CN1718190A - Nux vomica alkaloid liposome, and its prepn. method - Google Patents
Nux vomica alkaloid liposome, and its prepn. method Download PDFInfo
- Publication number
- CN1718190A CN1718190A CN 200410041337 CN200410041337A CN1718190A CN 1718190 A CN1718190 A CN 1718190A CN 200410041337 CN200410041337 CN 200410041337 CN 200410041337 A CN200410041337 A CN 200410041337A CN 1718190 A CN1718190 A CN 1718190A
- Authority
- CN
- China
- Prior art keywords
- liposome
- strychnine
- alkaloid
- cholesterol
- ammonium sulfate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 238000000034 method Methods 0.000 title claims abstract description 42
- 229930013930 alkaloid Natural products 0.000 title claims abstract description 40
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- 244000107975 Strychnos nux-vomica Species 0.000 title claims description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 67
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Abstract
An antineoplastic strychnos alkaloid liposome with 10w poison and high curative effect is proportionally prepared from strychnos alkaloid, phosphatide and cholesterol. Its preparing process by ammonium sulfate gradient method is also disclosed.
Description
One, technical field
The present invention relates to Chinese medicine liposome and preparation method thereof, be specially liposome of strychnine alkaloid and preparation method thereof.
Two, background technology
Semen Strychni is the dry mature seed of Semen Strychni scarabaeidae plant Semen Strychni Strychnos nux-vomica L., has effects such as diffusing heat in blood, detumescence, analgesia.Semen Strychni contains total alkaloids 2%～5%, is mainly strychnine (Strychnine, C
21H
22O
2N
2), strychnine (Brucine, C
23H
26O
4N
2) respectively account for about 1%～1.4%, the vomicine (Vomicine), pseudostrychnine (Pseudostrychnine), pseudobrucine (Pseudobrucine), α-colubrine (α-Colubrine), β-colubrine (β-Colubrine), loganin (Loganin, the C that contain trace in addition
17H
26O
10), chlorogenic acid, Palmic acid, fatty oil, protein, polysaccharide etc.
The Semen Strychni beginning is stated from Compendium of Material Medica, and after this all families book on Chinese herbal medicine all has more detailed record to the effect and the application of Semen Strychni.In recent years, Semen Strychni is used for the treatment of multiple difficult diseases, obtained significant curative effect, related disease has facial paralysis, paraplegia, cerebral thrombosis, hemiplegia, poliomyelitis sequela, sciatica, myasthenia gravis, rheumatoid arthritis, fracture, the carbuncle skin infection, tuberculosis, psychosis, functional anejaculation, tens of kinds more than of cervical erosion etc., and mainly concentrate on the central nervous system disorders aspect, mechanism studies show that, strychnine has excitation to whole cental system more, the reflection function of at first excited spinal cord, the respiratory center and the vasomotor center of next excited oblongata, and can improve corticocerebral sensory centre function, the energy excited vagus, the respiratory center irritability is improved, and exaggerated respiration is accelerated.
It is noticeable especially that to be Semen Strychni suppressing to have unique curative effect aspect the cancer pain.Experimental results show that, the pain relieving composition is mainly strychnine in the Semen Strychni, it has the paralysis effect to sensory nerve ending, its maincenter analgesic mechanism may be relevant with enkephalin content with increase brain monoamine neurotransmitter, the strychnine analgesic effect persistent period substantially exceeds Pethidine, has long half time, advantages such as no addiction.
Except that suppressing cancer pain, Semen Strychni is also very valuable to the lethal effect of cancerous cell.Find by cultured tumor cells in vitro, strychnine and nitrogen oxide thereof and strychnine and nitrogen oxide thereof have its growth effect of inhibition and form damaging action to tumor cell line K652, HeLa, HEP-2, its mechanism may be to suppress the protein synthesis of tumor cell, rather than directly effect.The experiment of the genetic toxicology research that is index with the sister's chromosome and the micronucleus of bone marrow cells in mice shows that strychnine has stronger antimutagenic effect, and the experimental result that suppresses tumor cell with the Semen Strychni Alkaloid is consistent.Semen Strychni is used for the treatment of gastric cancer, skin carcinoma, esophageal carcinoma etc. clinically also certain curative effect.
More both at home and abroad to the research of strychnine alkaloid, but lay particular emphasis on strychnine and strychnine the mechanism of action and toxicity to nervous system and cardiovascular system.Though Semen Strychni is used for treatment for cancer a large amount of clinical datas is arranged, but the Semen Strychni toxic and side effects is big, and effective dose and toxic dose are approaching, because the dosage form of existing Semen Strychni preparation is unreasonable, when clinical use, cause some poisoning cases, seriously restricted the application of Semen Strychni in treatment of cancer.For improving curative effect, reduce toxic and side effects, be necessary the anticancer effective site alkaloid of Semen Strychni is made targeting drug administration preparations such as liposome.
