CN1290495C - Lipid microspherical asarol prepn and its prepn process - Google Patents
Lipid microspherical asarol prepn and its prepn process Download PDFInfo
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Abstract
The present invention provides an asarone lipid microsphere preparation prepared from alpha-asarone (the chemical name is 2, 4, 5-trimethoxy-1-propenylbenzene) as an active component, oil for injection or oral administration commonly used in pharmacy, an emulsifier and water for injection/water for pharmacy. The lipid microsphere preparation prepared by the asarone lipid microsphere preparation has the advantages of good stability and no obvious change of the physicochemical properties after autoclaving. The results of safety tests show that the lipid microsphere preparation prepared by the asarone lipid microsphere preparation has sterility, no hemolytic activity, no allergy and no irritation, is tested to be qualified in a pyrogen test, and can meet the demand for the safety of clinical medication.
Description
Technical field
The present invention relates to a kind of lipid microspherical asarol preparation and preparation method thereof, belong to drug world.
Background technology
Alpha-ararin has another name called α-asaricin and asarone (Asarone), chemical name 2,4, and 5-trimethoxy-1-propenylbenzene is one of main effective ingredient of Chinese medicine Rhizoma Acori Graminei.It has been carried out extensive studies both at home and abroad since the sixties, proved that the alpha-ararin monomer has very strong pharmacologically active.The synthetic success at home first of nineteen eighty-two Liuzhou pharmaceutical factory has tablet, capsule and injection to go through to put on market subsequently.Clinical proof, this medicine are used to treat chronic tracheitis, bronchial asthma and epilepsy grand mal all better curative effect
[1-2]
Asarone is fat-soluble extremely strong chemical compound, is insoluble in water, and its oral formulations has tablet etc., but because its poorly water-soluble, so bioavailability is very low
[3]Pharmacy worker is at the demand that infects emergency case clinically, surfactant will be added in this product, increase dissolubility in its water, be prepared into Asarone injection liquid, be used to clinically be grown up and cough that child's bacterial pneumonia, intrapulmonary infection, acute/chronic bronchitis, bronchial asthma, obstructive emphysema, pulmonary heart disease, bronchiectasis and lung bronchogenic carcinoma and flu cause, disease such as cough up phlegm, pant, in use a few peoples can produce slight side reaction, as xerostomia, dizziness, feel sick, stomach upset, nervous and constipation etc., rare shock
[4]
The medicine scholar attempts to utilize a kind of specific carrier, and medicine directly is transported to intravital diseased region, just has medicine and leads elastic " targeted therapy ", and made unremitting effort for this reason.20th century the seventies, the clinical medicine scholar of the U.S. has at first realized this imagination at laboratory, this theory of drug delivery system (DDS) has appearred in the eighties world pharmacy industry thus.Under this theory, medicine is dissolved in is scattered in water through phospholipid emulsifying in the fatty oil and makes fat micro sphere preparation, wherein average particle size forms a kind of microsome disperse system about 200 nanometers, is called lipoid microsphere.Lipoid microsphere is novel targeted medicine, alternative builds up at diseased region, and medicine is transported to the target area to greatest extent, makes medicine exceeds conventional formulation in target area concentration several times to hundreds of times, and therapeutic effect obviously improves; Medicine is few in the normal structure abundance simultaneously, and the toxic and side effects of medicine and untoward reaction meeting obviously alleviate, and reach the effect of high-efficiency low-toxicity.In addition, the lipoid microsphere targeting preparation has the entrapment efficiency height, safety and good stability, characteristics such as convenient drug administration.The Alprostadil liposome microsphere injection (trade name: when triumphant) of for example Japanese Yutaka Mizushima professor invention, this novel carriers preparation has following characteristic: (1) targeting lipoid microsphere is easy to be gathered in diseased region with its distinctive characteristic.(2) persistence: under the barrier protection effect of lipoid microsphere, pulmonary's deactivation of medicine obviously reduces.(3) high efficiency: only need the dosage of conventional dosage forms 1/10th, curative effect is better.(4) low side effect: under the barrier protection of lipoid microsphere, obviously reduced the stimulation and the inflammatory reaction of blood vessel.(5) easy to use: directly intravenous injection, can be in out-patient treatment.Be subjected to when human body can cause various inflammation behind the infected by microbes such as antibacterial, virus, in the inflammatory reaction process, the macrophage in the tissue can gather inflammation part.At this moment, can be used as exogenous foreign body by the macrophage of inflammation part and engulf in the blood circulation process, and then make medicine concentrate and discharge, bring into play its therapeutical effect in inflammation part through the lipoid microsphere of the bag medicine carrying thing of vein (or oral) administration.But the lipoid microsphere targeting preparation uses and is decided by the physicochemical property of raw material and the clinical indication of raw material, is not all suitable lipoid microsphere targeting preparation that is prepared into of any raw material.At present, do not see any document and patent report both at home and abroad as yet about the lipid microspherical asarol preparation.
