CN102631320B - Betahistine hydrochloride liposome and preparation method thereof - Google Patents
Betahistine hydrochloride liposome and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a betahistine hydrochloride liposome and a preparation method of the betahistine hydrochloride liposome. The preparation method comprises the steps of: firstly dissolving lipide ingredients in methylene dichloride, and carrying out reduced-pressure evaporation in water bath until a film is formed; dissolving the film in diethyl ether, and then adding phosphate buffer containing betahistine into the solution; carrying out ultrasonic treatment on the mixed suspension liquid, placing the treated liquid on a rotary evaporator, and carrying out reduced-pressure vaporization until all the organic reagent is evaporated; and finally, obtaining the betahistine hydrochloride liposome. The betahistine hydrochloride is made into liposome, so that the medicine effect is obviously improved, the permeability of blood capillary can be improved, and the dosage of the medicine reaching blood vessels of the brain can be increased; the betahistine hydrochloride liposome is used for improving the treatment effect of Meniere syndrome, reduces the gastrointestinal irritation and the adverse drug reaction, and is beneficial to reducing the side effects such as stomach upset, nausea, dizziness and the like.
Description
Technical field
The present invention relates to a kind of Betahistine Hydrochloride liposome and preparation method thereof, belong to pharmaceutical preparation and preparation method thereof technical field.
Background technology
Betahistine Hydrochloride is to cerebrovascular, cardiovascular, particularly Arterial system at the bottom of vertebra is had to obvious dilating effect, can increase the heart, brain and blood flow around, improve blood circulation, and reduce systemic blood pressure, this external enwergy increases cochlea and blood flow of the front end, thereby elimination auditory vertigo, tinnitus and deafness sense, can also increase capillary permeability, promote the absorption of extracellular fluid, eliminate edema in lymph; Can resist the contracting blood vessel function of catecholamine and reduce arterial pressure, and having the platelet aggregation effect that suppresses the clotting of plasma and ADP induction, can extend rat external thrombus formation time, also having slight diuresis.Simultaneously the Betahistine Hydrochloride of general formulation exist some untoward reaction as, occasionally have xerostomia, stomach discomfort, cardiopalmus, skin pruritus etc., indivedual cases are even nauseating, dizzy, feeling of fullness in the head, perspiration etc.
Liposome has similar biomembranous bilayer structure, has affinity highly with cell membrane.By controlling the particle diameter of liposome, conduct drugs to specific target site, can improve therapeutic effect, reduce side effects of pharmaceutical drugs.Liposome is the targeting preparation that paid close attention to by people, and from the sixties, first the people such as Rachanan application, constantly has new Liposomal formulation to come out, as the Evacet of liposome company (TLC), cisplatin liposome using liposome as carrier.The Liposomal formulation of now existing 2 cancer therapy drugs and 3 antifungal drugs is given the ratification, and other still have the Liposomal formulation of ten multi-medicaments to enter into clinical experimental stage.For many years, liposome, further improving curative effect of medication, is reduced to toxicity, improve the aspects such as stability and do a lot, and make remarkable progress.
Plant sterol and the ratio of content of phospholipid are important structure factors relevant with biomembrane fluidity, and the ratio of phytosterol/phospholipids and the mobility of film are contravariant relation, and affect film fat phase transition temperature.And on plant sterol molecular side chain, there is an ethylidene to there is stronger antiopxidant effect, blocked the oxidation reaction of fatty acid chain.Now existingly take the control for cardiovascular disorders such as atherosclerosis, hyperlipidemia, coronary atherosclerotic heart disease, uncomfortable in chest, cardiopalmus of clinical medicine that plant sterol is main constituent.
Summary of the invention
The present invention relates to a kind of preparation method of Betahistine Hydrochloride liposome, pointed out the feature of Betahistine Hydrochloride liposome on pharmacodynamics simultaneously.
disclosed by the inventiona Betahistine Hydrochloride liposome, is characterized in that: comprise Betahistine Hydrochloride and Liposomal formulation, wherein, Betahistine Hydrochloride 5～30mg/mL; Liposomal formulation comprises lecithin, two kinds of lipid components of plant sterol, and wherein, the mass ratio of lecithin and plant sterol is 3:1～8:1, and the mass ratio of Betahistine Hydrochloride and TL composition is 1:1～1:15.