Find liposome from people such as nineteen sixty-five Bangham, particularly people such as Britain Gregoriadis in 1971 as since the pharmaceutical carrier, liposome has obtained development rapidly as a kind of new drug carrier in the research of field of medicaments with liposome.Liposome is the bilayer vesicle that is made of phospholipid molecule, and liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine as liposome, can seal water soluble drug again; Can protect the medicine that is wrapped effectively, improve bioavailability; Make medicine have targeting, can reduce the toxic and side effects of medicine; Liposome has slow-releasing and controlled-releasing action, is fit to multipath administration etc.Therefore, liposome has obtained increasingly extensive concern because its particular structure characteristics make pharmaceutical preparation enter the new world of target administration as a kind of new drug carrier, and obtain gratifying results in the world of medicine.
Three, summary of the invention
1. goal of the invention: the object of the present invention is to provide a kind of clinical suitable strychnine alkaloid liposome, this lipid physical ability improves the targeting of strychnine alkaloid to tumor tissues, and then improve strychnine alkaloid antineoplastic curative effect, reduce the toxicity and the side effect of strychnine alkaloid.
2. technical scheme:, the invention provides following technical scheme for achieving the above object:
A kind of strychnine alkaloid liposome is characterized in that the medicament that it is made up of the raw material that contains the following weight ratio range:
Strychnine alkaloid: 1 part
Phospholipid: 10～100 parts
Cholesterol: 0～50 part
Further preferred weight proportion scope is: 1 part of strychnine alkaloid, 0～90 part of phosphatidase 13,5～15 parts in cholesterol.
Further preferred again weight proportion scope is: 1 part of strychnine alkaloid, 0～70 part of phosphatidase 15,8～12 parts in cholesterol.
Described strychnine alkaloid liposome, wherein said strychnine alkaloid are meant the alkaloid that extracts from the dry mature seed of Semen Strychni scarabaeidae plant Semen Strychni Strychnos nux-vomicaL..This alkaloid can be a total alkaloids in Semen Strychni; Also can be arbitrary monosomic alkali of forming total alkaloids in Semen Strychni, as strychnine (Strychnine, C
21H
22O
2N
2), strychnine (Brucine, C
23H
26O
4N
2), vomicine (Vomicine), pseudostrychnine (Pseudostrychnine), pseudobrucine (Pseudobrucine), α-colubrine (α-Colubrine), β-colubrine (β-Colubrine), NSC 118079, strychnine nitrogen oxide etc.; This alkaloid also can be the mixture of above-mentioned each monosomic alkali combination in any.
Described strychnine alkaloid liposome, wherein said phospholipid can be any in lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidic acid, phosphatidyl glycerol, phosphatidylinositols, the cuorin etc. or their any mixture.
Described strychnine alkaloid liposome can further be made said dosage form on any pharmaceutics, as injection, oral liquid, exterior-applied gel, ointment, spray, nasal drop etc.Further preferred dosage form is intravenous fluid, oral liquid and exterior-applied gel.Prepare above-mentioned medicament and also can add other adjuvant, as sodium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, water etc.
Described strychnine alkaloid liposome, it is characterized in that its preparation can adopt known method, as passive medicine carrying method (film dispersion method, reverse evaporation, alcohol injection, ether injection method, freeze-drying, pro-liposome method etc.) and active loading method (pH value gradient method and ammonium sulphate gradient etc.).
Further preferred manufacturing procedure is the ammonium sulphate gradient in the active loading method.
The ammonium sulphate gradient of described preparation strychnine alkaloid liposome is characterized in that through following step preparation:
(1) take by weighing 5～20 parts in 0～100 part of phosphatidase 16 and cholesterol by weight, be dissolved in the chloroform, removal of solvent under reduced pressure forms lipid membrane.(2) add 10～100 times of the ammonium sulfate solutions of 0.03～0.3mol/L by weight, aquation and eluting lipid membrane form ammonium sulfate blank liposome suspension.(3) supersound process 5～20min, the particle diameter of minimizing liposome.(4) cross 0.1～0.45 μ m microporous filter membrane, further control the size of liposome.(4) remove not by liposomal encapsulated ammonium sulfate by dialysis or ultrafiltration and gel filtration chromatography method, form ammonium sulphate gradient blank liposome suspension.(5) add 1 part of strychnine alkaloid by weight and incubate 5～60min, make strychnine alkaloid by liposomal encapsulated in 30～80 ℃ of temperature.(6) add the sodium chloride that accounts for liposome turbid liquor 0.9% (weight ratio), cross 0.2 μ m microporous filter membrane, inflated with nitrogen, embedding is in ampoule.
