CN102440956B - Preparation method of self-emulsified sumatriptan and salt preparation thereof - Google Patents
Preparation method of self-emulsified sumatriptan and salt preparation thereof Download PDFInfo
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- CN102440956B CN102440956B CN 201110432649 CN201110432649A CN102440956B CN 102440956 B CN102440956 B CN 102440956B CN 201110432649 CN201110432649 CN 201110432649 CN 201110432649 A CN201110432649 A CN 201110432649A CN 102440956 B CN102440956 B CN 102440956B
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Abstract
The invention relates to a sumatriptan phospholipid compound oral preparation and a preparation method thereof. The preparation is prepared from the following components in parts by weight: 65-175 parts of self-emulsified sumatriptan phospholipid emulsion, 200-400 parts of lactose and 200-600 parts of microcrystalline cellulose. The preparation method comprises the following steps: preparing yolk lecithin into a yolk lecithin ethanol solution, and adding sumatriptan or/and sumatriptan salt to sufficiently react, thereby obtaining a self-emulsified sumatriptan phospholipid emulsion; and sufficiently dissolving lactose in a phosphate buffer, adding the lactose phosphate buffer into the self-emulsified sumatriptan phospholipid emulsion to sufficiently react, drying into a solid, adding microcrystalline cellulose into the solid, and sufficiently mixing to obtain the sumatriptan or/and sumatriptan salt preparation. The preparation prepared according to the technique has the advantages of high stability and high bioavailability.
Description
Technical field
Invention relates to a kind of migrainous medicine that is used for the treatment of, and specifically, relates to a kind of oral formulations that contains the sumatriptan phosphatide complexes and preparation method thereof.
Background technology
Migraine is take diffusivity or one-sided outbreak, sharp ache, repeatedly shows effect as the chronic neural blood vessel disorder disease of feature.China's sickness rate is about 4.2%～14.6%, and wherein the women is more than the male, and M-F is 1: 4.The whole world approximately has 10%～15% people to suffer from migraine.With the increase of operating pressure, migrainous sickness rate will present further ascendant trend with the quickening pace of modern life, become puzzlement modern's commonly encountered diseases and frequently-occurring disease.In July, 2007, China's Ministry of Public Health formally determines to increase one-level diagnosis and treatment subject Pain Management.
Along with the ill crowd's of migraine increase year by year, antimigraine drug market growth, the whole world is quick, and global antimigraine drug sales volume was 300,000,000 dollars in 1991, and near 1,500,000,000 dollars, the average growth rate per annum of 1993～2000 years reached 40% by 1997.Company predicts according to Decision Resource: several large main flow medical market antimigraine drug sales volumes in the world such as the U.S., France, Germany, Italy, Spain, Britain and Japan will be from 28.6 hundred million dollars of 5,600,000,000 dollars of rising to 2012 of 2002.Since nineteen ninety-nine, as prescription drugs the last 500 of being in great demand most of existing 4 product introduction whole world in the migrainous triptan medicine for the treatment of, and account for the share in whole migraine treatment medicine market 95%.Wherein, the sumatriptan of Glaxo Wellcome company was sold over 1,000,000,000 dollars in continuous 4 years.
Migrainous medicine comprises Ergotamine, dihydroergotamine and triptan, though wherein Ergotamine, dihydroergotamine can effectively be alleviated migraine, because side effect is large, specificity is not strong, is replaced by the triptan medicine gradually.Sumatriptan is first triptan medicine, and its discovery is considered to " milestone " of the exploitation of migraine medicine and breaks through.
Sumatriptan and salt thereof, particularly succinate are the analeptic of selectivity serotonine-1(5HT1), by the excited blood vessel 5-HT1D of high selectivity receptor, entocranial artery are shunk, and the blood redistribution is improved the cerebral blood flow supply.Blood vessel 5-HT1D receptor is preponderated in the carotid artery circulation, and the contraction of medicine concentrates on the arteriovenous anastomosis place in this circulation, therefore can alleviate neurogenic inflammation in cerebral dura mater, be widely used in clinically the migraine that the emergency treatment adult has tendency or there is no tendency at present.Sumatriptan has become the migrainous drug of first choice of domestic and international treatment since coming out in February, 1991.
