CN101088499A - Dry asarol emulsion and its prepn and application - Google Patents
Dry asarol emulsion and its prepn and application Download PDFInfo
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- CN101088499A CN101088499A CNA2006100211544A CN200610021154A CN101088499A CN 101088499 A CN101088499 A CN 101088499A CN A2006100211544 A CNA2006100211544 A CN A2006100211544A CN 200610021154 A CN200610021154 A CN 200610021154A CN 101088499 A CN101088499 A CN 101088499A
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Abstract
The present invention discloses one kind of dry AAA emulsion and its preparation and application, and the dry AAA emulsion has asarol as effective component, emulsifier and other supplementary material. The dry AAA emulsion has mature technological process, easy industrial production, high stability, high curative effect and other advantages. It is applied mainly in clinical treatment of bronchitis, lung infection, asthma and other diseases.
Description
Technical field:
The present invention relates to the pharmaceutical dosage form of medical technical field, relate in particular to a kind of dry asarol emulsion and preparation method thereof and application.
Background technology:
Asarone (Asarone), molecular formula C
12H
16O
3, molecular weight 208.Acicular crystal or crystallinity powder for white or off-white color; Odorless, tasteless.This product is easily molten in ethyl acetate, chloroform or ether, dissolves in ethanol or petroleum ether, and is insoluble in water.
Oral asarone absorbs rapidly, and 15min blood drug level reaches the peak, and be distributed in liver rapidly, internal organs such as kidney, bile, the heart, brain, lung, spleen, wherein liver, kidney concentration approach plasma concentration, all the other successively decrease successively.Part still absorbs through the intestinal liver by behind the bile excretion again, mainly discharges with urine at last, and fraction is by liver metabolism.Major metabolite is 2,4,5 one trimethoxy acrylic acid (cinnamic acid).Plasma protein binding rate is 61%, t
1/2About 3-4h.Because this product is fat-soluble extremely strong, and fusing point is low, the bioavailability of its oral formulations is on the low side, and absolute bioavailability only is 2.7%.
It is rational to have confirmed that asarone has very strong pharmacology to live, and has cough-relieving, eliminates the phlegm, driedly breathes heavily, calm, spasmolytic and anticonvulsant action.Fertile scorching two balls, staphylococcus aureus and colibacillary growth also there is in various degree inhibitory action.The clinical treatment of diseases such as bronchitis, intrapulmonary infection, pneumonia, asthma, epilepsy grand mal that are mainly used in.This medicine is particularly suitable for those has the low patient of hepatic renal dysfunction, cytometry to use.The asarone clinical practice does not see that there is the report of big toxicity relevant human body aspect for many years.
The asarone chemical structural formula is as follows:
The preparation of asarone has tablet, capsule, drop pill, syrup, injection, injectable powder, fat micro sphere preparation at present.
Because asarone is fat-soluble extremely strong, molten point is low, and when taking these oral formulations of asarone tablets, capsule, drop pill and syrup, bioavailability is lower, and individual variation is bigger, has limited the performance of asarone effect.