The ammonium sulphate gradient of further preferred preparation strychnine alkaloid liposome is characterized in that through following step preparation:
(1) take by weighing 15 parts in 00 part of phosphatidase 11 and cholesterol by weight, be dissolved in the chloroform, removal of solvent under reduced pressure forms lipid membrane.(2) ammonium sulfate solution of the 0.1mol/L of 57 times of amounts of adding phospholipid, cholesterol and strychnine weight sum, aquation and eluting lipid membrane form ammonium sulfate blank liposome suspension.(3) supersound process 15min, the particle diameter of minimizing liposome.(4) cross 0.2 μ m microporous filter membrane, the size of control liposome.(4) remove not by liposomal encapsulated ammonium sulfate by dialysis or gel filtration chromatography method, form ammonium sulphate gradient blank liposome suspension.(5) add 1.67 parts of strychnine alkaloids by weight and incubate 10～50min, make strychnine alkaloid by liposomal encapsulated in 40～70 ℃ of temperature.(6) add the sodium chloride that accounts for liposome turbid liquor 0.9% (weight ratio), cross 0.2 μ m micro-filtration membrane, inflated with nitrogen, embedding is in ampoule.
3. beneficial effect: an important feature of the present invention is the envelop rate height of liposome to strychnine alkaloid, can reach more than 60%; Can further improve more than 90% through the envelop rate of preferred manufacturing procedure strychnine alkaloid.The present invention adopts the particle diameter of micro-filtration membrane control liposome, makes strychnine alkaloid liposome particle diameter more than 95% less than 200nm.The prepared strychnine alkaloid liposome liquid that is creamy white is clear liquid to x ray fluoroscopy x.
The present invention adopts film dispersion method, reverse evaporation, alcohol injection, freeze-drying, ammonium sulphate gradient and pH value gradient method to prepare the strychnine alkaloid liposome respectively, with the envelop rate is that index compares and estimates above-mentioned 7 kinds of preparation methoies, and experimental result sees Table 1.The result shows that ammonium sulphate gradient is the highest to the envelop rate of strychnine alkaloid.
7 kinds of methods of table 1 prepare the envelop rate contrast of strychnine alkaloid liposome
| Preparation method | Envelop rate (%) | Remarks |
| Passive loading method: film dispersion method reverse evaporation alcohol injection sorbierite carrier deposit method freeze-drying active loading method: ammonium sulphate gradient pH value gradient method (citric acid) | 30.11 38.25 25.22 37.02 25.94 58.71 35.36 | The same yellowish white solid liposome of milky suspension particle white loose shape solid liposome milky suspension is the same |
The present invention selects L9 (3) 4 orthogonal table for use, is index with the strychnine alkaloid envelop rate, is investigation factor (each factor is selected three levels) with ratio, ammonium sulfate concentrations, the ammonium sulfate consumption of lecithin and cholesterol, carries out 9 experiments.Test arrangement and result are shown in table 2,3,4.Experimental result shows, factor C is that ammonium sulfate has the significance meaning with dizzy influence to envelop rate, and factor A and factor B do not have the significance meaning to the influence of envelop rate.The optimal preparation prescription is A
1B
3C
1, promptly soybean lecithin is 100: 15 with the ratio of cholesterol, and the concentration of ammonium sulfate solution is 0.1mol/L, and consumption is 20ml (is under the condition of 300mg at the lecithin consumption).
The arrangement of table 2 factor level
| Factor | Lecithin: cholesterol (A) | Ammonium sulfate solution concentration (B) mol/L | Ammonium sulfate solution consumption (C) ml |
| Water 12 flat 3 | 100∶15 100∶30 100∶45 | 0.20 0.15 0.10 | 20 25 30 |
Annotate: each experiment phospholipid consumption is 300mg, and the strychnine alkaloid addition is 5mg.
