CN1706377A - Norcantharidin emulsion capable of being sterilized through filtering and its prepn process - Google Patents
Norcantharidin emulsion capable of being sterilized through filtering and its prepn process Download PDFInfo
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- CN1706377A CN1706377A CN 200510046526 CN200510046526A CN1706377A CN 1706377 A CN1706377 A CN 1706377A CN 200510046526 CN200510046526 CN 200510046526 CN 200510046526 A CN200510046526 A CN 200510046526A CN 1706377 A CN1706377 A CN 1706377A
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Abstract
The present invention is norcantharidin emulsion capable of being sterilized through filtering and its preparation process. The medicine preparation may be orally taken or injected. It consists of norcantharidin 0.1-1 mg/ml, oil 0.5-15 wt%, emulsifier 0.5-15 wt%, emulsification assistant 0-3 wt% and isotonic regulator 1-10 wt%, as well as pH regulator, antioxidant, essence, etc. The preparation process includes the following steps: preparing oil phase through controlling temperature in 20-90 deg.c, adding emulsifier, adding norcantharidin and dissolving; preparing water phase through stirring water and isotonic regulator at 20-90 deg.c for 5 min until complete dissolving; adding the oil phase into the water phase to form the initial emulsion; regulating pH value to 3-9; homogenizing in homogenizing instrument to obtain homogeneous emulsion; and filtering with microporous filtering membrane to obtain the product. The preparation is used in preparing medicine for liver cancer, hepatitis, etc.
Description
Technical field:
The present invention relates to medical technical field, but exactly it is a kind of norcantharidin Emulsion and preparation method of filtration sterilization.
Background technology:
Norcantharidin (NCTD) is to be made by the Diels-Alder reaction is synthetic by furan and maleic anhydride, and is identical with the cantharidin configuration, only 1,2 no methyl (improvement Tianjin pharmacy 1995,7 (2) of the bright army of Cao norcantharidin synthesis technique; 35-36.)
[12]。NCTD is the colourless crystallization chemical compound, odorless, zest is arranged, and is soluble in acetone and hot water, and is molten at ethanol and cold water part omitted.Its chemical constitution is as follows:
Be mainly used in treatment hepatocarcinoma, esophageal carcinoma and gastric cancer, be particularly useful for the treatment of primary hepatocarcinoma, evident in efficacy.And obviously reduce the intensive urinary system zest of cantharidin, keep stronger anti-tumor activity and unique function of increasing leukocyte (13, Liu Zongchang doctor studies magazine (11): 28 1981.14, Yankee political affairs Guangxi Medical College journal (increasing number of the edition): 125.1981.15, poplar precious seal medical information compilation (Shijiazhuang first hospital) (2): 92.1962.)
[13-15]。After removing two methyl of cantharidin, urinary system stimulates basic the disappearance, and it is more obvious to rise white effect, and two main functional group that methyl are urinary system stimulations in this structure are described, to antitumor and to rise white effect then little.The inside and outside experiment confirm of body repeatedly since the eighties, norcantharidin can pass through the number of ways destruction of cancer cells, and normal histiocytic destruction is obviously weakened.Show in the experiment in vivo (16, the old family nor-Mylabris of the rising sun induces that K562 is apoptotic to influence Chinese Medicine journal 2,000 15 2 phases of volume.)
[16]NCTD has inhibitory action to the growth of cell strains such as human cervical carcinoma Hera, human esophagus cancer CaEs-17, people's hepatocarcinoma EBL-7402 and SMMC-7721, human promyelocytic leukemia HL-60, human leukemia K562.Experiment shows that also the rat liver cancer cell DNA is had stronger inhibitory action in the body, and suppression ratio is 88%.Have document announcement (17, Guo builds fragrant norcantharidin in external Xian Medical Univ's journal 1,994 15 3 phases of volume that influence to leukemia nucleus and protein synthesis.)
