CN102657697A - Propranolol-eugenol type basil oil nano-emulsion medicament and preparation method thereof - Google Patents
Propranolol-eugenol type basil oil nano-emulsion medicament and preparation method thereof Download PDFInfo
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- CN102657697A CN102657697A CN2012101349218A CN201210134921A CN102657697A CN 102657697 A CN102657697 A CN 102657697A CN 2012101349218 A CN2012101349218 A CN 2012101349218A CN 201210134921 A CN201210134921 A CN 201210134921A CN 102657697 A CN102657697 A CN 102657697A
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Abstract
The invention discloses a propranolol-eugenol type basil oil nano-emulsion medicament, which consists of the following raw materials in percentage by mass: 1-10 percent of propranolol, 10-30 percent of surfactant, 0-25 percent of cosurfactant, 1-15 percent of eugenol type basil oil and the balance of distilled water, wherein the mass percentage sum of the raw materials is 100 percent. A nano-emulsion has the characteristics of small emulsion drop particles, uniform distribution, low viscosity and high flowability. In a nano-emulsion dosage form, propranolol serving as a water-soluble medicament is organically combined with fat-soluble eugenol type basil oil, so that the dissolving and permeation capabilities of eugenol type basil oil are increased, and the stability and medicament effect of propranolol are enhanced. After the propranolol and the eugenol type basil oil are prepared into a nano-emulsion dosage form, the advantages of the propranolol and the eugenol type basil oil are combined, the hypertension resisting effect is enhanced remarkably, the half-life period of a medicament is prolonged, and the administration times are reduced.
Description
Technical field
The invention belongs to field of medicaments, relate to the novel form of a kind of antihypertensive drug Propranolol and Oleum Ocimi Gratissimi, particularly a kind of Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine and preparation method thereof.
Background technology
Propranolol (Propranolol).Chemical name: 1-isopropylamino-3-(1-naphthoxy)-2-propylate hydrochlorate.Its levo form activity is eager to excel in whatever one does than dextrorotation.Clinical its racemic modification of using.These article are to be applied to clinical beta receptor blocker the earliest.Can absorb rapidly and fully at gastrointestinal tract after oral, but the clearance rate of in liver, passing through first is very high, only about 30% gets into blood circulation.Blood plasma Chinese medicine concentration change is very big, so clinical medicine dose has remarkable individual variation.Mainly, most of through renal excretion at intrahepatic metabolism.
Compete beta receptor with noradrenergic nerve mediator or adrenomimetic drug because of medicine, thereby suppress norepinephrine energy is arranged organ through god β effect.To cardiovascular effect, stronger to heart β1Shou Ti blocking effect, can make decreased heart rate, myocardial contraction weakens; Can reduce myocardium self-disciplining, prolong effective refractory period (ERP), the conduction of slowing down reduces cardiac output, and myocardial oxygen consumption reduces, and blood pressure reduces slightly.Propranolol is relevant with the tension force size of cardiac sympathetic nerve to heart inhibitory action intensity, and like motion, orthosympathetic tension force increases during pathological state, propranolol is stronger to the inhibitory action of heart, during to normal person's rest a little less than the heart effect.But the propranolol reflexive causes Peripheral resistance increase, internal organs (liver, kidney etc.) OBF is reduced, coronary flow also reduces.
Oleum Ocimi Gratissimi Oleum Ocimi Gratissimi main component is monoterpene and sesquiterpene.Research shows Oleum Ocimi Gratissimi and principal monomer composition acetaminol tool vasorelaxation action thereof.
Existing antihypertensive drugs like the Propranolol tablet on the market also has the use of Oleum Ocimi Gratissimi now, though can absorb not exclusively from gastrointestinal absorption after oral, the dissolution rate of medicine is slow in addition, and bioavailability is poor; It is slow to add the Propranolol effect, makes the drug effect of Propranolol and Oleum Ocimi Gratissimi can't obtain utilizing.
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 Propranolol and the fat-soluble Oleum Ocimi Gratissimi of efficient blood pressure lowering being combined, and drug distribution evenly, good stability, permeability is high, dissolubility is good, bioavailability is high Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine.