Arrangement of table 3 orthogonal test and Calculation results
| A lecithin and cholesterol ratio | The B ammonium sulfate concentrations | C ammonium sulfate consumption | D (sky) | Envelop rate Yi (%) | |
| 1 2 3 4 5 6 7 8 9 | 1 1 1 2 2 2 3 3 3 | 1 2 3 1 2 3 1 2 3 | 1 2 3 2 3 1 3 1 2 | 1 2 3 3 1 2 2 3 1 | 71.19 61.82 52.46 57.12 36.48 73.01 35.85 76.51 62.69 |
| Ij IIj IIIj R SSj | 185.47 166.61 175.05 18.86 59.501 | 164.16 174.81 188.16 24.00 96.405 | 220.71 181.63 124.79 95.92 1550.964 | 170.36 170.68 186.09 15.73 53.889 | Summation 527.13 CT 30874.00 quadratic sums 32634.76 SS total 1760.76 |
Table 4 The results of analysis of variance
| Soruces of variation | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value | Significance |
| A B C error D | 59.501 96.405 1550.964 53.889 | 2 2 2 2 | 29.751 48.202 775.482 26.945 | 1.10 1.79 28.78 | P＜005 |
The present invention selects L for use
9(3)
4Orthogonal table is an index with the strychnine alkaloid envelop rate, with temperature incubate temperature, temperature incubates the time and the strychnine alkaloid addition is investigation factor (each factor is selected three levels), carry out 9 times the experiment.Test arrangement and table 5,6,7,8 as a result.The result shows that factor A, factor B and factor C all do not have the significance meaning to the influence of envelop rate.The optimal preparation process conditions are A
1B
1C
1, promptly to incubate temperature be 40 ℃ to temperature, and the temperature time of incubating is 20min, and the strychnine addition is 2mg.
The arrangement of table 5 factor level
| Factor | Temperature is incubated temperature (A) ℃ | Temperature is incubated the time (B) min | Strychnine addition (C) mg |
| Water 12 flat 3 | 40 50 60 | 20 30 40 | 2 4 6 |
Annotate: each experiment phospholipid consumption is 150mg, cholesterol 22.5mg, and 0.1mol/L ammonium sulfate solution consumption is 10ml.
Arrangement of table 6 orthogonal test and Calculation results
| A (temperature is incubated the time) | B (temperature is incubated temperature) | C (medicine addition) | D (sky) | Envelop rate Yi (%) | |
| 1 2 3 4 5 6 7 8 9 | 1 1 1 2 2 2 3 3 3 | 1 2 3 1 2 3 1 2 3 | 1 2 3 2 3 1 3 1 2 | 1 2 3 3 1 2 2 3 1 | 94.23 49.42 53.61 51.88 56.84 72.07 42.48 52.17 53.67 |
| Ij IIj IIIj R SSj | 197.26 180.79 148.32 48.94 413.409 | 188.59 158.43 179.35 30.16 159.183 | 218.47 154.97 152.93 65.54 925.767 | 204.74 163.97 157.66 47.08 435.393 | Summation 526.37 CT 30785.04 quadratic sums 32718.79 SS total 1933.75 |
Table 7 The results of analysis of variance
| Soruces of variation | Sum of sguares of deviation from mean | Degree of freedom | Variance | The F value | Marginal value | Significance |
| A B C error D | 413.409 159.183 925.767 435.393 | 2 2 2 2 | 206.705 79.592 462.884 217.696 | 0.95 0.37 2.13 |
Table 8 amplifies the checking result
| Lot number | Ammonium sulphate gradient blank liposome consumption ml | Strychnine addition mg | Envelop rate % |
| 040420-1 040420-2 040420-3 | 20 20 20 | 4.1 4.0 4.2 | 89.49 91.13 87.46 |
Four, the specific embodiment
Exemplify 8 embodiment below, the present invention is further specified.
Embodiment 1
The preparation of total alkaloids in Semen Strychni (abbreviation total alkali) liposome and intravenous injection, oral liquid and exterior-applied gel:
Prescription: Strychnos alkaloid 5mg, soybean lecithin 300mg, cholesterol 45mg, other pharmaceutic adjuvant is an amount of
Method for making: the preparation of (1) Strychnos alkaloid liposome turbid liquor: take by weighing in soybean lecithin and the cholesterol dissolving fourth 30ml chloroform, place 2000ml pyriform bottle, in on the Rotary Evaporators with the condition of 30 ℃ of 60～100r/min rotating speeds, constant temperature water bath under rotation boil off chloroform and make lipoid in the even film forming of pyriform bottle inwall, put dry 4～12h in the vacuum desiccator then.Add 0.1mol/L ammonium sulfate solution 20ml again, after earlier slow on the Rotary Evaporators soon with rotation aquation and eluting lipid membrane under the 60～150r/min rotating speed, 40 ℃, the condition of vacuum 500～600mbar (anti-oxidation).All behind the eluting, supersound process 10min promptly gets the blank liposome (not pastille) of sealing ammonium sulfate.Adopt 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, promptly get blank liposome less than 200nm.Place polydextran gel SephadexG-50 post (glass column then, interior diameter 2.5cm, the high 30cm of post, glucosan consumption 5g, wet method dress post) goes up with PBS liquid (sodium dihydrogen phosphate 1.9mmol, sodium hydrogen phosphate 8.1mmol, sodium chloride 0.15mol, adding distil water is to 1000ml) eluting do not seal ammonium sulfate to separate, and collects milky liposome eluent 22ml, the ammonium sulphate gradient blank liposome.Take by weighing Strychnos alkaloid 5mg and add in the ammonium sulphate gradient blank liposome,, promptly get the Strychnos alkaloid liposome turbid liquor in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators.