Drug administration by injection dosage is accurate, rapid-action, but because asarone is water insoluble, also be insoluble to materials such as acidity or alkalescence, therefore present Asarone injection liquid (2mL: 8mg) often need to add organic solvent such as ethanol, Polyethylene Glycol or solubilisings such as surfactant such as Tween 80 in the preparation on the market, in order to solve its stability problem, also need add antioxidant, complexing of metal ion agent in the prescription, regulate pH value, ultrafiltration and logical noble gas etc., with solve injection quality instability easy to change, easily produce sedimentary problem.Thus Zhi Bei Asarone injection not only side effect big, tangible hemolytic reaction is arranged, and all unstable to light and heat, easily cause its degraded during sterilization.Compare with injection, injectable powder stores convenient transportation, but still contains additives such as Polyethylene Glycol, surfactant in the injectable powder, and problems such as its hemolytic, unstability still exist.And the asarone boiling point is low, and during lyophilizing, asarone is volatile, cause in the injectable powder asarone content to reduce and batch with criticize between content differ bigger; Contain surfactants such as tween, easily cause product to be difficult for lyophilizing, product appearance is not good.For increasing the dissolubility of asarone in water, people are dissolved in asarone in the oil and make fat micro sphere preparation, increased the photo and thermal stability of asarone, when giving said preparation, asarone is rapid-action, dosage is accurate, medicine-feeding part does not have toxicities such as tangible pain, redness, the interior holdup time of body is long, under the carrier band effect of oil phase, helps asarone and spreads to brain to the gathering of diseased regions such as inflammation with by blood brain barrier simultaneously, thereby improve its curative effect, reduce its toxicity.But fat micro sphere preparation is liquid condition, neither convenience when production, storage, transportation, clinical practice; Emulsion droplet is easy to assemble; High temperature sterilize can damage medicine and adjuvant; And but oxidation reaction etc. easily takes place in the phospholipid that the asarone Xiang Shuizhong in lay up period oil spreads and is under the solution state; Water in the fat micro sphere preparation is easy to freeze, thereby easily causes the emulsion droplet breakdown of emulsion; This makes that the storage life of lipid microspherical asarol preparation is shorter.Therefore, be necessary to develop and develop new Aarin preparation, to satisfy patient's demand.
Summary of the invention:
Dry emulsion is the focus of studying recently, and it is that the Emulsion drying is got except that drying branch.It had both had the advantage of Emulsion: increase stability of drug, rapid-action, dosage accurately, be easy in permeable membrane, the body holdup time long, be easy to diseased regions such as inflammation assemble and by blood brain barrier to the brain diffusion etc.; Remedied the shortcoming of some Emulsions again simultaneously: because this product is in the pressed powder state, the asarone that emulsion droplet is difficult in gathering, the lay up period emulsion droplet is difficult for to external world's diffusion, has improved the stability of adjuvant in the Emulsion, and further improved the stability of principal agent, thereby improved preparation quality, prolong its storage life; Reduced the volume of pharmaceutical composition, thereby reduced requirement production, transportation, storage, clinical administration condition; During clinical practice, optionally add one or more the mixture in entry or NaCl solution or the solution such as glucose solution or fat milk, through vibration be recovered to after the hydration Emulsion or more further with fat milk or further with other aqueous solution, help clinical flexible medication; For extensive patients provides safer, stable, effective Aarin preparation.
Main technical schemes of the present invention is this dry emulsion with the asarone of effective dose for leading and contain oil phase, emulsifying agent and other adjuvant, described other adjuvant can be protective agent, etc. one or more the mixture of opening in the adjuvants such as regulator, stabilizing agent, PH regulator, antiseptic, correctives, local anesthetic, suspending agent and metal chelating agent such as ooze.
Contain in common every 1000-5000ml medicinal liquid:
Asarone 0.1g-200g
Oil 0.1-2000ml
Emulsifying agent 1g-250g
Medicine: oil=2: 1～1: 8000 (W/W) is preferably 1: 1～1: 6000 (W/W), more preferably 1: 2～1: 4000 (W/W).
Oil can be one or more the mixture in the oil of any kind ofs such as Oleum Glycines, Oleum Camelliae, Oleum Ricini, fish oil, Adeps Phocae vitulinae, beaver oil, olive oil, safflower oil, Oleum Gossypii semen, Semen Maydis oil, three sad/certain herbaceous plants with big flowers acid glycerides and median chain triglyceride oil, and the consumption in system is 0.01%-40% (w/v); Can be one or both the mixture in Oleum Glycines, the median chain triglyceride oil, the consumption of oil in system be 0.01%-40% (w/v), is preferably 0.05%-20% (w/v), more preferably 0.1%-10% (w/v).
Mean diameter after dry asarol emulsion of the present invention redissolves is within 50nm-1500nm.