The technical scheme that realizes the foregoing invention purpose is: a kind of Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine, and its raw material and each raw materials quality percentage ratio are:
Oleum Ocimi Gratissimi 1%～15%
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 further object of the invention provides the method for preparing of above-mentioned Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine, it is characterized in that, comprises the following steps:
1) takes by weighing Propranolol, surfactant, cosurfactant, Oleum Ocimi Gratissimi, distilled water fully;
2) with Oleum Ocimi Gratissimi, surfactant and cosurfactant mixing and stirring;
3) Propranolol is dissolved in the distilled water;
3) under 25 ℃ of conditions, the solution of step 3) preparation is slowly splashed into step 2) in the solution of preparation; Increase along with the distillation water yield; The system stickiness increases; When the amount that adds distilled water made system become the oil-in-water type nano-emulsion by Water-In-Oil, the system viscosity got final product from the most heavy-gravity state is thinning.
A kind of Propranolol of the present invention, the administration of Ocimum Basilicum oil nanometer emulsion administered through oral; Improved the dissolubility of Oleum Ocimi Gratissimi greatly; Reduce medicine first pass effect in vivo; Promote Oleum Ocimi Gratissimi gastrointestinal absorption, and novelty water soluble drug and fat-soluble medicine are organically combined, improved the treatment ability of medicine.Oleum Ocimi Gratissimi is fat-soluble vegetable oil, and human body is to the transhipment of medicine and absorb extremely difficultly, and nano-emulsion substrate is that Oleum Ocimi Gratissimi provides good dissolving environment, can absorb through lymph when oral, the barrier when overcoming first pass effect and molecule through gastrointestinal tract.Through adding Oleum Ocimi Gratissimi, also improved the blood pressure lowering ability of Propranolol on the other hand, make that blood pressure lowering is more stable, better effects if.
Propranolol of the present invention, Ocimum Basilicum oil nanometer emulsion compared with prior art have the following advantages:
1. the diameter of aspirin particle of Propranolol of the present invention, Oleum Ocimi Gratissimi resisting hypertension nano-emulsion is being situated between between 10～100nm.
2. Propranolol of the present invention, Oleum Ocimi Gratissimi 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 Propranolol of the present invention, the administration of Oleum Ocimi Gratissimi 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. Propranolol of the present invention, Ocimum Basilicum oil nanometer 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.
Description of drawings
Fig. 1 is Propranolol of the present invention, Ocimum Basilicum oil nanometer emulsion electromicroscopic photograph.
Fig. 2 is Propranolol of the present invention, Ocimum Basilicum oil nanometer emulsion granularmetric analysis figure.
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.
The hypertensive hypotensive effect of rat that Test Example 1 Oleum Ocimi Gratissimi and acetaminol Dichlorodiphenyl Acetate desoxycortone (DOCA) cause.
Experiment to Oleum Ocimi Gratissimi and acetaminol is divided into 2 groups, and promptly the clear-headed rat matched group of inductive male Wistar rat hypertension group of DOCA and unilateral nephrectomy is given 4 weeks of DOCA and excipient (olive oil) respectively.At the last 1d of above-mentioned processing, with rat anesthesia, the equal arterial pressure of abdominal aortic cannulation lining (MAP), the inferior vena cava cannula administration, write down basic MAP and heart rate (HR) after, give reagent with the mode of escalated dose gradually, MAP that the record reagent causes and HR variation.The result is shown to DOCA hypertension group and control rats iv Oleum Ocimi Gratissimi (1～20 mg/kg) and acetaminol (1～10 mg/kg), reaches dosage immediately and produces hypotensive effect relatively and make the bradycardia.Compare with the unilateral nephrectomy matched group, Oleum Ocimi Gratissimi and acetaminol obviously increase the maximum reducing value of DOCA Hypertensive Rats MAP, and its bradycardia effect is uninfluenced; Bistrium to the blood pressure lowering maximum of DOCA Hypertensive Rats also apparently higher than the unilateral nephrectomy matched group.If inject the hypotensive effect that hexamethonium C6 or methyl atropine then do not influence EOOG and acetaminol in advance, but can obviously weaken the effect of 2 reagents to HR.Above result shows, but intravenous injection acetaminol or Oleum Ocimi Gratissimi dosage reduce the inductive clear-headed rat hypertension of DOCA relatively, and its effect is better than the effect to the unilateral nephrectomy rat.Oleum Ocimi Gratissimi and acetaminol directly act on vascular smooth muscle and distend the blood vessels, rather than through strengthening the movable hypotensive effect that produces of sympathetic nervous system.