(2) preparation of Strychnos alkaloid liposome intravenous injection: above-mentioned Strychnos alkaloid liposome turbid liquor is added an amount of sodium chloride accent etc. ooze,, be poured in 2～10ml ampoule, inflated with nitrogen, sealing by fusing, lettering, packing, 4 ℃ of preservations after 0.2 μ m micro-filtration membrane degerming.
(3) preparation of Strychnos alkaloid liposome oral fluid: above-mentioned Strychnos alkaloid liposome turbid liquor is added adjuvants such as an amount of sucrose, tocopherol and sodium benzoate, and after 0.2 μ m micro-filtration membrane degerming, fill is in the brown oral liquid bottle of 10～20ml.
(4) preparation of Strychnos alkaloid liposome exterior-applied gel: get carbomer 2g, add 50ml distilled water swelling,, promptly get water white blank gel-type vehicle with 20% sodium hydrate aqueous solution adjust pH to 6～7; Above-mentioned Strychnos alkaloid liposome turbid liquor in right amount with adding in the blank gel-type vehicle after the 0.2 μ m micro-filtration membrane degerming, is ground with even, packing, promptly.
(5) entrapment efficiency determination: adopt ultraviolet spectrophotometry and SephadexG-50 column chromatography (glucosan consumption 1.5g, interior diameter 1.5cm, the high 20cm of post) measure the envelop rate of liposome to Strychnos alkaloid: 1. liposome with do not seal separating of Strychnos alkaloid: get Strychnos alkaloid liposome and blank liposome and go up sample 0.5ml respectively, PBS liquid eluting, flow velocity 2ml/min, collect 10ml (liposome outflow part) successively, 2ml (do not contain liposome and free drug substantially, be used to judge whether liposome and free drug separate), 20ml (containing non-encapsulated Strychnos alkaloid).2. ultraviolet absorptivity is measured.Above-mentioned three duplicate samples are got two 2ml respectively, and adding rupture of membranes agent 2ml (isopropyl alcohol: dehydrated alcohol=4: 1), mixing.Corresponding eluent (the same sample of processing method) with blank liposome is a background, measures trap in maximum absorption wavelength 255 places.
The envelop rate of Strychnos alkaloid is greater than 90% in the liposome of this method preparation.
Embodiment 2
The preparation of strychnine liposome:
Prescription: strychnine 10mg, soybean lecithin 600mg, cholesterol 90mg, other pharmaceutic adjuvant are an amount of
Method for making: take by weighing soybean lecithin and cholesterol and be dissolved in the 60ml chloroform, place 2000ml pyriform bottle, in on the Rotary Evaporators with the condition of 30 ℃ of 60r/min rotating speeds, constant temperature water bath under rotation boil off chloroform and make lipoid in the even film forming of pyriform bottle inwall, put dry 4～12h in the vacuum desiccator then.Add 0.1mol/L ammonium sulfate solution 40ml again, on the Rotary Evaporators with the condition of 60～150r/min rotating speed, 40 ℃, vacuum 500～600mbar (anti-oxidation) under rotation aquation and eluting lipid membrane.All behind the eluting, supersound process 10min adopts 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, promptly gets the blank liposome less than 200nm.Place then on the polydextran gel Sephadex G-50 post and do not seal ammonium sulfate to separate, collect milky liposome eluent 40～45ml, get the ammonium sulphate gradient blank liposome with PBS liquid eluting.Taking by weighing strychnine 10mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, after 0.2 μ m micro-filtration membrane degerming, promptly get the strychnine liposome turbid liquor, inflated with nitrogen and embedding are in 4 ℃ of preservations of 10ml ampoule.
The strychnine liposome is the milky suspension clear and bright to light.Adopt Sephadex G-50 column chromatography to separate liposome and non-encapsulated strychnine, adopt ultraviolet spectrophotometry to measure trap in the 255nm place, the envelop rate that records strychnine is 93.5%.