Summary of the invention
Technical scheme of the present invention provides a kind of lipid microspherical asarol preparation, and the present invention also provides the preparation method of this fat micro sphere preparation.
The invention provides a kind of lipid microspherical asarol preparation, it is to be active component by asarone, add injection/oil for oral use pharmaceutically commonly used, emulsifying agent, the fat micro sphere preparation that water for injection/the preparation water is prepared from, wherein the particle size distribution range of lipoid microsphere is at 0.05 micron～1 micron, and mean diameter is 0.1 micron～0.4 micron.
Wherein, described fat micro sphere preparation is intravenously administrable fat micro sphere preparation, oral fat micro sphere preparation.
Wherein, it is that 1 milliliter～50 milliliters, emulsifying agent 0.1 gram～5 grams are (when needs are regulated osmotic pressure that the every 100mL fat micro sphere preparation of lipid microspherical asarol preparation of the present invention contains 50 milligrams～1000 milligrams of asarone, injection or oil for oral use, add glycerol for injection), all the other are water for injection or water for pharmaceutical purposes.
Further, oil for oral use is soybean oil for oral use in the described oral fat micro sphere preparation; Its content is: containing 600 milligrams of asarone, soybean oil for oral use in every 100mL fat micro sphere preparation and be 10 milliliters, emulsifying agent is 1.0 grams, and all the other are water for pharmaceutical purposes.Wherein, emulsifying agent is a kind of or its mixing in fabaceous lecithin, Pu Luonike (F-68), arabic gum, gelatin and the pharmaceutically acceptable emulsifying agent.
Further, containing 240 milligrams of asarone, injection soybean oil among the every 100mL of described used for intravenous injection fat micro sphere preparation is 10 milliliters, emulsifying agent 1 gram (when needs are regulated osmotic pressure, adding glycerol for injection 2.5 grams), and all the other are water for injection.Wherein, emulsifying agent is a kind of or its mixing among injection fabaceous lecithin, the Pu Luonike (F-68).
The present invention also provides the preparation method of lipid microspherical asarol preparation of the present invention, and wherein, the preparation method of intravenously administrable fat micro sphere preparation comprises the steps:
A, take by weighing each raw material, the adjuvant of recipe quantity;
B, the crude drug asarone of getting recipe quantity are dissolved in the oil of preheating, the fabaceous lecithin of recipe quantity or Pu Luonike and glycerol are dissolved in the water of preheating again;
C, above-mentioned water or oil phase are changed in the tissue mashing machine, under the high-speed stirred condition, drip oil phase and go into water or drip water to go into oil phase, be dispersed in aqueous phase or water is dispersed in the oil phase to oil phase, colostrum;
D, get above-mentioned colostrum and be transferred in the high pressure dispersing emulsification machine, homogenize to mean diameter reaches below 0.5 micron, filtering with microporous membrane, the embedding of gained fat micro sphere preparation in infusion bottle or ampoule, inflated with nitrogen, pressure sterilizing, promptly.