[17]NCTD has a facilitation to the DNA of mice normal marrow cell is synthetic, to leukaemia's DNA is synthetic certain inhibitory action is arranged simultaneously.Norcantharidin has the leukocytic effect of significant rising, the treatment primary hepatocarcinoma evident in efficacy (9, the progress Chinese medicine information 19923 phase 31-32 of Zhao Jing and anticancer animal drugs Mylabris.10、WangG..S.Medical?Uses?of?Mylabris?in?Ancient?and?Recent?Studies.Journal?ofEthnopharmaco，1989；26：147。11、Yi?S.N.et?al.Inhibition?Effect?of?Norcantharidin?onK562?Human?Myeloiol?Leukemia?Cell?in?Vitro.LeukemiaResearch，1991；15(10)；883。1)
[9、10、11]。Recently, is external document also supported (McCluskey A, etal.The inhibition of protein phosphatases 1 and 2A:a new target for rationalanti-cancer drug design? Anticancer Drug Des.2001 Dec; 16 (6): 291-303.; Chen YN, et al.Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis inhuman hepatoma cells.Int J Cancer.2002 Jul 10; 100 (2): 158-65; Yang EB, et al.Norcantharidin inhibits growth of human HepG2 cell-transplanted tumor in nudemice and prolongs host survival.Cancer Lett.1997 Jul 15; 117 (1): 93-8.Yan MS, et al.The preliminary observation on immunosuppressive effect of norcantharidin inmice.Immunopharmacol Immunotoxicol.1993 Jan; 15 (1): 79-85; Wu LT, et al.Effect of norcantharidin on N-acetyltransferase activity in HepG2 cells.Am J ChinMed.2001; 29 (1): 161-72.) the existing norcantharidin dosage form of the antitumor action of norcantharidin is tablet (coated tablet or Film coated tablets) and injection (norcantharidin sodium injection), all there is certain problem in the existing norcantharidin dosage form, exist stripping slow as tablet, the compatibility variation (reaction of anhydride in the norcantharidin molecular structure and hydroxyl, amino groups) of medicine and adjuvant etc., there is the blood vessel irritation problem in injection, is unfavorable for long-term prescription and high concentration medication.For solving this type of problem, different research worker applications corresponding patent, as: the slow-releasing injection type application (patent) of demehylcantharidin for antitumor number: 01112887.9; Norcantharidin liposome and preparation method thereof application (patent) of treatment malignant tumor number: 02156853.7; Norcantharidin drop pill and preparation method thereof application number: 03159066.7; Norcantharidin soft capsule and preparation method thereof application number: 200410021279.8, but do not see the Emulsion that patent of the present invention is related.
We find through a large amount of tests, adopt the norcantharidin of debita spissitudo, the prescription of proper proportion to form and suitable technology, can prepare small grain size preparation (less than 250nm), and oral administration or injection can increase absorption, improve curative effect.
Summary of the invention:
But the norcantharidin Emulsion and the preparation method that the objective of the invention is a kind of filtration sterilization are avoided the variety of issue that adopts high temperature hot pressing sterilization zone.
Existing fat milk technology of preparing is behind high pressure homogenize, 115 ℃ of sterilizations were sterilized 20 minutes in 30 minutes or 121 ℃, because it is big that traditional handicraft prepares the granularity of Emulsion, can not adopt the filter method degerming (if adopt 0.3um or less than the microporous filter membrane of 0.3um could breakdown of emulsion), need through the high temperature pressure sterilizing, so can reduce medicine stability, increase toxicity.A very practicable method is that existing formulation and technology is reformed, the Emulsion of preparation small grain size, thereby can adopt filter method or low temperature sterilization method to sterilize, can solve medicine, stability of formulation problem, can save cost again, improve the safety of medicine, guarantee the curative effect of medicine.
The granularity of Emulsion is also very important for special targeting administration.As the targeting of liver, generally speaking, the sick cell of hepatocarcinoma, hepatitis etc. is a hepatic parenchymal cells, if utilize galactose to carry out targeting drug delivery as part, the granularity of Emulsion is crucial, generally requires less than 100nm, otherwise is difficult to realize.In addition, sometimes need to realize the liver non-parenchymal cell targeting, as for anti-hepatic fibrosis medicines, there is data to show, liver nonparenchymal cell (NPC) plays an important role in the process of hepatic fibrosis as the medium that HSC, kupffer cell and sinusoidal endothelial cell discharge, can realize this purpose by the density that changes part on the Emulsion surface, but its prerequisite remains the granularity of Emulsion less than 100nm.