The sumatriptan that has gone on the market at present comprises subcutaneous injection agent, nose aerosol and oral tablet, onset in 10-30 minute after administration respectively, and effective percentage is respectively injection 80%, aerosol 60%, tablet 55%.But compare with oral formulations, the injection untoward reaction is more, and price is more expensive.Accept and the compliance aspect from the patient, oral formulations is still the most extensive in clinical practice.
Sumatriptan is due to fat-soluble all lower with water solublity, and oral absorption is incomplete, because the factors such as first pass effect affect bioavailability only 14%, this is the key factor of its oral formulations clinical practice of restriction and curative effect, but does not have up to now develop to go out the oral formulations that can effectively improve the sumatriptan bioavailability.At home and abroad there is no at present the report that sumatriptan is prepared into phosphatide complexes, but have report puerarin phosphate composition, silymarin phosphatide complexes can effectively improve its solubility property.But whether the phosphatide complexes of sumatriptan can improve the solubility property of sumatriptan and improve bioavailability and then increase curative effect is still waiting proof.
Find after deliberation, sumatriptan phosphatide complexes moisture-sensitive, caking, poor fluidity directly incapsulates and may cause dissolution low.The sumatriptan phosphatide complexes is as the intermediate of sumatriptan oral formulations, and its formula forms and process conditions all have considerable influence to bioavailability.
Summary of the invention
One of purpose of the present invention is to provide the self emulsifying sumatriptan or/and the formula of sumatriptan salt phospholipid emulsion formulations and preparation thereof, and it provides preferred plan for the high preparation of preparation bioavailability.
For achieving the above object, technical scheme of the present invention is:
The self emulsifying sumatriptan is or/and sumatriptan salt phospholipid emulsion formulations is composed of the following components by weight:
Phospholipid Emulsion 65-175 part of described self emulsifying lyophilizing sumatriptan;
Lactose 200-400 part;
The described sumatriptan salt of microcrystalline Cellulose 200-600 part is one or more in sumatriptan hydrochlorate, nitrate, phosphate, formates, METHAPHOSPHORIC ACID salt, citrate, benzoate, fumarate, maleate, tartrate and succinate.
Contain described self emulsifying sumatriptan or/and the pharmaceutical formulation of sumatriptan salt phospholipid emulsion formulations is composed of the following components according to listed as parts by weight:
Described self emulsifying sumatriptan is or/and phospholipid Emulsion 65-175 part of sumatriptan salt;
Lactose 200-400 part;
Microcrystalline Cellulose 200-600 part.
Preferably, described pharmaceutical formulation, composed of the following components according to listed as parts by weight:
120 parts of described self emulsifying sumatriptan phospholipid Emulsions;
300 parts of lactose;
400 parts of microcrystalline Cellulose.
Two of purpose of the present invention is to provide a kind of sumatriptan or/and the preparation method of sumatriptan salt pref, and the method is simple to operate, is applicable to large-scale production.
For achieving the above object, technical scheme of the present invention is:
Preparation method based on the self emulsifying lyophilizing sumatriptan preparation of described pharmaceutical formulation specifically comprises the following steps:
The A sumatriptan is or/and the preparation of sumatriptan salt phospholipid breast
The Ovum Gallus domesticus Flavus lecithin of getting formula ratio is prepared into the alcoholic solution of Ovum Gallus domesticus Flavus lecithin, and adds the Ma Qutan of formula ratio or/and sumatriptan salt fully reacts, and gets sumatriptan or/and sumatriptan salt phospholipid is newborn;
B contains the sumatriptan of lactose or/and the preparation of sumatriptan salt phospholipid Emulsion
The lactose of formula ratio is added fully dissolving in phosphate buffer, get the lactose phosphate buffer solution; Described lactose phosphate buffer solution is added steps A gained sumatriptan or/and fully mix in sumatriptan salt phospholipid Ruzhong, must contain the sumatriptan of lactose or/and sumatriptan salt phospholipid Emulsion; The pH value of this step reaction is 3.03-7.03;
The C sumatriptan is or/and the preparation of sumatriptan salt pref
Step B gained sumatriptan or/and sumatriptan salt phospholipid Emulsion is dried to solids, is added the microcrystalline Cellulose of formula ratio in described solids, and fully mix, get sumatriptan or/and the sumatriptan salt pref.
