liquefaction iodized oil as embodiment 1 to remove the ethiodized Oil that uses 0.8ml.Ethiodized Oil/B-15000/paclitaxel compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in ethiodized Oil/B-15000/formulation for paclitaxel fully.
Embodiment 11. surpasses the manufacturing of liquefaction iodized oil/B-15000/paclitaxel/HCO 60 compositionss
Except that the B-15000 that contains 0.002mg HCO 60 (hydrogenated castor seed oil) that uses 0.2ml replaces making compositions and matched group the B-15000 as embodiment 1.Super liquefaction iodized oil/B-15000/paclitaxel/HCO 60 compositionss of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/HCO 60 preparations fully.
Embodiment 12. surpasses the manufacturing of liquefaction iodized oil/B-15000/paclitaxel/polysorbas20 (Tween20) compositions
Except that the B-15000 that contains 10mg polysorbas20 (uncommon trellis code) that uses 0.2ml replaces making compositions and matched group the B-15000 as embodiment 1.Super liquefaction iodized oil/B-15000/paclitaxel/polysorbas20 compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/polysorbas20 preparation fully.
Embodiment 13. surpasses the manufacturing of liquefaction iodized oil/B-15000/paclitaxel/lecithin phatidylcholine compositions
Except that the B-15000 that contains 10mg lecithin phatidylcholine (uncommon trellis code) that uses 0.2ml replaces making compositions and matched group the B-15000 as embodiment 1.Super liquefaction iodized oil/B-15000/paclitaxel/lecithin phatidylcholine compositions of making only can be observed little water droplet (100～500nm) at microscopically.Owing to do not observe the precipitation of paclitaxel, thereby can confirm that paclitaxel is dissolved in super liquefaction iodized oil/B-15000/paclitaxel/lecithin phatidylcholine preparation fully.
The blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast is to form with oil phase that is dissolved with paclitaxel and independent water or the water that additionally is dissolved with anticarcinogen.The blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast makes oil phase and water mix homogeneously, thereby can be made as the preparation of water-in-oil type (w/o) Emulsion by as physical force such as whirling motion processing.Blend compositions of the present invention can be used as and is dissolved with water-in-oil emulsion paclitaxel, stable and obtains, therefore, and can be by other administrations except that intravenously administrable approach in the past.Compare with super liquefaction iodized oil/B-15000/doxorubicin preparation in the past, the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and the physical stability of Emulsion be improved significantly.In addition, the blend compositions of paclitaxel/oil contrast media of the present invention/aqueous contrast and emulsification preparation can also be dissolved with other anticarcinogen simultaneously.Therefore, paclitaxel/oil contrast media of the present invention/aqueous contrast preparation has overcome the stability problem that exists in super liquefaction iodized oil/B-15000/doxorubicin preparation in the past as a kind of new formulation.Simultaneously,, the invention provides new route of administration, promptly carry out administration by the arterial chemotherapy Embolization to being the main paclitaxel that uses as injection with the intravenously administrable.
Claims (41)
1. be used for preparing the blend compositions of chemoembolization with Emulsion, it comprises the oil contrast media of 50%～98.9% volume ratio and the aqueous contrast of 0.1%～50% volume ratio, and described oil contrast media is dissolved with the paclitaxel of 0.01%～1% w/v.
2. be dissolved with the chemoembolization water-in-oil emulsion compositions of paclitaxel, said composition comprises the oil contrast media of 50%～98.9% volume ratio and the aqueous contrast of 0.1%～50% volume ratio, and described oil contrast media is dissolved with the paclitaxel of 0.01%～1% w/v.
3. compositions as claimed in claim 1 or 2, wherein, described oil contrast media is that amount of iodine is the iodized oil of 30 weight %～50 weight %, and this iodized oil is selected from the group that is made of iodate poppy seed oil and iodate soybean oil, and described iodate poppy seed oil comprises super liquefaction iodized oil and ethiodized Oil.
4. compositions as claimed in claim 3, wherein, the amount of iodine in the described oil contrast media is 35 weight %～48 weight %.
5. compositions as claimed in claim 1 or 2, wherein, described aqueous contrast is selected from the group that is made of metrizamide, Diatrizoate, ioxaglic acid salt, iopentol, iopamidol, iomeprol, iotrolan, iohexol, ioversol, ioxilan, iopromide, iodixanol and iobitridol.
6. compositions as claimed in claim 4, wherein, described aqueous contrast is selected from the group that is made of metrizamide, Diatrizoate, ioxaglic acid salt, iopentol, iopamidol, iomeprol, iotrolan, iohexol, ioversol, ioxilan, iopromide, iodixanol and iobitridol.
