CN103908678B - A kind of hirudin phosphatide complexes and preparation method thereof and application - Google Patents
A kind of hirudin phosphatide complexes and preparation method thereof and application Download PDFInfo
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Abstract
The invention provides a kind of hirudin phosphatide complexes and preparation method thereof and application, described hirudin phosphatide complexes is made up of hirudin and phospholipid, the mol ratio of described hirudin and phospholipid is that 1:1(is with average molecular weight), hirudin is dissolved in ethanol for (1) by preparation method, obtains the first solution；(2) phospholipid is dissolved with aprotic solvent, obtain the second solution: the first solution and the second solution are sufficiently mixed under (3) stirring condition, remove organic solvent, add Osmitrol, dissolve, filtration, lyophilization and get final product；Lipotropy and the stability of described hirudin phosphatide complexes are greatly improved, and the bioavailability in nephridial tissue significantly improves, and can be used for treating early diabetic nephropathy.
Description
Technical field
The present invention relates to a kind of complex and preparation method thereof and application, especially one hirudin complex and preparation method thereof and application.
Background technology
Hirudin is a kind of single-stranded loop peptide compounds extracted from Hirudo head, and molecular weight is 7000 dalton, is made up of 65 amino acid residues.Hirudin is the important effective ingredient of the one contained in Hirudo, has very strong anticoagulation and antithrombotic acitivity.Along with the development of molecular biology and technique for gene engineering, the lepirudin 023 ludon essentially identical with natural hirudin structure and pharmacologically active is successfully synthesized, and has promoted the clinical practice of hirudin.Such as; in treatment diabetes and complication; Hirudo have effect (the Zhejiang College Of Traditional Chinese Medicine journal improving type 2 diabetes mellitus insulin resistant; 29th volume the 4th phase in 2005); hirudin can reduce microalbumin in urine, improve high solidifying situation; the kidney of diabetic nephropathy and hypertensive renal patient there is good protective effect (clinical rational drug use, the 3rd volume the 22nd phase in 2010).
Hirudin is water-soluble biological macromole, fat-soluble difference, enter internal after be distributed mainly on extracellular fluid, not easily through blood brain barrier, degradable, be not combined (Chinese herbal medicine, the 34th volume the 8th phase in 2003) with plasma protein.These characteristics make that hirudin is more difficult effectively to be absorbed by gastrointestinal mucosa, and therefore its route of administration is mainly drug administration by injection.But the elimination half-life that hirudin is in blood plasma was less than 1 hour, the patient needing long-term anticoagulant is brought very big inconvenience by this.Adopting liposomal encapsulated hirudin is a kind of effective means (CHINA JOURNAL OF CHINESE MATERIA MEDICA, the 32nd volume the 9th phase in 2007) improving hirudin bioavailability, but due to the problem such as envelop rate, particle diameter, current hirudin liposome is used for mucosal drug delivery approach.Therefore, research and develop a kind of truly have curative effect, injectable administration, lasting medicine hirudin pharmaceutical composition become the target of the unremitting pursuit of those skilled in the art.
Summary of the invention
The technical problem to be solved is in that to provide a kind of hirudin phosphatide complexes.
Another technical problem to be solved by this invention is in that the preparation method providing above-mentioned hirudin phosphatide complexes.
Another technical problem to be solved by this invention is in that to provide the application of above-mentioned hirudin phosphatide complexes.
For solving above-mentioned technical problem, the technical scheme is that
A kind of hirudin phosphatide complexes, is made up of hirudin and phospholipid, and the mol ratio of described hirudin and phospholipid is that 1:1(is with average molecular weight), described hirudin phosphatide complexes is prepared by following method:
(1) being dissolved in ethanol by hirudin, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is 1:5-30(g/mL)；
(2) phospholipid is dissolved with aprotic solvent, obtain the second solution, wherein, the amount ratio of described phospholipid and aprotic solvent is 1:10-200(g/mL), described aprotic solvent is the combination in any of any one or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, the first solution and the second solution are sufficiently mixed, remove organic solvent, add Osmitrol, dissolve, filter, lyophilization and get final product.
Above-mentioned hirudin phosphatide complexes, described hirudin can be the natural hirudin that separation and Extraction obtains in various ways, it is also possible to be with the lepirudin 023 ludon of biotechnology synthesis.
Above-mentioned hirudin phosphatide complexes, described phospholipid can be the soybean phospholipid of injection, it is also possible to is the Ovum Gallus domesticus Flavus lecithin of injection.
Preferably, above-mentioned hirudin phosphatide complexes, described ethanol is volumetric concentration 70-90%(v/v) ethanol water.
The preparation method of a kind of hirudin phosphatide complexes, specifically comprises the following steps that
(1) being dissolved in ethanol by hirudin, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is 1:5-30(g/mL)；
(2) phospholipid is dissolved with aprotic solvent, obtain the second solution, wherein, the amount ratio of described phospholipid and aprotic solvent is 1:10-200(g/mL), described aprotic solvent is the combination in any of any one or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) the first solution and the second solution being sufficiently mixed under stirring condition, wherein, the mol ratio of described hirudin and phospholipid is that 1:1(is with average molecular weight), remove organic solvent, add Osmitrol, dissolve, filter, lyophilization and get final product.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (1), the volumetric concentration of ethanol is 70-90%(v/v).