Embodiment 3
The preparation of vauqueline liposome and intravenous injection thereof, oral liquid and external-use gel:
Prescription: strychnine 15mg, soybean lecithin 900mg, cholesterol 135mg, other pharmaceutic adjuvant are an amount of
Method for making: the preparation of (1) vauqueline liposome suspension: take by weighing soybean lecithin 900mg and cholesterol 135mg and be dissolved in the 60ml chloroform, place 2000ml pyriform bottle, in on the Rotary Evaporators with the condition of 30 ℃ of 60r/min rotating speeds, constant temperature water bath under rotation boil off chloroform and make lipoid in the even film forming of pyriform bottle inwall, put dry 4～12h in the vacuum desiccator then.Add 0.1mol/L ammonium sulfate solution 60ml again, on the Rotary Evaporators with rotation aquation and eluting lipid membrane under the 60～150r/min rotating speed, 40 ℃, the condition of vacuum 500～600mbar.All behind the eluting, supersound process 10min adopts 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration.Place then on the polydextran gel Sephadex G-50 post and do not seal ammonium sulfate to separate, collect milky liposome eluent 60～65ml, get the ammonium sulphate gradient blank liposome with PBS liquid eluting.Taking by weighing strychnine 15mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, after 0.2 μ m micro-filtration membrane degerming, promptly get the vauqueline liposome suspension, inflated with nitrogen and embedding are in 4 ℃ of preservations of 10ml ampoule.
The vauqueline liposome suspension is the milky suspension clear and bright to light.Adopt Sephadex G-50 column chromatography to separate liposome and non-encapsulated strychnine, adopt ultraviolet spectrophotometry to measure trap in the 260nm place, the envelop rate that records strychnine is 96.1%.
(2) preparation of vauqueline liposome intravenous injection: above-mentioned vauqueline liposome suspension is added an amount of sodium chloride accent etc. ooze,, be poured in 2～10ml ampoule, inflated with nitrogen, sealing by fusing, lettering, packing, 4 ℃ of preservations after 0.2 μ m micro-filtration membrane degerming.
(3) preparation of vauqueline liposome oral liquid: above-mentioned vauqueline liposome suspension is added adjuvants such as an amount of sucrose, tocopherol and sodium benzoate, and after 0.2 μ m micro-filtration membrane degerming, fill is in the brown oral liquid bottle of 10～20ml.
(4) preparation of vauqueline liposome exterior-applied gel: get carbomer 1g, add 25ml distilled water swelling,, promptly get water white blank gel-type vehicle with 20% sodium hydrate aqueous solution adjust pH to 6～7; Above-mentioned vauqueline liposome suspension is added in the blank gel-type vehicle in right amount, grind with even, packing, promptly.
Embodiment 4
The preparation of NSC 118079 liposome:
Prescription: NSC 118079 5mg, soybean lecithin 300mg, cholesterol 45mg, other pharmaceutic adjuvant are an amount of
Method for making: take by weighing soybean lecithin 300mg and cholesterol 45mg and be dissolved in the 30ml chloroform, place 2000ml pyriform bottle, in on the Rotary Evaporators with the condition of 30 ℃ of 60r/min rotating speeds, constant temperature water bath under rotation boil off chloroform and make lipoid in the even film forming of pyriform bottle inwall, put dry 4～12h in the vacuum desiccator then.Add 0.1mol/L ammonium sulfate solution 20ml again, in earlier slow back on the Rotary Evaporators soon with rotation aquation and eluting lipid membrane under the 60～150r/min rotating speed, 40 ℃, the condition of vacuum 500～600mbar.All behind the eluting, supersound process 10min adopts 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, promptly gets the blank liposome less than 200nm.Place then on the polydextran gel SephadexG-50 post and do not seal ammonium sulfate to separate, collect milky liposome eluent 20～22ml, get the ammonium sulphate gradient blank liposome with PBS liquid eluting.Taking by weighing NSC 118079 5mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, after 0.2 μ m micro-filtration membrane degerming, promptly get the NSC 118079 liposome turbid liquor, inflated with nitrogen and embedding are in 4 ℃ of preservations of 10ml ampoule.
The NSC 118079 liposome is the milky suspension clear and bright to light.Adopt Sephadex G-50 column chromatography to separate liposome and non-encapsulated NSC 118079, adopt ultraviolet spectrophotometry to measure trap in the 262nm place, the envelop rate that records NSC 118079 is 36.1%.