7. compositions as claimed in claim 4, wherein, described aqueous contrast is an iopamidol.
8. compositions as claimed in claim 1 or 2, wherein, described compositions also contains the emulsifying agent of 0.0001 weight %～20 weight %.
9. compositions as claimed in claim 8, wherein, described emulsifying agent is selected from the group that is made of phospholipid, nonionic surfactant, anionic surfactant, cationic surfactant and bile salts.
10. compositions as claimed in claim 9, wherein, described phospholipid has been selected from by covalent bonding on phosphatidylcholine and derivant, PHOSPHATIDYL ETHANOLAMINE and derivant thereof, Phosphatidylserine and derivant thereof and the phospholipid group that the polymer class lipid of hydrophilic polymer constitutes.
11. compositions as claimed in claim 9, wherein, described nonionic surfactant is selected from the group that is made of poloxamer, hydrogenated castor seed oil, sorbitan ester, polyoxyethylene sorbitan aliphatic ester and polyoxyethylene ether.
12. compositions as claimed in claim 9, wherein, described anion surfactant is selected from the group that is made of Phosphatidylserine and derivant, phosphatidic acid and derivant thereof and dodecyl sodium sulfate.
13. compositions as claimed in claim 9; wherein; described cationic surfactant is selected from by 1; 2-dioleoyl-3-trimethyl ammonium-propane, dimethyl dioctadecyl ammonium DDA N,N-Dimethyl-N-octadecyl-1-octadecanaminium bromine, N-[1-(1; 2-two oily acyloxy) propyl group]-N, N, N-trimethyl ammonium chlorine, 1; 2-dioleoyl-3-ethyl phosphatidylcholine and 3 β-[N-[(N ', N '-dimethylamino) ethane] carbamoyl] group that constitutes of cholesterol.
14. compositions as claimed in claim 9, wherein, described bile salts is selected from the group that is made of cholic acid and salt thereof and derivant, deoxycholic acid and salt thereof and derivant, chenocholic acid and salt thereof and derivant, ursodesoxycholic acid and salt thereof and derivant or lithocholic acid and salt derivative thereof.
15. compositions as claimed in claim 8, wherein, described oil contrast media is the iodate poppy seed oil, and described aqueous contrast is an iopamidol.
16. compositions as claimed in claim 1 or 2, wherein, the additional anticarcinogen that described compositions contains is selected from the group that is made of doxorubicin/amycin, 5-fluorouracil, carboplatin, cisplatin, carmustine, dacarbazine, etoposide, vinorelbine, hycamtin, irinotecan, estramustine.
17. compositions as claimed in claim 16, described compositions are used for by arterial chemotherapy Embolization treatment hepatocarcinoma.
18. compositions as claimed in claim 7, wherein, the additional anticarcinogen that described compositions contains is selected from the group that is made of doxorubicin/amycin, 5-fluorouracil, carboplatin, cisplatin, carmustine, dacarbazine, etoposide, vinorelbine, hycamtin, irinotecan or estramustine.
19. compositions as claimed in claim 18, wherein, described compositions is used for by arterial chemotherapy Embolization treatment hepatocarcinoma.
20. compositions as claimed in claim 8, wherein, described compositions is used for by arterial chemotherapy Embolization treatment hepatocarcinoma.
21. compositions as claimed in claim 8, wherein, the additional anticarcinogen that described compositions contains is selected from the group that is made of doxorubicin/amycin, 5-fluorouracil, carboplatin, cisplatin, carmustine, dacarbazine, etoposide, vinorelbine, hycamtin, irinotecan or estramustine.
22. compositions as claimed in claim 21, wherein, described compositions is used for by arterial chemotherapy Embolization treatment hepatocarcinoma.
23. be dissolved with the manufacture method of the chemoembolization of paclitaxel with blend compositions, this method comprises following steps: 1) in oil contrast media, add the paclitaxel of 0.01%～1% (w/v), make its dissolved step; 2) step of the aqueous contrast of interpolation 0.1%～50% (volume ratio).
24. the manufacture method of water-in-oil type paclitaxel emulsion compositions, this method comprises following steps: 1) in oil contrast media, add the paclitaxel of 0.01%～1% (w/v), make its dissolved step; 2) add the step and 3 of the aqueous contrast of 0.1%～50% (volume ratio)) apply physical force, mix described oil contrast media mutually with aqueous contrast mutually, make it become the step of homogenizing.
25. as claim 23 or 24 described methods, wherein, described oil contrast media is that amount of iodine is the iodized oil of 30 weight %～50 weight %, and this iodized oil is selected from the group of iodate poppy seed oil and iodate soybean oil formation, and described iodate poppy seed oil comprises super liquefaction iodized oil and ethiodized Oil.
