CN102697900A - Compound spirolactone nanoemulsion drug - Google Patents
Compound spirolactone nanoemulsion drug Download PDFInfo
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- CN102697900A CN102697900A CN2012101637041A CN201210163704A CN102697900A CN 102697900 A CN102697900 A CN 102697900A CN 2012101637041 A CN2012101637041 A CN 2012101637041A CN 201210163704 A CN201210163704 A CN 201210163704A CN 102697900 A CN102697900 A CN 102697900A
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Abstract
The invention discloses a compound spirolactone nanoemulsion drug. The nano drug is prepared from the following materials in mass percentage: 1%-15% of spirolactone, 15%-35% of surfactant, 5%-20% of cosurfactant, 5%-20% of oil, 0.5%-10% of hawthorn extract, 0.5%-10% of asarum extract and the balance of distilled water, wherein the sum of the mass percentages of the ingredients is 100%. According to the invention, after the spirolactone is prepared into nanoemulsion dosage form, the ability of penetrating blood brain barrier is obviously increased, the bioavailability of active compound is obviously improved, the half-life period of the drug is prolonged, and the administration times are reduced. The dissolving and penetrating abilities of the drug of the spirolactone are improved by the nanoemulsion, and the stability of the spirolactone is increased. The spirolactone nanoemulsion drug has obvious synergistic effect after being combined with aqueous extract of the hawthorn and asarum, and the curative effect of the drug is brought into full play.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novel form of antihypertensive drug spironolactone, particularly a kind of compound recipe spironolactone nanoemulsion medicine.
Background technology
Spironolactone (spironolactone, Antisterone, Aldactine, Aldonar, Verospiron, spirolang) chemistry 17 beta-hydroxies by name-3-oxygen-7 α-(thioacetyl)-17 α-pregnant steroid-4-alkene-21-carboxylic acid gamma lactone, molecular formula is C
24H
32O
4S, molecular weight 416.57, CAS 52-01-7.
Have antihypertensive drugs on the market now like the spironolactone tablet; Though can be after oral from gastrointestinal absorption; But infiltration rate is slow, absorption is incomplete, and the dissolution rate of tablet Chinese traditional medicine is slow in addition, and bioavailability is poor; Add spironolactone effect itself slowly, make the drug effect of spironolactone can't obtain rapidly utilizing.
?
Summary of the invention
To the shortcomings and deficiencies that exist in the above-mentioned prior art, the object of the present invention is to provide a kind of being evenly distributed, good stability, bioavailability is high, compound recipe spironolactone nanoemulsion medicine evident in efficacy.
The technical scheme that realizes the foregoing invention purpose is: a kind of compound recipe spironolactone nanoemulsion medicine; This Nano medication is made up of the raw material of following quality percentage: spironolactone 1%～15%, surfactant 15%～35%, cosurfactant 5%～20%, oil 5%～20%, Fructus Crataegi extract 0.5%～10%, Herba Asari extract 0.5%～10%, surplus are distilled water, and the mass percent sum of mentioned component is 100%.
Described surfactant is with non-ionic surfactant polyoxyethylene ether-40 castor oil hydrogenated (Cremophor RH 40), any one in castor oil polyoxyethylene ether 40 (EL40), Tween 80 or the poloxamer 188.These surfactants are to human body low toxicity, safe, non-stimulated.
Described oil is any one of edible oil apoplexy due to endogenous wind such as soybean oil, Oleum Brassicae campestris, oleic acid, ethyl oleate, isopropyl myristate (IPM) or ethyl acetate.
In order to reach better effect; The present invention adds cosurfactant dehydrated alcohol, 1 in above-mentioned surfactant, any one in 2-propylene glycol, glycerin, Macrogol 200 (PEG200), PEG400 (PEG400) or the Macrogol 600 (PEG600).
Cosurfactant is good medicine cosolvent equally in the structure of compound recipe spironolactone nano-emulsion among the present invention, and the present invention adds the bland surface that helps like ethanol, 1 in medicine, 2-propylene glycol, glycerin or Macrogol 200; PEG400; Macrogol 600, except the hydrotropy effect, cosurfactant mainly is in order to adjust HLB VALUE OF SURFACTANTS (HLB); Make oil water interfacial tension further reduce, increase 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 compound recipe spironolactone nano-emulsion.
