CN108542909A - A kind of aspirin phosphatide solidification composition filling, preparation method and pharmaceutical preparation - Google Patents
A kind of aspirin phosphatide solidification composition filling, preparation method and pharmaceutical preparation Download PDFInfo
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Abstract
The invention belongs to technical field of medicine.The invention discloses a kind of aspirin phosphatide solidification composition fillings, are made by aspirin, phosphatide, adsorbent, viscosity modifier and hydrolysis inhibitor；The invention discloses a kind of preparation methods of aspirin phosphatide solidification composition filling comprising aspirin crushing, mixture preparation and mixture solidification and etc.；The invention also discloses a kind of aspirin phospholipid drug preparations, are tablet, capsule or granular preparation made from aspirin phosphatide solidification composition filling.After aspirin and phosphatide form compound in the present invention, release of the aspirin in stomach can be reduced, drug gastrointestinal side effect can be substantially reduced, compliance is improved, drug solubility energy can be improved, enhances drug absorption, drug bioavailability is improved, adverse drug reaction is reduced；The preparation method of aspirin phosphatide solidification composition filling, simple for process, favorable reproducibility is, it can be achieved that modern commercial produces.
Description
Technical field
The present invention relates to technical field of medicine, more particularly, to a kind of aspirin phosphatide solidification composition filling, its system
Preparation Method and pharmaceutical composition.
Background technology
Aspirin (Aspirin) also known as acetylsalicylic acid are one of three big classical drugs in history, are gone through as one kind
The long analgesic-antipyretic of history, effectiveness is obviously cheap, is still most widely used antipyretic-antalgic anti-inflammatory agent so far, and
And it is the standard preparation for comparing and evaluating other drugs.Since the 1960s, pharmacological research shows aspirin persistence
COX-1 activity is inactivated, inhibits platelet function, no dosage dependent interaction, extremely low concentration (nmol/L) that inhibition can be rapidly reached
Effect has specific blood coagulation resisting function, so as to the drug as pre- preventing thrombosis.《Chinese Consensus of experts》It is recommended that one
Aspirin prolonged application dosage is 75~100mg/ day during grade is prevented, and the prolonged application dosage of secondary prevention for 75~
150mg/ days.
The maximum toxic side effect of aspirin is exactly easily to cause rotten to the corn gastrointestinal tract mucosa, bleeding and ulcer etc..Except analgesia,
Antipyretic outer, aspirin further increases poison for being required for Long-term taking medicine when treating the diseases such as rheumatic fever, arthritis, antithrombotic
The incidence of side effect.Although people have carried out improving dosage form, suppository is such as increased, avoids drug from being touched with gastrointestinal tract, medication
It is extremely inconvenient；Enteric coated preparations are for another example made, although reducing the incidence of toxic side effect to a certain extent, there is portion under one's belt
Leakage phenomenon can occur for fragment, can cause to stimulate to stomach in this way, cause to damage to stomach lining；If free salicylic acid in enteric coatel tablets
Content it is high, salicylism can be caused to react, still do not tackled the problem at its root.
Invention content
To solve the problems, such as salicylism existing for Genprin, the present invention provides one kind capable of reducing gastrointestinal tract
Stimulation, protection gastric mucosa and the aspirin phosphatide solidification composition filling for solving the problems, such as salicylism；
The present invention provides a kind of methods that aspirin phosphatide solidification composition filling can be made；
The present invention also provides one kind pharmaceutical preparation made from aspirin phosphatide solidification composition filling.
To achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is by weight 1：1~3：1~4：0.1~0.4：0.05~0.2 is made；Adsorbent is microcrystalline cellulose, low substitution hydroxyl
Propyl cellulose, croscarmellose sodium, dried starch, sodium carboxymethyl starch, silica, crospovidone or pregelatinated
At least one of starch；Viscosity modifier is tricaprylin, caprylic/capric glyceryl ester, caprylic/capric/linoleic acid
At least one of triglyceride, propylene/dicaprate or butanediol dicaprylate/dicaprate；Hydrolysis inhibits
Agent is at least one of tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid or succinic acid.
Liquid phosphatide has protective effect to gastrointestinal tract mucous, can increase the viscous of rete malpighii jointly with mucin glycoprotein
Property；Slow down H+By the speed of rete malpighii, the bicarbonate of stomach epithelial secretion is made to have the sufficient time to neutralize therewith；In addition may be used also
To form hydrophobic layer in mucomembranous surface, prevent protein in mucus and cell hydrolyzed.