26. method as claimed in claim 25, wherein, the amount of iodine in the described oil contrast media is 35 weight %～48 weight %.
27. method as claimed in claim 26, wherein, described iodized oil is the iodate poppy seed oil.
28. as claim 23 or 24 described methods, wherein, described aqueous contrast is selected from the group that is made of metrizamide, Diatrizoate, ioxaglic acid salt, iopentol, iopamidol, iomeprol, iotrolan, iohexol, ioversol, ioxilan, iopromide, iodixanol and iobitridol.
29. method as claimed in claim 27, wherein, described aqueous contrast is selected from the group that is made of metrizamide, Diatrizoate, ioxaglic acid salt, iopentol, iopamidol, iomeprol, iotrolan, iohexol, ioversol, ioxilan, iopromide, iodixanol and iobitridol.
30. method as claimed in claim 27, wherein, described aqueous contrast is an iopamidol.
31. method as claimed in claim 29, wherein, described aqueous contrast is an iopamidol.
32. as claim 23 or 24 described methods, wherein, the step of the mixture sterilization after described method also is included under the aseptic condition and will makes with sterilized oil contrast media and the blended step of paclitaxel or with EO gas or gamma-radiation.
33. as claim 23 or 24 described methods, wherein, described method comprises the step of the emulsifying agent of other interpolation 0.0001 weight %～20 weight %.
34. method as claimed in claim 34, wherein, described emulsifying agent is selected from the group that is made of phospholipid, nonionic surfactant, anionic surfactant, cationic surfactant and bile salts.
35. method as claimed in claim 34, wherein, described phospholipid has been selected from by covalent bonding on phosphatidylcholine and derivant, PHOSPHATIDYL ETHANOLAMINE and derivant thereof, Phosphatidylserine and derivant thereof and the phospholipid group that the polymer class lipid of hydrophilic polymer constitutes.
36. method as claimed in claim 34, wherein, described nonionic surfactant is selected from the group that is made of poloxamer, hydrogenated castor seed oil, sorbitan ester, polyoxyethylene sorbitan aliphatic ester and polyoxyethylene ether.
37. method as claimed in claim 34, wherein, described anion surfactant is selected from the group that is made of Phosphatidylserine and derivant, phosphatidic acid and derivant thereof and dodecyl sodium sulfate.
38. method as claimed in claim 34; wherein; described cationic surfactant is selected from by 1; 2-dioleoyl-3-trimethyl ammonium-propane, dimethyl dioctadecyl ammonium DDA N,N-Dimethyl-N-octadecyl-1-octadecanaminium bromine, N-[1-(1; 2-two oily acyloxy) propyl group]-N, N, N-trimethyl ammonium chlorine, 1; 2-dioleoyl-3-ethyl phosphatidylcholine and 3 β-[N-[(N ', N '-dimethylamino) ethane] carbamoyl] group that constitutes of cholesterol.
39. method as claimed in claim 34, wherein, described bile salts is selected from the group that is made of cholic acid and salt thereof and derivant, deoxycholic acid and salt thereof and derivant, chenocholic acid and salt thereof and derivant, ursodesoxycholic acid and salt thereof and derivant or lithocholic acid and salt thereof and derivant.
40. as claim 23 or 24 described methods, wherein, described method also comprises makes additional anticarcinogen be dissolved in step in the described aqueous contrast, and described anticarcinogen is selected from the group that is made of doxorubicin, 5-fluorouracil, carboplatin, cisplatin, carmustine, dacarbazine, etoposide, vinorelbine, hycamtin, irinotecan, estramustine.
41. method as claimed in claim 33, wherein, described method also comprises makes additional anticarcinogen be dissolved in step in the described aqueous contrast, and described anticarcinogen is selected from the group that is made of doxorubicin, 5-fluorouracil, carboplatin, cisplatin, carmustine, dacarbazine, etoposide, vinorelbine, hycamtin, irinotecan and estramustine.