The preparation method of Betahistine Hydrochloride liposome of the present invention, is characterized in that, step is as follows:
(1) 3:1～8:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 20～30mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 40～80mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 5～30mg/mL, its pH is 5.7～8.0;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 15～30 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 500～1000bar, then by liposome, extrudes instrument (filter membrane aperture is between 0.2 μ m～10 μ m), obtains Betahistine Hydrochloride liposome.
The PBS buffer that described step (3) preparation contains Betahistine Hydrochloride 5～30mg/mL, its pH is 5.7～8.0.
Described step (6) is passed through high pressure homogenizer by the above-mentioned suspension making, pressure is 500～1000bar, then by liposome, extrude instrument (filter membrane aperture is between 0.2 μ m～10 μ m), obtain Betahistine Hydrochloride liposome, particle diameter is between 0.2 μ m～10 μ m.
Described Betahistine Hydrochloride liposome, is characterized in that: can be prepared into the tablet, capsule, oral liquid, the injection that contain Betahistine Hydrochloride liposome.
Betahistine Hydrochloride liposome mean diameter of the present invention is at 0.2 μ m～10 μ m, and the concentration of Betahistine Hydrochloride is 5～30mg/mL, and liposome is neutral, also can positively charged or negative charge; Envelop rate is 50%～90%, and pH value is 5.8～8.0, and outward appearance is milky suspension.
The present invention replaces cholesterol with plant sterol and prepares Betahistine Hydrochloride liposome.Plant sterol character and cholesterol seemingly, can angiocardiopathy preventings, and clinical also had research, but be never applied in liposome preparation technology.In description, mainly contrasted plant sterol and cholesterol and prepared respectively the difference that liposome arrives rat brain medicine effective content, illustrated that plant sterol is applicable to preparing Betahistine Hydrochloride liposome more.
good effect of the present invention is:betahistine Hydrochloride is made to liposome, can obviously strengthen drug effect, can increase the penetrating power of blood capillary, making medicine arrive cerebrovascular dosage increases, can be used for improving the therapeutic effect of Meniere's disease, can also reduce GI irritation, reduce adverse effect simultaneously, contribute to reduce stomach discomfort, the dizzy side effect that waits of feeling sick.The cholesterol that appliable plant sterol simultaneously of the present invention replaces traditional liposomal preparation technology regulates the mobility of liposome membrane, can improve the oxidation resistance of liposome.Plant sterol is mainly the functional activity composition as angiocardiopathy preventing, and in the present invention, plant sterol can be assisted the drug effect that improves Betahistine Hydrochloride.
Betahistine Hydrochloride liposome has good stability, can obviously strengthen drug effect, can increase the penetrating power of blood capillary, making medicine arrive cerebrovascular dosage increases, can be used for improving the therapeutic effect of Meniere's disease, can also reduce GI irritation, reduce adverse effect simultaneously, contribute to reduce stomach discomfort, the dizzy side effect that waits of feeling sick.The present invention goes back the mobility that cholesterol that appliable plant sterol replaces traditional liposomal preparation technology regulates liposome membrane, can improve the oxidation resistance of liposome, the effective treatment to cardiovascular, cerebrovascular double diseases.
Accompanying drawing explanation
Fig. 1 is acid hydrochloride salt betahistine standard curve.
specific implementation method:
embodiment is used for further illustrating the present invention below, but content of the present invention is not limited to this.
embodiment 1
Preparation method of the present invention:
(1) 3:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 20mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 40mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 5mg/mL, its pH is 5.7;
(4) by the described solution mix homogeneously of step (2) (3), ultrasonic 15 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 500bar, then by liposome, extrudes instrument (filter membrane aperture is 0.4 μ m), obtains Betahistine Hydrochloride liposome (experimental group one).
Matched group preparation method:
(1) 3:1 takes lecithin, cholesterol in mass ratio, then both is dissolved with 20mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 40mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 5mg/mL, its pH is 5.7;
(4) by the described solution mix homogeneously of step (2) (3), ultrasonic 15 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 500bar, then by liposome, extrudes instrument (filter membrane aperture is 0.4 μ m), obtains Betahistine Hydrochloride liposome (matched group one).
embodiment 2
Preparation method of the present invention:
(1) 4:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 25mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 60mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 10mg/mL, its pH is 6.5;
(4) by the described solution mix homogeneously of step (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 800bar, then by liposome, extrudes instrument (filter membrane aperture is between 0.3 μ m), obtains Betahistine Hydrochloride liposome (experimental group two).