Emulsifying agent can be a soybean phospholipid, lecithin, Polyethylene Glycol monophosphatide phatidylcholine (PEG-PC), Polyethylene Glycol monophosphatide acyl ethanolamine (PEG-PE), Polyethylene Glycol one distearoyl phosphatidylcholine (PEG-DSPC), Polyethylene Glycol one DSPE (PEG-DSPE), poloxamer, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, Polyethylene glycol 660 hydroxy stearate), vitamin E polyethylene glycol succinic acid ester (TPGS), Tweens, the polyoxyethylene aliphatic alcohol ether class, the mixture of one or more in the pharmaceutically acceptable emulsifying agent such as cholesterol, the consumption in system are 0.1-5% (w/v); Be preferably one or more the mixture in soybean phospholipid, tween, lecithin, the poloxamer, the consumption of emulsifying agent in system is 0.1-5% (w/v), is preferably 0.2-4% (w/v), more preferably 0.5%-3% (w/v).
Protective agent can be one or more mixture in glucose, lactose, mannitol, sorbitol, xylitol, maltose, glycine, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc., and the consumption in system is 1%-80% (w/v); Be preferably one or more the mixture in glucose, sucrose, trehalose, the maltose, the consumption of protective agent in system is 1%-80% (w/v), is preferably 2-60% (w/v), more preferably 3%-30% (w/v).
Stabilizing agent can be cholesterol, cysteine, anhydrous sodium sulphuric acid (hydrogen) sodium, oleic acid, enuatrol, cholic acid or deoxycholic acid and sodium salt thereof, Vc, V
E, one or more mixture in nitrogen, dibenzylatiooluene, a-tocopherol, a-tocopherol acetate, hydroquinone etc.; Stabilizing agent dosage is＞0-5% (w/v).
To open regulator can be one or more mixture in glycerol, glucose, the sodium chloride etc. Deng oozing etc., and consumption is＞0-5% (w/v).
The PH regulator can be hydrochloric acid, sodium hydroxide, the mixture of one or more in acetic acid, sodium acetate, phosphoric acid, sodium phosphate, citric acid, the sodium citrate etc., and adjusting PH is 1-13.
Antiseptic can be one or more the mixture in parabens, the benzyl alcohol etc., and consumption is＞0-2.5% (w/v).
Correctives can be one or more the mixture in natural stevioside, glucose, lactose, mannitol, sorbitol, xylitol, maltose, sucrose, trehalose, Oleum menthae, the arabic gum etc., and the consumption of correctives is＞0-30% (w/v).
Local anesthetic can be one or more the mixture in lignocaine, the procaine hydrochloride etc., and consumption is＞0-2.5% (w/v).
Suspending agent can be one or more the mixture in gelatin, the sodium carboxymethyl cellulose etc., and consumption is＞0-5% (w/v).
The mixture of one or more during metal chelating agent can be ethylenediaminetetraacetic acid class, sodium calcium edetate, desferrioxamine etc., consumption is＞0-2% (w/v).
Single dose for each/each the bottle/each the bag in contain principal agent asarone 200ug-40mg.
Preparation technology is as follows:
1) asarone is joined in the oil phase in some way, and the emulsifying agent that adds respective amount as required in aqueous phase or oil phase or water oil biphase in;
2) water is added under stirring condition in the oil phase or oil phase added aqueous phase or directly water, oil phase are mixed under stirring condition, in the time of 2-98 ℃, stir, by the homogenizing instrument or use the microjet instrument,, obtain uniform Emulsion solution homogenize repeatedly;
3) Emulsion is further dry, be dried to moisture and be till the 0.1%-10%, obtain dry asarol emulsion at last;
4) face with the preceding adding water for injection of amount on demand or water or NaCl solution or fat milk or glucose solution or other aqueous solution, be recovered to after the hydration vibration Emulsion or further with fat milk or further with other aqueous solution, for intramuscular injection, vein, oral or topical.