After aspirin and liquid phosphatide form compound, release of the aspirin in stomach can be reduced, can be substantially reduced
Drug gastrointestinal side effect, moreover it is possible to improve drug solubility energy, enhance drug absorption, improve drug bioavailability, reduce
Adverse drug reaction.
Adsorbent makes liquid phosphatide solidification, more composition more stablize, and is suitble to modern commercial production.
Preferably, liquid phosphatide be phosal 35SB, phosal 53MCT, phosal 75SA, phosal 50PG,
At least one of the soft phosphatide of phosal 50SA+, soybean or the soft phosphatide of sunflower.
Preferably, the content of phosphatidyl choline is 25~75wt% in liquid phosphatide.
Preferably, adsorbent be microcrystalline cellulose, croscarmellose sodium, silica, crospovidone or
At least one of pregelatinized starch.
Preferably, silica uses amino modified mesoporous silicon oxide.
Preferably, amino modified mesoporous silicon oxide is made by following methods, prepare the nitric acid that pH value is 6.0~6.5
The cetyl trimethyl ammonium of 0.4~0.9 parts by weight is dissolved in aqueous ammonium nitrate solution by 80 parts by weight of aqueous ammonium, molten
It is defoamed naturally after solution stirring, above-mentioned solution is then preheating to 70~85 DEG C, then 4~5 parts by weight ethyl orthosilicates are added
And stirred at 70~85 DEG C 2~3 minutes, then noted while agitating with the linear velocity of 1~2m/s along liquid level tangential direction
Entering alkali reaction solution makes the pH value of solution be 9~10, and 1~2 hour obtained mesoporous silicon oxide mixed liquor is stirred at 70~85 DEG C,
Then mesoporous silicon oxide mixed liquor is concentrated into 40~50 parts by weight and its pH value is adjusted to 7~8, then 0.1 is added thereto
The disodium glutamate of~0.3 parts by weight and in 30~40 DEG C of stir process 2~3 hours is finally filtered, water cleaning and ethyl alcohol
Amino modified mesoporous silicon oxide is made in cleaning；Alkali reaction solution is addition 5~10wt% sodium hydroxides and 0.1~0.5wt%
The ammon amount of Span is the ammonia spirit of 15~20wt%.
Aspirin mostlys come from Genprin after stomach dissolution for the irritation of stomach and causes in acidity
Damage to gastric mucosa, especially when the free salicylic acid generated after stomach dissolves out causes salicylism；Though in the present invention
It has so used liquid phosphatide to carry out cladding to aspirin and has slowed down H+Into the rate of stomach environment, but itself or nothing
Method avoids H completely+Into stomach, the product after being combined with aspirin liquid phosphatide due to adsorbent is inhaled by adsorbent again
Attached solidification, the contact that adsorbent and aspirin liquid phosphatide combination product can be comprehensive, therefore amino is carried out to adsorbent
Modification can in aspirin liquid phosphatide combination product H+H when release+It is neutralized in advance by the amino of adsorbent surface minor matters,
It is further reduced the H for entering stomach after aspirin hydrolyzes+Preferably to protect stomach to reduce injury of the aspirin to stomach.
Adsorbent uses amino modified mesoporous silicon oxide, the structure that its suction-operated of mesoporous silicon oxide is strong and its is mesoporous simultaneously
The aspirin liquid phosphatide combination product being suitable in the absorption present invention, can also make adsorbent and aspirin liquid phosphatide knot
It is more secured to close product combination, preferably handles the H released+。
When preparing amino modified mesoporous silicon oxide, first prepares mesoporous silicon oxide and utilized again on the surface of silica
Amino-acid salt is modified.The method that mesoporous silicon oxide uses teos hydrolysis is prepared, first by template bromination 16
Alkane trimethyl ammonium is dissolved in acid ammonium nitrate solution, is then added ethyl orthosilicate, is passed through into solution with that
Alkaline solution realizes the hydrolysis under alkaline environment；The amino modified stage is carried out immediately after the completion of preparing mesoporous silicon oxide,
It is amino-acid modified that concentration adjusts pH value to be subsequently added into.Alkaline solution in the present invention is used by sodium hydroxide, Span
The ammonium hydroxide of low concentration can only be used, a little sodium hydroxide is added thus due to needing high-temperature process with the mixed liquor of ammonium hydroxide composition
The pH value for adjusting solution, additionally due to foam can bring harmful effect in whole process, simultaneously because template cetyl
Trimethyl ammonium will produce a large amount of bubbles when having surface-active action, stirring or injection alkaline solution, and sorbitan fatty acid is added
Ester plays the role of defoaming.Alkaline solution is added by the way of injection, and one can play the role of auxiliary stirring, and two can be with
Playing makes the purpose of alkaline solution evenly in vertical direction mixing, so that the hydrolysis of ethyl orthosilicate is whole uniform
, rather than it is layered and carries out, ensure that the external pattern of mesoporous silicon oxide obtained is more uniform, inherent duct is also evenly.