In view of needs improve stability of drug, avoid the various problems brought because of high temperature sterilize, and the targeting drug delivery requirement of special organ, tissue, cell, reduce the granularity of Emulsion, but preparation filtration sterilization Emulsion is particularly important.
But we have invented a kind of norcantharidin Emulsion prescription of filtration sterilization by a large amount of tests, it is characterized in that: percentage by weight is: norcantharidin 0.01～0.1% (0.1mgml/～1mg/ml), oil (long-chain oil in comprising) 1.5%～15%, emulsifying agent 0.5%～15%, co-emulsifier 0%～3%, isoosmotic adjusting agent 1%～10%, in addition, still contain pH regulator agent, antioxidant, can add antiseptic (antibacterial), sweeting agent, essence in case of necessity.This Emulsion can adopt the following microporous filter membrane of 0.3um or 0.3um, or G5, G6 sintered glass funnel carry out filtration sterilization, also can be where necessary in conjunction with 100～110 ℃ temperature sterilization 30 minutes.Described norcantharidin Emulsion can oral or drug administration by injection.Described oil comprises long-chain oil and midchain oil, and wherein midchain oil is: hot certain herbaceous plants with big flowers acid glyceride (Delios ) (being called medium chain triglycerides MCT), hot certain herbaceous plants with big flowers acid glyceride; Long-chain oil is: soybean oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, safflower oil.Can adopt midchain oil or long-chain oil separately respectively, also can adopt miscella, its mixed proportion is " midchain oil: long-chain oil=1: 0.1～mix at 1: 10 ".In addition, the injection oil phase can also be one or more mixture in vitamin E, tocopherol, ethyl oleate, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, Ethyl linoleate, oleic acid sorbitol ester, olein, Oleum Cocois C8/C10 monoglyceride or dibasic acid esters, Oleum Cocois C8/C10 propylene glycol dibasic acid esters, Oleum Cocois C8/C10 triglyceride, Oleum Cocois C8/C10 triglyceride, the acetylizad monoglyceride of purification, the purification Oleum helianthi monoglyceride etc.Described emulsifying agent is characterized in that: comprise one or more mixture that adopt in phospholipid, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, polyethylene glycol 660hydroxystearate), vitamin E polyethylene glycol succinic acid ester (TPGS), DSPE-PEG derivant (DSPE-PEG), the poloxamer (Poloxamer); Can add co-emulsifier as required, as oleic acid, sad, certain herbaceous plants with big flowers is sour, one or more mixture in the lauric acid, Palmic acid, linoleic acid, linoleic acid, stearic acid, docosahexenoic acid (DHA), cholic acid, deoxycholic acid.The isoosmotic adjusting agent of described Emulsion is one or more mixture in glycerol, glucose, mannitol, xylitol, the sucrose.The pH regulator agent is one or more in hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphoric acid, sodium phosphate, citric acid, the sodium citrate etc., and best pH scope is 3～9; Antioxidant is noble gas, EDTA and its esters, alpha-tocopherol, α-tocopheryl acetate, alpha-lipoic acid, vitamin C and derivant thereof, as one or more mixture in the sodium L-ascorbate-2-phosphate.Antiseptic (antibacterial) is benzyl alcohol, benzoic acid (and salt), sorbic acid (and salt), parabens.Described Emulsion particle size range is 5nm～1000nm, and particle mean size is less than 250nm, and is aseptic in order further to guarantee, also can adopt 100～110 ℃ and sterilize on the basis of filtration sterilization.Described sweeting agent is sucrose, glucide, aspartame, protein sugar etc.; Essence is cream flavour, Fructus Citri tangerinae essence, cocoanut flavour, flavoring pineapple essence etc.But the norcantharidin method of preparing emulsion of filtration sterilization is characterized in that preparation process is as follows:
1) preparation oil phase: control temperature 20-90 ℃ of oil phase, add emulsifying agent (or being added in aqueous phase), strong agitation adds norcantharidin, strong agitation mixing, dissolving to dissolving.
