CN110123752A - A kind of probucol dried emulsifier composition and preparation method thereof and pharmacy application - Google Patents
A kind of probucol dried emulsifier composition and preparation method thereof and pharmacy application Download PDFInfo
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Abstract
The invention belongs to technical field of medicine, it is related to a kind of probucol dried emulsifier composition and preparation method thereof and pharmacy application.The present invention prepares probucol dried emulsifier composition by emulsification, vacuum distillation, Freeze Drying Technique.In composition, the 4.5%~4.9% of the total recipe quantity of gross mass Zhan of hydrophilic emulsifying agent.The 6.23%~11.72% of the total recipe quantity of gross mass Zhan of lipophilic emulsifier, the 71.9%~78.6% of the total recipe quantity of gross mass Zhan of freezing drying protective agent.The 10.2%~10.9% of the total recipe quantity of quality Zhan of probucol.In hydrophilic emulsifying agent, poloxamer188, gelatin, polyoxyethylene stearate (40) ester mass ratio be 16.7: 3.3: 1.In freezing drying protective agent, mannitol, sucrose mass ratio be 1: 1.Resulting composition, accelerated stability test 3 months, sample be it is stable, the rat vivo biodistribution availability relative to Probucol reaches as high as 228.11%, prevents and treats experimental atherosclerosis in rats effect and is remarkably reinforced compared with Probucol.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of probucol dried emulsifier composition and its preparation side
Method and pharmacy application.
Background technique
In recent years, acute myocardial infarction rate in China's was 5/10000ths, had 1,000,000 or more patients to die of the disease every year；
Cerebral infarction disease incidence is 13/10000ths, disables and the death rate, city are 11/10000ths. five or so, rural area is 10/10000ths left
It is right.The method for clinically solving cardiovascular and cerebrovascular acute infarct at present has: the surgeries such as drug thrombolysis method, anticoagulation method and bracket merging
Intervenient cure.These methods have saved many life, but its side effect is also apparent from.Though thromboembolism treatment medicine has developed to the 4th
Generation, but common drawback is the drug for being single fibrinolysis activity, the not no comprehensively solve thrombus problem in terms of eliminating fatty patch,
And all there is hemorrhage side effect, many patients are during thrombolysis because that thrombus fritter blocks again or bleeding is dead.Anticoagulation medicine
Hemorrhage side effect also tend to cause bad clinical event.And interventional therapy inherently have to blood vessel and its endothelium it is traumatic,
The pain of injury, foreign body sensation caused by patient, restenosis, Contrast Media-induced Nephrotoxicity even operative failure and the side effects such as lethal be also it is aobvious and
It is clear to.
Drug treatment clinically focuses on the means such as stable, the prevention and treatment thrombosis of patch in cardiovascular and cerebrovascular diseases event control
System aspect has certain benefit.Oral medicine substantially has: Statins, anticoagulant such as clopidogrel and aspirin, eliminating thrombus and removing obstruction in channels glue
Capsule, Tongxinluo medicinal capsule, formulation of ' Xuefu Zhuyu Decoction etc..Injection has: thrombus leads to (notoginseng total saponin), polydanshinolate, fibrinolytic enzyme
Deng.But heart and brain blood cannot be fundamentally solved still without obvious fatty patch and the safe and reliable drug of subsiding for clinic so far
Pipe blocks problem.Clinical application is developed so far, drug can prevent and subside established atherosclerotic plaque at all and
Prevent cardiovascular and cerebrovascular from blocking, hence it is evident that reduce cardiocerebrovasculaevents events, reduction or replacement fibrinolytic method thrombolysis and stenter to implant etc. intervene hand
Section?
Probucol raw material and its tablet, Yuan Yan producer are U.S. Marion Merrell Dow company, last century 70
Age listing, after in the states such as English, day, method, moral, Canada, Australia, Austria, Italy, South Africa, Spain, Sweden phase
After production and application [Martindale:The Extra Pharmacopoeia, 32th ed, 1999；p1277-1278].But
After Marion Merrell Dow merges into Hoechst Marion Roussel (HMR) company, the medicine is withdrawn from nineteen ninety-five
American market, and the technique of the kind and production line are sold to Japanese first drugmaker.HMR tells Scrip, from American market
Withdrawing from probucol is business reason, that is, its sales volume is unsatisfactory, and because of new drug 3-hydroxy-3-methylglutaryl coenzyme A reductase
The competition of inhibitor, the medicine sales volume are also declining.When withdrawing from probucol, HMR successfully cooperates with Sandoz, in the U.S.
Have listed a HMG CoA reductase inhibitor drug, Lescol (Fluvastatin).U.S. FDA removes the medicine
It is uninterpreted the reason of market out, have no that the product withdraw from the report in market in other countries.After medicine listing, initial stage medication is preferable,
Afterwards because of a large amount of similar medicine exploitation listings, the especially listing of Statins makes it by unfrequented.The sales volume of probucol can not be with
Statins compares, but it is known that in China and Japan still in slow increasing trend year by year.