Particularly, the preparation method of described intravenously administrable fat micro sphere preparation comprises the steps:
A, take by weighing each raw material: 50 milligrams～1000 milligrams of asarone, oil for injection are 1 milliliter～50 milliliters (when needs are regulated osmotic pressuries, adding glycerol for injection 1 gram～5 grams), emulsifying agent: 0.1 gram～5 grams, all the other are water for injection;
B, get asarone and be dissolved in the oil for injection that is preheated to 80 ℃, take by weighing fabaceous lecithin and glycerol again and be dissolved in an amount of water for injection that is preheated to 80 ℃;
C, above-mentioned water is changed in the tissue mashing machine, under 10000 rev/mins stirring condition, slowly drip oil phase and go into water, change with per minute 10000 and stirred 3 minutes, 3 times repeatedly, until the oil phase homodisperse that is dissolved with asarone;
D, get above-mentioned colostrum and add the water for injection that is preheated to 80 ℃ and make and reach full dose, be transferred in the high pressure dispersing emulsification machine, homogenize 3 times, the sampling and measuring particle diameter, reach below 0.5 micron to mean diameter,, get above-mentioned fat micro sphere preparation embedding in infusion bottle or ampoule by 3 microns filtering with microporous membranes, inflated with nitrogen was sterilized 45 minutes down for 105 ℃.
The another kind of preparation method of described intravenously administrable fat micro sphere preparation comprises the steps:
A, take by weighing each raw material: 50 milligrams～1000 milligrams of asarone, oil for injection are 1 milliliter～50 milliliters (when needs are regulated osmotic pressuries, adding glycerol for injection 1 gram～5 grams), emulsifying agent: 0.1 gram～5 grams, all the other are water for injection;
B, the asarone of recipe quantity is added in the oil for injection of the recipe quantity that is preheated to 80 ℃, be stirred to and make its dissolving and be uniformly dispersed;
C, with the fabaceous lecithin of recipe quantity, glycerol for injection disperses to mix with high-speed tissue mashing machine with an amount of water for injection that is preheated to 80 ℃, change with per minute 10000 and stirred 3 minutes, 3 times repeatedly, until the fabaceous lecithin homodisperse;
D, in the above-mentioned oil phase that is dissolved with asarone, stir and slowly add the aqueous dispersion liquid that contains fabaceous lecithin, glycerol for injection down, disperse to mix with high-speed tissue mashing machine, obtain colostrum, get above-mentioned colostrum and add the water for injection that is preheated to 80 ℃ and make and reach full dose, change over to again in the high pressure dispersing emulsification machine, homogenize 3 times, the sampling and measuring particle diameter, to mean diameter below 0.5 micron, by 3 microns filtering with microporous membranes;
E, get above-mentioned fat micro sphere preparation embedding in infusion bottle or ampoule, inflated with nitrogen, 105 ℃ of sterilizations 45 minutes.
The fat micro sphere preparation of above-mentioned prepared, system mixes and the emulsifying principle according to similar, fat-soluble asarone dissolving is scattered in the oil, be prepared into fat micro sphere preparation with water and emulsifying agent again, can significantly increase the dissolubility of asarone, improve its stability, can be thereby directly asarone is prepared into for intravenous injection (or oral) fat micro sphere preparation of clinical use.
Because asarone has antibacterial widely, antiinflammatory action, consider that asarone is insoluble in the characteristics of water, it is dissolved in is scattered in water through phospholipid emulsifying in the fatty oil and makes fat micro sphere preparation, not only overcome asarone soluble derivative unstable chemcial property, easily oxidative degradation, the deficiency that often has anaphylaxis and toxic and side effects to take place; Simultaneously can reduce dosage, the asarone selectivity is built up in diseased region, reduce medicine, reach the effect of high-efficiency low-toxicity in the normal structure abundance.