The mechanism of spironolactone blood pressure lowering comprises: 1. at kidney retardance Na
+, K
+Exchange process has weak diuresis and the effect of protecting potassium row sodium, brings high blood pressure down thereby reduce blood volume.2. reduce the damage and the fibrosis of cardiac muscle, vascular tissue.3. passing through increases blood vessel NO biological activity, thereby improves endothelial function.
Spironolactone is the poor efficiency diuretic; With aldosterone similar chemical constitution is arranged; Both play the effect of striving unexpectedly at the cortex section position of Distal convoluted tubule and collecting tubule; Be that direct antagonism takes place on the level of the glucocorticoid receptor (GR) of cytoplasma membrane, thereby disturb aldosterone, promote Na the re-absorbed facilitation of above-mentioned position sodium
+And Cl
-Discharge and produce diuresis, because of Na
+, K
+Exchanging mechanism receives to press down K
+Discharge reduce, so be potassium-sparing diuretic.Diuresis is slow, gentle and lasting.Be mainly used in the hypertensive ancillary drug of treatment.A little less than acting on, generally not single using.
Modern medicine study shows that Fructus Crataegi has the blood lipid regulation metabolism, and the effect of hypercholesterolemia reducing (TC), low density lipoprotein, LDL (LDL) and raising high density lipoprotein (HDL) is promptly arranged, and has the effect of coronary blood flow increasing, strong blood pressure lowering.Fructus Crataegi contains materials such as saccharide, protein, fat, vitamin C, carotene, starch, malic acid, citric acid, calcium and ferrum, has effects such as blood fat reducing, blood pressure, heart tonifying and arrhythmia.Because Fructus Crataegi is rich in multiple organic acid, can keep the vitamin C in the Fructus Crataegi, even under the situation of heating, also unlikely being destroyed, vitamin C still can be preserved.Fructus Crataegi also is rich in beneficiating ingredients (number of chemical compositions such as flavonoid poly flavane, trimerization flavane, tannin) such as triterpenes olefin(e) acid such as the plain acid of carotene, calcium, oleanolic acid, bird, crataegin and flavonoid; Ability vasodilator, reinforcement and adjusting cardiac muscle; Increase ventricle and heart motional amplitude and crown blood flow volume, reduce serum cholesterol and bring high blood pressure down; In addition, Fructus Crataegi also has the auxiliary treatment effect to diseases such as cardiomotility dysfunction, vascular neurosis, vibratility arrhythmia; Crataegus pin natifida var. Major also contains Quercitroside; It has blood vessel dilating, promotes the function that tracheal cilia motion, expectoration are relievingd asthma; So Fructus Crataegi is the desirable health food and the food that better curative effect is arranged of anti-angiocardiopathy, is applied to the control of hypertension, hyperlipidemia, coronary heart disease etc. recently, and better effects is all arranged.Clinical research confirmation, Fructus Crataegi can significantly reduce serum cholesterol and triglyceride, effectively prevents and treats atherosclerosis; Fructus Crataegi can also play heart tonifying and prevent anginal effect through strengthening myocardial contraction, increase cardiac output, coronary artery dilator blood vessel, coronary blood flow increasing, reduction myocardial oxygen consumption etc.In addition, the total flavones in the Fructus Crataegi has the effect of blood vessel dilating and lasting blood pressure lowering.
Herba Asari has good effect to blood pressure lowering.Herba Asari extractum, thin up become the solution (every 1ml contains crude drug 2g, is called for short A.H) of 1:2.At heart-lung preparation dog medium-sized vein injection A.H.0.1～0.4ml/kg.The result shows, LVSP rises, LVEDP descends, MAP rises, CO rises, HR rises, SV descends, dp/dtmax rises ,-dp/dtmax rises, t-dp/dtmax descends, Vpm rises, Vce-cpip rises, Vmax rises; In anesthetized open-chest dog, intravenous injection 0.05～0.4ml/kg A.H is except that can making MAP decline and SV rising, and other result and heart-lung preparation are tested basically identical; The forward anterior descending branch of the Lis-sajous figure that above-mentioned two experiments record all is shifted to the upper right side.Thereby got rid of forward and backward effects of load, the improvement that shows pumping function is like due to A.H enhancing myocardial contractility.Dl-demethylcoclaurine that contains in A.H and the Herba Asari (being called for short H.G) and isoproterenol (being called for short I.S) three compare.The three all can the enhancing canine left chamber function as a result, but A.H can make SV increase, and H.G and I.S but make the SV minimizing.Its reason possibly make increased heart rate appropriateness, ventricular diastole more relevant with A.H.