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (3), the first solution and the well-mixed reaction temperature of the second solution are the room temperature boiling temperature to hirudin solution and the mixed liquor of phospholipid solution, to realize being heated to reflux.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (3), the first solution and the second solution well-mixed response time are 5min-2h.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, the method removing organic solvent in described step (3) is distillation under vacuum or atmospheric distillation.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, 5 times-20 times that in described step (3), the consumption (counting with mL) of Osmitrol is hirudin and phospholipid quality summation (in g) value.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (3), in Osmitrol, the concentration of mannitol is 1-20%(g/mL).
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, described step (3) is filtered into the aseptic filtration that filtering accuracy is more than 0.22 μm.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (3), lyophilization is the lyophilization for the purpose of dewatering.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, specifically comprise the following steps that
(1) hirudin is dissolved in 80%(v/v) in ethanol, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is 1:15(g/mL)；
(2) Ovum Gallus domesticus Flavus lecithin is dissolved with chloroform, obtain the second solution, wherein, the amount ratio of described Ovum Gallus domesticus Flavus lecithin and chloroform is 1:50(g/mL), described aprotic solvent is the combination in any of any one or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, second solution is dropped in the first solution, being heated to reflux, react 30min, heating in water bath is vaporized solvent, add 2% mannitol solution to redissolve, wherein, 5 times that the consumption (counting with mL) of Osmitrol is hirudin and phospholipid quality summation (in g), 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes.
The application in preparing the medicine for treating early diabetic nephropathy of the above-mentioned hirudin phosphatide complexes.
Above-mentioned hirudin phosphatide complexes redissolves with water for injection, is made into finite concentration, namely can be used for treating early diabetic nephropathy.
The invention has the beneficial effects as follows:
Above-mentioned hirudin phosphatide complexes, it is be prepared from by specific method, phospholipid is the basic component of cell membrane, strong with the affinity of cell membrane, after hirudin forms phosphatide complexes with lecithin with specific consumption and specific complex method, by the biomacromolecule that molecular separating force is formed, the lipotropy and the stability that make hirudin are greatly improved, as pharmaceutical carrier, phospholipid can promote that hirudin is transferred to each organ-tissue from blood better, enter cell, after intravenous administration, hirudin bioavailability in nephridial tissue significantly improves, to the renal function improving early diabetic nephropathy patient, there is important clinical value；Its preparation method is simple, is suitable for the needs that large-scale industrial produces.
Accompanying drawing explanation
Fig. 1 is the infrared spectrogram of hirudin；
Fig. 2 is the infrared spectrogram of soybean phospholipid；
Fig. 3 is the infrared spectrogram of hirudin soybean phospholipid complex；
Fig. 4 is hirudin Drug-time curve in hirudin and hirudin phosphatide complexes rat tail vein drug administration by injection nephridial tissue dialysis solution;
Fig. 5 is diabetic nephropathy tissue pathological slice；
Fig. 6 is the section of diabetic nephropathy tissue T GF-β SABC；
Fig. 7 is the section of diabetic nephropathy tissue VEGF SABC.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme of the present invention is further described.
Embodiment 1
Weigh 0.7g hirudin, be dissolved in 3.5mL90% ethanol.Separately take 0.08g soybean phospholipid, be dissolved in 16mL methanol.Under stirring, the alcoholic solution of hirudin is dropped in the methanol solution of soybean phospholipid, be heated to reflux, react 2h, removal of solvent under reduced pressure, adds 4mL20% Osmitrol and redissolves, 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtains off-white color hirudin phosphatide complexes 1.02g, yield 64%.
Embodiment 2
Weigh 2g hirudin, be dissolved in 60mL70% ethanol.Separately take 0.23g soybean phospholipid, be dissolved in 2.3mL oxolane.Under stirring, the tetrahydrofuran solution of soybean phospholipid is dropped in the alcoholic solution of hirudin, it is heated to reflux, reaction 5min, removal of solvent under reduced pressure, add 44.6mL1% mannitol solution and redissolve, 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes 2.42g, yield 90%.
Embodiment 3
Weigh 1.2g hirudin, be dissolved in 18mL80% ethanol.Separately take 0.14g Ovum Gallus domesticus Flavus lecithin, be dissolved in 7mL chloroform.Under stirring, the chloroform soln of Ovum Gallus domesticus Flavus lecithin is dropped in the alcoholic solution of hirudin, it is heated to reflux, reaction 30min, heating in water bath is vaporized solvent, adds 6.7mL2% mannitol solution and redissolves, 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes 1.37g, yield 93%.
Embodiment 4
Weigh 1.4g lepirudin 023 ludon, be dissolved in 14mL85% ethanol.Separately take 0.16g Ovum Gallus domesticus Flavus lecithin, be dissolved in 16mL ether.Under stirring, the alcoholic solution of lepirudin 023 ludon is dropped in the diethyl ether solution of Ovum Gallus domesticus Flavus lecithin, room temperature reaction 1h, heating in water bath is vaporized solvent, add 15.6mL4% mannitol solution to redissolve, 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtain off-white color lepirudin 023 ludon phosphatide complexes 2.13g, yield 84%.