Embodiment 5
The preparation of Strychnos alkaloid freeze-dried lipidosome:
Prescription: Strychnos alkaloid 15mg, egg lecithin 900mg, cholesterol 135mg, other pharmaceutic adjuvant are an amount of
Method for making: take by weighing egg lecithin 900mg and cholesterol 135mg is dissolved in the 60ml chloroform.Other takes by weighing mannitol 1.5g and (is convenient to aquation and eluting, the minimizing particle diameter) places 2000ml pyriform bottle, the chloroform solution that adds lipoid, in on the Rotary Evaporators with the condition of 30 ℃ of 60r/min rotating speeds, constant temperature water bath under rotation boil off chloroform and make lipoid in sorbitol surface and the even film forming of pyriform bottle inwall, put dry 12h in the vacuum desiccator then.Add 0.1mol/L ammonium sulfate solution 60ml again, on the Rotary Evaporators with the condition of 60～150r/min rotating speed, 40 ℃, vacuum 500～600mbar (anti-oxidation) under rotation aquation and eluting lipid membrane.All behind the eluting, supersound process 10min adopts 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, place bag filter then, with 10 times of amount PBS liquid dialysis 2 times, each 6h (band agitating device), do not seal ammonium sulfate to remove, promptly get the ammonium sulphate gradient blank liposome.Taking by weighing Strychnos alkaloid 15mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, add mannitol 1g dissolving, after 0.2 μ m micro-filtration membrane degerming, promptly get the Strychnos alkaloid liposome turbid liquor, be sub-packed in by (10ml/ bottle) in the cillin bottle first pre-freeze, put lyophilization in the freezer dryer then, promptly get the Strychnos alkaloid freeze-dried lipidosome.Every adding water for injection 10ml jolting dissolving gets final product before using.
The Strychnos alkaloid freeze-dried lipidosome is the white loose sprills, and the envelop rate of freezing preceding Strychnos alkaloid is 92.7%, and the envelop rate that the back Strychnos alkaloid is dissolved in lyophilizing again is 31.6%.
Embodiment 6
The preparation of strychnine freeze-dried lipidosome:
Prescription: strychnine 15mg, egg lecithin 900mg, cholesterol 135mg, other pharmaceutic adjuvant are an amount of
Method for making: take by weighing egg lecithin 900mg and cholesterol 135mg and be dissolved in the 90ml ether, add 0.1mol/L ammonium sulfate solution 60ml, jolting makes emulsifying, in removing ether with rotation under the 120r/min rotating speed, 40 ℃, vacuum 90mbar condition on the Rotary Evaporators, supersound process 10min, adopt 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, place bag filter then, with 10 times of amount PBS liquid dialysis 2 times, each 6h (band agitating device), do not seal ammonium sulfate to remove, promptly get the ammonium sulphate gradient blank liposome.Taking by weighing strychnine 15mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, add mannitol 1g dissolving, after 0.2 μ m micro-filtration membrane degerming, promptly get the strychnine liposome turbid liquor, be sub-packed in by (10ml/ bottle) in the cillin bottle first pre-freeze, put lyophilization in the freezer dryer then, promptly get the strychnine freeze-dried lipidosome.Every adding water for injection 10ml jolting dissolving gets final product before using.
The strychnine freeze-dried lipidosome is the white loose sprills, and the envelop rate of freezing preceding strychnine is 89.5%, and the envelop rate that the back strychnine is dissolved in lyophilizing again is 33.9%
Embodiment 7
The preparation of vauqueline liposome:
Prescription: strychnine 5.0mg, phosphatidylcholine 300mg, gallbladder are an amount of with pure 50mg, other pharmaceutic adjuvant
Method for making: take by weighing phosphatidylcholine and cholesterol and be dissolved in the 60ml ether, place 1000ml pyriform bottle, add 0.1mol/L ammonium sulfate solution 20ml, in boiling off ether with under the 120r/min rotating speed, 40 ℃, the condition of vacuum 90mbar on the Rotary Evaporators, supersound process 10min, adopt 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, promptly get blank liposome less than 200nm.Place then on the polydextran gel Sephadex G-50 post and do not seal ammonium sulfate to separate, collect milky liposome eluent 20～22ml, get the ammonium sulphate gradient blank liposome with PBS liquid eluting.Taking by weighing strychnine 5mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, after 0.2 μ m micro-filtration membrane degerming, promptly get the vauqueline liposome suspension, inflated with nitrogen and embedding are in 4 ℃ of preservations of 10ml ampoule.
The envelop rate of above-mentioned vauqueline liposome is 81.5%.
Embodiment 8
The preparation of strychnine liposome:
Prescription: strychnine 5.0mg, PHOSPHATIDYL ETHANOLAMINE 300mg, cholesterol 45mg, other pharmaceutic adjuvant are an amount of
Method for making: take by weighing PHOSPHATIDYL ETHANOLAMINE and cholesterol and be dissolved in the 60ml ether, place 1000ml pyriform bottle, add 0.1mol/L ammonium sulfate solution 20ml, in boiling off ether with under the 120r/min rotating speed, 40 ℃, the condition of vacuum 90mbar on the Rotary Evaporators, supersound process 10min, adopt 0.2 μ m micro-filtration membrane that blank liposome is extruded filtration, promptly get blank liposome less than 200nm.Place then on the polydextran gel Sephadex G-50 post and do not seal ammonium sulfate to separate, collect milky liposome eluent 20～22ml, get the ammonium sulphate gradient blank liposome with PBS liquid eluting.Taking by weighing strychnine 5mg adds in the ammonium sulphate gradient blank liposome, in incubating 20min with temperature under the 70r/min, 40 ℃, the condition of vacuum 500～600mbar on the Rotary Evaporators, after 0.2 μ m micro-filtration membrane degerming, promptly get the strychnine liposome turbid liquor, inflated with nitrogen and embedding are in 4 ℃ of preservations of 10ml ampoule.
