CN102727721A - Benazepril hydrochloride-hyacinth oil nanoemulsion antihypertensive drug - Google Patents
Benazepril hydrochloride-hyacinth oil nanoemulsion antihypertensive drug Download PDFInfo
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- CN102727721A CN102727721A CN2012102212975A CN201210221297A CN102727721A CN 102727721 A CN102727721 A CN 102727721A CN 2012102212975 A CN2012102212975 A CN 2012102212975A CN 201210221297 A CN201210221297 A CN 201210221297A CN 102727721 A CN102727721 A CN 102727721A
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- benazepril hydrochloride
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Abstract
The invention discloses a benazepril hydrochloride-hyacinth oil nanoemulsion antihypertensive drug. Raw materials for the drug comprise, by mass percentage, 1% to 18% of benazepril hydrochloride, 15% to 40% of surfactant, 0 to 20% of cosurfactant and 1% to 20% hyacinth oil, with the balance being distilled water, wherein the sum of the mass percentage of the raw materials is 100%. Nanoemulsion provided in the invention has small and uniformly-distributed emulsion droplet particles, low viscosity and good fluidity. In the dosage form of nanoemulsion, the water-soluble drug benazepril hydrochloride and fat-soluble hyacinth oil are organically combined together, which improves the solubility and permeability of hyacinth oil and the stability and efficacy of benazepril hydrochloride. When the dosage form of nanoemulsion is prepared from benazepril hydrochloride and hyacinth oil, the advantages of both benazepril hydrochloride and hyacinth oil are combined; therefore, an antihypertensive effect of the drug provided in the invention is obviously improved, the half-life of the drug is prolonged, and administration frequency is reduced.
Description
Technical field
The invention belongs to field of medicaments, relate to the novel form of a kind of antihypertensive drug benazepril hydrochloride and hyacinth oil, particularly a kind of benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug.
Background technology
[0002] benazepril hydrochloride (Benazepril HCL).CAS number: 86541-74-4.Molecular formula: C
24H
29ClN
2O
5, molecular weight: 460.95.
Benazepril hydrochloride is an angiotensin-convertion enzyme inhibitor.Form energetic benazeprilat after the hydrolysis, become a kind of emulative angiotensin converting enzyme inhibitor, the prevention angiotensin i-converting is an Angiotensin II; Vascular resistance is reduced; The aldosterone secretion reduces, and plasma renin activity increases, but does not cause the compensatory fluid retention; Also can alleviate ventricular afterload, not speed heart rate.Benazeprilat also lowers cardiac load: these article expansion artery and vein; Reduce peripheral vascular resistance or cardiac afterload, reduce PC embedding pressure or cardiac preload, also reduce pulmonary vascular resistance; Thereby improve cardiac output, make exercise tolerance and time lengthening.And suppress the degraded of Kallidin I, vascular resistance is reduced, produce hypotensive effect.Can improve left ventricular hypertrophy, improve the diabetic sugar tolerance.
Be rich in cinnamic aldehyde in the hyacinth oil, cinnamic aldehyde.Cinnamic aldehyde has cis and trans two kinds of isomers, and no matter existing commercial cinnamic aldehyde is natural or synthetic cinnamic aldehyde, all is trans body.Cinnamic aldehyde, 3-phenyl-2-acrylic aldehyde (Cinnamic aldehyde).Structural formula: C
6H
5CHCHCHO.Molecular weight: 132.16.Be colourless or weak yellow liquid.Fragrance: the fragrance of intensive Oleum Cinnamomi and Oleum Cinnamomi is arranged, gentle hot fragrance breath, the pungent that do not have, fragrance is lasting strongly.Cinnamic aldehyde is strong clearly than cinnamic alcohol fragrance.Be insoluble in water, glycerol and oil alcohol, be soluble in alcohol, the ether.Can volatilize with steam.Unstable in highly acid or strongly basic medium, be prone to cause variable color, in air, be prone to oxidation.Blood vessel dilating and hypotensive effect.Adrenal cortex property hypertension there is hypotensive effect.
Have the antihypertensive drugs of example hydrochloric acid benazepril tablet now on the market; The use of hyacinth 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 benazepril hydrochloride effect, makes the drug effect of benazepril hydrochloride and hyacinth 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 benazepril hydrochloride and the fat-soluble hyacinth oil of efficient blood pressure lowering being combined, and drug distribution evenly, good stability, permeability is high, dissolubility is good, bioavailability is high benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug.