Preferably, viscosity modifier is tricaprylin.
Preferably, hydrolysis inhibitor is at least one of tartaric acid, citric acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
The preparation method of aspirin phospholipid composite includes mainly that aspirin and liquid mixture of phospholipids are prepared and mixed
Close object solidification two parts, after the cured processing of mixture, can make composition more stablize, can be more suitable for preserve and
Transport is also more suitable for modern commercial production.
Preferably, in step a, aspirin is crushed to its D90It is 10~30 μm.
Preferably, in step b, first hydrolysis inhibitor is distributed in viscosity modifier and is then added in liquid phosphatide.
A kind of aspirin phospholipid drug preparation is tablet, capsule made from aspirin phosphatide solidification composition filling
Or granular preparation.
Therefore, the invention has the advantages that：
(1) the existing preparation process of phosphatide complexes is that solid-state phosphatide and drug are dissolved in organic dissolution, then will be organic
Dissolving removes, and different dosage forms finally are made in phosphatide complexes as needed；Unavoidably there is organic residue problem in the technique,
And in production it is noted that organic solvent is explosion-proof, direct labor's security protection and waste water and gas discharge.Ah Si in the present invention
The preparation method of woods phosphatide solidification composition filling, no organic residue, environmental pollution is small, simple for process, and favorable reproducibility is, it can be achieved that the modern times
It commercially produces.
(2) after aspirin and phosphatide form compound in the present invention, release of the aspirin in stomach can be reduced, can be shown
It writes and reduces drug gastrointestinal side effect, improve compliance；
(3) the aspirin phosphatide solidification composition filling in the present invention can improve drug solubility energy, enhance drug absorption, improve medicine
Object bioavilability reduces adverse drug reaction；
Description of the drawings
Fig. 1 is Examples 1 to 9 cumulative in vitro dissolution rate curve.
Specific implementation mode
Technical scheme of the present invention is further described With reference to embodiment.
Obviously, the described embodiments are merely a part of the embodiments of the present invention, instead of all the embodiments.Based on this
Embodiment in invention, all other reality obtained by those of ordinary skill in the art without making creative efforts
Example is applied, shall fall within the protection scope of the present invention.
In the present invention, if not refering in particular to, all equipment and raw material is commercially available or the industry is common,
Method in following embodiments is unless otherwise instructed this field conventional method.
Embodiment 1
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 940g, viscosity modifier 179.9g, and hydrolysis inhibits
Agent 74.8g；
Liquid phosphatide is phosal 35SB, and the content of phosphatidyl choline is 50wt% in liquid phosphatide, and adsorbent is titanium dioxide
Silicon, viscosity modifier are tricaprylin, and hydrolysis inhibitor is citric acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is the capsule made from aspirin phosphatide solidification composition filling.