The fat micro sphere preparation of the present invention's preparation, particle diameter belongs to inferior nano-emulsion category between 50～1000nm.Outward appearance is opaque, is emulsus, can add Pu Luonike (F-68) and help emulsifying, or only need use fabaceous lecithin as emulsifying agent.Physicochemical property is stable behind pressure sterilizing, and safety testing is the result show, aseptic, the nonpyrogenic of fat micro sphere preparation of the present invention's preparation, and do not have hemolytic, no anaphylaxis, nonirritant, meet the requirement of clinical application for safety and stability.After asarone is prepared into lipoid microsphere,, can reduce the dosage of asarone simultaneously, reach the desirable curative effect of high-efficiency low-toxicity owing to, help to improve the stability of asarone with drug encapsulation.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
The particle diameter and the distribution thereof of Fig. 1 asarone vein fat micro sphere preparation
The specific embodiment
The preparation of embodiment 1 fat micro sphere preparation of the present invention
Soybean lecithin for injection 1.5g and glycerol for injection 2.5g are inserted high-speed tissue mashing machine, add an amount of water for injection, be prepared into the homodisperse phase with 12000 rev/mins speed; Decentralized photo and the oil for injection that is dissolved with 240 milligrams of asarone are preheated to 60～80 ℃ respectively for 10 milliliters, make colostrum after the mixing, colostrum is added injection water to 100 milliliter, insert the emulsifying repeatedly of high pressure dispersing emulsification machine, by 3 microns filtering with microporous membranes, fill the nitrogen fill again in peace roasting or infusion bottle, sterilization, promptly get the used for intravenous injection fat micro sphere preparation, also can be oral.
The preparation of embodiment 2 fat micro sphere preparations of the present invention
Soybean lecithin for injection 1.2g is prepared into homodisperse earlier mutually with Pu Luonike (F-68) 0.3g and water for injection; The oil for injection that is dissolved with 480 milligrams of asarone that adds preheating is made colostrum for 10 milliliters, adds the injection water and is assigned to 100 milliliters; High-pressure emulsification by 0.8 micron filtering with microporous membrane, fills the nitrogen fill in peace roasting or infusion bottle again, and sterilization promptly makes the used for intravenous injection fat micro sphere preparation.
The preparation of embodiment 3 fat micro sphere preparations of the present invention
Injection soybean phospholipid 1.5g is prepared into homodisperse earlier mutually with glycerol for injection 2.5g and water for injection; The oil for injection that is dissolved with 240 milligrams of asarone that adds preheating is made colostrum for 20 milliliters, adds the injection water and is assigned to 100 milliliters, and high-pressure emulsification fills the nitrogen fill again, promptly makes the vein fat micro sphere preparation.
The preparation of embodiment 4 fat micro sphere preparations of the present invention
Soybean lecithin 1.0g and Pu Luonike (F-68) 0.3g and glycerol for injection 2.5g and water for injection are prepared into homodisperse earlier mutually; The oil for injection that is dissolved with 240 milligrams of asarone that adds preheating is made colostrum for 10 milliliters, adds the injection water and is assigned to 100 milliliters, high-pressure emulsification, by 0.8 micron filtering with microporous membrane, fill the nitrogen fill again in peace roasting or infusion bottle, sterilization promptly makes the vein fat micro sphere preparation.
The preparation of embodiment 5 fat micro sphere preparations of the present invention
Soybean lecithin for injection 100g and water for injection are made decentralized photo be preheated to 80 ℃, mix with the 1000 milliliters of oils for injection (being preheated to 80 ℃) that are dissolved with asarone 24 grams, be prepared into 10000 milliliters even fat micro sphere preparation by the high pressure dispersing emulsification machine, by 3 microns filtering with microporous membranes, fill the nitrogen fill again in peace roasting or infusion bottle, gland, sterilization promptly gets the vein fat micro sphere preparation.
The preparation of embodiment 6 fat micro sphere preparations of the present invention
Soybean lecithin for injection 110g and glycerol for injection 250g and water for injection are made decentralized photo be preheated to 80 ℃, mix with the 1000 milliliters of oils for injection (being preheated to 80 ℃) that are dissolved with asarone 48 grams, be prepared into 10000 milliliters even fat micro sphere preparation by the high pressure dispersing emulsification machine, by 0.8 micron filtering with microporous membrane, fill the nitrogen fill again in peace roasting or infusion bottle, gland, sterilization promptly gets the vein breast.