Test Example 2 Propranolol of the present invention, Ocimum Basilicum oil nanometer emulsion antihypertensive drug size are analyzed
The present invention detects (Fig. 1) through transmission electron microscope, and drop type of being is spherical, good dispersion, no adhesion.Detect (Fig. 2) its diameter Distribution between 30.4～71.4nm through the Ma Erwen Particle Size Analyzer, mean diameter is 55.8nm.
Test Example 3 Propranolol of the present invention, the stability analysis of Ocimum Basilicum oil nanometer emulsion antihypertensive drug
Whether through the stability that Propranolol of the present invention, Ocimum Basilicum oil nanometer 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 Propranolol of the present invention for preparing in right amount, Oleum Ocimi Gratissimi Nano medication in centrifuge tube; With centrifugal 10 min of the rotating speed of 15 000r/min; After the centrifugal test; Propranolol of the present invention, Ocimum Basilicum oil nanometer 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 Propranolol for preparing in right amount, Oleum Ocimi Gratissimi nanoemulsion medicine 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 Propranolol, the every duplicate samples of Ocimum Basilicum oil nanometer 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 Propranolol for preparing in right amount, Ocimum Basilicum oil nanometer 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 Propranolol, Ocimum Basilicum oil nanometer 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 Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine.Result of the test is illustrated under the long term test condition, and the outward appearance of Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine keeps clear and bright, homogeneous always, does not see phenomenons such as layering, complexion changed, flocculation and breakdown of emulsion; Propranolol in the system and Ocimum Basilicum 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 Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine is 34.11 months (is standard with time weak point person).
Test Example 4 rat tails manometrys are measured the drug effect (with Oleum Ocimi Gratissimi and the contrast of commercially available Propranolol sheet) of Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine
40 of SHR rats are divided into 4 groups at random, 10 every group, are made as the Propranolol sheet respectively; The Ocimum Basilicum line of oils; Propranolol, Ocimum Basilicum oil nanometer emulsion group and positive blank control group, first three groups give Propranolol sheet suspension, Oleum Ocimi Gratissimi and Propranolol, each 15mg/kgd of Ocimum Basilicum oil nanometer 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 | 201.3±10.4 |
| The Propranolol sheet | 138.9±10.9 |
| Oleum Ocimi Gratissimi | 178.2±11.8 |
| Propranolol, Ocimum Basilicum oil nanometer emulsion | 127.4±8.1 |
| WKY normal control group | 124.9±10.4 |
The result shows; Propranolol, Ocimum Basilicum oil nanometer emulsion and positive controls, Propranolol sheet and Ocimum Basilicum line of oils are relatively; Difference is all extremely remarkable; Show that Propranolol not only can significantly reduce the blood pressure of positive rat, and antihypertensive effect and commercially available Propranolol sheet compare effect with Oleum Ocimi Gratissimi more remarkable.
Test Example 5 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 Propranolol 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 Propranolol tablet contrast, untoward reaction and death in measuring does not appear in Propranolol, Ocimum Basilicum oil nanometer 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 Propranolol tablet contrast; In experimental period; Each experimental group animal growth is good in Propranolol, the metering of Ocimum Basilicum oil nanometer 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 Propranolol tablet contrast; In experimental period; In Propranolol, the metering of Ocimum Basilicum oil nanometer emulsion; Medicine of the present invention 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 6 pharmacokinetics
Result of the test shows that Propranolol, the oral back of Ocimum Basilicum oil nanometer emulsion gastrointestinal absorption be (94%) fully, 1.25 hours blood drug level peakings, and bioavailability is 76% (the Propranolol bioavailability is merely 30%).Very high with the combination rate of plasma protein, be 93%, the half-life is 3.5 hours, through RE, is mainly metabolite, fraction (1%) be the original shape thing.
Accurately take by weighing Oleum Ocimi Gratissimi 6g, EL40 25g and ethanol 5g and under room temperature (25 ℃) condition, stir, then to wherein slowly splashing into the distilled water that is dissolved with Propranolol.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 Propranolol, Ocimum Basilicum oil nanometer emulsion, and the amount that add entry this moment is that 59g, Propranolol are 5g.This ratio is the optimal proportion of Propranolol, Ocimum Basilicum oil nanometer emulsion.