2) preparation water: water and glycerol (or other isoosmotic adjusting agent, also comprise emulsifying agent in case of necessity) are stirred 5min down at 20～90 ℃, make it complete miscibility.
3) in the time of 20～80 ℃, oil phase is added water (or water adding oil phase), the strong agitation mixing forms colostrum.
4) regulate pH value to 3～9.
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 520～600kg/cm
2, second step re-adjustment to 100～140kg/cm
2(or microjet instrument, the first step is regulated homogenize pressure to 4000-8000psi, the second step re-adjustment is to 10000-20000psi) with solution homogenize repeatedly, obtain uniform Emulsion, carry out filtration sterilization with 0.3um or less than the microporous filter membrane of 0.3um (or G5, G6 sintered glass funnel), encapsulation (in case of necessity can be further under 100～110 ℃ temperature sterilization 30 minutes) promptly gets this product.
Prepared preparation can be used for hepatocarcinoma, the esophageal carcinoma, harmonization of the stomach carcinoma of gastric cardia etc. and reach low leukocyte counts disease, hepatitis, liver cirrhosis, hepatitis b virus carrier.Also can be used as the cancer premedicate or be used for combined chemotherapy.
Pharmacological action:
One, anti-mice S180 effect
With mice S180 is animal model, observes norcantharidin Emulsion to its inhibitory action.The route of administration intravenous injection, continuous 7 days.Dosage: 5mg/kg.The results are shown in Table 1.
Table 1, anti-mice S180 result of the test
| Preparation | Injection | Oral | Commercially available injection | Marketed tablet |
| Tumour inhibiting rate % | ??56.2 | ??40.6 | (42.5 injection site damage) | 33.1 |
Hence one can see that, and the anti-mice S180 of preparation of the present invention effect is better than the commercial preparation.And commercially available injection has very big zest to the blood vessel of injection site, and preparation of the present invention is not seen tangible zest during each medicine.
Two, hemolytic test
The experimental condition room temperature: 22 ℃, relative humidity: 55%.
Test specimen: embodiment 1,2,3,4,5,6,7 and commercially available injection, formulation concentrations all is diluted to 0.1mg/ml with 5% glucose.
Test method and result
The rabbit ear edge vein exploitating blood, with bamboo let stir defibrinate after, with normal saline washing back centrifugal (2000rpm), remove supernatant, again with the normal saline cyclic washing for several times (all centrifugal supernatant of abandoning) until the supernatant redfree, it is standby to be made into 2% red blood cell suspension with normal saline by volume then.
Get 7 in test tube, press shown in the table 2, each pipe adds the medicinal liquid of different volumes and the red blood cell suspension of equal volume respectively, wherein the 6th manages not dosing, be 5% glucose injection (or 10% glucose injection) blank, the 7th pipe adding distil water is done complete haemolysis contrast (positive control pipe).After each pipe shakes up gently, put in 37 ℃ of water-baths temperature and incubated 4 hours, observe whether each pipe has haemolysis and erythrocyte aggregation phenomenon in 0.25 hour to 4.0 hours, press the judgement of table 3 standard.The results are shown in Table 4.
The external hemolytic test application of sample of table 2. table
| Application of sample volume (ml) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ?4 | ??5 | ??6 | ??7 | |
| 2% red blood cell suspension, 5% glucose injection | ??2.5 ??2.0 | ??2.5 ??2.1 | ??2.5 ??2.2 | ?2.5 ?2.3 | ??2.5 ??2.4 | ??2.5 ??2.5 | ??2.5 ??0 |
| The distilled water need testing solution | ????0 ????0.5 | ??0 ??0.4 | ??0 ??0.3 | ??0 ??0.2 | ????0 ????0.1 | ????0 ????0 | ??2.5 ??0 |
Table 3. haemolysis result judges
| Degree | Sign | Phenomenon |
| The full haemolysis coagulation of no haemolysis part haemolysis | ±+ | Erythrocyte all sinks, upper strata liquid water white transparency.Clear and bright redness of solution or brownish red,, there is a small amount of erythrocyte at the pipe end.The clear and bright redness of solution, the pipe end, is acellular residual.The erythrocyte aggregation in bulk does not disperse after shaking up. |
The external hemolytic test result of table 4.