Compound recipe spironolactone nano-emulsion of the present invention, one side has improved the dissolubility of spironolactone greatly, has reduced medicine first pass effect in vivo, promotes the gastrointestinal absorption of medicine.Spironolactone is two types of medicines of BCS, and utmost point indissoluble is separated in water, makes the transhipment of medicine and absorption become difficult, and nano-emulsion substrate is that spironolactone provides good dissolving environment.Can absorb the barrier when overcoming first pass effect and molecule when oral through lymph through gastrointestinal tract; Through composite Fructus Crataegi water extract and Herba Asari water extract, make that the blood pressure lowering of this medicine is more steady on the other hand, effect is more lasting.
Compound recipe spironolactone nano-emulsion of the present invention compared with prior art has the following advantages:
1. the diameter of aspirin particle of spironolactone resisting hypertension nano-emulsion of the present invention is between 10.1～50.7nm; Mean diameter is 22.89 nm; Be that spironolactone is dissolved in oil phase; Add surfactant and cosurfactant, be titrated to even, transparent nano-emulsion system with the distilled water that dissolves Fructus Crataegi water extract and Herba Asari water extract.The compound recipe spironolactone nano-emulsion that forms contains spironolactone and reaches 9.2%.
2. spironolactone resisting hypertension nano-emulsion of the present invention is evenly distributed, and transparent, the good stability of system has lower surface tension, and water-in-oil type nanoemulsion has good flowability.
3. engulfed by reticuloendothelial cell rapidly after the spironolactone resisting hypertension nano-emulsion of the present invention administration, make the rapid onset of medicine, and keep constant blood drug level and pharmacodynamics effect, improve bioavailability of medicament, reduce amount of drug and access times.
4. spironolactone resisting hypertension nano-emulsion of the present invention combines through Chinese medicine and western medicine, brings into play both advantages, and blood pressure lowering is rapid, rapid-action on the one hand, and another firm face efficacy stability, persistent meet the treatment standard of highly effective and safe.
5. spironolactone resisting hypertension nano-emulsion efficacy stability of the present invention, living power consumption is low.
6. 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 compound recipe spironolactone nanoemulsion medicine size of the present invention is analyzed
Optimal proportion of the present invention detects through transmission electron microscope, and drop type of being is spherical, good dispersion, no adhesion; Detect its diameter Distribution between 10.1～50.7nm through the Ma Erwen Particle Size Analyzer, mean diameter is 22.89 nm.
Test Example 2 compound recipe spironolactone nano-emulsion antihypertensive drug of the present invention stability analyses
Whether through the stability that compound recipe spironolactone nano-emulsion antihypertensive drug of the present invention is 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 compound recipe spironolactone nano-emulsion antihypertensive drug of the present invention for preparing in right amount in centrifuge tube; With centrifugal 15 min of the rotating speed of 10 000r/min; After the centrifugal test; Compound recipe spironolactone nano-emulsion antihypertensive drug of the present invention still keeps the clear before centrifugal, wild effect such as do not see that layering, muddiness or crystal are separated out.
2. light stability test
The compound recipe spironolactone nano-emulsion antihypertensive drug for preparing is in right amount packed in transparent good colourless, the Clear glass bottles and jars, 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 the every duplicate samples of compound recipe spironolactone nano-emulsion antihypertensive drug all keeps clear, wild effect such as do not see that layering, muddiness or crystal are separated out.