Can be lyophilization, spray drying, vacuum distillation drying, microwave drying in the drying described in the above-mentioned preparation method, one or more the comprehensive utilization in blotting etc.; Be preferably lyophilization.
At the certain way described in the above-mentioned preparation method can be directly to join asarone in the oil phase, also can be that adjuvants such as all or part of asarone and emulsifying agent are dissolved in earlier in the organic solvents such as ether, ethanol, connect and remove organic solvent and get dry thing, and then this dry thing is dissolved in the oil phase.
Dry asarol emulsion can be used for treatment of diseases such as bronchitis, intrapulmonary infection, pneumonia, asthma, epilepsy grand mal.
The assay of asarone is analyzed with HPLC, and chromatographic condition is as follows:
With octadecylsilane (ODS) bonding is filler mutually; Methanol: water (60: 40) is mobile phase; The detection wavelength is 313m.
Particle size analyzer: use Malvem Zetasizer nano-ZS90 in this experiment as the instrument of measuring particle diameter.
Advantage of the present invention is: processing technology maturation, reliable, good stability, make that medicament contg is more controlled, curative effect is high, significantly improved the stability and the curative effect of asarone, for extensive patients provides safer, stable, effective preparation.
Embodiment
The concrete mode of form is described in further detail foregoing of the present invention more by the following examples, but should not be interpreted as at this point that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, corresponding modify, replacement or change according to art technology knowledge and means are made include within the scope of the invention.
Embodiment 1:
1) asarone 0.2g is dispersed in the 2ml injection soybean oil;
2), and add the 20g lignocaine with 20g soybean lecithin for injection and proper amount of water for injection mix homogeneously;
3) with 1) add to stirring 2) in, high-speed stirred forms colostrum in the time of 30 ℃, and by high pressure homogenizer, with solution homogenize repeatedly, obtains uniform emulsion;
4) regulate ph value of emulsion between 5-9, stir;
5) sucrose solution of adding 8% is as protective agent, and water for injection adds to 1000ml;
6) obtain white block through freeze drying process, inflated with nitrogen gets exsiccant dry asarol emulsion;
7) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 2:
1) in dosing apparatus, asarone 0.5g is dissolved in the 1ml injection soybean oil;
2) with the injection lecithin of 10g and an amount of water mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 2000ml altogether;
4) add 5% mannitol as protective agent, cross the 0.22um microporous filter membrane and go out bacterium, aseptic subpackaged under 100 grades of conditions, remove moisture through lyophilization, inflated with nitrogen gets exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 3:
1) asarone 0.1g is dispersed in the 60ml injection soybean oil;
2) with 12g soybean lecithin for injection and TPGS and proper amount of water for injection mix homogeneously;
3) with 1) add to stirring 2) in, high-speed stirred forms colostrum in the time of 30 ℃, and by high pressure homogenizer, with solution homogenize repeatedly, obtains uniform emulsion;
4) regulate ph value of emulsion between 3-5, stir;
5) sucrose solution of adding 8% is as protective agent, and water for injection adds to 1000ml;
6) obtain white block through freeze drying process, inflated with nitrogen gets exsiccant dry asarol emulsion;
7) dry emulsion that makes is measured on demand adding NaCl solution, be recovered to Emulsion after the hydration vibration.
Embodiment 4:
1) asarone 0.2g and 6g soybean lecithin for injection are dissolved in an amount of ether, fling to ether, obtain dry thing;
2) dry thing is dispersed in the 60ml injection soybean oil;
3) with 12g soybean lecithin for injection and proper amount of water for injection mix homogeneously;
4) with 1) add to stirring 2) in, high-speed stirred forms colostrum in the time of 30 ℃, and by high pressure homogenizer, with solution homogenize repeatedly, obtains uniform emulsion;
5) regulate ph value of emulsion between 11-13, stir;
6) add 8% maltose solution as freeze drying protectant after, add 1% disodiumedetate, add water for injection at last and add to 1000ml;
7) obtain white block through freeze drying process, inflated with nitrogen gets exsiccant dry asarol emulsion;
8) dry emulsion that makes is measured the adding glucose solution on demand, be recovered to Emulsion after the hydration vibration.