| Time (hour) | Test tube number | ||||||
| ????1 | ????2 | ????3 | ????4 | ????5 | ????6 | ????7 | |
| ????0.25 ????0.5 ????0.75 ????1.0 ????2.0 ????3.0 ????4.0 | ????- ????- ????- ????- ????- ????- ????- | ????- ????- ????- ????- ????- ????- ????- | ????- ????- ????- ????- ????- ????- ????- | ????- ????- ????- ????- ????- ????- ????- | ????- ????- ????- ????- ????- ????- ????- | ????- ????- ????- ????- ????- ????- ????- | ????+ ????+ ????+ ????+ ????+ ????+ ????+ |
As shown in Table 4, the present invention's prescription does not have the haemolysis problem.
The specific embodiment: detailed component of the present invention is provided by the following example, but protection scope of the present invention not only is confined to this.Particle size analyzer: use PSS.NICOMPTM 380 in this experiment as the instrument of measuring particle diameter.Other Instruments, microjet instrument (Microfluidic company, the U.S.), homogenizer etc.
Advantage of the present invention is:
Adopt prepared preparation of the present invention, its granularity little (less than 250nm) can be passed through the filter method degerming, can also sterilize under lower temperature, thereby improve stability of drug, improves drug safety.Because granularity is little, oral administration or injection can increase absorption, improve curative effect.Rationally with respect to existing injection, prepared preparation of the present invention do not have a vascular stimulation, and commercially available zest is very big, the patient is difficult to accept, the finishing of the influence treatment course of treatment; With respect to marketed tablet, prepared preparation of the present invention has swallows easily, and it is wide to be fit to the crowd, and particularly for the patient who has a delicate constitution, the Orally taken emulsion of small grain size is more excellent, stable curative effect.
The specific embodiment:
Embodiment 1:
Prescription is formed: norcantharidin 0.01g, and phosphatidase 10 .9g, poloxamer 0.3g, Oleum Glycines 1.5g, glycerol 2.2g, hydrochloric acid is an amount of, and all the other are water for injection (or distilled water), altogether 100ml.
Manufacture method:
1) preparation oil phase: Oleum Glycines is heated to 90 ℃, adds phospholipid, strong agitation adds medicine to dissolving, and strong agitation 5min dissolving is cooled to 30 ℃;
2) preparation water: glucose, poloxamer, glycerol are added in the water for injection (or distilled water), under 50, stir 5min, make it to dissolve fully;
3) when 30, oil phase is added water, strong agitation 10min forms colostrum;
4), regulate pH value to 3 with an amount of hydrochloric acid solution;
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 6000psi, and the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 14000psi, crosses the degerming of 0.22um microporous filter membrane, packing, and inflated with nitrogen seals and promptly gets this product.
Particle size range is 5nm～700nm, and mean diameter is 125nm.Prepared Emulsion can oral or injection.
Embodiment 2:
Prescription is formed: norcantharidin 0.01g, and egg yolk lecithin 1.5g, HS150.5g, TPGS 1g, midchain oil (hot certain herbaceous plants with big flowers acid glyceride) 0.5g, Oleum Glycines 14.5g, vitamin E 0.1g, glycerol 2.5g, hydrochloric acid is an amount of, and all the other are water, altogether 100ml.
Manufacture method:
1) preparation oil phase: midchain oil, Oleum Glycines, vitamin E are heated to 50 ℃, add egg yolk lecithin, HS15, TPGS, medicine, strong agitation is cooled to 30 ℃ to dissolving, strong agitation 10min dissolving;
2) preparation water: glycerol adds in the water for injection, 40 ℃ of following stirring and dissolving;
3) in the time of 20 ℃, water is added oil phase, strong agitation 5min forms colostrum;
4), regulate pH value to 4 with an amount of hydrochloric acid solution;
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 580kg/cm
2, the second step re-adjustment is to 140kg/cm
2, with solution homogenize repeatedly, obtain uniform Emulsion, cross the G5 sintered glass funnel and carry out filtration sterilization (sterilizing 30 minutes in conjunction with 100～110 ℃ temperature in case of necessity), packing, inflated with nitrogen seals and promptly gets this product.