The envelop rate of above-mentioned strychnine liposome is 73.6%.
Claims (8)
1. strychnine alkaloid liposome is characterized in that it is by containing the medicament that the following weight proportion raw material is formed:
Strychnine alkaloid: 1 part
Phospholipid: 10～100 parts
Cholesterol: 0～50 part
2. according to claim 1 described strychnine alkaloid liposome, wherein the weight ratio of each raw material is 1 part of strychnine alkaloid, 0～90 part of phosphatidase 13,5～15 parts in cholesterol.
3. according to claim 1 described strychnine alkaloid liposome, wherein said strychnine alkaloid is meant the alkaloid that extracts from the dry mature seed of Semen Strychni scarabaeidae plant Semen Strychni Strychnos nux-vomica L or its processed product.This alkaloid can be a total alkaloids in Semen Strychni; Also can be arbitrary monosomic alkali of forming total alkaloids in Semen Strychni, as strychnine (Strychnine, C
21H
22O
2N
2), strychnine (Brucine, C
23H
26O
4N
2), vomicine (Vomicine), pseudostrychnine (Pseudostrychnine), pseudobrucine (Pseudobrucine), α-colubrine (α-Colubrine), β-colubrine (β-Colubrine), NSC 118079, strychnine nitrogen oxide etc.; This alkaloid also can be the mixture of above-mentioned each monosomic alkali combination in any.
4. according to claim 1 described strychnine alkaloid liposome, wherein said phospholipid comprises lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidic acid, phosphatidyl glycerol, phosphatidylinositols, cuorin etc.
5. according to claim 1,2 described strychnine alkaloid liposomees, it is characterized in that it further is prepared into said dosage form on any pharmaceutics, as injection, oral liquid, exterior-applied gel etc.
6. according to claim 1 described strychnine alkaloid liposome, it is characterized in that being prepared with ammonium sulphate gradient.
7. method for preparing the strychnine alkaloid liposome is characterized in that through following step preparation:
(1) take by weighing 5～15 parts in 0～90 part of phosphatidase 13 and cholesterol by weight, be dissolved in the chloroform, removal of solvent under reduced pressure forms lipid membrane.(2) add 10～100 parts of the ammonium sulfate solutions of 0.03～0.3mol/L by weight, aquation and eluting lipid membrane form the blank liposome suspension.(3) supersound process 5～20min, the particle diameter of minimizing liposome.(4) cross 0.1～0.45 μ m micro-filtration membrane, the size of control liposome.(5) remove not by liposomal encapsulated ammonium sulfate by dialysis or ultrafiltration and gel filtration chromatography method, form ammonium sulphate gradient blank liposome suspension.(6) add 1 part of strychnine alkaloid by weight and incubate 5～60min, make strychnine alkaloid by liposomal encapsulated in 30～80 ℃ of temperature.(7) add the sodium chloride that accounts for liposome turbid liquor 0.9% (weight ratio), cross 0.2 μ m micro-filtration membrane, inflated with nitrogen, embedding is in ampoule.
8. according to the preparation method of claim 7 described strychnine alkaloid liposomees, it is characterized in that: (1) takes by weighing 15 parts in 00 part of phosphatidase 11 and cholesterol by weight, is dissolved in the chloroform, and removal of solvent under reduced pressure forms lipid membrane.(2) ammonium sulfate solution of the 0.1mol/L of 57 times of amounts of adding phospholipid, cholesterol and strychnine weight sum, aquation and eluting lipid membrane form ammonium sulfate blank liposome suspension.(3) supersound process 15min, the particle diameter of minimizing liposome.(4) cross 0.2 μ m microporous filter membrane, the size of control liposome.(4) remove not by liposomal encapsulated ammonium sulfate by dialysis or gel filtration chromatography method, form ammonium sulphate gradient blank liposome suspension.(5) add 1.67 parts of strychnine alkaloids by weight and incubate 20min, make strychnine alkaloid by liposomal encapsulated in 40 ℃ of temperature.(6) add the sodium chloride that accounts for liposome turbid liquor 0.9% (weight ratio), cross 0.2 μ m micro-filtration membrane, inflated with nitrogen, embedding is in ampoule.
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| CN 200410041337 CN1718190A (en) | 2004-07-09 | 2004-07-09 | Nux vomica alkaloid liposome, and its prepn. method |
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