Embodiment 5:
1) in dosing apparatus, asarone 0.2g is dissolved in the 10ml injection soybean oil;
2) with 12g soybean lecithin for injection and Polyethylene Glycol one DSPE (PEG-DSPE) mixture and proper amount of water for injection mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) mannitol of adding 5% and 5% glucose are removed moisture as protective agent through lyophilization, and inflated with nitrogen gets exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 6:
1) in dosing apparatus, asarone 0.2g is dissolved in 10ml three sad/certain herbaceous plants with big flowers acid glycerides;
2), and add 0.1g ethyl hydroxybenzoate and 0.1g propylparaben with the tween 80 of 5g and an amount of water mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 2000ml altogether;
4) add 5% trehalose as protective agent, remove moisture, get exsiccant dry asarol emulsion through lyophilization; 5) dry emulsion that makes is measured on demand added water, after the hydration vibration, be recovered to Emulsion.
Embodiment 7:
1) in dosing apparatus, asarone 200mg is dissolved in the 15ml injection Oleum Camelliae;
2), and add the 0.08g benzyl alcohol with the injection lecithin of 4g and mixture, 0.3g glycerol and the proper amount of water for injection mix homogeneously of tween;
3) with 1) under stirring condition, add 2) in, in the time of 20 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make the medicinal liquid of 2000ml;
4) glucose of adding 10% is removed moisture as protective agent through lyophilization, gets exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 8:
1) in dosing apparatus, asarone 2g is dissolved in 10ml injection soybean oil and the median chain triglyceride oil mixture;
2) with 2.0g soybean lecithin for injection and 1.0gHS15 and proper amount of water for injection mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) mannitol of adding 5% and 5% glucose are removed moisture as protective agent through lyophilization, and inflated with nitrogen gets exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration;
6) Emulsion is mixed with fat milk, and mixing.
Embodiment 9:
1) in dosing apparatus, asarone 4g is dissolved in the 25ml olive pulls in the oil;
2), and add the mixture of 10g oleic acid and sodium sulfite with the mixture and the proper amount of water for injection mix homogeneously of 10g phospholipid and poloxamer;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) mannitol that adds 6% glucose and 3% is removed moisture as protective agent through lyophilization, exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 10:
1) in dosing apparatus, asarone 10g is dissolved in the 25ml injection safflower oil;
2), and add the 1g enuatrol with lecithin and the proper amount of water for injection mix homogeneously of 10g;
3) with 2) under stirring condition, add 1) in, in the time of 20 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) add 1% glucose as protective agent, remove moisture through lyophilization, exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 11:
1) in dosing apparatus, asarone 4g is dissolved in the 25ml Oleum Ricini;
2) with 10g lecithin and 1g gelatin and proper amount of water for injection mix homogeneously, and the mixture of adding 1gVC and cysteine;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) mannitol that adds 6% glucose and 3% is removed moisture as protective agent through lyophilization, exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 12:
1) in dosing apparatus, asarone 0.1g and 1g soybean lecithin for injection are dissolved in the 100ml injection soybean oil;
2) with 5g soybean lecithin for injection and proper amount of water for injection mix homogeneously;
3) with 2) under stirring condition, add 1) in, in the time of 30 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 1000ml altogether;
4) mannitol of adding 5% and 5% glucose are removed moisture as protective agent through lyophilization, and inflated with nitrogen gets exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 13:
1) in dosing apparatus, asarone 0.2g is dissolved in the 800ml safflower oil;
2), and add 50gVc with lecithin and the proper amount of water for injection mix homogeneously of 10g;
3) with 2) under stirring condition, add 1) in, in the time of 80 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make medicinal liquid 2000ml altogether;
4) add 80% mannitol as protective agent, spray-dried removal moisture, exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 14:
1) in dosing apparatus, asarone 80g is dissolved in the ethanol, again this ethanol liquid is dispersed in the 1200ml olive oil;
2), and add the 40g ethyl hydroxybenzoate with the natural stevioside of poloxamer, 0.1g of 5g and the mixture and the water mix homogeneously of xylitol
3) with 2) under stirring condition, add 1) in, in the time of 80 ℃, stir the back by even matter instrument, with solution homogenize repeatedly, obtain uniform solution.Make the medicinal liquid of 4000ml;
4) add 40% maltose as protective agent, moisture is removed in distilling under reduced pressure, and adds silicon dioxide and go redundant moisture with suction, exsiccant dry asarol emulsion;
5) dry emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Embodiment 15:
1) asarone 4g is dispersed in the 60ml injection soybean oil;
2) the 20.0g soybean lecithin for injection is dispersed in an amount of water for injection;
3) with 1) add to stirring 2) in, form colostrums 20 ℃ of high-speed stirred, and,, obtain uniform emulsion solution homogenize repeatedly by high pressure homogenizer;
4) regulate ph value of emulsion between 5-9, stir;
5) glucose solution of adding 7% is as freeze drying protectant, and water for injection adds to 1000ml;
6) obtain white block through freeze drying process, inflated with nitrogen gets exsiccant asarone freeze-dried emulsion;
7) freeze-dried emulsion that makes is measured on demand added water, be recovered to Emulsion after the hydration vibration.
Experimental result:
1
Change of size before and after table 1 lyophilizing
| Mean diameter (nm) | ||
| Before the lyophilizing | After the lyophilizing | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 embodiment 9 embodiment 10 embodiment 11 embodiment 12 embodiment 13 embodiment 14 embodiment 15 | 51 90 213 241 300 293 344 366 493 667 635 673 847 1124 157 | 74 111 242 287 319 314 392 388 511 774 656 804 926 1207 192 |
2
Two kinds of dosage form physicochemical properties of table 2 are (embodiment 18) relatively
| Asarone content | Emulsion droplet mean diameter (nm) | The bacterium inspection | |||
| Normal injection freeze-dried powder (%) | Self-control freeze-dried emulsion (%) | Self-control freeze-dried emulsion (after the aquation) | The normal injection freeze-dried powder | The self-control freeze-dried emulsion | |
| March in 0 month 2 month January | 100 98.1 97.2 95.1 | 100 99.8 98.6 98.0 | 154 164 176 190 | Qualified | Qualified |
Hence one can see that, and the particle diameter before and after the Emulsion lyophilizing is not significant to be changed, and long term storage has stability preferably, and medicament contg, particle diameter, bacterium inspection have no significant change.
Claims (21)
1, a kind of dry emulsion that contains asarone is characterized in that: as effective ingredient, and contain oil phase, emulsifying agent and other adjuvant with the asarone in the dry emulsion.
2, dry asarol emulsion according to claim 1, described oil phase can be one or more the mixture in the pharmaceutically acceptable oil such as Oleum Glycines, Oleum Camelliae, Oleum Ricini, fish oil, Adeps Phocae vitulinae, beaver oil, olive oil, safflower oil, Oleum Gossypii semen, Semen Maydis oil, three sad/certain herbaceous plants with big flowers acid glycerides and median chain triglyceride oil, and the consumption in system is 0.01%-40% (w/v); Preferred oil phase is being that one or both mixture in Oleum Glycines, the median chain triglyceride oil is 0.05%-20% (w/v); The best is preferably 0.01%-10% (w/v).