Embodiment 2
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 270g, liquid phosphatide 810g, adsorbent 540g, viscosity modifier 79.9g, and hydrolysis inhibits
Agent 44.8g；Liquid phosphatide is phosal 35SB, and the content of phosphatidyl choline is 50wt% in liquid phosphatide, and adsorbent is by ammonia
Base is modified mesoporous silicon oxide, and viscosity modifier is tricaprylin, and hydrolysis inhibitor is citric acid；
Amino modified mesoporous silicon oxide is made by following methods, prepares 80 parts by weight of aqueous ammonium nitrate solution that pH value is 6.0, will
The cetyl trimethyl ammonium of 0.6 parts by weight is dissolved in aqueous ammonium nitrate solution, is defoamed naturally after dissolving stirring, then will be upper
It states solution and is preheating to 80 DEG C, then 4 parts by weight ethyl orthosilicates are added and are stirred 3 minutes at 80 DEG C, then in stirring
Make the pH value of solution for 10 with the linear velocity injection alkali reaction solution of 1m/s along liquid level tangential direction simultaneously, it is small that 2 are stirred at 80 DEG C
When mesoporous silicon oxide mixed liquor is made, mesoporous silicon oxide mixed liquor is then concentrated into 40 parts by weight and is adjusted to its pH value
7, then the disodium glutamate of 0.2 parts by weight is added thereto and in 35 DEG C of stir process 2 hours, is finally filtered, water cleaning
It is cleaned with ethyl alcohol and amino modified mesoporous silicon oxide is made；Alkali reaction solution is addition 5wt% sodium hydroxides and 0.2wt% sorbs
The ammon amount of alcohol fatty acid ester is the ammonia spirit of 16wt%.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is the capsule made from aspirin phosphatide solidification composition filling.
Embodiment 3
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 940g, viscosity modifier 259.8g, and hydrolysis inhibits
Agent 74.8g；
Liquid phosphatide is by phosal 35SB and phosal 53MCT by weight 1：The mixture of 1 composition, phosphorus in liquid phosphatide
The content of phosphatidylcholine is 50wt%, and adsorbent is silica, and viscosity modifier is tricaprylin, and hydrolysis inhibitor is
Citric acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is tablet, capsule made from aspirin phosphatide solidification composition filling
Or granular preparation.
Embodiment 4
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 940g, viscosity modifier 259.8g, and hydrolysis inhibits
Agent 74.8g；
Liquid phosphatide is by phosal 35SB, phosal 53MCT and phosal 75SA by weight 1：1：The mixing of 1 composition
Object, the content of phosphatidyl choline is 50wt% in liquid phosphatide, and adsorbent is silica, and viscosity modifier is pungent by glycerine three
Acid esters, hydrolysis inhibitor are by citric acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is the capsule made from aspirin phosphatide solidification composition filling.
Embodiment 5
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 1100g, viscosity modifier 179.9g, hydrolysis suppression
Preparation 74.8g；
Liquid phosphatide is phosal 35SB, and the content of phosphatidyl choline is 50wt% in liquid phosphatide, and adsorbent is microcrystalline cellulose
Element and silica are by weight 1：The mixture of 1 composition, viscosity modifier are tricaprylin, and hydrolysis inhibitor is by wine
Stone acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing, after the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation, for capsule is made by aspirin phosphatide solidification composition filling.
Embodiment 6
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 110g, viscosity modifier 179.9g, and hydrolysis inhibits
Agent 74.8g；
Liquid phosphatide is phosal 35SB, and the content of phosphatidyl choline is 50wt% in liquid phosphatide, and adsorbent is by crystallite fibre
Dimension element, silica and crospovidone are by weight 3：2：The mixture of 6 compositions, viscosity modifier is tricaprylin,
Hydrolysis inhibitor is tartaric acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；, same in water-bath after the completion of degassing
When vacuumize hydrolysis inhibitor, viscosity modifier and aspirin be added in environment, then stir evenly obtained aspirin liquid
State mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is the capsule made from aspirin phosphatide solidification composition filling.
Embodiment 7
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 110g, viscosity modifier 179.9g, and hydrolysis inhibits
Agent 74.8g,；
Liquid phosphatide is by phosal 50PG and phosal 50SA+ by weight 1：The mixture of 1 composition, phosphorus in liquid phosphatide
The content of phosphatidylcholine is 50wt%, and adsorbent is silica and pregelatinized starch by weight 6：The mixture of 5 compositions, glues
It is by caprylic/capric glyceryl ester to spend conditioning agent, and hydrolysis inhibitor is oxalic acid.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 20 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；, same in water-bath after the completion of degassing
When vacuumize hydrolysis inhibitor, viscosity modifier and aspirin be added in environment, then stir evenly obtained aspirin liquid
State mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is tablet, capsule made from aspirin phosphatide solidification composition filling
Or granular preparation.