At home, probucol and its tablet, when being that inventor herein takes service in former army's medicine enterprise, 1996, for the first time
It is imitative to grind U.S. variety and the successful norcholesterol chemical synthetic drug of declaration.The pharmacopeia for recording this product has, and United States Pharmacopeia 22 editions (1990
Year version), 23 editions (nineteen ninety-five version), 24 editions to 40 editions (version in 2000 to version in 2017)；Chinese Pharmacopoeia version in 2000,2005
Version, versions in 2010 and version in 2015；Japanese Pharmacopoeia 17 editions (version in 2016, also recorded granule)；Martindale's drug is complete works of
Its raw material and tablet are recorded always from 27 editions (version in 1977) to 35 editions (latest edition).These countries and mechanisms hereafter version before this
Pharmacopeia and drug complete works record situation, our company is unknown.
In recent years studies have shown that the intracorporal lipid of people is swallowed after oxidation by macrophage, form foam cells,
After foam cells is dead, it is adhered to the vascular wall of damage, forms atherosclerotic plaque.Probucol can be in lipid oxidation
Before damage and after having formed atherosclerotic plaque, by the formation of its inoxidizability prevention of arterial atherosclerotic plaque and make
Established fat plaque regression, so that atherosclerosis is prevented and treated, prevention and treatment cardiovascular and cerebrovascular obstruction.
Earlier studies have shown that the inoxidizability of probucol is 5~6 times of [Mao SJT of vitamin E
Etal.Arteriosclerosis, 1989；9:751a], later research then proves, inoxidizability can cause obviously anti-dynamic
Pulse atherosclerosis effect.
The discovery of Zhao Shui equality, probucol is while reducing cholesterol, it is also possible to be sent out by up-regulation heme oxygenase 1
Wave antioxidation, this may be its antiatherosclerosis important channel [Zhao Shui equality China artery sclerosis magazine,
2008；16 (6): 440~4].
It applies radiance etc. to study and discuss, the interaction and cholesterol transport between cyclophilin A and small recessed protein molecular are close
Correlation, after OX-LDL handles RAW264.7 cell 48h, the protein expression of cyclophilin A gradually weakens.Efficient liquid phase detection is intracellular
Cholesterol level, discovery are gradually increased with the extension for handling the time, the content of intracellular cholesteryl.Prompt OX-LDL to cell
Oxidative damage the expression of cyclophilin A may be made to lower, thus part inhibit cyclophilin A even small recessed albumen cholesterol turn
Transport function.And after being intervened with probucol, intracellular fat drips are significantly reduced, intracellular TC content by 456 ± 14mg/g reduce to
The ratio of 251 ± 14mg/g albumen, CE/TC is down to 32.9% ± 2.5% by 42.3% ± 5.9%, the egg of intracellular cyclophilin A
White expression increases by 81.3% ± 3.6% (the equal < 0.05 of P), has conspicuousness compared with OX-LDL group difference.Prompt probucol significant
Fight OX-LDL to the inhibiting effect of macrophage cyclophilin A, raise the expression of cyclophilin A, and alleviate OX-LDL damage after
The accumulation of macrophage inner cholesterol, the Macrophage derived RAW264.7 cell lotus esterification i.e. foamed mistake for delaying OX-LDL to induce
Journey [the China artery sclerosis magazine such as painting radiance, 2006；14 (4): 293~6].
Domestic more than 10 data that we retrieve, introduce Probucol independent clinical application some months to 2 years, disease
Example many cases from tens to 300, as a result obvious norcholesterol, stablize patch, inhibit coronary atherosclerosis and arteria carotis congee
Sample hardening reduces cardiovascular event, promotes neurological functional recovery, effective anti peroxidation of lipid, inhibition foam after acute cerebral infarction
Cell deposits in retina, and improving diabetic macular edema symptom than Atorvastatin has better clinical efficacy [seedling
High equal Aged in China magazine, 2013；The China such as the Wang Min of 33:4844~4845. circulation magazine, 2014；29 (1): 31~34.
The practical medicine of Zhang Xiaoyan China, 2014；9 (31): 77~78. kings are into equality China Dispensary, and 2014；25 (10): 908~910.