3, dry asarol emulsion according to claim 1, described emulsifying agent can be a soybean phospholipid, lecithin, Polyethylene Glycol monophosphatide phatidylcholine (PEG-PC), Polyethylene Glycol monophosphatide acyl ethanolamine (PEG-PE), Polyethylene Glycol one distearoyl phosphatidylcholine (PEG-DSPC), Polyethylene Glycol one DSPE (PEG-DSPE), poloxamer, HS15 (Polyethylene Glycol 12-hydroxy stearic acid ester, Polyethylene glycol 660 hydroxystearate), vitamin E polyethylene glycol succinic acid ester (TPGS), Tweens, the polyoxyethylene aliphatic alcohol ether class, the mixture of one or more in the pharmaceutically acceptable emulsifying agent such as cholesterol, the consumption in system are 0.1-5% (w/v); Preferred emulsifier can be that one or more the mixture in soybean phospholipid, lecithin, tween and the poloxamer is 0.2-4% (w/v), and the best is preferably 0.5%-3% (w/v).
4, dry asarol emulsion according to claim 1, it is characterized in that described other adjuvant can be protective agent, etc. one or more mixture in the adjuvants such as opening regulator, stabilizing agent, PH regulator, antiseptic, correctives, local anesthetic, suspending agent and metal chelating agent such as ooze.
5, dry asarol emulsion according to claim 4, described protective agent can be one or more the mixture in glucose, lactose, mannitol, sorbitol, xylitol, maltose, glycine, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc., and the consumption in system is 1%-80% (w/v); Be 2-60% (w/v) with one or more the mixture in glucose, sucrose, trehalose, the maltose preferably, the best is preferably 3%-30% (w/v).
6, dry asarol emulsion according to claim 4, described stabilizing agent can be cholesterol, anhydrous sodium sulphuric acid (hydrogen) sodium, oleic acid, cysteine, enuatrol, cholic acid or deoxycholic acid and sodium salt thereof, Vc, V
E, one or more the mixture in nitrogen, dibenzylatiooluene, a-tocopherol, a-tocopherol acetate, hydroquinone etc., consumption is＞0-5% (w/v).
7, dry asarol emulsion according to claim 4, described grade ooze etc. that to open regulator can be one or more mixture in glycerol, glucose, the sodium chloride etc., and consumption is＞0-5% (w/v).
8, dry asarol emulsion according to claim 4, described PH regulator can be hydrochloric acid, sodium hydroxide, the mixture of one or more in acetic acid, sodium acetate, phosphoric acid, sodium phosphate, citric acid, the sodium citrate etc., regulating the pH value scope is 1-13.
9, dry asarol emulsion according to claim 4, described antiseptic can be one or more the mixture in parabens, the benzyl alcohol etc., and consumption is＞0-2.5% (w/v).
10, dry asarol emulsion according to claim 4, described correctives can be one or more the mixture in natural stevioside, glucose, lactose, mannitol, sorbitol, xylitol, maltose, sucrose, trehalose, Oleum menthae, the arabic gum etc., and consumption is＞0-30% (w/v).
11, dry asarol emulsion according to claim 4, described local anesthetic can be one or more the mixture in lignocaine, the procaine hydrochloride etc., consumption is＞0-2.5% (w/v).
12, dry asarol emulsion according to claim 4, described suspending agent can be one or more the mixture in gelatin, the sodium carboxymethyl cellulose etc., and consumption is＞0-5% (w/v).
The mixture of one or more during 13, dry asarol emulsion according to claim 4, described metal chelating agent can be ethylenediaminetetraacetic acid class, sodium calcium edetate, desferrioxamine etc., consumption is＞0-2% (w/v).
14, according to claim 1 and 4 described dry asarol emulsions, it is characterized in that: contain in every 1000-5000ml medicinal liquid: asarone 0.1g-200g, oily 0.1ml-2000ml, emulsifying agent 1g-250g.
15,, it is characterized in that single dose is each/contain principal agent asarone 200ug-40mg in each bottle/each bag according to claim 1 and 4 described dry asarol emulsions.
16, according to claim 1 and 4 described dry asarol emulsions, it is characterized in that: medicine: oil=2: 1-1: 80000 (w/w) are preferably 1: 1 ~ 1: 60000 (W/W), more preferably 1: 2 ~ 1: 40000 (W/W).
