CN102716159A - Acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug - Google Patents
Acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug Download PDFInfo
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- CN102716159A CN102716159A CN2012102212994A CN201210221299A CN102716159A CN 102716159 A CN102716159 A CN 102716159A CN 2012102212994 A CN2012102212994 A CN 2012102212994A CN 201210221299 A CN201210221299 A CN 201210221299A CN 102716159 A CN102716159 A CN 102716159A
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Abstract
The invention discloses an oil-in-water type acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug. The antihypertensive drug comprises raw materials by mass percentage: 1%-20% of acebutolol hydrochloride, 15%-40% of surface active agents, 0-20% of cosurfactant, 1%-25% of celery oil and the balance distilled water, and the mass percent sum of the raw materials is 100%. The nanometer emulsion is small in emulsion droplet particle, even in distribution, small in viscosity and good in flowability. The nanometer emulsion organically combines water-solubility medicine acebutolol hydrochloride and liposoluble celery oil, and improves the dissolving and infiltration capacity of the celery oil and the stability and medical effect of the acebutolol hydrochloride. After the acebutolol hydrochloride and the celery oil are prepared into the nanometer emulsion, advantages of the acebutolol hydrochloride and the celery oil are combined, the antihypertensive effect is obviously improved, the half-life period of the drug is prolonged, and dosing time is reduced.
Description
Technical field
The invention belongs to field of medicaments, relate to the novel form of a kind of antihypertensive drug Acebutolol and Celery oil, particularly a kind of Acebutolol, Celery oil nano-emulsion antihypertensive drug.
Background technology
Acebutolol is N-[3-acetyl group-4-[2-hydroxyl-3-[(isopropyl) amino] propoxyl group] phenyl] (Acebutolol hydrochloride).CAS number: 34381-68-5.Molecular formula: C
18H
29ClN
2O
4Molecular weight: 372.89.Acebutolol is white to little yellow white crystals or a crystalline powder, odorless, bitter in the mouth.Soluble in water, methanol and glacial acetic acid are soluble in dehydrated alcohol slightly.
Acebutolol is a kind of selective-, has slight endogenous sympathomimetic amine activity simultaneously, in order to the treatment arrhythmia.Show that through laboratory animal these article possess heart β1-Shou Ti selectively acting, its antagonism is particularly evident by vasorelaxation action due to the isoproterenol (β 2) than antagonism by tachycardic effect due to the isoproterenol (β 1).This medicine has membrane stabilizing action when higher concentration.The conclusion of clinical use shows, when dosage usually, the β1-Shou Ti retardation of these article shows: heart rate and by tachycardia due to the motion when 1. slowing down tranquillization; Painstaking effort output when 2. reducing tranquillization and motion.
Celery oil, Herba Apii graveolentis contain tart antihypertensive compositions, and rabbit, dog intravenous injection are had obvious hypotensive effect.Clinical all effective for constitutional, gestational and climacteric hypertension.Isolated a kind of alkaline components has sedation to animal from seed of Herba Apii graveolentis, and people's physical ability is played stable effect, helps stable emotion, eliminates irritated.The contained blood pressure lowering of Herba Apii graveolentis, blood fat reducing composition butylphthalide, butylphthalide are one type of chemical compounds with sedation.At present, from Celery oil, extracted 5 kinds of these constituents, 3-n-butyl wherein-O-phthalic acyl lactone (3-n-butyl-phthalid) and Herba Apii graveolentis valeridin (Sedanolide) content in Herba Apii graveolentis are more, are 4 mg/litre.Animal test results shows that these two kinds of components have sedation to mice, and are also effective in cure to insomniac and neurastheniac.Research finds that also it is active that these two kinds of materials also have anti-cancer.The most noticeable is, 3-n-butyl-O-phthalic acyl lactone has the effect of vasodilator smooth muscle, and small artery resistance around reducing recovers vessel wall elasticity, microcirculation improvement, thus bring high blood pressure down.