The world Gui Yumin, Zhao Ming ophthalmology magazine, 2014；14 (11): 2047~2053.].External " Japanese heart journal ", " U.S.'s heart
Dirty magazine ", 15 or more of the publications such as " United States cardiovascular magazine " totally 2000 many cases be substantially reduced about Probucol it is coronal
The report of Atheromatosis patient percutaneous transluminal coronary angioplasty (PTCA) restenosis afterwards, by Probucol antioxygen
The research for changing antiatherosclerosis is pushed to a new high.It is foremost be Montreal, CAN cardiac studies a series of researchs
Report: report double blind in 1997, multicenter, placebo, angioscope combination intravascular ultrasound inspection research, 317 angiopoiesis
Art patient starts medication, 500mg/ times for preoperative 1 month, 2 times a day, postoperative continuation medication 6 months, restenosis rate: probucol
Group is 20.7%, and probucol adds multi-vitamins group to be 28.9%, placebo 38.9%, and multi-vitamins group is
40.3%.Operability again: probucol group is 11.2%, joint group 16.2%, placebo 26.6%, vitamin group
It is 24.4%.The Libby professor of United States Medicine Tribune is in report published article comments of page 12 on the 4th of September in 1997: " this recent studies on
It is very encouraging, because it is to illustrate that drug has the first item of remarkable effect really to design well in terms of reducing restenosis
Clinical test ".Domestic cardiovascular specialist is also in the 6 editions researchs for having translated freely this respect on the 26th of August in 1999 of Chinese medicine Tribune.
The above research team proved that probucol has same purpose to heart thin vessels in 1998 again.Three articles after 1999
Prove the mechanism of action of restenosis after the anti-PTCA of probucol then to improve vascular remodeling [Anderson T J etal.N Engl
J Med, 1995；322 (8): 488~93.Anderson T J etal.Circulation, 1996；93 (9): 1647~
1650. high bridge are good for text .J Cardiol, and 1997；30:67.Lee Y J etal.Jpn Heart J, 1996；37:327~
332.Watanabe K etal, Am Heart J, 1996；132:23~29.Tardif TC etal.N Engl J Med,
1997；337:365~372.Tardif TC etal.Circulation, 1998；97:429. G et
Al.Circulation, 1999；99:30~35.Zakirova AN etal.Ter Arkn 1998；70 (1): 29~32.].
Aforesaid data proves that probucol independent medication has obvious study of anti-atherogenic effect, with Statins drug combination
Then effect is more preferable, and research report of the Tadateru Takayama of Nihon University medical board in the 68th association, section is sufficiently demonstrate,proved
This point is illustrated, A group takes Atorvastatin, daily 10mg；P group takes probucol, daily 500mg；A+P group takes atropic
Cut down statin and probucol.As a result: 6 months, intravascular ultrasound (IVUS) showed that A+P group is substantially reduced plaque volume, about
65%, p < 0.05；A group reduces about 15%；P group reduces about 20%.A+P group obviously increases cavity volume, about 80%, p < 0.05；A
Increase about 40% with P group.The patch echo of P group and A+P group obviously increases, and A+P group (about 90%) is greater than P group (about
30%), this two groups equal p < 0.05.After treatment, the lipid pool of A+P group disappears, and probucol and Atorvastatin drug combination can
It eliminates and stablizes atherosclerotic plaque.Both at home and abroad during 2007 to 2018, more than 30 Research Literature introductions are shared
Probucol, Statins (Atorvastatin, Simvastatin, Rosuvastatin etc.) two or bright with aspirin three-drug therapy
It shows anti-inflammatory, resisting cardiovascular atherosclerosis, reduces cardiocerebrovasculaevents events, is hypoglycemic.Case load from tens to 562,
Follow up time longest 10 years.Its mechanism of action have reduce cardiac-cerebral ischemia blood stream of patients become in whole blood height cut viscosity, cut in whole blood
Viscosity, whole blood undercut viscosity and plasma viscosity improve deformable index, so as to improve microcirculation；Reduce Vulnerable plaque
Number, increase stablize patch number；The formation for reducing LDL, inhibiting ox-LDL, the lipoprotein reduced in blood circulation are related
Property phospholipase A2 (Lp-PLA2) it is horizontal, especially approach such as inhibition macrophages secrete Lp-PLA2；From multi-faceted, multiple target point
To study of anti-atherogenic effect, there is the secondary prevention atherosclerosis the authors suggested that as ischemic heart infarction and cerebral apoplexy
New therapy approach.Separately there are some researches prove probucol and Cilostazol drug combination can reduce cardiovascular event danger
[Bonpei Takase et al.Med Princ Pract 2014；23:59~65.], the Asia multicenter of 1534 patients,
Randomized controlled trial then further proves, probucol is used in conjunction with aspirin or Cilostazol, painstaking effort can be effectively reduced and run affairs
Part, and Small side effects [Neurology.2018:509~518 The Lancet].
Study of anti-atherogenic effect described above, either independent medication or drug combination are Probucol
The effect of agent, and the vivo biodistribution availability of the dosage form only has 2~8%, the reason is that its water solubility is small, if dosage changing form improves it
Can water-soluble and bioavilability, the effect of this antiatherosclerosis, the fatty patch that disappears increase?