The preparation of embodiment 7 fat micro sphere preparations of the present invention
Soybean lecithin for injection 120g and water for injection are made decentralized photo be preheated to 80 ℃, mix with the 1000 milliliters of oils for injection (being preheated to 80 ℃) that are dissolved with asarone 24 grams, be prepared into 10000 milliliters even fat micro sphere preparation by the high pressure dispersing emulsification machine, by 0.8 micron filtering with microporous membrane, fill the nitrogen fill again in peace roasting or infusion bottle, gland, sterilization promptly gets the vein breast.
The preparation of embodiment 8 fat micro sphere preparations of the present invention
Soybean lecithin 120g, ethyl hydroxybenzoate 10g and water for pharmaceutical purposes are made decentralized photo be preheated to 80 ℃, mix with the 1000 milliliters of medicinal soybean oils (being preheated to 80 ℃) that are dissolved with asarone 48 grams, be prepared into 10000 milliliters even fat micro sphere preparation by high-speed tissue mashing machine, gland promptly gets oral breast.
Embodiment 9 raw material consumptions are preferred
The present invention has at first carried out preferably the prescription of lipid microspherical asarol preparation.Adopt uniform design commonly used in the pharmacy respectively oil for injection consumption, asarone consumption, injection fabaceous lecithin consumption to be investigated.Each factor level design is as follows, the results are shown in Table 1.
A: oil for injection (mL) 1～50
B: asarone (mg) 50～1000
C: injection fabaceous lecithin (g) 0.1～5
Table 1 lipid microspherical asarol preparation prescription factor-level
| Factor | Level | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| A B C | 1 50 0.1 | 5 100 0.5 | 10 240 1.0 | 20 480 2.0 | 30 600 3.0 | 40 720 4.0 | 50 1000 5.0 |
Above 3 factors, 7 levels are evenly shown U by 7 levels
7(7
4) and use table to arrange test, by the different lipid microspherical asarol preparation of preparation method preparation of the present invention, with asarone accelerated test and the room temperature long-time stability that keep sample serves as to investigate index, preferred best prescription, the result shows: contain 240 milligrams of asarone in the every 100mL fat micro sphere preparation of lipid microspherical asarol preparation of preparation, wherein containing oil for injection is 10 milliliters, emulsifying agent 1.0 grams, glycerol for injection (regulating) 2.5g according to osmotic pressure, when all the other are water for injection, the gained test sample was placed 6 months for 4 ℃ at low temperature, high temperature was placed 6 months for 45 ℃, room temperature is placed after 12 months for 25 ℃, the physical appearance of sample, pH and envelop rate, have no significant change, have good stability.Experimental result in view of the above obtains the best prescription of lipid microspherical asarol preparation of the present invention.
Below carry out physicochemical property and safety detects test by fat micro sphere preparation to the foregoing description preparation.
The mensuration of test example 1 diameter of aspirin particle of the present invention
Particle diameter and distribution thereof to fat micro sphere preparation of the present invention are measured, concrete grammar is as follows: vein and each 10mL of oral fat micro sphere preparation of getting the present invention's preparation, be added in the 400mL water, with Malvern-2000 type laser light scattering particle size analyzer (Britain), measure the particle diameter and the distribution thereof of gained fat micro sphere preparation, the results are shown in Figure 1.
As seen from Figure 1, the size of gained vein fat micro sphere preparation meets normal distribution.50% particle diameter of vein fat micro sphere preparation is less than 155nm, and 90% particle diameter is less than 195nm.This measurement result meets the related request of used for intravenous injection fat micro sphere preparation.
Test example 2 medicine stabilities of the present invention detect
We place 45 ℃ of 6 months, high temperature to the lipid microspherical asarol preparation of the present invention preparation in 4 ℃ of low temperature and place after 25 ℃ of 6 months, room temperature place 12 months, and the outward appearance of test sample, pH and envelop rate are investigated the stability of this product, the results are shown in Table 1.