Have the antihypertensive drugs of example hydrochloric acid acebutolol tablet now on the market; The use of Celery oil is also arranged, though can absorb not exclusively from gastrointestinal absorption after oral; The dissolution rate of medicine is slow in addition; Bioavailability is poor, and it is slow to add the Acebutolol effect, makes the drug effect of Acebutolol and Celery oil to be fully used.
Summary of the invention
To the shortcomings and deficiencies that exist in the prior art; The object of the present invention is to provide a kind of can the water soluble drug Acebutolol and the fat-soluble Celery oil of efficient blood pressure lowering being combined, and drug distribution evenly, good stability, permeability is high, dissolubility is good, bioavailability is high Acebutolol, Celery oil nano-emulsion antihypertensive drug.
The technical scheme that realizes the foregoing invention purpose is: a kind of Acebutolol, Celery oil nano-emulsion antihypertensive drug, the particle diameter that it is characterized in that this medicine are between 15.7～55.1nm, and mean diameter is 33.6nm, and its raw material and each raw materials quality percentage ratio are:
Acebutolol 1%～20%
Surfactant 15%～40%
Cosurfactant 0～20%
Celery oil 1%～25%
All the other compositions are distilled water, and the mass percent sum of above-mentioned raw materials is 100%.
Described surfactant be in polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or the poloxamer 188 any one or with the mixture of span80, these surfactants are to human body low toxicity, safe, non-stimulated.
Described cosurfactant is a dehydrated alcohol, 1, the mixture of any one or a few in 2-propylene glycol, PEG400 or the glycerin.
The present invention adds bland cosurfactant such as ethanol, 1 in medicine; 2-propylene glycol, glycerin or PEG400; Except the hydrotropy effect; Cosurfactant mainly is in order to adjust HLB VALUE OF SURFACTANTS (HLB), to make oil water interfacial tension further reduce, increasing the profit property and the rigidity of limitans.Cosurfactant is incorporated in the interfacial film, promotes the very formation of membranelle of radius of curvature, enlarges the breast district area of nano-emulsion.
A kind of Acebutolol of the present invention, the administration of Celery oil nano-emulsion administered through oral; Improved the dissolubility of Celery oil greatly; Reduce medicine first pass effect in vivo; Promote Celery oil gastrointestinal absorption, and novelty water soluble drug and fat-soluble medicine are organically combined, improved the treatment ability of medicine.Celery oil is fat-soluble vegetable oil, and human body is to the transhipment of medicine and absorb extremely difficultly, and nano-emulsion substrate is that Celery oil provides good dissolving environment, can absorb through lymph when oral, the barrier when overcoming first pass effect and molecule through gastrointestinal tract.Through adding Celery oil, also improved the blood pressure lowering ability of Acebutolol on the other hand, make that blood pressure lowering is more stable, better effects if.
Acebutolol of the present invention, Celery oil nano-emulsion compared with prior art have the following advantages:
1. the diameter of aspirin particle of Acebutolol of the present invention, Celery oil resisting hypertension nano-emulsion is between 15.7～55.1nm; Mean diameter is 33.6nm; Be with adding surfactant and cosurfactant in the Celery oil, being titrated to even, transparent nano-emulsion system with the distilled water that is dissolved with Acebutolol.The hydrochloric acebutolol of nano-emulsion that forms reaches more than 8.3%, and Celery oil reaches more than 9.4%.
2. Acebutolol of the present invention, Celery oil resisting hypertension nano-emulsion are evenly distributed, and transparent, the good stability of system has lower surface tension, has good flowability, taking convenience.
3. engulfed by reticuloendothelial cell rapidly after Acebutolol of the present invention, the administration of Celery oil resisting hypertension nano-emulsion; Make the rapid onset of medicine; And keep constant blood drug level and pharmacodynamics effect, and improve bioavailability of medicament, strengthen drug effect, reduce amount of drug and access times.