Hydrophobic drug, which improves water solubility, can two methods: chemical structure transformation and modified form.Because both at home and abroad also without general
It spreads out and examines fruitful modified form preparation listing, and chemical structure retrofit work time-consuming, high funds higher compared with modified form,
High risk, therefore, our company determines that the modified form work for first doing probucol, chemical structure transformation carry out after.
Modified form mainly has: solid dispersion technology, cyclodextrin inclusion technique, co-rotational procedure, superfine communication technique, suction
Receive promotor technology etc..In recent years, the fast development of nanotechnology is that the oral administration biaavailability of raising insoluble drug is continuous
New strategy is provided.Drug is made by nanometer formulation using nanotechnology, is had the advantage that
1. size of pharmaceutical particles can be reduced, increase specific surface area, to improve the solubility or dissolution of insoluble drug
Speed (Noyes-whitney equation).
2. granularity decline and specific surface area increase so that medicament nano granule can promote nanometer system with certain adhesiveness
Contact of the agent with biomembrane can extend drug and increase drug in the absorption of gastrointestinal tract in the residence time of gastrointestinal tract, and then improve
Drug oral bioavilability.
3. the stability of drug in the gastrointestinal tract also can be improved in nanometer formulation, the shadow of gastrointestinal tract complex physiologic environment is reduced
It rings.
4. the water-wet behavior on nanometer formulation surface can promote it to diffuse through mucomembranous surface hydrostatic-layer, and then increase drug and inhale
Receive etc..
Currently, the nano medicament carrying system for improving insoluble drug oral absorption mainly has nano suspension, polymer
Nanoparticle, liposome nanometer carrier, nano-micelle, nano-emulsion, nanocrystal, inorganic nano material and organic/inorganic is compound receives
Rice drug-loading system etc..
The above content is mostly data in studying, and really listing is for clinic person and few, Juan etc. describe partially on
City lipid nanometer formulation [Zhang Juan, Zhang Na Chinese Journal of New Drugs and Clinical Remedies, 2012；31 (4): 188~193.]:
Existing probucol modified form work can substantially be summarized as following a few classes:
Solid dispersions
Probucol, SDS, PVP K17 ternary grind mixture good absorbing [A Pongpeerapat et altogether
Al.International Journal of Pharmaceutics, 2008；352:309~316].It is ground altogether in conjunction with spray drying
More favorable for absorption [Takeshi Io et al.Mol Pharm, 2010；7 (1): 299].Probucol and methacrylic acid-first
Base methyl acrylate polymer and lauryl sodium sulfate grind mixture water solubility, dissolution rate, simulation gut cell membrane infiltration work altogether
With good, it is insoluble in stomach do not absorb [T Fukami et al.MOLECULAR PHARMACEUTICS, 2009；6 (3): 1029~
1035].Spray drying process can be used for the solid dispersions of probucol Yu PVP-K30 amorphous powder.PVP-K30 to PLBK without
Setting crystal form has stabilization, not plycrystalline diamond.Probucol from 1: 2~1: 9: the dissolution rate of PVP-K30 solid dispersions is more next
It is bigger, dissolution improve be attributed to the formation of probucol metamict crystals, the presence of polymer, particle become smaller [P Thybo et
Al.Pharmaceutical Development and Technology, 2008；13:375~386].1: 9 weight ratio it is general
It spreads out and examines and PVP solid dispersions 5 months stabilizations of room temperature.The dispersion AUC of 15mg probucol is equivalent to that 500mg is general to be spreaded out
Examine piece [Kubo Y et al.Yakugaku Zasshi, 2011；131 (4): 629~634.Y KUBO et al.Biol
Pharm Bull, 2009；32 (11): 1880~1884].
Emulsion
Probucol galactoside emulsion is incorporated into probucol in hepatic parenchymal cells by surface of hepatocytes receptor,
Galactoside emulsion injection acts on more excellent [E lshida et compared with the liver cell targeting of its liposome
Al.Pharmaceutical Research, 2004；21 (6) 932~939].
Microemulsion
Hydrophobic drug probucol is dissolved in methylene chloride, is added drop-wise in chitosan-acetic acid solution, O/W micro emulsion is formed
Sodium tripolyphosphate (TPP) solution is slowly added dropwise in liquid at room temperature, is cross-linked to form the chitin nanometer of load probucol.It sees
Examine its general characteristic, calculate drugloading rate and encapsulation rate, and in analogue body condition research probucol chitin nanometer body
Outer release characteristics.Chitin nanometer has good slow releasing function to probucol, for part intravenous injection or bracket
Coating administration, makes drug in lesions position slow release, new long-acting approach [Gao Li is provided for Probucol In Treatment restenosis
Equal Chinese Journal of New Drugs, 2009；18 (19): 1892~1896].