3. temperature stability test
The compound recipe spironolactone nano-emulsion antihypertensive drug for preparing is in right amount packed in transparent good colourless, the Clear glass bottles and jars, 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 compound recipe spironolactone nano-emulsion antihypertensive drug all keeps 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 compound recipe spironolactone nano-emulsion antihypertensive drug.Result of the test is illustrated under the long term test condition, and the outward appearance of compound recipe spironolactone nano-emulsion antihypertensive drug keeps clear and bright, homogeneous always, does not see phenomenons such as layering, complexion changed, flocculation and breakdown of emulsion; Spironolactone content in the system prolongs in time and reduces gradually, the equation of linear regression that its content-time changing curve provides, and the effect duration that calculates compound recipe spironolactone nano-emulsion antihypertensive drug is 29.62 months.
Test Example 3 rat tails manometrys are measured the drug effect (with commercially available spironolactone sheet contrast) of compound recipe spironolactone nano-emulsion antihypertensive drug
3 of SHR rats are divided into 3 groups at random; Every group 10, be made as SHR positive controls, spironolactone sheet group, compound recipe spironolactone nano-emulsion group (product with embodiment 1 preparation is a trial target) respectively, give spironolactone sheet solution, each 20 mg/kgd of compound recipe spironolactone nano-emulsion respectively; Be dissolved in the drinking-water; All administrations from drinking-water, 1 time/d, continuous 14 weeks.WKY6 only is the normal control group, and matched group is not given medicine, and drinking-water is not limit.
Measure and respectively organize rat arteria caudalis blood pressure.(before the medication) pressure measurement was 1 time when Mus was 6 weeks age, and Mus 7 weeks of age (1 week after the medication) pressure measurement 1 time is whenever later on surveyed 1 blood pressure at a distance from two weeks, up to the experiment end.The result sees table 1.
Table 1 is respectively organized the comparison (x ± s, n=6) of rat SBP
| Group | Systolic pressure (mmHg) |
| Positive control | 198.0±10.3 |
| The spironolactone sheet | 141.4±11.5 |
| Compound recipe spironolactone nano-emulsion | 133.4±9.5 |
| WKY normal control group | 123.6±5.7 |
The result shows that compound recipe spironolactone nano-emulsion and positive controls and spironolactone sheet compare, and difference is all extremely remarkable, show that spironolactone not only can significantly reduce the blood pressure of positive rat, and antihypertensive effect is compared better effects if with the spironolactone tablet.
Test Example 4 toxicity tests (product with embodiment 1 preparation is a trial target)
1. toxicological study project and conclusion:
Product of the present invention is in strict accordance with non-clinical safety evaluation methodology of new drug and commercially available spironolactone 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.
These article are to chmice acute toxicity test conclusion: with commercially available spironolactone tablet contrast, untoward reaction and death in the dosage do not appear in compound recipe spironolactone nano-emulsion.
The result of genetic toxicity tests such as the Salmonella reversion test of product 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 spironolactone tablet contrast; In experimental period; Each experimental group animal growth is good in the compound recipe spironolactone nano-emulsion dosage; 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.
These article long term toxicity test conclusion: with commercially available spironolactone tablet contrast; In experimental period; In the compound recipe spironolactone nano-emulsion dosage; 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 (product with embodiment 1 preparation is a trial target)
Result of the test shows; Compound recipe spironolactone nano-emulsion antihypertensive drug oral absorption is good, and bioavailability is greater than 92%, and plasma protein binding rate is more than 93%; Getting in the body back 80% is activated canrenone (canrenone) by the rapid metabolism of liver; Oral 5h left and right sides onset, 12h～48h reaches the peak, and effect still can be kept 3 after the drug withdrawal.The non-activity metabolite is excreted in the urine with the metabolite form from kidney and biliary excretion.