The technical scheme that realizes the foregoing invention purpose is: a kind of benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug; The particle diameter that it is characterized in that this medicine is between 25.1～62.4nm; Mean diameter is 48.2nm, and its raw material and each raw materials quality percentage ratio are:
Benazepril hydrochloride 1%～18%
Surfactant 15%～40%
Cosurfactant 0～20%
Hyacinth oil 1%～20%
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 benazepril hydrochloride of the present invention, the administration of hyacinth oil nano-emulsion administered through oral; Improved the dissolubility of hyacinth oil greatly; Reduce medicine first pass effect in vivo; Promote hyacinth oil gastrointestinal absorption, and novelty water soluble drug and fat-soluble medicine are organically combined, improved the treatment ability of medicine.Hyacinth 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 hyacinth 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 hyacinth oil, also improved the blood pressure lowering ability of benazepril hydrochloride on the other hand, make that blood pressure lowering is more stable, better effects if.
Benazepril hydrochloride of the present invention, hyacinth oil nano-emulsion compared with prior art have the following advantages:
1. the diameter of aspirin particle of benazepril hydrochloride of the present invention, hyacinth oil resisting hypertension nano-emulsion is between 25.1～62.4nm; Mean diameter is 48.2nm; Be with adding surfactant and cosurfactant in the hyacinth oil, being titrated to even, transparent nano-emulsion system with the distilled water that is dissolved with benazepril hydrochloride.The hydrochloric benazepril of nano-emulsion that forms reaches more than 8%, and hyacinth oil reaches more than 9.8%.
2. benazepril hydrochloride of the present invention, hyacinth 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 benazepril hydrochloride of the present invention, the administration of hyacinth 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. benazepril hydrochloride of the present invention, hyacinth 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 benazepril hydrochloride of the present invention, hyacinth 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 25.1～62.4nm through the Ma Erwen Particle Size Analyzer, mean diameter is 48.2nm.
Test Example 2 benazepril hydrochlorides of the present invention, the stability analysis of hyacinth oil nano-emulsion antihypertensive drug
Whether through the stability that benazepril hydrochloride of the present invention, hyacinth 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 benazepril hydrochloride of the present invention for preparing in right amount, hyacinth oil nano-emulsion antihypertensive drug in centrifuge tube; With centrifugal 10 min of the rotating speed of 15 000r/min; After the centrifugal test; Benazepril hydrochloride of the present invention, hyacinth 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 benazepril hydrochloride for preparing in right amount, hyacinth 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 benazepril hydrochloride, the every duplicate samples of hyacinth 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 benazepril hydrochloride for preparing in right amount, hyacinth 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 benazepril hydrochloride, hyacinth 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 benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug.Result of the test is illustrated under the long term test condition, and the outward appearance of benazepril hydrochloride, hyacinth 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; Benazepril hydrochloride in the system and hyacinth 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 benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug is 37.15 months (is standard with time weak point person).
Test Example 3 rat tails manometrys are measured the drug effect (with hyacinth oil and the contrast of commercially available Benazepril hydrochloride contents in tablets) of benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug (embodiment 1)
40 of SHR rats are divided into 4 groups at random, 10 every group, are made as Benazepril hydrochloride contents in tablets respectively; The hyacinth line of oils; Benazepril hydrochloride, hyacinth oil nano-emulsion group and positive blank control group, first three groups give Benazepril hydrochloride contents in tablets suspension, hyacinth oil and benazepril hydrochloride, each 15mg/kgd of hyacinth 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 | 199.3±10.4 |
| Benazepril hydrochloride contents in tablets | 141.6±11.3 |
| Hyacinth oil | 178.8±12.6 |
| Benazepril hydrochloride, hyacinth oil nano-emulsion | 131.9±8.1 |
| WKY normal control group | 127.1±8.4 |
The result shows; Benazepril hydrochloride, hyacinth oil nano-emulsion and positive controls, Benazepril hydrochloride contents in tablets and hyacinth line of oils are relatively; Difference is all extremely remarkable; Show that benazepril hydrochloride not only can significantly reduce the blood pressure of positive rat, and antihypertensive effect and commercially available Benazepril hydrochloride contents in tablets compare effect with hyacinth oil more remarkable.