Nano suspension
Drug form is spherical in probucol self-assembled nanometer suspension, and drugloading rate is 101.04mg mL-1, partial size
For 364.9nm, zeta potential is -24.1mV；Through influence factor and stability experiment it is found that nano dry milk liquid has good stability；Blood medicine
Peak concentration improve 290% compared with tablet [the Chinese Pharmaceutical Journal such as Lv Shoulei, 2010；45 (21): 1634~1638].Alkyl
The hydrocarbon chain length of sodium sulphate has an impact to the formation of probucol nanoparticle, and influence sequence is: C18S > C16S > C12S
> C8S > C6S.More stable [the Wanawongthai C et al.Int J of the bigger probucol nanoparticle of amount of surfactant
Pharm, 2009；376 (1~2): 169~75].Jiang Shijun monodisperse self-assembled nanometer suspension improves general sieve of insoluble drug
Cloth examines the research of oral administration biaavailability, Master's thesis, East China University of Science's pharmaceutical engineering and technology specialty, December 20 in 2011
Day finalizes a text.Precision weighs the surfactant such as surfactant A and drug probucol (80: 40, w/w) of recipe quantity, is placed in
In 50ml round-bottomed flask, appropriate dehydrated alcohol is added, ultrasound makes it completely dissolved, and rotary evaporation is depressurized under 37 DEG C of water bath conditions and is removed
Organic solvent is removed, the ultrapure water that 2ml is preheated to 37 DEG C is then added, aquation is shaken in 37 DEG C of water-baths to get single point of probucol
Dissipate self-assembled nanometer suspension, freeze-drying.Bioavilability significantly improves.2017/0119660 A1 fat-soluble medicine of US is dissolved in third
Alcohol, acetone, poloxamer188, sorbierite, NaCMC etc. are dissolved in water, organic liquor certain revolving speed at a temperature of be added dropwise to aqueous,
Homogeneous latex emulsion is formed, spray drying does capsule, piece etc., improves and absorbs.CN201010563283 with CN201110398548 two 2014
The Introduction To Cn Patent nanometer formulation of probucol of year authorization.
Self-micro emulsifying medicament delivery system
Best prescription group become self-emulsifying microemulsion matrix (isopropyl myristate: Cremophor EL: La-brasol=30:
And probucol 15% 52.5: 17.5).Self-micro emulsifying medicament delivery system (SMEDDS) can significantly improve probucol In Vitro Dissolution
Degree, increase rat it is intracorporal absorb [such as Ma Lili China Medicine University journal, 2009；40 (1): 41~46].Olive in prescription
Olive oil accounts for oily Phase Proportion, oil mutually account for prescription ratio and surfactant and cosurfactant ratio be respectively 0.33,0.5 and
It is more excellent prescription when 2.0.Probucol self-emulsifying microemulsion can be quickly and easily obtained using Star point design-effect surface optimization
The more excellent prescription of drug delivery system, the model prediction established are good.[such as Wu Juan Fudan Journal (medicine), 2010；37
(1): 63~67].
Quantitative study
A Zaghloul et al is mentioned by blood concentration in In Vitro Dissolution and internal blood concentration relational model predictor
Out quantitative design, preparation, analysis optimize from microemulsion prescription method [A Zaghloul et al.Pharmazie, 2008；
63:654~660].Pass through blood concentration [D G Fatouros in In Vitro Dissolution and internal blood concentration relational model predictor
Et al.European Journal of Pharmaceutics and Biopharmaceutics, 2008；69:887~
898]。
The present inventor's work
After the present inventor declares successfully probucol raw material and piece at home, Probucol clathrate, solid dispersion were done
The research of body, emulsion, inclusion compound primary total dosage due to auxiliary material amount is big is excessive and abandons, and solid dispersions and emulsion are because steady
Qualitative condition requires harshness not to be further continued for studying.
Though above-mentioned all researchs are made into certain dosage form, also remote with a distance from clinical application.
Probucol raw material is white or off-white color crystalline powder；It is water-soluble: 2~5ng/ml [N Yagi et
Al.Chem Pharm Bull, 1996；44 (1): 241~244.]；Crystal form: having two kinds of crystal forms of crystal form I and II, in placement process
Crystal form II is automatically converted to crystal form I, crystal form I fusing point: 125 DEG C, 116 DEG C of crystal form II [J J Gerber et al.Journal
Of Crystallographic and Spectroscopic Research, 1993；23 (11): 863~869.]；Biological medicament
Agent credit class: II class [[H Uchiyama et al.European Journal of Pharmaceutics and
Biopharmaceutics 2010；76:238~244.].
The mouth medication of former piece are as follows: 500mg each time, twice daily, with meal with clothes；It releases immediately；Absorptivity are as follows: 2
~8%；It is distributed mainly in lipoprotein and adipose tissue.
Summary of the invention
The present invention provides a kind of probucol dried emulsifier composition, to increase the water solubility and preparation of lipophilic drugs probucol
In dissolution rate.
A second object of the present invention is to provide a kind of preparation method of probucol dried emulsifier composition, details exists
It is hereinafter described.