The lipid microspherical asarol stability of formulation of table 1 the present invention preparation is investigated the result
| Time | Outward appearance | pH | Asarone envelop rate (%) | ||||||
| 4℃ | 25℃ | 45℃ | 4℃ | 25℃ | 45℃ | 4℃ | 25℃ | 45℃ | |
| 6 months March of 0 month 2 month January, JIUYUE was 12 months | Homogeneous homogeneous homogeneous homogeneous homogeneous-- | Homogeneous homogeneous homogeneous homogeneous homogeneous homogeneous homogeneous | Homogeneous homogeneous homogeneous homogeneous homogeneous-- | 5.62 5.60 5.57 5.55 5.54 - - | 5.67 5.65 5.64 5.62 5.63 5.64 5.63 | 5.67 5.65 5.66 5.64 5.63 - - | 96.38 96.25 96.32 96.18 96.15 - - | 96.28 96.43 96.50 96.25 96.13 96.23 96.31 | 96.38 96.41 96.27 96.25 96.18 - - |
By table 1 as seen, adopt the fat micro sphere preparation of the present invention's preparation to have good stability.4 ℃ of placements of low temperature 6 months, 45 ℃ of placements of high temperature 6 months, room temperature are placed after 12 months for 25 ℃, and the outward appearance of sample, pH and envelop rate have no significant change.
To sum up the result adopts the fat micro sphere preparation of the present invention's preparation to have good stability as can be known, can reach in the national new drug research technological guidance principle requirement about preparation stability.
The method of quality control of test example 3 medicines of the present invention
The content assaying method of asarone among the present invention adopts reversed phase high-performance liquid chromatography (RP-HPLC) to measure the content of asarone
[5]Method: adopt C18 post (4.6mm * 200mm, 5 μ m), with methanol-water (60: 40) is mobile phase, flow velocity 1.0mL/min, ultraviolet detection wavelength 313nm. result: average recovery rate 99.25%, RSD=0.87% (n=9), asarone concentration and peak area in 8～100 μ g/mL scopes are good linear relation, r=0.9999.
The mensuration of test example 4 medicine fat micro sphere preparation envelop rates of the present invention
With the asarone is index: adopt the centrifugal fat micro sphere preparation of supercentrifugation, and 40000r/min, centrifugal 30min gets supernatant 0.5mL, uses anhydrous alcohol solution, with high effective liquid chromatography for measuring asarone content, can determine the content M of entrapped asarone
1The asarone total amount is M in the fat micro sphere preparation
0, be calculated as follows the weight envelop rate Q of lipid microspherical asarol preparation to asarone IIA.
Q＝M
1/M
0×100％
The result is index with the asarone, and the prepared vein fat micro sphere preparation envelop rate of the present invention is all greater than 96%.
Test example 5 asepsis test in medication of the present invention:
Get with the inventive method self-control fat micro sphere preparation, check according to sterility test method (2000 editions appendix XI of Chinese Pharmacopoeia H), qualified with the fat micro sphere preparation sterility test of the inventive method preparation.
Test example 6 medicine pyrogen tests of the present invention:
Get with the inventive method self-control fat micro sphere preparation, check according to pyrogen test (2000 editions appendix XI of Chinese Pharmacopoeia D), with the fat micro sphere preparation nonpyrogenic of the inventive method preparation.
The 7 drug sensitivity tests of the present invention of test example:
Test method: Cavia porcellus is divided into 3 groups at random by body weight, every group 6,1,2 liang of group Cavia porcellus every other day once, 0.5mL/ sensitization of continuous three lumbar injection asarone used for intravenous injection fat micro sphere preparations, 1,2 liang of group only excites respectively at 14 days behind the first time lumbar injection and 21 days digital veins of the foot injection asarone used for intravenous injection fat micro sphere preparation 1.0mL/; 3 groups of Cavia porcellus every other day once, 0.5mL/ sensitization of continuous three lumbar injections, 20% egg clear liquid, 14 days digital veins of the foot after injection are injected 20% egg clear liquid 1.0mL/ and are only excited, and all observe symptoms of allergic in 15 minutes after booster injection for three groups.