Following examples step is with embodiment 1:
Embodiment 2
Oleum Ocimi Gratissimi 15g, EL40 20g, span80 10g, distilled water 54g, Propranolol 1g.
Embodiment 3
Oleum Ocimi Gratissimi 10g, RH40 25g, span80 5g, distilled water 53g, 1,2-propylene glycol 5g, Propranolol 2g.
Embodiment 4
Oleum Ocimi Gratissimi 5g, Tween 80 20g, span80 10g, distilled water 55g, PEG400 5g, Propranolol 5g.
Oleum Ocimi Gratissimi 1g, poloxamer 188 20g, span80 5g, glycerin 5g, distilled water 59g, Propranolol 10g.
Embodiment 6
Oleum Ocimi Gratissimi 15g, EL40 25g, distilled water 49g, PEG400 5g, glycerin 5g, Propranolol 1g.
Embodiment 7
Oleum Ocimi Gratissimi 5g, RH40 25g, glycerin 25g, distilled water 40.5g, Propranolol 4.5g.
Embodiment 8
Oleum Ocimi Gratissimi 7g, RH40 30g, ethanol 25g, distilled water 37g, Propranolol are 1g.
Embodiment 9
Oleum Ocimi Gratissimi 4.5g, Tween 80 25g, glycerin 15g, distilled water 49g, Propranolol 6.5g.
Oleum Ocimi Gratissimi 5g, Tween 80 30g, PEG400 5g, distilled water 55g, Propranolol 5g.
Embodiment 11
Oleum Ocimi Gratissimi 5g, Tween 80 25g, PEG400 5g, 1,2-propylene glycol 5g, distilled water 50g, Propranolol 10g.
Claims (3)
1. a Propranolol, Oleum Ocimi Gratissimi nanoemulsion medicine is characterized in that its raw material and mass percent thereof are:
Propranolol 1%～10%
Surfactant 10%～30%
Cosurfactant 0～25%
Oleum Ocimi Gratissimi 1%～15%
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. Propranolol according to claim 1, Oleum Ocimi Gratissimi nanoemulsion medicine is characterized in that, the particle diameter of this medicine is situated between between 10～100nm.
3. the method for preparing of the described Propranolol of claim 1, Oleum Ocimi Gratissimi nanoemulsion medicine is characterized in that, comprises the following steps:
1) takes by weighing Propranolol, surfactant, cosurfactant, Oleum Ocimi Gratissimi, distilled water fully;
2) with Oleum Ocimi Gratissimi, surfactant and cosurfactant mixing and stirring;
3) Propranolol is dissolved in the distilled water;
3) under 25 ℃ of conditions, the solution of step 3) preparation is slowly splashed into step 2) in the solution of preparation; Increase along with the distillation water yield; The system stickiness increases; When the amount that adds distilled water made system become the oil-in-water type nano-emulsion by Water-In-Oil, the system viscosity got final product from the most heavy-gravity state is thinning.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474061A (en) * | 2016-12-08 | 2017-03-08 | 黑龙江童医生儿童生物制药有限公司 | A kind of propranolol hydrochloride Orally taken emulsion and preparation method thereof |
| CN109953950A (en) * | 2017-12-26 | 2019-07-02 | 武汉科福新药有限责任公司 | A kind of nanometer emulsion oral solution and preparation method thereof comprising Propranolol or its salt |
-
2012
- 2012-05-04 CN CN2012101349218A patent/CN102657697A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106474061A (en) * | 2016-12-08 | 2017-03-08 | 黑龙江童医生儿童生物制药有限公司 | A kind of propranolol hydrochloride Orally taken emulsion and preparation method thereof |
| CN106474061B (en) * | 2016-12-08 | 2019-01-22 | 黑龙江童医生儿童生物制药有限公司 | A kind of Propranolol Hydrochloride Orally taken emulsion and preparation method thereof |
| CN109953950A (en) * | 2017-12-26 | 2019-07-02 | 武汉科福新药有限责任公司 | A kind of nanometer emulsion oral solution and preparation method thereof comprising Propranolol or its salt |
| CN109953950B (en) * | 2017-12-26 | 2021-08-06 | 武汉科福新药有限责任公司 | Propranolol or propranolol salt-containing nano-emulsion oral solution and preparation method thereof |
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Application publication date: 20120912 |