Particle size range is 5nm～1000nm, and mean diameter is 233nm.Prepared Emulsion can oral or injection.
Embodiment 3:
Prescription is formed: norcantharidin 0.05g, and soybean phospholipid 5g, TPGS 0.5g, hot certain herbaceous plants with big flowers acid glyceride 5g, soybean oil 5g, xylitol 5g, hydrochloric acid (sodium hydroxide) is an amount of, and all the other are distilled water, altogether 100ml.
Manufacture method:
1) preparation oil phase: hot certain herbaceous plants with big flowers acid glyceride, soybean oil are heated to 60 ℃, add soybean phospholipid, TPGS, medicine, strong agitation is cooled to 40 ℃ to dissolving;
2) preparation water: xylitol is added in the entry, 40 ℃ of following stirring and dissolving (using the active carbon depyrogenation in case of necessity);
3) in the time of 40 ℃, water is added oil phase, strong agitation 5min forms colostrum;
4), regulate pH value to 7 with an amount of hydrochloric acid (sodium hydroxide) solution;
5) cross the microjet instrument, the first step is regulated homogenize pressure to 6000psi, and the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 14000psi, crosses the degerming of 0.3um microporous filter membrane, packing, and inflated with nitrogen seals and promptly gets this product.Prepared Emulsion can oral or injection.
Particle size range is 10nm～1000nm, and mean diameter is 222nm.
Embodiment 4:
Prescription is formed: norcantharidin 0.05g, and soybean phospholipid 5g, poloxamer 5g, HS15 5g, hot certain herbaceous plants with big flowers acid glyceride 10g, safflower oil 5g, oleic acid 0.1g, tocopherol 0.1g, glycerol 2.2g, sodium hydroxide is an amount of, and all the other are water, altogether 100ml.
Manufacture method:
1) preparation oil phase: hot certain herbaceous plants with big flowers acid glyceride, safflower oil are heated to 60 ℃, add soybean phospholipid, medicine, oleic acid, tocopherol, strong agitation 5min dissolving;
2) preparation water: HS15, poloxamer and glycerol are added in the entry, stir 10min down at 50 ℃;
3) in the time of 45 ℃, water is added oil phase, strong agitation 5min forms colostrum;
4) use proper amount of sodium hydroxide solution, regulate pH value to 9;
5) cross the microjet instrument, the first step is regulated homogenize pressure to 6000psi, and the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 13000psi, crosses the degerming of 0.22um microporous filter membrane, packing, and inflated with nitrogen,
Seal and promptly get this product.Prepared Emulsion can oral (can regulate taste) or injection.
Particle size range is 5nm～900nm, and mean diameter is 127nm.
Embodiment 5:
Prescription is formed: norcantharidin 0.1g, and soybean phospholipid 10g, TPGS 4g, poloxamer 1g, hot certain herbaceous plants with big flowers acid glyceride 14g, soybean oil 1.4g, linoleic acid 0.1g, thioctic acid 0.1g, mannitol 5g, sodium hydroxide is an amount of, and all the other are water, altogether 100ml.
Manufacture method:
1) preparation oil phase: hot certain herbaceous plants with big flowers acid glyceride, soybean oil are heated to 60 ℃, add medicine, linoleic acid, thioctic acid, soybean phospholipid, TPGS, strong agitation 10min;
2) preparation water: poloxamer and mannitol are added in the water for injection, stir 5min down at 60 ℃;
3) in the time of 45 ℃, water is added oil phase, strong agitation 10min forms colostrum;
4) use proper amount of sodium hydroxide solution, regulate pH value to 7;
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 600kg/cm
2, the second step re-adjustment is to 140kg/cm
2, with solution homogenize repeatedly, obtain uniform Emulsion, cross the G6 sintered glass funnel and carry out filtration sterilization, packing, inflated with nitrogen seals and promptly gets this product.Prepared Emulsion can oral (can regulate taste) or injection.