17, according to claim 1 and 4 described dry asarol emulsions, it is characterized in that: the mean diameter after institute's antigalactic redissolves is within 50nm-1500nm.
18, a kind of preparation method as claim 1 and 4 described dry emulsions, it is characterized in that: preparation process is as follows:
1) asarone is joined in the oil phase in some way, and the emulsifying agent that adds respective amount as required in aqueous phase or oil phase or water oil biphase in;
2) water is added under stirring condition in the oil phase or oil phase added aqueous phase or directly water, oil phase are mixed under stirring condition, in the time of 2-98 ℃, stir, by the homogenizing instrument or use the microjet instrument,, obtain uniform Emulsion solution homogenize repeatedly;
3) Emulsion is further dry, be dried to moisture and be till the 0.1%-10%, obtain dry asarol emulsion at last;
4) face with the preceding adding water for injection of amount on demand or water or NaCl solution or fat milk or glucose solution or other aqueous solution, be recovered to after the hydration vibration Emulsion or further with fat milk or further with other aqueous solution, for intramuscular injection, vein, oral or topical.
19, as the preparation method of dry asarol emulsion as described in the claim 18, it is characterized in that: the comprehensive utilization of one or more during described drying can be lyophilization, spray drying, vacuum distillation drying, microwave drying, blot etc.; Be preferably lyophilization.
20, as the preparation method of dry asarol emulsion as described in the claim 18, it is characterized in that: described certain way can be directly to join asarone in the oil phase, also can be that adjuvants such as all or part of nicergoline and emulsifying agent are dissolved in earlier in the organic solvents such as ether, ethanol, connect and remove organic solvent and get dry thing, and then this dry thing is dissolved in the oil phase.
21 according to claim 1 and 18 described dry asarol emulsions, it is characterized in that: the clinical treatment of diseases such as bronchitis, intrapulmonary infection, pneumonia, asthma, epilepsy grand mal that can be used for of this pharmaceutical composition.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100211544A CN101088499B (en) | 2006-06-12 | 2006-06-12 | Dry asarol emulsion and its prepn and application |
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| CN2006100211544A CN101088499B (en) | 2006-06-12 | 2006-06-12 | Dry asarol emulsion and its prepn and application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104666281A (en) * | 2015-03-12 | 2015-06-03 | 陈长潭 | Asarin aerosol inhalant and preparation method thereof |
| CN106943362A (en) * | 2016-06-30 | 2017-07-14 | 广东隆赋药业股份有限公司 | A kind of injection asarin composite |
| CN108938566A (en) * | 2018-10-18 | 2018-12-07 | 中国药科大学 | Asarone self-emulsifying drug delivery systems |
| CN109223718A (en) * | 2018-10-18 | 2019-01-18 | 中国药科大学 | Asarone solid self-emulsifying preparation and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1290495C (en) * | 2005-05-11 | 2006-12-20 | 四川思达康药业有限公司 | Lipid microspherical asarol prepn and its prepn process |
| CN1313086C (en) * | 2005-05-30 | 2007-05-02 | 许群 | Aarin preparation for injection and preparing process thereof |
-
2006
- 2006-06-12 CN CN2006100211544A patent/CN101088499B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104666281A (en) * | 2015-03-12 | 2015-06-03 | 陈长潭 | Asarin aerosol inhalant and preparation method thereof |
| CN106943362A (en) * | 2016-06-30 | 2017-07-14 | 广东隆赋药业股份有限公司 | A kind of injection asarin composite |
| CN108938566A (en) * | 2018-10-18 | 2018-12-07 | 中国药科大学 | Asarone self-emulsifying drug delivery systems |
| CN109223718A (en) * | 2018-10-18 | 2019-01-18 | 中国药科大学 | Asarone solid self-emulsifying preparation and preparation method thereof |
| CN108938566B (en) * | 2018-10-18 | 2021-04-20 | 中国药科大学 | Asarin self-emulsifying system |
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| CN101088499B (en) | 2012-11-14 |
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