Test Example 4 toxicity tests
1. toxicological study project and conclusion:
Medicine of the present invention has carried out acute toxicity test in strict accordance with non-clinical safety evaluation methodology of new drug and commercially available Benazepril hydrochloride contents in tablets agent contrast; 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 Benazepril hydrochloride contents in tablets agent contrast, untoward reaction and death in measuring does not appear in benazepril hydrochloride, hyacinth 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 Benazepril hydrochloride contents in tablets agent contrast; In experimental period; Each experimental group animal growth is good in benazepril hydrochloride, the metering of hyacinth 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 Benazepril hydrochloride contents in tablets agent contrast; In experimental period; In benazepril hydrochloride, the metering of hyacinth 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, benazepril hydrochloride of the present invention, the oral back of hyacinth oil resisting hypertension nanoemulsion medicine (embodiment 1) oral absorption are rapid, absorbance>67%.Oral back benazepril hydrochloride is a benazeprilat at hepatic metabolism.The about 4h of its T1/2.Protein binding rate is 95%.Mainly eliminate through kidney regulating liver-QI (bile).
Embodiment 1
Accurately take by weighing hyacinth oil 9.8g, 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 benazepril hydrochloride.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 benazepril hydrochloride, hyacinth oil nano-emulsion, and the amount that add entry this moment is that 50.2g, benazepril hydrochloride are 8g.This ratio is the optimal proportion of benazepril hydrochloride, hyacinth oil resisting hypertension nano-emulsion.
Following examples step is with embodiment 1:
Embodiment 2
Hyacinth oil 10.1g, EL40 25g, 1,2-propylene glycol 15g, the amount of water is 45.3g, benazepril hydrochloride is 4.6g.
Embodiment 3
Hyacinth oil 9.6g, RH40 25g, glycerin 10g, the amount of water is 50.3g, benazepril hydrochloride is 5.1g.
Embodiment 4
Hyacinth oil 10.7g, RH40 25g, ethanol 20g, the amount of water is 40.4g, benazepril hydrochloride is 3.9g.
Embodiment 5
Hyacinth oil 8.1g, Tween 80 20g, glycerin 5g, the amount of water is 57.3g, benazepril hydrochloride is 9.6g.
Embodiment 6
Hyacinth oil 11.7g, Tween 80 27g, the amount of PEG400 3g water is 50.3g, benazepril hydrochloride is 8g.
Embodiment 7
Hyacinth oil 15g, EL40 20g, span80 10g, the amount of water is 50g, benazepril hydrochloride 5g.
Embodiment 8
Hyacinth oil 10g, RH40 25g, span80 5g, the amount of water is 45g, 1,2-propylene glycol 5g, benazepril hydrochloride 10g.
Embodiment 9
Hyacinth oil 5g, Tween 80 20g, span80 10g, the amount of water is 45g, PEG400 5g, benazepril hydrochloride 15g.
Embodiment 10
Hyacinth oil 1g, poloxamer 188 20g, span80 5g, glycerin 5g, the amount of water is 51g, benazepril hydrochloride 18g.
Embodiment 11
Hyacinth oil 20g, EL40 25g, the amount of water is 44g, PEG400 5g, glycerin 5g, benazepril hydrochloride 1g.
Claims (2)
1. a benazepril hydrochloride, hyacinth oil nano-emulsion antihypertensive drug is characterized in that its raw material and mass percent thereof are:
Benazepril hydrochloride 1%～18%
Surfactant 15%～40%
Cosurfactant 0～20%
Hyacinth oil 1%～20%
All the other compositions are distilled water, and the mass percent sum of above-mentioned raw materials is 100%;
Described surfactant is: any one in polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or the poloxamer 188 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. benazepril hydrochloride according to claim 1, hyacinth oil nano-emulsion antihypertensive drug is characterized in that the particle diameter of this medicine is between 25.1～62.4nm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200833A (en) * | 2019-06-03 | 2019-09-06 | 五邑大学 | A kind of phloretin nano-emulsion preparation and its preparation method and application |
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Application publication date: 20121017 |