Result of the test: two groups of Cavia porcelluss of asarone used for intravenous injection fat micro sphere preparation are attacked with original liquid respectively at 14 days and the 21st day behind the 1st lumbar injection anaphylactic reaction are not all taken place; And positive controls (3 groups) Cavia porcellus occurs dyspnea in injecting in back 2 minutes, and tic is fallen down, and is then dead, and Cavia porcellus death all occurs in injects in back 1～3 minute.
Conclusion (of pressure testing): under this experimental condition, asarone used for intravenous injection fat micro sphere preparation is not had sensitization to trying Cavia porcellus.
The 8 medicine hemolytic tests of the present invention of test example:
Test method: get 7 in test tube, 1～5 pipe adds the asarone used for intravenous injection fat micro sphere preparation of 0.1mL, 0.2mL, 0.3mL, 0.4mL, 0.5mL respectively, and be diluted to 2.5mL with 10% glucose injection, add in No. 6 test tubes in 10% glucose injection 2.5mL, No. 7 test tubes and add distilled water 2.5mL (complete hemolysis contrast).Last every pipe all adds 2% rabbit erythrocyte suspension 2.5mL, shakes up gently, puts in 37 ℃ of water-baths, writes down the haemolysis and the coagulation situation of 15min, 30min, 45min, 1h, 2h, 3h, each pipe of 4h respectively.
Result of the test: asarone used for intravenous injection fat micro sphere preparation 1～5 pipe did not all cause haemolysis and agglutination in 4 hours.
Conclusion (of pressure testing): under this experiment condition, asarone used for intravenous injection fat micro sphere preparation does not have haemolysis and agglutination to rabbit erythrocyte.
The 9 medicine irritation tests of the present invention of test example:
Test method: get 2 of new zealand rabbits, all slowly inject asarone used for intravenous injection fat micro sphere preparation 5mL/kg and (consider that asarone used for intravenous injection fat micro sphere preparation will have targeting distribution, characteristics of high efficiency and low toxicity in left auricular vein, it will obviously reduce than Asarone injection liquid consumption when using, but for guaranteeing the safety of fat micro sphere preparation, the present invention in the medicine irritation experimental study with reference to Asarone injection liquid consumption, 16-24mg is grown up one time, be diluted to the solution intravenous drip of 0.01-0.02% with 5% or 10% glucose injection, 2 times on the one.With people 50kg weighing machine, it then is 0.6～1mg/kg/ days).Auris dextra edge vein is injection 10% glucose injection 5mL/kg slowly, once a day, injection is three days continuously, begin for the first time in injection, observe the injection site every day and have or not edema, erythema, last was injected back 24 hours, cut ear from the basal part of the ear and put 10% formalin fixingly, did the pathology cut sections for microscopic examination then.
Result of the test: asarone used for intravenous injection fat micro sphere preparation is given injection every day of rabbit ear edge vein once, and continuous three days, the generation that edema and erythema are arranged was not seen in 2 rabbit ear injection sites.Histopathology is observed, and rabbit ear epidermal structure is normal.Under the epidermis papillary layer and reticular layer do not have inflammatory cell ooze out, no hemorrhage, no thrombosis formation in the blood vessel.Accessory structure is normal.
Conclusion (of pressure testing): asarone used for intravenous injection fat micro sphere preparation is to rabbit ear edge vein blood vessel nonirritant.
As can be seen from the above results, adopt the fat micro sphere preparation of the present invention's preparation safe and reliable, no anaphylaxis, hemolytic and zest meet the related request of clinical application.
The fat micro sphere preparation that adopts the inventive method preparation has been carried out anaphylaxis, hemolytic and irritation test, and result of the test shows that the fat micro sphere preparation stability of the present invention's preparation is strong, and no anaphylaxis, hemolytic and zest meet the related request of clinical application.