Particle size range is 15nm～1000nm, and mean diameter is 96nm.
Embodiment 6:
Prescription is formed: norcantharidin 0.02g, and vitamin E 0.5g, midchain oil 3g, TPGS 1g, HS15 1g, xylitol 10g, hydrochloric acid is an amount of, and all the other are water for injection, altogether 100ml.
Manufacture method:
1) preparation oil phase: midchain oil is heated to 60 ℃, adds vitamin E, HS15, TPGS, medicine, be stirred to dissolving, be cooled to 20 ℃, stir 5min;
2) preparation water: xylitol is added in the entry, stir 10min down, make it to dissolve fully at 50 ℃;
3) in the time of 20 ℃, water is added oil phase, strong agitation 5min forms colostrum;
4), regulate pH value to 5.5 with an amount of hydrochloric acid solution;
5) cross the microjet instrument, the first step is regulated homogenize pressure to 8000psi, and the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 16000psi, crosses the degerming of 0.22um microporous filter membrane, packing, and inflated with nitrogen seals and promptly gets this product.(can add sweeting agent, essence in the oral formulations).
Particle size range is 5nm～800nm, and mean diameter is 166nm.
Embodiment 7:
Prescription is formed: norcantharidin 0.02g, and ethyl oleate 1g, midchain oil 2g, Semen Maydis oil 1g, TPGS1g, soybean phospholipid 2.5g, poloxamer 0.1g, oleic acid 0.01g, tocopherol 0.1g, sucrose 10g, hydrochloric acid is an amount of, and all the other are water, altogether 100ml.
Manufacture method:
1) preparation oil phase: ethyl oleate, midchain oil, Semen Maydis oil are heated to 60 ℃, add medicine, TPGS, soybean phospholipid, oleic acid, tocopherol, the strong agitation dissolving;
2) preparation water: poloxamer and sucrose are added in the entry, stir 5min down, make it complete miscibility at 60 ℃;
3) in the time of 45 ℃, water is added oil phase, strong agitation 15min forms colostrum;
4), regulate pH value to 7 with an amount of sodium radio-phosphate,P-32 solution;
5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 4000psi, and the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 20000psi, crosses the microporous filter membrane degerming, packing, and inflated with nitrogen seals and promptly gets this product.Prepared Emulsion can oral or injection.Can add antiseptic (antibacterial), sweeting agent, essence in the oral formulations.
Particle size range is 10nm～900nm, and mean diameter is 132nm.
Claims (8)
- But 1, a kind of norcantharidin Emulsion of filtration sterilization, it is characterized in that: every milliliter of percentage by weight is in the medicine: norcantharidin 0.01～0.1%, be 0.1mgml/～1mg/ml, oil 0.5%～15%, emulsifying agent 0.5%～15%, co-emulsifier 0%～3%, isoosmotic adjusting agent 1%～10%, in addition, still contain pH regulator agent, antioxidant, antiseptic, sweeting agent, essence.
- But 2, the norcantharidin Emulsion of a kind of filtration sterilization according to claim 1, it is characterized in that: oil comprises long-chain oil and midchain oil, wherein midchain oil is: hot certain herbaceous plants with big flowers acid glyceride, suffering or certain herbaceous plants with big flowers acid glyceride; Long-chain oil is: soybean oil, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, safflower oil; Can adopt midchain oil or long-chain oil separately respectively, also can adopt miscella, its mixed proportion is " midchain oil: long-chain oil=1: 0.1～mix at 1: 10 "; In addition, oil phase can also be one or more mixture in vitamin E, tocopherol, ethyl oleate, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, Ethyl linoleate, oleic acid sorbitol ester, olein, Oleum Cocois C8/C10 monoglyceride or dibasic acid esters, Oleum Cocois C8/C10 propylene glycol dibasic acid esters, Oleum Cocois C8/C10 triglyceride, Oleum Cocois C8/C10 triglyceride, the acetylizad monoglyceride of purification, the purification Oleum helianthi monoglyceride etc.