4. Acebutolol of the present invention, Celery oil resisting hypertension nano-emulsion efficacy stability, it is low to consume energy.
5. the present invention processes and can be made into oral liquid behind the nano-emulsion and directly take, also can seal or through processing such as lyophilized powder technology through capsule.
The specific embodiment
The inventor provides concrete method for preparing embodiment and uses the test of pesticide effectiveness to further specify the effect of medicine of the present invention.
Test Example 1 Acebutolol of the present invention, Celery oil nano-emulsion antihypertensive drug size are analyzed
The present invention detects through transmission electron microscope, and drop type of being is spherical, good dispersion, no adhesion.Detect its diameter Distribution between 15.7～55.1nm through the Ma Erwen Particle Size Analyzer, mean diameter is 33.6nm.
Test Example 2 Acebutolols of the present invention, the stability analysis of Celery oil nano-emulsion antihypertensive drug
Whether through the stability that Acebutolol of the present invention, Celery oil nano-emulsion antihypertensive drug are observed in following centrifugal test, light stability test, temperature stability test etc., observing the present invention has layering, muddiness or crystal wild effect such as to separate out.
1. high speed centrifugation test
Get the Acebutolol of the present invention for preparing in right amount, Celery oil nano-emulsion antihypertensive drug in centrifuge tube; With centrifugal 10 min of the rotating speed of 15 000r/min; After the centrifugal test; Acebutolol of the present invention, Celery oil nano-emulsion antihypertensive drug still keep the clear before centrifugal, wild effect such as do not see that layering, muddiness or crystal are separated out.
2. light stability test
The Acebutolol for preparing in right amount, Celery oil nano-emulsion antihypertensive drug are packed in transparent good colourless, the transparent vial, and sealing is positioned over 10d under the normal illumination condition, respectively at 1d, 2d, 4d, 6d, 8d, the 10d observation of taking a sample.The result shows that Acebutolol, the every duplicate samples of Celery oil nano-emulsion antihypertensive drug all keep clear, wild effect such as do not see that layering, muddiness or crystal are separated out.
3. temperature stability test
The Acebutolol for preparing in right amount, Celery oil nano-emulsion antihypertensive drug are packed in the good flint glass bottle of transparency, sealing, be positioned over 4 ℃, room temperature (25 ℃) with 40 ℃ three in keep sample under the temperature conditions and investigate each 30d, every at a distance from 5d sampling observation.The result shows that Acebutolol, Celery oil nano-emulsion antihypertensive drug all keep clear under these three kinds of temperature conditions, wild effect such as do not see that layering, muddiness or crystal are separated out.
4. long-term stable experiment
3 batches of nano-emulsions are sealed in the Brown Glass Brown glass bottles and jars only; Placed (25 ± 2) ℃, relative humidity (60 ± 5) % condition following 12 months; Respectively at 0,3,6,9 and time sampling in 12 months; Investigate the character and the changes of contents of nano-emulsion, and the list of references statistical analysis technique, the effect duration of calculating Acebutolol, Celery oil nano-emulsion antihypertensive drug.Result of the test is illustrated under the long term test condition, and the outward appearance of Acebutolol, Celery oil nano-emulsion antihypertensive drug keeps clear and bright, homogeneous always, does not see phenomenons such as layering, complexion changed, flocculation and breakdown of emulsion; Acebutolol in the system and Celery oil content prolong in time and reduce gradually; The equation of linear regression that its content-time changing curve provides, the effect duration that calculates Acebutolol, Celery oil nano-emulsion antihypertensive drug is 38.15 months (is standard with time weak point person).