Embodiment 8
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 810g, adsorbent 810g, viscosity modifier 81g, hydrolysis inhibitor
40.5g；
Liquid phosphatide is by the soft phosphatide of soybean and the soft phosphatide of sunflower by weight 1：The mixture of 1 composition, phosphatide in liquid phosphatide
The content of phatidylcholine is 25wt%, and adsorbent is by microcrystalline cellulose, silica, crospovidone and pregelatinized starch by weight
Measure ratio 7：10：2：The mixture of 5 compositions, viscosity modifier are caprylic/capric/linoleic acid triglyceride, and hydrolysis inhibitor is apple
Acid and ascorbic acid are by weight 1：The mixture of 1 composition.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 10 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation is the tablet made from aspirin phosphatide solidification composition filling.
Embodiment 9
A kind of aspirin phosphatide solidification composition filling, by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis
Inhibitor is made, wherein aspirin 810g, liquid phosphatide 2430g, adsorbent 3240g, viscosity modifier 324g, and hydrolysis inhibits
Agent 162g,；
Liquid phosphatide is by phosal 35SB and the soft phosphatide of soybean by weight 1：The mixture of 1 composition, phosphatide in liquid phosphatide
The content of phatidylcholine is 75wt%；
Adsorbent be by low-substituted hydroxypropyl cellulose, croscarmellose sodium, dried starch, sodium carboxymethyl starch by weight
Than 1：1：1：1 by weight the mixture formed；
Viscosity modifier is by the capric acid of tricaprylin, propylene/dicaprate and butanediol dicaprylate/bis-
Ester is by weight 1：1：The mixture of 1 composition；
Hydrolysis inhibitor is by tartaric acid, malic acid, citric acid and succinic acid by weight 1：1：1：The mixture of 1 composition.
A kind of preparation method of aspirin phosphatide solidification composition filling, is made by following steps：
A) aspirin is crushed to its D90It is 30 μm, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；, same in water-bath after the completion of degassing
When vacuumize hydrolysis inhibitor, viscosity modifier and aspirin be added in environment, then stir evenly obtained aspirin liquid
State mixture of phospholipids；Wherein first hydrolysis inhibitor is distributed in viscosity modifier and is added；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
A kind of aspirin phospholipid drug preparation, for the particle being directly packaged to be by aspirin phosphatide solidification composition filling
Preparation.
The performance test of the present invention：
(1) In Vitro Dissolution measures：
Dissolving-out method：With reference to Chinese Pharmacopoeia leaching the second method of method, rotating speed 75rpm, 900ml are containing 10 mMs of cholic acid
PH6.8 phosphate buffers；The cumulative leaching rate of above-described embodiment 1~9 is as shown in table 1.
The cumulative in vitro dissolution rate of 1 Examples 1 to 9 of table
Dissolution the result shows that, different embodiment sample In Vitro Dissolution situations do not have a notable difference, and 30min dissolutions are more than 85%, belong to
In Fast Stripping preparation.
(2) SD rat gastrointestinal tracts irritant test
Selection example 1,7 sample of embodiment carry out SD rat gastrointestinal tract irritant tests.
Table 2SD rat gastrointestinal tract irritant test samples
| Sample | Specification | Producer |
| Physiological saline | —— | Shanghai Baxter Healthcare Ltd. |
| 1 sample of embodiment | 81mg/ | Zhejiang Hai Chang biological medicines Co., Ltd |
| 8 sample of embodiment | 81mg/ | Zhejiang Hai Chang biological medicines Co., Ltd |
| Acetylsalicylic acid tablet | 500mg/ pieces | Shandong XinHua Pharmacy stock Co., Ltd |
| Aspirin enteric-coated capsule | 100mg/ | Mayne PharmaP International Pty Ltd. |
Experimental method：The SD mouse 50 that quarantine is qualified, healthy are taken, are divided into 5 groups, every group 10.Animal weigh after through mouth gavage to
Medicine 14 days, dosage 300mg/kg.After administration, animal is deprived of food but not water overnight, carries out gross anatomy observation, and right
Main organs are weighed, and stomach does pathological section.SD mouse gastric injury degree is as shown in table 3 after experiment.
SD mouse gastric injury degree counts after table 3 is tested
Note：0- is normal；1- is slight；2- moderates；3- severes.
Acetylsalicylic acid tablet, 1 sample of embodiment, 7 sample of embodiment and aspirin enteric-coated capsule group and saline control
Group compares, light with 2 sample of embodiment and aspirin enteric-coated capsule group gastric injury, and 8 sample sets of embodiment are taken second place, acetylsalicylic acid tablet
Agent group capsule group gastric injury is apparent.It is for statistical analysis to the above degree of impairment using rank sum test, aspirin enteric-coated capsule group
Compared with 2 sample sets of embodiment, 8 sample sets of embodiment, P>0.05, no difference of science of statistics；Compared with acetylsalicylic acid tablet group, P<
0.05, there is significant difference.