Preferably, described preparation method, in step B, will contain the sumatriptan of lactose or/and the processing of sumatriptan salt phospholipid breast homogenizing: pressure is 30-50psi, 30-50 circulation.
Preferably, described preparation method is in step B, and will contain the sumatriptan of lactose or/and the processing of sumatriptan salt phospholipid breast homogenizing: pressure is 40psi, 40 circulations, and filter.
Preferred described preparation method is in step C, step B gained is contained the sumatriptan of lactose or/and sumatriptan salt phospholipid Emulsion is dried to solids, the mode of described drying is frozen dried, and the step of frozen dried is: 1)-50 ~-35 ℃ of pre-freezes 60 minutes; 2) under vacuum condition: under-50 ~-30 ℃ of conditions freezing 150-240 minute; Then under-35 ~-20 ℃ of conditions freezing 180-360 minute; Then under-30 ~-15 ℃ of conditions freezing 150-240 minute; Then under-5-5 ℃ condition 150-240 minute, then under 5-15 ℃ of condition 150-240 minute; Then under 15 ℃ of conditions 60-150 minute; Then under 30 ℃ of conditions 30-90 minute.
Preferred described preparation method is in steps A, and the Ovum Gallus domesticus Flavus lecithin of getting formula ratio is prepared into the alcoholic solution of Ovum Gallus domesticus Flavus lecithin under 60 ℃ of conditions.
Preferred described preparation method is in step B, and the pH value of reaction is 4.7.
Three of purpose of the present invention is to provide a kind of sumatriptan or/and the sumatriptan salt pref, and its bioavailability is high.
For achieving the above object, technical scheme of the present invention is:
The sumatriptan that described preparation method makes is or/and the sumatriptan salt pref.
Beneficial effect of the present invention is: this preparation is oral formulations, has overcome because the factors such as first pass effect affect the low defective of bioavailability, compares with two kinds of sumatriptan sheets of commodity " red with quiet " by name, and relative bioavailability is 126.6-154.3%.The sumatriptan phosphatide complexes of this preparation process preparation has overcome its moisture-sensitive, caking, and poor fluidity directly incapsulates and may cause the defectives such as dissolution is low.Be applicable to large-scale production.
The specific embodiment
The sumatriptan that this experiment is selected is or/and sumatriptan salt is specially [3-[2-(dimethylamino) ethyl]-N-Methyl-1H-indole-5-methylsulfonamides], its molecular formula is C
14H
21N
3O
2S。
Embodiment 1 formula screening
1 self emulsifying sumatriptan phospholipid emulsion formulations
Formula 1) composed of the following components by weight: 150 parts of sumatriptans; 500 parts of Ovum Gallus domesticus Flavus lecithins.
Formula 2) composed of the following components by weight: 250 parts of sumatriptans; 1500 parts of Ovum Gallus domesticus Flavus lecithins.
Formula 3) composed of the following components by weight: 200 parts of sumatriptans; 1000 parts of Ovum Gallus domesticus Flavus lecithins.
In above-mentioned formula, sumatriptan also can substitute with sumatriptan salt, comprises one or more in sumatriptan hydrochlorate, nitrate, phosphate, formates, METHAPHOSPHORIC ACID salt, citrate, benzoate, fumarate, maleate, tartrate and succinate.The purpose of self emulsifying sumatriptan phospholipid Emulsion is: medicine can increase dissolubility in phospholipid self emulsifying process, improves bioavailability, thereby reduces drug dose, alleviates toxic and side effects.So above-mentioned sumatriptan also can substitute with its esters.