Test Example 3 rat tails manometrys are measured the drug effect (with Celery oil and the contrast of commercially available Acebutolol sheet) of Acebutolol of the present invention, Celery oil nano-emulsion antihypertensive drug (embodiment 1)
40 of SHR rats are divided into 4 groups at random, 10 every group, are made as the Acebutolol sheet respectively; The Herba Apii graveolentis line of oils; Acebutolol, Celery oil nano-emulsion group and positive blank control group, first three groups give Acebutolol sheet suspension, Celery oil and Acebutolol, each 15mg/kgd of Celery oil nano-emulsion respectively, are dissolved in administration in the drinking-water; 1 time/d, continuous 12 weeks.10 of WKY rats are the normal control group, and 10 positive controls of SHR rat are not given medicine, normal drinking-water.
Measure and respectively organize rat arteria caudalis blood pressure.(before the medication) pressure measurement was 1 time when Mus was 6 weeks age, and blood pressure is surveyed in Mus 7 weeks of age (1 week after the medication) pressure measurement 1 time later on week about 1 time, finished up to experiment.The result sees table 1.
Table 1 respectively organize rat SBP comparison (x ± s, n=10)
| Group | Systolic pressure (mmHg) |
| Positive control | 199.2±12.4 |
| The Acebutolol sheet | 144.1±11.3 |
| Celery oil | 171.2±12.6 |
| Acebutolol, Celery oil nano-emulsion | 130.6±8.1 |
| WKY normal control group | 126.1±8.4 |
The result shows; Acebutolol, Celery oil nano-emulsion and positive controls, Acebutolol sheet and Herba Apii graveolentis line of oils are relatively; Difference is all extremely remarkable; Show that Acebutolol not only can significantly reduce the blood pressure of positive rat, and antihypertensive effect and commercially available Acebutolol sheet compare effect with Celery oil more remarkable.
Test Example 4 toxicity tests
1. toxicological study project and conclusion:
Medicine of the present invention is in strict accordance with non-clinical safety evaluation methodology of new drug and commercially available Acebutolol tablet contrast having carried out acute toxicity test; Repeat administration toxicity test, genetic toxicity test (comprising Ames test, mouse bone marrow cells micronucleus test, the test of In vitro culture mammalian cell chromosome mutation), reproductive toxicity test (general reproductive toxicity test, sensitive period to teratogenic agent toxicity test, perinatal toxicity test), carcinogenic test, immunotoxicity test and local irritation test, result of the test is following.
Medicine of the present invention is to chmice acute toxicity test conclusion: with commercially available Acebutolol tablet contrast, untoward reaction and death in measuring does not appear in Acebutolol, Celery oil nano-emulsion.
The result of genetic toxicity tests such as the Salmonella reversion test of medicine of the present invention, mouse sperm deformity test and testicular chromosome aberration test is all negative.
The result that rat 30d feeds product of the present invention shows: with commercially available Acebutolol tablet contrast; In experimental period; Each experimental group animal growth is good in Acebutolol, the metering of Celery oil nano-emulsion; All in normal range, histopathologic examination is no abnormality seen also for indexs such as body weight, food ration, routine blood test, blood biochemistry, organ coefficient.
Medicine long term toxicity test conclusion of the present invention: with commercially available Acebutolol tablet contrast; In experimental period; In Acebutolol, the metering of Celery oil nano-emulsion; This medicine was not seen the rat untoward reaction in three months at continuous gastric infusion, and all in normal range, its main organs of pathologic finding and target organ do not see that all the toxic pathology that this guiding drug rises changes to each item inspection index.
Test Example 5 pharmacokinetics
Result of the test shows that Acebutolol of the present invention, Celery oil resisting hypertension nanoemulsion medicine (embodiment 1) oral absorption rate are 87%, and first pass effect is 15%, and bioavailability is 73%; Metabolic rate is 76%, and plasma protein binding rate is 85%, and oral back plasma drug level peak time is 1h; T1/2 is 7h, and distribution volume is 3L/kg, can be distributed to each one of health widely; Can see through placental barrier, also can secrete in milk, in the less entering brain.Blood, main metabolites are diacetolol.This metabolite has the beta receptor blocking effect that equates with acebutolol, and its t1/2 is 12h.36h behind 1 oral article, the concentration of diacetolol is 13 times of parent in the blood.Two kinds of materials all can be secreted in bile, and enterohepatic circulation is all arranged.In these article of intravenous injection 48h, the 25-60% that injection rate arranged approximately with original shape through renal excretion.