Third object of the present invention is to provide a kind of probucol dried emulsifier compositions to treat Atherosclerosis in preparation
Probucol bioavilability can be improved in the application of chemical drug object, the probucol dried emulsifier composition, enhances anti-atherogenic
Induration, prevention and treatment cardiovascular and cerebrovascular obstruction, reduces cardiocerebrovasculaevents events, and it is horizontal to improve the obstruction of clinical prevention cardiovascular and cerebrovascular.
Probucol dried emulsifier composition of the present invention includes hydrophilic emulsifying agent, lipophilic emulsifier, assistant for emulsifying agent, freezing
Drying protectant, probucol.
The hydrophilic emulsifying agent includes poloxamer188, gelatin, polyoxyethylene stearate (40) ester.
The lipophilic emulsifier includes glycerin monostearate, soybean lecithin powder, preferably glycerin monostearate.
The assistant for emulsifying agent includes glycerol, ethyl alcohol, preferred alcohol.
The freezing drying protective agent includes mannitol, glucose, sucrose, lactose, preferably mannitol, sucrose.
The 4.5%~5.3% of the total recipe quantity of gross mass Zhan of the hydrophilic emulsifying agent, preferably 4.5%~4.9%.
The 0%~14.2% of the total recipe quantity of gross mass Zhan of the lipophilic emulsifier.
The 71.9%~83.8% of the total recipe quantity of gross mass Zhan of the freezing drying protective agent, preferably 71.9%~
78.6%.
The total recipe quantity 9.3%~10.9% of the quality Zhan of the probucol, preferably 10.2%~10.9%.
In the hydrophilic emulsifying agent, poloxamer188, gelatin, polyoxyethylene stearate (40) ester mass ratio be 16.7:
3.3∶1。
In the freezing drying protective agent, mannitol, sucrose mass ratio be 1: 1.
The preparation method of dried emulsifier composition of the present invention the following steps are included:
(1) hydrophilic emulsifying agent being mixed with water, the volume number of water is 100~110 times of hydrophilic emulsifying agent total mass number,
Under 40 DEG C of water bath conditions, stirring and dissolving is transparent aqueous solution.
(2) 95% ethyl alcohol is added in probucol, lipophilic emulsifier, ethyl alcohol volume number is that probucol and lipophilic emulsify
10~20 times of agent gross mass.It 40 DEG C~50 DEG C of bath temperature, stirs to Quan Rong, obtains ethanol solution.
(3) under newborn even or stirring condition, the ethanol solution of heat preservation is slowly added dropwise in 40 DEG C of aqueous solutions.
(4) vacuum distillation ethyl alcohol to no alcohol taste, bath temperature is no more than 40 DEG C.
(5) freezing drying protective agent is added into vinasse, when necessary plus water, stirring to solid are all dissolved.
(6) white emulsion is distributed into medicine bottle, every bottle of 5ml or so respectively when mixing at any time, and every bottle of guarantee containing general
It spreads out and examines 100mg.
(7) it is freeze-dried, -20 DEG C to -40 DEG C of pre-freeze material, is determined according to eutectic point.
(8) vacuum is opened, if good lyophilized technique, -10 DEG C are run 5~8 hours, and 10 DEG C run 3~5 hours, 25 DEG C of operations 5
~8 hours, summer can be set higher than 5 DEG C of room temperature or so for last 1 hour.
The probucol dried emulsifier composition treats the application of atherosclerosis drug in preparation, its feature is as follows:
In the medicine bottle of the 100mg containing probucol, warm water 5ml or so is shaken up, and can be taken.
Atherosclerotic plaque is from I type to IV type with the presence of a large amount of macrophages, and fatty patch is exactly that macrophage is thin
Endocytosis has bitten a large amount of lipid oxides and has become foam wanshing, of the invention to pass through macrophage close to nanoscale dried emulsifier
Cell membrane plays the rouge that disappears, anti-oxidant to study of anti-atherogenic effect of its number of mechanisms.Va type patch: mainly it is rich in rouge
Matter should belong to instability mode patch, still have a large amount of macrophages in fibrous cap, reason is the same as I type to IV type.Vb type: mainly with calcification
Based on, dosage form of the present invention may can be allowed into the forms such as calcium salt by the way that anti-oxidant promotor lipoic acid is used in combination and disappear without effect
Except it.Vc type, mainly fibrous plaque should belong to stable type patch, and a large amount of collagen fibrous proteins are contained in fibrous cap, not soluble in water,
The dissolubility therefore novel form should surge, but cannot be too big.VI type patch is to avoid sending out by the basic recession of first five type patch
Raw.
Specific embodiment
By specific embodiment, technical scheme is described further, but the present invention is not limited in this
A little embodiments.