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| JP (1) | JP2005503398A (en) |
| KR (1) | KR100539451B1 (en) |
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| CN100518719C (en) * | 2006-07-05 | 2009-07-29 | 中国科学院大连化学物理研究所 | Method for preparing composite substrate multifunctional arterial embolic agent |
| CN101953845A (en) * | 2010-05-28 | 2011-01-26 | 中国人民解放军第二军医大学 | Transcatheter arterial chemoembolization embolism agent containing autophagy inhibitor |
| CN102260216A (en) * | 2010-05-28 | 2011-11-30 | 李茂全 | 5-fluorouracil lipophilic derivative-iodide oil |
| CN109821055A (en) * | 2019-02-01 | 2019-05-31 | 厦门大学 | A kind of drug-lipiodol solvent and preparation method thereof |
| CN110167602A (en) * | 2016-11-18 | 2019-08-23 | 株式会社三养生物制药 | Chemoembolization emulsion compositions and preparation method thereof |
| CN110302434A (en) * | 2019-07-14 | 2019-10-08 | 大连医科大学 | A kind of Lipiodol embolizatim agent and preparation method thereof for being easy to inject |
| CN111298189A (en) * | 2018-12-11 | 2020-06-19 | 陈传果 | Iodized oil suppository easy to inject and preparation method thereof |
| CN115137870A (en) * | 2016-03-14 | 2022-10-04 | 生物相容性英国公司 | Emulsions comprising particles |
| CN115137870B (en) * | 2016-03-14 | 2024-05-10 | 生物相容性英国公司 | Emulsion comprising particles |
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| DE10115740A1 (en) * | 2001-03-26 | 2002-10-02 | Ulrich Speck | Preparation for restenosis prophylaxis |
| DE10244847A1 (en) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medical device for drug delivery |
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| CN105228612A (en) * | 2013-03-12 | 2016-01-06 | 阿布拉科斯生物科学有限公司 | The method for the treatment of pulmonary carcinoma |
| FR3017295B1 (en) * | 2014-02-07 | 2018-01-12 | Guerbet | COMPOSITION FOR VECTORIZING AN ANTICANCER AGENT |
| CN106170307B (en) * | 2014-02-14 | 2020-07-28 | 波士顿科学国际有限公司 | Rapidly degrading embolic particles with therapeutic agent release |
| FR3039767B1 (en) | 2015-08-04 | 2017-09-08 | Guerbet Sa | COMPOSITION FOR VECTORIZING AN ANTICANCER AGENT |
| KR20200032092A (en) * | 2017-07-17 | 2020-03-25 | 인스티튜트 구스타브 루시 | Water-in-oil emulsion for injection and use thereof |
| CN114042042B (en) * | 2021-11-29 | 2023-07-25 | 广东粤港澳大湾区国家纳米科技创新研究院 | W/O/W type temperature-sensitive embolic agent |
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2001
- 2001-09-26 WO PCT/KR2001/001613 patent/WO2003022264A1/en active Application Filing
- 2001-09-26 CN CNB018236316A patent/CN100544713C/en not_active Expired - Lifetime
- 2001-09-26 JP JP2003526393A patent/JP2005503398A/en active Pending
-
2002
- 2002-07-20 KR KR1020020042795A patent/KR100539451B1/en active IP Right Grant
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100518719C (en) * | 2006-07-05 | 2009-07-29 | 中国科学院大连化学物理研究所 | Method for preparing composite substrate multifunctional arterial embolic agent |
| CN101953845A (en) * | 2010-05-28 | 2011-01-26 | 中国人民解放军第二军医大学 | Transcatheter arterial chemoembolization embolism agent containing autophagy inhibitor |
| CN101953845B (en) * | 2010-05-28 | 2011-11-09 | 中国人民解放军第二军医大学 | Hepatic artery chemoembolization embolism agent containing autophagy inhibitor |
| CN102260216A (en) * | 2010-05-28 | 2011-11-30 | 李茂全 | 5-fluorouracil lipophilic derivative-iodide oil |
| CN115137870A (en) * | 2016-03-14 | 2022-10-04 | 生物相容性英国公司 | Emulsions comprising particles |
| CN115137870B (en) * | 2016-03-14 | 2024-05-10 | 生物相容性英国公司 | Emulsion comprising particles |
| CN110167602A (en) * | 2016-11-18 | 2019-08-23 | 株式会社三养生物制药 | Chemoembolization emulsion compositions and preparation method thereof |
| US11534447B2 (en) | 2016-11-18 | 2022-12-27 | Samyang Holdings Corporation | Emulsion composition for chemoembolization and method for producing same |
| CN111298189A (en) * | 2018-12-11 | 2020-06-19 | 陈传果 | Iodized oil suppository easy to inject and preparation method thereof |
| CN109821055A (en) * | 2019-02-01 | 2019-05-31 | 厦门大学 | A kind of drug-lipiodol solvent and preparation method thereof |
| CN110302434A (en) * | 2019-07-14 | 2019-10-08 | 大连医科大学 | A kind of Lipiodol embolizatim agent and preparation method thereof for being easy to inject |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100539451B1 (en) | 2006-01-10 |
| JP2005503398A (en) | 2005-02-03 |
| KR20030023470A (en) | 2003-03-19 |
| WO2003022264A1 (en) | 2003-03-20 |
| CN100544713C (en) | 2009-09-30 |
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