2 pharmaceutical formulations
Pharmaceutical formulation 1) composed of the following components according to listed as parts by weight: sumatriptan is or/and 65 parts of sumatriptan salt phospholipid Emulsions; 200 parts of lactose; 200 parts of microcrystalline Cellulose.
Pharmaceutical formulation 2) composed of the following components according to listed as parts by weight: sumatriptan is or/and 175 parts of sumatriptan salt phospholipid Emulsions; 400 parts of lactose; 600 parts of microcrystalline Cellulose.
Pharmaceutical formulation 3) composed of the following components according to listed as parts by weight: sumatriptan is or/and 120 parts of sumatriptan salt phospholipid Emulsions; 300 parts of lactose; 400 parts of microcrystalline Cellulose.
Above-mentioned formula is prepared sumatriptan succinate lyophilized formulations by adnexa freeze-dry process flow process.
The preparation method of embodiment 2 self emulsifying lyophilizing sumatriptans
The concrete steps of 1 technique are:
The A sumatriptan is or/and the preparation of sumatriptan salt phospholipid breast
The Ovum Gallus domesticus Flavus lecithin of getting formula ratio is prepared into the alcoholic solution of Ovum Gallus domesticus Flavus lecithin, and adds the Ma Qutan of formula ratio or/and sumatriptan salt fully reacts, and gets sumatriptan or/and sumatriptan salt phospholipid is newborn;
The B sumatriptan is or/and the preparation of sumatriptan salt phospholipid breast
The lactose of formula ratio is added fully dissolving in phosphate buffer, get the lactose phosphate buffer solution; Described lactose phosphate buffer solution is added steps A gained sumatriptan or/and fully mix in sumatriptan salt phospholipid pre-Ruzhong, must contain the sumatriptan of lactose or/and sumatriptan salt phospholipid is newborn; The pH value of this step reaction is 3.03-7.03;
The C sumatriptan is or/and the preparation of sumatriptan salt pref
Step B gained is contained the sumatriptan of lactose or/and sumatriptan salt phospholipid breast is dried to solids, add the microcrystalline Cellulose of formula ratio in described solids, and fully mix, get sumatriptan or/and the sumatriptan salt pref.
Above-mentioned sumatriptan is or/and the sumatriptan salt pref can be prepared into capsule by " Chinese Pharmacopoeia 2010 ".
Use above-mentioned technique with the pharmaceutical formulation 1 of embodiment 1), pharmaceutical formulation 2) and pharmaceutical formulation 3) make capsule preparations.
2 selection process screenings
Sumatriptan salt-Ovum Gallus domesticus Flavus lecithin ratio, emulsifying pH of buffer, lactose ratio are the pre-newborn key factor of preparation lyophilizing, the emulsion dispersion temperature and time has appreciable impact for the quality of preparation simultaneously, therefore on the basis of embodiment 1 formula, further component design ratio, with further optimization of C/C composites:
| Formula | Phospholipid Emulsion (STN-PE) | pH | Phospholipid Emulsion-lactose ratio | Dispersion temperature | Jitter time |
| 1 | 150:1500 | 3.53 | 65:200 | 50℃ | 10min |
| 2 | 150:1500 | 4.74 | 120:300 | 50℃ | 10min |
| 3 | 150:1500 | 7.03 | 175:400 | 50℃ | 10min |
| 4 | 150:1500 | 8.52 | 175:400 | 50℃ | 10min |
| 5 | 200:1000 | 3.03 | 65:200 | 60℃ | 20min |
| 6 | 200:1000 | 4.74 | 120:300 | 60℃ | 20min |
| 7 | 200:1000 | 7.03 | 175:400 | 60℃ | 20min |
| 8 | 400:1000 | 3.03 | 65:200 | 60℃ | 20min |
| 9 | 500:1000 | 4.74 | 120:300 | 60℃ | 20min |
| 10 | 600:1000 | 7.03 | 175:400 | 60℃ | 20min |
STN-PE: refer to sumatriptan succinate and Ovum Gallus domesticus Flavus lecithin ratio.