Test Example 6 compound recipe spironolactone nano-emulsion antihypertensive drug are to the influence (product with embodiment 1 preparation is a trial target) of nervous plain II (Ang II) level of rat liver fibrosis progress medium vessels
90 rats are divided into 3 groups at random.Normal control group (8) wherein: normal drinking water diet, subcutaneous injection pure soy bean 3 mlkg
-1Body weight, 2 times weekly; Model group (42): 5 % (volume fraction) ethanol is unique beverage, high fat, hypercholesterolemia, low protein diet, subcutaneous injection 40 % (volume fraction) carbon tetrachloride soybean oil solution, 3 mlkg
-1Body weight, 2 times weekly, first dose doubles; Spironolactone group (40): the same model group of modeling method, and with 100 mgkg
-1D
-1The spironolactone of dosage is irritated stomach.Weigh weekly 1 time, and the adjustment dosage.The mensuration of Ang II level: the dead a collection of animal in 2,4,6,8 last two component other places of week, Ang II level in its serum of measured by radioimmunoassay and the LH.The result shows that in the test, since Ang II level all significantly raise than normal matched group in the 2nd week in spironolactone group and model group rat blood and the LH; Since the 4th the week, in the compound recipe spironolactone nano-emulsion antihypertensive drug group blood Ang II level than the same period model group significantly raise, and in the LH Ang II level than the same period model group significantly reduce.
Embodiment 1
Accurately take by weighing EL40 15g, ethyl acetate 10g, spironolactone 1g, 1,2-propylene glycol 20g stirs under room temperature (25 ℃) condition, then to wherein slowly splashing into the distilled water that has dissolved Fructus Crataegi extract and Herba Asari extract.Increase along with the distillation water yield; The system stickiness increases, and when the distillation water yield made that system becomes the oil-in-water type nano-emulsion by Water-In-Oil, the system viscosity was thinning from the most heavy-gravity state; What produced this moment is water white compound recipe spironolactone nano-emulsion; The distillation water yield that adds is 34g, Fructus Crataegi water extract 10g, Herba Asari water extract 10g.
Embodiment 2
Tween 80 28g, isopropyl myristate 15g, spironolactone 8g, ethanol 12g, distilled water 29g, Fructus Crataegi water extract 4g, Herba Asari water extract 4g.
Embodiment 3
RH40 20g, oleic acid 20g, spironolactone 10g, PEG400 10g, distilled water 28g, Fructus Crataegi water extract 5g, Herba Asari water extract 7g.
Embodiment 4
EL40 30g, ethyl oleate 7g, spironolactone 6g, glycerin 8g, distilled water 39g, Fructus Crataegi water extract 3.5g, Herba Asari water extract 6.5g.
Embodiment 5
Poloxamer 188 28g, Oleum Brassicae campestris 5g, spironolactone 12g, PEG200 18g, distilled water 27.5g, Fructus Crataegi water extract 9g, Herba Asari water extract 0.5g.
Embodiment 6
RH40 35g, soybean oil 10g, spironolactone 15g, Macrogol 600 5g, distilled water 33g, Fructus Crataegi water extract 0.5g, Herba Asari water extract 1.5g.
Claims (2)
1. compound recipe spironolactone nanoemulsion medicine; It is characterized in that; This Nano medication is made up of the raw material of following quality percentage: spironolactone 1%～15%, surfactant 15%～35%, cosurfactant 5%～20%, oil 5%～20%, Fructus Crataegi extract 0.5%～10%, Herba Asari extract 0.5%～10%, surplus are distilled water, and the mass percent sum of mentioned component is 100%;
Described surfactant is any one in polyoxyethylene ether-40 castor oil hydrogenated, castor oil polyoxyethylene ether 40, Tween 80 or the poloxamer 188;
Described oil is any one in soybean oil, Oleum Brassicae campestris, oleic acid, ethyl oleate, isopropyl myristate, the ethyl acetate;
Described cosurfactant is a dehydrated alcohol, 1, any one in 2-propylene glycol, glycerin, Macrogol 200, PEG400 or the Macrogol 600.
2. compound recipe spironolactone nanoemulsion medicine according to claim 1 is characterized in that the particle diameter of this nano-emulsion is between 1～100nm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796763A (en) * | 2016-03-27 | 2016-07-27 | 济南邦文医药科技有限公司 | Spirolactone-containing medicine composition for treating hypertension and preparation method thereof |
-
2012
- 2012-05-24 CN CN2012101637041A patent/CN102697900A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796763A (en) * | 2016-03-27 | 2016-07-27 | 济南邦文医药科技有限公司 | Spirolactone-containing medicine composition for treating hypertension and preparation method thereof |
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Application publication date: 20121003 |