List of references
[1] Yang Yu. the alpha-ararin sheet is treated 148 routine chronic obstructive pulmonary disease. new drug and clinical, 1986,5:210
[2] Zhang Yangda, Zhou Shushun, Xu Aiqiu etc. alpha-ararin treatment epilepsy 114 examples. new drug and clinical, 1990,9:91
[3] Wu rushes. the bioavailability of asarone tablets. and Chinese Hospitals pharmaceutical journal, 2003,23:597
[4] Asarone injection liquid medicine operation instructions
[5] become red. the content of rp-hplc determination injection asarone. medical Leader, 2004 23:587
Claims (6)
1, a kind of lipid microspherical asarol preparation, it is characterized in that: it is to be active component with the alpha-ararin, add the fat micro sphere preparation that injection pharmaceutically commonly used or oil for oral use, emulsifying agent, water for injection/water for pharmaceutical purposes are prepared from, it is 10-20 milliliter, emulsifying agent 1 gram～1.5 grams that wherein every 100mL fat micro sphere preparation contains 240 milligrams～600 milligrams of alpha-ararins, injection or oil for oral use, and all the other are water for injection or water for pharmaceutical purposes; Wherein said injection or oil for oral use are soybean oil, and described emulsifying agent is a kind of or its mixing among fabaceous lecithin, the Pu Luonike F-68.
2, lipid microspherical asarol preparation according to claim 1 is characterized in that: described fat micro sphere preparation is used for intravenous injection fat micro sphere preparation or oral fat micro sphere preparation.
3, according to the described lipid microspherical asarol preparation of claim 2, it is characterized in that: used oil is a soybean oil for oral use in the described oral fat micro sphere preparation; Its content is: containing 600 milligrams of asarone, soybean oil for oral use in every 100mL fat micro sphere preparation and be 10 milliliters, fabaceous lecithin is 1 gram, and all the other are water for pharmaceutical purposes.
4, lipid microspherical asarol preparation according to claim 2, it is characterized in that: used oil is the injection soybean oil in the every 100mL used for intravenous injection fat micro sphere preparation described in the described used for intravenous injection fat micro sphere preparation, containing 240 milligrams of asarone, injection soybean oil in every 100mL fat micro sphere preparation is 10 milliliters, injection fabaceous lecithin 1 gram, and all the other are water for injection.
5, according to each described lipid microspherical asarol preparation of claim 1-4, it is characterized in that: the particle size distribution range of lipoid microsphere is at 0.05 micron～1 micron, and mean diameter is 0.1 micron～0.4 micron.
6, a kind of method for preparing the described lipid microspherical asarol preparation of claim 1, it is characterized in that: the preparation method of described used for intravenous injection fat micro sphere preparation comprises the steps:
A, take by weighing each raw material, the adjuvant of recipe quantity;
B, the crude drug asarone of getting recipe quantity are dissolved in the oil phase of preheating, again the aqueous phase that injection fabaceous lecithin or one or both mixing of Pu Luonike F-68 of recipe quantity are dissolved in preheating;
C, above-mentioned water or oil phase are changed in the tissue mashing machine, under the high-speed stirred condition, drip oil phase and go into water or drip water to go into oil phase, be dispersed in aqueous phase or water is dispersed in the oil phase to oil phase, colostrum;
D, get above-mentioned colostrum and be transferred in the high pressure dispersing emulsification machine, homogenize to mean diameter reaches below 0.5 micron, filtering with microporous membrane, the embedding of gained fat micro sphere preparation in infusion bottle or ampoule, inflated with nitrogen, pressure sterilizing, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510020878 CN1290495C (en) | 2005-05-11 | 2005-05-11 | Lipid microspherical asarol prepn and its prepn process |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510020878 CN1290495C (en) | 2005-05-11 | 2005-05-11 | Lipid microspherical asarol prepn and its prepn process |
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| Publication Number | Publication Date |
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| CN1706370A CN1706370A (en) | 2005-12-14 |
| CN1290495C true CN1290495C (en) | 2006-12-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200510020878 Expired - Fee Related CN1290495C (en) | 2005-05-11 | 2005-05-11 | Lipid microspherical asarol prepn and its prepn process |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1313086C (en) * | 2005-05-30 | 2007-05-02 | 许群 | Aarin preparation for injection and preparing process thereof |
| CN101088499B (en) * | 2006-06-12 | 2012-11-14 | 陈云生 | Dry asarol emulsion and its prepn and application |
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