Matched group preparation method:
(1) 4:1 takes lecithin, cholesterol in mass ratio, then both is dissolved with 25mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 60mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 10mg/mL, its pH is 6.5;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 800bar, then by liposome, extrudes instrument (filter membrane aperture is between 0.3 μ m), obtains Betahistine Hydrochloride liposome (matched group two).
embodiment 3
Preparation method of the present invention:
(1) 5:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 25mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 60mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 20mg/mL, its pH is 6.8;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 900bar, then by liposome, extrudes instrument (filter membrane aperture is between 0.5 μ m), obtains Betahistine Hydrochloride liposome (experimental group three).
Matched group preparation method:
(1) 5:1 takes lecithin, cholesterol in mass ratio, then both is dissolved with 25mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 60mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 20mg/mL, its pH is 6.8;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 900bar, then by liposome, extrudes instrument (filter membrane aperture is between 0.5 μ m), obtains Betahistine Hydrochloride liposome (matched group three).
embodiment 4
Preparation method of the present invention:
(1) 8:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 30mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 80mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 30mg/mL, its pH is 8.0;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 30 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 1000bar, then by liposome, extrudes instrument (filter membrane aperture is between 10 μ m), obtains Betahistine Hydrochloride liposome (experimental group four).
Matched group preparation method:
(1) 8:1 takes lecithin, cholesterol in mass ratio, then both is dissolved with 30mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 80mL ether impouring lipid film, be that thin film is dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 30mg/mL, its pH is 8.0;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 30 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 1000bar, then by liposome, extrudes instrument (filter membrane aperture is between 10 μ m), obtains Betahistine Hydrochloride liposome (matched group four).
Below experiment shows that acid hydrochloride salt betahistine liposome has higher bioavailability compared with general formulation, can improve drug effect, and prove that reagent provided by the invention and consumption are optimum condition:
1. chromatographic condition: Agilent HC-C
18chromatographic column, with acetonitrile: acetic acid mixed solution (12% sulphuric acid 10mL, 1% tetrabutylammonium hydroxide amine 40mL and water 650 mL, after mixing, add 2.5g sodium lauryl sulphate, dissolve, shake up, regulating pH is 3.3) be (28:72) mobile phase, ultraviolet detection wavelength is 260nm, and number of theoretical plate calculates and should be not less than 1500 by acid hydrochloride salt betahistine peak, and sample introduction is counted its RSD of pin and is less than 20%.
2. get the about 0.1g of acid hydrochloride salt betahistine reference substance, being dissolved in water and being settled to 100mL is stock solution.Get stock solution 1.5,2.0,2.25,2.5,2.75mL, add mobile phase to 25mL, get each concentration liquid 10 μ L injection liquid chromatographies, draw peak area separately.Take concentration as abscissa, and peak area is that vertical coordinate obtains regression equation: y=11977x-16799, R
2=0.9992.These results suggest that acid hydrochloride salt betahistine concentration is good in the concentration range internal linear relation of 100～170 mg/mL.As Fig. 1
3. getting body weight is 180～220g male rat, is divided at random two groups.Press 4.32mgkg for one group
-1dosage gavage give Betahistine Hydrochloride liposome turbid liquor, another group gives isodose commercially available Betahistine Hydrochloride tablet.After successive administration 7 days, after last administration 1h, put to death rat, get cerebral tissue, clean with normal saline flushing, filter paper blots, and weighs; Accurately weighed being placed in homogenizer, add appropriate normal saline (internal organs weight: normal saline=1g:10mL) homogenate, get homogenate and be all placed in centrifuge tube, add 2mL25% hydrochloric acid solution vortex and mix 3 minutes, be placed in 40 ℃ of water-baths and be hydrolyzed 30 minutes.Let cool, add 5mL deionized water, vortex mixes 3 minutes, 8000rmin
-1centrifugal 15min, draws supernatant, the accurate 20 μ L sample introductions of drawing, and injection liquid chromatography, records peak area.Contrast mark curve draws the Betahistine Hydrochloride content of each cerebral tissue.