Each formula pre-newborn particle size distribution of lyophilizing after microjet emulsifying is as follows:
| Formula | Particle diameter (nm) before lyophilizing | Redissolve particle diameter (nm) after lyophilizing |
| 1 | 232.7 | There is granule to separate out |
| 2 | 219.4 | There is granule to separate out |
| 3 | 229.2 | There is granule to separate out |
| 4 | 231.5 | There is granule to separate out |
| 5 | 191.9 | 190.0 |
| 6 | 182.9 | 184.0 |
| 7 | 188.3 | 193.4 |
| 8 | 184.6 | 182.2, bimodal |
| 9 | 195.8 | 186.8, bimodal |
| 10 | 198.7 | 188.4, multimodal |
Hence one can see that, and in embodiment 2, formula 5-7 is scheme more preferably, and its formula is:
Formula 5) composed of the following components according to listed as parts by weight: 65 parts of the phospholipid Emulsions of self emulsifying lyophilizing sumatriptan (sumatriptan and Ovum Gallus domesticus Flavus lecithin ratio 150:500 press the total restatement of sumatriptan and Ovum Gallus domesticus Flavus lecithin); 200 parts of lactose; 200 parts of microcrystalline Cellulose.
Formula 6) composed of the following components according to listed as parts by weight: 120 parts of the phospholipid Emulsions of self emulsifying lyophilizing sumatriptan (sumatriptan and Ovum Gallus domesticus Flavus lecithin ratio 200:1000 press the total restatement of sumatriptan and Ovum Gallus domesticus Flavus lecithin); 300 parts of lactose; 400 parts of microcrystalline Cellulose.
Formula 7) composed of the following components according to listed as parts by weight: 175 parts of the phospholipid Emulsions of self emulsifying lyophilizing sumatriptan (sumatriptan and Ovum Gallus domesticus Flavus lecithin ratio 250:1500 press the total restatement of sumatriptan and Ovum Gallus domesticus Flavus lecithin); 400 parts of lactose; 600 parts of microcrystalline Cellulose.
3 freeze-dry process
Drying mode in processing step C is preferably lyophilization.The lyophilizing of formula 5-7 preparation in embodiment 2 was filled in 10ml lyophilizing bottle design lyophilizing program in pre-newborn minute:
4 capsule stability are investigated
With the preparation capsule under following condition, be placed in surface plate:
Condition 1 is set to that sample is 70% at 40 ℃, relative humidity, placed 30 days under illumination 4500Lx condition constant temperature; Condition 2 is set to that sample is 80% at 60 ℃, relative humidity, placed 30 days under illumination 6500Lx condition constant temperature;
Respectively at 0,15,30 day, sumatriptan content in capsule is detected, this product is in the situation that condition 1 is stable, 6 samples of wherein filling a prescription stable best, and when condition 2, capsule 's content has the phenomenon of more obvious coagulation in bulk.
Embodiment 3 bioavailability detect
1 laboratory animal
Kunming mice, Mus 7-8 in age week, sex male and female half and half, quality 25 ± 2g.Provided by Third Military Medical University's Experimental Animal Center.Animal licence: SCXK-(Chongqing)-2007-004.
2 experimental apparatus
HPLC(Waters 515 pumps, 2497 detectors), Alltech C18 reverse chromatograms post (250 * 4.6mm, 5 μ m), Nitrogen evaporator (Techne, the U.S.), heater (DRI-BLOCK DB.20, Britain), SPE extraction equipment (Alltech), pure water instrument (Millipore, Simplicity 185, France), centrifuge (Eppendorf, Centrifuge 5415R, Germany), cryogenic refrigerator (Thermo Electron Corporation, 702, the U.S.), peristaltic pump (BT00-100M/YZ1515, Baoding LanGe constant flow pump Co., Ltd), FK-1b divides cartridge controller (Baoding LanGe constant flow pump Co., Ltd), vacuum diaphragm pump (GM-0.33, rise in Tianjin).