Embodiment 1: the preparation of probucol dried emulsifier composition
2.32g poloxamer188,0.464g gelatin, 0.139g polyoxyethylene stearate (40) ester, 6.032g probucol,
It is operated according to the preparation method of the probucol dried emulsifier composition, probucol dried emulsifier composition is obtained, with 20180107
For batch, 2.895 μm of average particle size.
Embodiment 2: the preparation of probucol dried emulsifier composition
2.32g poloxamer188,0.464g gelatin, 0.139g polyoxyethylene stearate (40) ester, 6.032g probucol,
3.675g glycerin monostearate operates according to the preparation method of the probucol dried emulsifier composition, it is dry to obtain probucol
Emulsion composition, for 20171205 batches, 3.72 μm of average particle size.
Embodiment 3: the preparation of probucol dried emulsifier composition
2.32g poloxamer188,0.464g gelatin, 0.139g polyoxyethylene stearate (40) ester, 6.032g probucol,
7.35g glycerin monostearate is operated according to the preparation method of the probucol dried emulsifier composition, obtains the dry cream of probucol
Agent composition, for 20180111 batches, 5.521 μm of average particle size.
Embodiment 4: the accelerated stability test data of probucol dried emulsifier composition
Embodiment 5: the bioavilability of probucol dried emulsifier composition
Male and healthy SD rat 17, weight 290g, continue within adaptive feeding one week to feed to weight up to 400~500g.
Oral Probucol and different probucol dried emulsifier compositions, in the intracorporal pharmaco-kinetic processes of rat, embodiment 1
The bioavilability point of composition described in the composition, embodiment 2, composition described in embodiment 3 relative to Probucol
It Yue Wei 99.75%, 104.88%, 228.11%.
Embodiment 6: the antiatherosclerosis test of probucol dried emulsifier composition
190 SD male rats, 180~200g of weight start to test after laboratory adapts to 4d.Experimental animal is by administration
Time handles and detects in three batches individual index, and every batch of is respectively divided into control group, model group (high lipid food group) and probucol
Piece, example 1 group close the administration group of object, 3 composition of 2 composition of embodiment and embodiment, and every group of 10 rats, remaining 10 are seen
Situation is shared in each group.In 1~3d that experiment starts, in addition to control group is fed with normal diet, other each group rat abdominal cavities
67.5 ten thousand/kg VitD3 is injected, 3d is continuously injected, with injection VitD3, starts to feed high lipid food, the feeding of first rat
High lipid food 2 months, stomach-filling gave 4 kinds drug 1 month；Second batch rat continues to give to high lipid food and gastric infusion 2 months
High lipid food 5 months, gastric infusion 3 months；Third batch rat continues to high lipid food and gastric infusion 1 month, i.e., to high in fat
Feed 6 months, gastric infusion 4 months.The dosage of gastric infusion according to the pharmacokinetic results of 4 kinds of drugs, Probucol,
Example 1 group closes object, 2 composition dosage of embodiment is 100mg/kg, and 66.7mg/kg is administered in 3 composition of embodiment, daily
Each gastric infusion is primary, and control group and model group rats are not administered.
It can be seen that first described animal according to the HE coloration result of the pathological section for the aorta being separated,
At high lipid food three months, administration one month, model group rats aorta wall obviously destroys necrosis, secondary calcium deposition.Four
In a medication group, example 1 group close object group active blood vessel wall have light damage and necrosis, other three medicine group aortas without
Significant change.Illustrate, at this point, study of anti-atherogenic effect occurs for Probucol.
The third batch animal, at high lipid food six months, when being administered four months, model group rats aorta wall was seriously broken
It is bad, there are a large amount of lipid gangrenosum acne substance, fibrous cap, cholesterol crystal, inflammatory cell infiltration, a small amount of foam cells, largely
Secondary calcium deposition.In four medication groups, the active blood vessel wall of 2 composition group of Probucol and embodiment has serious destruction
And adiponecrosis, example 1 group close the rat aorta of object group and 3 composition group of embodiment without significant change.One wouldn't energy
The phenomenon that explanation is, example 1 group closes that object group effect early period is bad, and anaphase effect is good, and 2 composition group of embodiment then just phase
Instead.What is certain is that Probucol is at high lipid food six months, study of anti-atherogenic effect be not enough to
The effect that the atherosclerotic plaque that disappears is formed, and probucol dried emulsifier composition of the invention can obviously subside artery congee
The formation of sample plaque.
Because first and third batch each group result can describe the problem, therefore second batch result no longer provides.
Oil red O stain detection liver cell steatosis test result supports the anti-of the probucol dried emulsifier composition
Atherosclerosis Trial result.
Research report of the Tadateru Takayama of Nihon University medical board in association, the 68th section prove, general sieve
Cloth, which is examined, can reduce intravascular fatty plaque volume about 20%, if probucol dried emulsifier composition of the invention can improve general sieve
Cloth examines 2~3 times of drug effect, then can reduce or substitute Stent and dredging vascellum, above-mentioned antiatherosclerosis test knot
Fruit explanation, the present invention have this may.