4. result
Betahistine Hydrochloride liposome prepared by method of the present invention is after administration, and the medicament contg of rat cerebral tissue is as table 1,
Table 1 experimental group rat cerebral tissue Betahistine Hydrochloride content (n=10)
| ? | Betahistine Hydrochloride liposome group (%) | Betahistine Hydrochloride tablet group (%) |
| Experimental group one | 0.3420±0.0046 | 0.0872±0.0148 |
| Experimental group two | 0.3543±0.0547 | 0.0997±0.0186 |
| Experimental group three | 0.3681±0.0458 | 0.1072±0.0143 |
| Experimental group four | 0.3726±0.0843 | 0.1192±0.0376 |
Betahistine Hydrochloride liposome prepared by contrast method is after administration, and the medicine assay of rat cerebral tissue is as table 2,
Table 2 control rats cerebral tissue Betahistine Hydrochloride content (n=10)
| ? | Betahistine Hydrochloride liposome group (%) | Betahistine Hydrochloride tablet group (%) |
| Matched group one | 0.2034±0.0058 | 0.0872±0.0148 |
| Matched group two | 0.2883±0.0148 | 0.0997±0.0186 |
| Matched group three | 0.3068±0.0862 | 0.1072±0.0143 |
| Matched group four | 0.3187±0.0057 | 0.1192±0.0376 |
Above-mentioned experiment shows, Betahistine Hydrochloride liposome has higher bioavailability than conventional tablet, is more conducive to increase the penetrating power of blood capillary, and making medicine arrive cerebrovascular effective dose increases.Can be used for treating Meniere disease, vascular headache and cerebral arteriosclerosis, and can be used for treating acute cerebrovascular disease, as cerebral thrombosis, cerebral embolism etc.The Betahistine Hydrochloride liposome the present invention relates to also can be prepared into tablet, capsule, oral liquid and injection.
Table 3. experimental group and the comparison of control rats cerebral tissue Betahistine Hydrochloride content
| ? | Experimental group (%) | Matched group (%) |
| One | 0.3420±0.0046 | 0.2034±0.0058 |
| Two | 0.3543±0.0547 | 0.2883±0.0148 |
| Three | 0.3681±0.0458 | 0.3068±0.0862 |
| Four | 0.3726±0.0843 | 0.3187±0.0057 |
Experimental group appliable plant sterol substitutes the cholesterol of matched group and prepares liposome, as can be seen from Table 3, Betahistine Hydrochloride content contained in experimental group rat is higher, illustrate that plant sterol is more suitable for as preparing Betahistine Hydrochloride liposome than cholesterol, and the application of plant sterol can improve the drug effect of Betahistine Hydrochloride.
Betahistine Hydrochloride liposome of the present invention has larger advantage in application, and Lipidosome itself has advantages of the drug toxicity of reduction simultaneously.The present invention for treatment cardiovascular and cerebrovascular disease drug provision new thinking.
Claims (1)
1. a Betahistine Hydrochloride liposome, is characterized in that: comprise Betahistine Hydrochloride and Liposomal formulation, wherein, Betahistine Hydrochloride 5～30mg/mL; Liposomal formulation comprises lecithin, two kinds of lipid components of plant sterol, and wherein, the mass ratio of lecithin and plant sterol is 3:1～8:1, and the mass ratio of Betahistine Hydrochloride and TL composition is 1:1～1:15;
The preparation method of described Betahistine Hydrochloride liposome, step is as follows:
(1) 3:1～8:1 takes lecithin, plant sterol in mass ratio, then both is dissolved with 20～30mL dichloromethane, and after dissolving completely, reduction vaporization to thin film forms;
(2) by 40～80mL ether impouring lipid film, make thin film be dissolved in ether completely;
(3) phosphate buffer that preparation contains Betahistine Hydrochloride 5～30mg/mL, its pH is 5.7～8.0;
(4) by the described solution mix homogeneously in (2) (3), ultrasonic 15～30 minutes;
(5) mixed solution after ultrasonic, puts on Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension making is passed through to high pressure homogenizer, pressure is 500～1000bar; Then by liposome, extrude instrument and extrude, filter membrane aperture, at 0.2 μ m～10 μ m, obtains.
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| CN101559039A (en) * | 2009-05-27 | 2009-10-21 | 中国农业科学院油料作物研究所 | Method for producing nattokinase liposome from phytosterol |
| CN102366400A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Betahistine hydrochloride injection and its production technology |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101559039A (en) * | 2009-05-27 | 2009-10-21 | 中国农业科学院油料作物研究所 | Method for producing nattokinase liposome from phytosterol |
| CN102366400A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Betahistine hydrochloride injection and its production technology |
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