3 tested medicine groupings
Experimental group is the capsule (being called for short the experiment capsule) of embodiment 2 formula 6 preparations.By the center preparation of basic courses department of Third Military Medical University Nano medication, lot number is 20101118, and specification is 100mg.
Matched group is sumatriptan tablet, and commodity are by name red with quiet, and specification is 100mg.
4 pharmacokinetic studies
With 180 kunming mice male and female half and half, be divided at random 2 groups.Wherein matched group gives the commercial preparation pellet with quiet, gavage, and dosage is 6mg/kg, is designated as the TSTN group; Experimental group is tested capsule, and dosage is that 6mg/kg is designated as the LSTN group.Plucked the eyeball blood sampling in 0.5,1,2,3,4,5,6,8,12 hour and carry out determination of plasma concentration before administration and after administration.
5 medications: single gastric infusion.
6 dosage settings and definite foundation
According to the regulation in " chemicals Non-clinical Pharmacokinetics investigative technique guideline ", with reference to list of references and the quiet description dosage of red ketone (50-100mg/ time), according to the formula 1 in " pharmacological experiment method ":
The moving dosage that reaches tissue distribution assays of medicine of determining single-dose is 6mg/kg.
7 plasma samples are processed
After during detection, frozen 1:5 diluting plasma sample room temperature being melted again, press SPE method extraction STN.
8 Solid-Phase Extraction (SPE)
Follow these steps to carry out the SPE extraction:
Methanol 1ml activation → pure water 1ml balance → sample introduction 200 μ l (flow velocity＜1ml/min) → pure water 1ml cleaning → methanol 1ml eluting (collection eluent) → N
237 ℃ dry up (5L/min) → 200 μ l mobile phase redissolution, and-4 ℃ standby.
9 two kinds of preparation pharmacokinetic parameters
After single oral dose 6mg/kgLS and TS, average blood drug level AUC
0-tBe respectively 2951.1 and 2176.5ng/L; AUC
0-∞Be respectively 3497.9 and 2266.9ng/L; C
maxBe respectively 575.6 and 525.8ng/L; T
1/2Be respectively 5.292 and 1.169 hour; MRT
0-tBe respectively 5.1 and 3.7.
LSTN refers to 6 pharmaceutical formulations in example 2
TSTN refers to marketed tablet
LSTN-2 refers to formula 5 preparations in example 2
TSTN refers to marketed tablet
The individual pharmacokinetics parameter of two kinds of sumatriptan preparations under this dosage relatively, AUC
0-tAnd AUC
0-∞After statistics, the p value is all less than 0.01, LS group C
maxHigh than the TS group, p=0.055.
10 relative bioavailability are investigated
Relative bioavailability is calculated,
F=AUC Test sample / AUC Reference product * 100%
Relative bioavailability is 126.6-154.3%.