Claims (17)
1. a kind of probucol dried emulsifier composition, characterized in that the composition by hydrophilic emulsifying agent, lipophilic emulsifier,
Assistant for emulsifying agent, freezing drying protective agent, probucol composition.
2. a kind of probucol dried emulsifier composition according to claim 1, characterized in that the hydrophilic emulsifying agent packet
Include poloxamer188, gelatin, polyoxyethylene stearate (40) ester.
3. a kind of probucol dried emulsifier composition according to claim 1, characterized in that the lipophilic emulsifier packet
Include glycerin monostearate, soybean lecithin powder, preferably glycerin monostearate.
4. a kind of probucol dried emulsifier composition according to claim 1, characterized in that the assistant for emulsifying agent includes
Glycerol, ethyl alcohol, preferred alcohol.
5. a kind of probucol dried emulsifier composition according to claim 1, characterized in that the freeze-drying protection
Agent includes mannitol, glucose, sucrose, lactose, preferably mannitol, sucrose.
6. hydrophilic emulsifying agent according to claim 2, characterized in that the 4.5%~5.3% of the total recipe quantity of gross mass Zhan,
It is preferred that 4.5%~4.9%.
7. lipophilic emulsifier according to claim 3, characterized in that the 0%~11.72% of the total recipe quantity of gross mass Zhan,
It is preferred that 6.23%~11.72%.
8. freezing drying protective agent according to claim 5, characterized in that the 71.9% of the total recipe quantity of gross mass Zhan~
83.8%, preferably 71.9%~78.6%.
9. a kind of probucol dried emulsifier composition according to claim 1, characterized in that the quality Zhan of probucol is total
The 9.3%~10.9% of recipe quantity, preferably 10.2%~10.9%.
10. hydrophilic emulsifying agent according to claim 6, characterized in that poloxamer188, gelatin, polyoxyethylene stearate
(40) mass ratio of ester is 16.7: 3.3: 1.
11. freezing drying protective agent according to claim 8, characterized in that mannitol, sucrose mass ratio be 1: 1.
12. a kind of preparation method of probucol dried emulsifier composition, characterized in that the following steps are included:
(1) hydrophilic emulsifying agent is mixed with water, the volume number of water is 100~110 times of hydrophilic emulsifying agent total mass number, at 40 DEG C
Under water bath condition, stirring and dissolving is transparent aqueous solution；
(2) 95% ethyl alcohol is added in probucol, lipophilic emulsifier, ethyl alcohol volume number is that probucol and lipophilic emulsifier are total
10~20 times of quality, stir to Quan Rong, obtain transparent ethanol solution by 40 DEG C~50 DEG C of bath temperature；
(3) under newborn even or stirring condition, the ethanol solution of heat preservation is slowly added dropwise in 40 DEG C of aqueous solutions；
(4) vacuum distillation ethyl alcohol to no alcohol taste, bath temperature is no more than 40 DEG C；
(5) freezing drying protective agent is added into vinasse, when necessary plus water, stirring to solid are all dissolved；
(6) white emulsion is distributed into medicine bottle, every bottle of 5ml or so respectively when mixing at any time, guarantees that every bottle is spreaded out containing general
Examine 100mg；
(7) it is freeze-dried, -20 DEG C to -40 DEG C of pre-freeze material, is determined according to eutectic point；
(8) vacuum is opened, if good lyophilized technique, -10 DEG C are run 5~8 hours, and 10 DEG C run 3~5 hours, 25 DEG C of operations 5~8
Hour, summer can be set higher than 5 DEG C of room temperature or so for last 1 hour.
13. the dry cream of a kind of probucol that the preparation method of probucol dried emulsifier composition obtains as claimed in claim 12
Agent composition, characterized in that accelerated stability test 3 months, sample was stable.
14. a kind of probucol dried emulsifier composition is in the application of preparation treatment atherosclerosis drug.
15. a kind of probucol dried emulsifier composition as claimed in claim 14 is in preparation treatment atherosclerosis drug
Using use is characterized in, a dosage unit is a medicine bottle, and each medicine bottle 100mg containing probucol is direct in medicine bottle
Warm water 5ml or so, shakes up, and can take.
16. a kind of probucol dried emulsifier composition as claimed in claim 14 is in preparation treatment atherosclerosis drug
Using, characterized in that the composition reaches as high as 228.11% relative to the rat vivo biodistribution availability of Probucol.
17. a kind of probucol dried emulsifier composition as claimed in claim 14 is in preparation treatment atherosclerosis drug
Using, characterized in that composition of the rat vivo biodistribution availability up to 228.11% relative to Probucol, but be not limited to
The composition, the effect for preventing and treating experimental atherosclerosis in rats are remarkably reinforced compared with Probucol.
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Application publication date: 20190816 |