Embodiment 1
Accurately take by weighing Celery oil 9.4g, EL40 28g and ethanol 4g and under room temperature (25 ℃) condition, stir, then to wherein slowly splashing into the distilled water that is dissolved with Acebutolol.Increase along with the distillation water yield; The system stickiness increases; When the amount that adds distilled water makes system become the oil-in-water type nano-emulsion by Water-In-Oil; The system viscosity is thinning from the most heavy-gravity state, and what produced this moment promptly is water white Acebutolol, Celery oil nano-emulsion, and the amount that add entry this moment is that 50.3g, Acebutolol are 8.3g.This ratio is the optimal proportion of Acebutolol, Celery oil resisting hypertension nano-emulsion.
Following examples step is with embodiment 1:
Embodiment 2
Celery oil 10.1g, EL40 25g, 1,2-propylene glycol 15g, the amount of water is 45.3g, Acebutolol is 4.6g.
Embodiment 3
Celery oil 9.1g, RH40 20g, glycerin 10g, the amount of water is 52g, Acebutolol is 8.9g.
Embodiment 4
Celery oil 9.5g, RH40 20g, ethanol 15g, the amount of water is 48.5g, Acebutolol is 7g.
Embodiment 5
Celery oil 8.1g, Tween 80 18g, glycerin 6g, the amount of water is 56.8g, Acebutolol is 11.1g.
Embodiment 6
Celery oil 9.2g, Tween 80 27g, PEG400 9g, the amount of water is 48g, Acebutolol is 6.8g.
Embodiment 7
Celery oil 15g, EL40 20g, span80 10g, the amount of water is 50g, Acebutolol 5g.
Embodiment 8
Celery oil 10g, RH40 25g, span80 5g, the amount of water is 45g, 1,2-propylene glycol 5g, Acebutolol 10g.
Embodiment 9
Celery oil 5g, Tween 80 20g, span80 10g, the amount of water is 45g, PEG400 5g, Acebutolol 15g.
Embodiment 10
Celery oil 1g, poloxamer 188 20g, span80 5g, glycerin 5g, the amount of water is 49g, Acebutolol 20g.
Embodiment 11
Celery oil 25g, EL40 25g, the amount of water is 44g, PEG400 3g, glycerin 2g, Acebutolol 1g.
Claims (2)
1. a water bag type Acebutolol, Celery oil nano-emulsion antihypertensive drug is characterized in that its raw material and mass percent thereof are:
Acebutolol 1%～20%
Surfactant 15%～40%
Cosurfactant 0～20%
Celery oil 1%～25%
All the other compositions are distilled water, and the mass percent sum of above-mentioned raw materials is 100%;
Described surfactant be in polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or the poloxamer 188 any one or with the mixture of span80;
Described cosurfactant is a dehydrated alcohol, 1, the mixture of any one or a few in 2-propylene glycol, PEG400 or the glycerin.
2. a kind of Acebutolol according to claim 1, Celery oil nano-emulsion antihypertensive drug is characterized in that the particle diameter of this medicine is between 15.7～55.1nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102212994A CN102716159A (en) | 2012-06-30 | 2012-06-30 | Acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102212994A CN102716159A (en) | 2012-06-30 | 2012-06-30 | Acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug |
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|---|---|
| CN102716159A true CN102716159A (en) | 2012-10-10 |
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| CN2012102212994A Pending CN102716159A (en) | 2012-06-30 | 2012-06-30 | Acebutolol hydrochloride and celery oil nanometer emulsion antihypertensive drug |
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Application publication date: 20121010 |