This experiment test sample is that (fill a prescription 6 in example 2, preparation LS) and methodological study are (TS) pharmacokinetics of two kinds of sumatriptan preparations in Mice Body of sumatriptan sheet " red with quiet " with reference to product to self emulsifying sumatriptan freeze-drying capsules.Result of study shows, the LS better stability of preparation, and after emulsion, particle size distribution is more even, and long-time stability are good; After two kinds of STN preparation single-doses, the AUC of LS group
0-∞, AUC
0-t, etc. high than TS group.The result of study prompting, the LS preparation is than the TS preparation, and relative bioavailability is 126.6-154.3%.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (2)
1. the preparation method of self emulsifying sumatriptan preparation, is characterized in that, specifically comprises the following steps:
The A sumatriptan is or/and the preparation of sumatriptan salt phospholipid breast
Get 500-1500 weight portion Ovum Gallus domesticus Flavus lecithin and be prepared into the alcoholic solution of Ovum Gallus domesticus Flavus lecithin, and add the sumatriptan of 150-250 weight portion or/and sumatriptan salt fully reacts, get sumatriptan or/and sumatriptan salt phospholipid is newborn;
Described sumatriptan salt is one or more in sumatriptan hydrochlorate, nitrate, phosphate, formates, METHAPHOSPHORIC ACID salt, citrate, benzoate, fumarate, maleate, tartrate and succinate;
B contains the sumatriptan of lactose or/and the preparation of sumatriptan salt phospholipid Emulsion
By weight 200-400 part lactose is added fully dissolving in phosphate buffer, get the lactose phosphate buffer solution; Described lactose phosphate buffer solution is added steps A gained 65-175 weight portion sumatriptan or/and fully mix in sumatriptan salt phospholipid Ruzhong, must contain the sumatriptan of lactose or/and sumatriptan salt phospholipid Emulsion; The pH value of this step reaction is 3.03-7.03;
The C sumatriptan is or/and the preparation of sumatriptan salt pref
Step B gained sumatriptan or/and sumatriptan salt phospholipid Emulsion is dried to solids, is added 200-600 weight portion microcrystalline Cellulose in described solids, and fully mix, get sumatriptan or/and the sumatriptan salt pref; The mode of described drying is frozen dried, and the step of frozen dried is: 1)-50 ~-35 ℃ of pre-freezes 60 minutes; 2) under vacuum condition: under-50 ~-30 ℃ of conditions freezing 150-240 minute; Then under-35 ~-20 ℃ of conditions freezing 180-360 minute; Then under-30 ~-15 ℃ of conditions freezing 150-240 minute; Then under-5-5 ℃ condition 150-240 minute, then under 5-15 ℃ of condition 150-240 minute; Then under 15 ℃ of conditions 60-150 minute; Then under 30 ℃ of conditions 30-90 minute.
2. preparation method according to claim 1, is characterized in that, in described step B, described lactose is 300 parts, and described self emulsifying sumatriptan phospholipid Emulsion is 120 parts; In described step C, described microcrystalline Cellulose is 400 parts.
3, preparation method according to claim 1, is characterized in that, in step B, will contain the sumatriptan of lactose or/and the processing of sumatriptan salt phospholipid breast homogenizing: pressure is 30-50psi, 30-50 circulation.
4, preparation method according to claim 1, is characterized in that, in step B, will contain the sumatriptan of lactose or/and the processing of sumatriptan salt phospholipid breast homogenizing: pressure is 40psi, 40 circulations, and filter.
5, preparation method according to claim 1, is characterized in that, in steps A, the Ovum Gallus domesticus Flavus lecithin of getting formula ratio is prepared into the alcoholic solution of Ovum Gallus domesticus Flavus lecithin under 60 ℃ of conditions.
6, preparation method according to claim 1, is characterized in that, in step B, the pH value of reaction is 4.7.
7, the sumatriptan that makes of the described preparation method of claim 1-6 any one is or/and the sumatriptan salt pref.
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| WO2008127679A1 (en) * | 2007-04-11 | 2008-10-23 | Cephalon, Inc. | Lyophilized pharmaceutical compositions and methods of making and using same |
| CN101301279A (en) * | 2008-06-18 | 2008-11-12 | 海南锦瑞制药有限公司 | Sumatriptan succinate rapid disintegrating tablet and preparation thereof |
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2011
- 2011-12-21 CN CN 201110432649 patent/CN102440956B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1415285A (en) * | 2002-10-16 | 2003-05-07 | 上海医药工业研究院 | Inhalant of Shumaputan dry-powder and its preparation method |
| WO2008127679A1 (en) * | 2007-04-11 | 2008-10-23 | Cephalon, Inc. | Lyophilized pharmaceutical compositions and methods of making and using same |
| CN101301279A (en) * | 2008-06-18 | 2008-11-12 | 海南锦瑞制药有限公司 | Sumatriptan succinate rapid disintegrating tablet and preparation thereof |
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