The result shows that aspirin phospholipid combination composite capsule and tablet can reduce gastrointestinal irritation.
It should be understood that those skilled in the art, can be improved or be become according to the above description
It changes, and all these modifications and variations should all belong to the protection domain of appended claims of the present invention.
Claims (10)
1. a kind of aspirin phosphatide solidification composition filling, it is characterised in that：
It is by aspirin, liquid phosphatide, adsorbent, viscosity modifier and hydrolysis inhibitor by weight 1：1~3：1~4：
0.1~0.4：0.05~0.2 is made；
The adsorbent is microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, dried starch, carboxylic
At least one of methyl starch sodium, silica, crospovidone or pregelatinized starch；
The viscosity modifier be tricaprylin, caprylic/capric glyceryl ester, caprylic/capric/linoleic acid triglyceride,
At least one of propylene/dicaprate or butanediol dicaprylate/dicaprate；
The hydrolysis inhibitor is at least one of tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid or succinic acid.
2. a kind of aspirin phosphatide solidification composition filling according to claim 1, it is characterised in that：
The liquid phosphatide be 35 53 75 50 PG of SA, phosal of MCT, phosal of SB, phosal of phosal,
At least one of 50 SA+ of phosal, the soft phosphatide of soybean or the soft phosphatide of sunflower.
3. a kind of aspirin phosphatide solidification composition filling according to claim 1 or 2, it is characterised in that：
The content of phosphatidyl choline is 25~75wt% in the liquid phosphatide.
4. a kind of aspirin phosphatide solidification composition filling according to claim 1, it is characterised in that：
The adsorbent is that microcrystalline cellulose, croscarmellose sodium, silica, crospovidone or pregelatinated form sediment
At least one of powder.
5. a kind of aspirin phosphatide solidification composition filling according to claim 1, it is characterised in that：
The viscosity modifier is tricaprylin.
6. a kind of aspirin phosphatide solidification composition filling according to claim 1, it is characterised in that：
The hydrolysis inhibitor is at least one of tartaric acid, citric acid.
7. it is a kind of according to claims 1 or 2 or the preparation method of the 4 or 5 or 6 aspirin phosphatide solidification composition fillings, it is special
Sign is to be made by following steps：
A) aspirin is crushed, it is spare；
B) liquid phosphatide is placed in container, heating water bath simultaneously stirs, while vacuumizing degassing；After the completion of degassing water-bath simultaneously
It vacuumizes and hydrolysis inhibitor, viscosity modifier and aspirin is added in environment, then stir evenly obtained aspirin liquid
Mixture of phospholipids；
C) adsorbent is added in wet granulator, aspirin liquid mixture of phospholipids wet granulation is then added, be made
Aspirin phospholipid composite.
8. a kind of preparation method of aspirin phosphatide solidification composition filling according to claim 7, it is characterised in that：
In the step a, aspirin is crushed to its D90It is 10~30 μm.
9. a kind of preparation method of aspirin phosphatide solidification composition filling according to claim 7, it is characterised in that：
In the step b, first hydrolysis inhibitor is distributed in viscosity modifier and is then added in liquid phosphatide.
10. a kind of aspirin phospholipid drug preparation, it is characterised in that：It is by claims 1 or 2 or 3 or 4 or 5 or 6
Tablet, capsule or granular preparation made from aspirin phosphatide solidification composition filling.
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| US20100173876A1 (en) * | 2000-12-19 | 2010-07-08 | The Board Of Regents Of The University Of Texas System | Oil-based nsaid compositions and methods for making and using same |
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| CN1543358A (en) * | 2000-12-19 | 2004-11-03 | �ÿ���˹ϵͳ��ѧ���»� | Nsaid formulations comprising lecithin oils for protecting the gastrointestinal tract and providing enhanced therapeutic activity |
| US20100173876A1 (en) * | 2000-12-19 | 2010-07-08 | The Board Of Regents Of The University Of Texas System | Oil-based nsaid compositions and methods for making and using same |
| CN103957888A (en) * | 2011-09-29 | 2014-07-30 | PLx制药公司 | Ph dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
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