- But 3, the norcantharidin Emulsion of a kind of filtration sterilization according to claim 1 is characterized in that: described emulsifying agent comprises one or more mixture that adopt in phospholipid, HS15, vitamin E polyethylene glycol succinic acid ester, DSPE-PEG derivant, the poloxamer; Can add co-emulsifier as required, as oleic acid, sad, certain herbaceous plants with big flowers is sour, one or more mixture in the lauric acid, Palmic acid, linoleic acid, linoleic acid, stearic acid, docosahexenoic acid, cholic acid, deoxycholic acid.
- But 4, the norcantharidin Emulsion of a kind of filtration sterilization according to claim 1 is characterized in that: its isoosmotic adjusting agent is one or more mixture in glycerol, glucose, mannitol, xylitol, the sucrose; The pH regulator agent is one or more in hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphoric acid, sodium phosphate, citric acid, the sodium citrate etc., and the pH scope is 3～9; Antioxidant is noble gas, EDTA and its esters, alpha-tocopherol, α-tocopheryl acetate, alpha-lipoic acid, vitamin C and derivant thereof, as one or more mixture in the sodium L-ascorbate-2-phosphate, antiseptic is benzyl alcohol, benzoic acid or its salt, sorbic acid or its salt, parabens.
- But 5, the norcantharidin Emulsion of a kind of filtration sterilization according to claim 1 is characterized in that: the particle size range of institute's antigalactic is 5nm～1000nm, and particle mean size is less than 250nm.
- But 6, the norcantharidin Emulsion of a kind of filtration sterilization according to claim 1 is characterized in that: described sweeting agent is sucrose, glucide, aspartame, protein sugar etc.; Essence is cream flavour, Fructus Citri tangerinae essence, cocoanut flavour, flavoring pineapple essence.
- But 7, a kind of preparation method of norcantharidin Emulsion of filtration sterilization as claimed in claim 1 is characterized in that preparation process is as follows:1) preparation oil phase: control temperature 20-90 ℃ of oil phase, add emulsifying agent or be added in aqueous phase, strong agitation adds norcantharidin, strong agitation mixing, dissolving to dissolving;2) preparation water: with water and isoosmotic adjusting agent, also comprise emulsifying agent in case of necessity, stir 5min down, make it complete miscibility at 20～90 ℃;3) in the time of 20～80 ℃, oil phase is added water or water adding oil phase, the strong agitation mixing forms colostrum;4) regulate pH value to 3～9;5) cross the homogenizing instrument, the first step is regulated homogenize pressure to 520～600kg/cm 2, second step re-adjustment to 100～140kg/cm 2Or mistake microjet instrument, the first step is regulated homogenize pressure to 4000-8000psi, the second step re-adjustment with solution homogenize repeatedly, obtains uniform Emulsion to 10000-20000psi, (or G5, G6 sintered glass funnel carry out filtration sterilization with 0.3um or less than the microporous filter membrane of 0.3um, encapsulation can further be sterilized 30 minutes under 100～110 ℃ temperature in case of necessity, promptly got this product.
- But 8, a kind of norcantharidin Emulsion of filtration sterilization as claimed in claim 1, it is characterized in that: prepared preparation can be used to prepare the oral or injectable drug of treatment hepatocarcinoma, the esophageal carcinoma, harmonization of the stomach carcinoma of gastric cardia and low leukocyte counts disease, hepatitis, liver cirrhosis, hepatitis b virus carrier, also can be used for preparing cancer premedicate or combined chemotherapy medicine.
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| CN 200510046526 CN1706377A (en) | 2005-05-27 | 2005-05-27 | Norcantharidin emulsion capable of being sterilized through filtering and its prepn process |
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| CN 200510046526 CN1706377A (en) | 2005-05-27 | 2005-05-27 | Norcantharidin emulsion capable of being sterilized through filtering and its prepn process |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800913A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating clouding formation phenomenon of TPGS and application thereof in medicinal preparation |
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2005
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800913A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating clouding formation phenomenon of TPGS and application thereof in medicinal preparation |
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Open date: 20051214 |