Embodiment 5
Weigh 4.2g lepirudin 023 ludon, be dissolved in 80mL75% ethanol.Separately take 0.48g Ovum Gallus domesticus Flavus lecithin, be dissolved in 25mL dioxane.Under stirring, the dioxane solution of Ovum Gallus domesticus Flavus lecithin is dropped in the alcoholic solution of lepirudin 023 ludon, room temperature reaction 1.5h, remove solvent under reduced pressure, add 70mL10% mannitol solution to redissolve, 0.22 μm of filtering with microporous membrane, filtrate lyophilization, obtain off-white color lepirudin 023 ludon phosphatide complexes 7.58g, yield 65%.
Embodiment 6
Take 0.1g hirudin, 0.1 soybean phospholipid respectively and be equivalent to hirudin phosphatide complexes described in the embodiment 3 of 0.1g hirudin, and appropriate potassium bromide mixed pressuring plate, it is placed in infrared spectrometer, in 400-4000cm-1Scanning.As shown in Figure 1, Figure 2 and Figure 3, the infrared spectrogram of contrast hirudin and hirudin phosphatide complexes is it can be seen that 1439cm-1The peak that is significantly stronger than by force in hirudin, carbon nitrogen stretching vibration peak peak in the composite strong, and peak broadens, the strong electricity inductive effect of inhaling of the quaternary nitrogen being likely to be due in phospholipid in phosphatidylcholine structure causes the conjugated electrons number on original C-N key to increase, thus causing the influx and translocation of C-N key, and cause the absworption peak blue shift (3cm of C-N key-1), thus illustrating, hirudin Phosphatidylcholine Complex is formed, simultaneously as the amide Ⅰ (1629cm in hirudin albumen-1) and amide II be with (1558cm-1) peak before and after compound is strong and peak position does not all change, it was shown that the one-level α-helixstructure of hirudin albumen and maintaining all is not destroyed with the disulfide bond of stable space conformation, hydrogen bond, it was shown that the activity of hirudin should be uninfluenced after compound.
Embodiment 7
Weigh about 10mg hirudin and the hirudin phosphatide complexes being equivalent to 10mg hirudin described in embodiment 3 respectively, it is dissolved in pH6.86 phosphate buffer, it is placed in 50,55,60,65 DEG C of waters bath with thermostatic control, sampled in 60,120,180,240 minutes, with isopropanol to about 50 μ g/mL, according to the concentration change of hirudin in solution under following high-efficient liquid phase chromatogram condition mensuration different temperatures, being 0.96h according to the half-life that classical constant temperature accelerated test Arrhenius equation calculates hirudin, the half-life of hirudin phosphatide complexes is 16.62 hours.After phospholipid compound, the half-life of hirudin adds 17 times.
Chromatographic condition: chromatographic column KromasilC18 (250 × 4.6mm, 5 μm), mobile phase: acetonitrile-methanol-water-formic acid (20:55:24:1), column temperature 30 DEG C, flow velocity lmL/min, detects wavelength 276nm.
Embodiment 8
Healthy male Wistar rat 8, is randomly divided into 2 groups, often group 4.After Rat Fast 12h, chloral hydrate anesthesia, skin before longitudinal incision kidney under the rib of left side, otch is about 1cm, extrudes forward from back, makes left kidney dissociate to skin from incision, puncture at renal cortex position with the wire dialysis needle (molecular cut off 100,000) of full heparin, keeping needle gage kidney epidermis to be about 1mm, dialysis solution is ultra-pure water, and flow velocity is 200 μ L/h.After balance 1h, tail vein injection is administered: hirudin group tail vein injection 0.5mL hirudin normal saline solution (hirudin 0.1mg/mL), hirudin phosphatide complexes normal saline solution (in hirudin 0.1mg/mL) described in complex group tail vein injection 0.5mL embodiment 3.The dialysis solution that every 0.5h collects measures hirudin content with ELISA method.By the hirudin content in the renal tissue dialysis solution that records with PKSolver2.0 software processes, obtaining Drug-time curve as shown in Figure 4, pharmacokinetic parameter is as shown in table 1.
Table 1 hirudin and hirudin phosphatide complexes rat tail vein drug administration by injection
The pharmacokinetic parameter of hirudin in nephridial tissue dialysis solution
Hirudin phosphatide complexes is at the half-life (t in kidney of rats portion1/2) for 2.3 times of hirudin, the relative bioavailability (F of complexrel) it being better than hirudin, complex apparent volume of distribution (V) adds 2 times, and prompting phospholipid compound makes hirudin have certain targeting feature.
Embodiment 9
The efficacy experiment of early diabetic nephropathy rat model
1, packet and modeling method: healthy male Wistar rat 40, randomly draw 10 for Normal group, the nephrectomy on the left of all the other 30 rats underwent, tail vein injection STZ (streptozotocin) 30mg/kg after 1 week, blood glucose value > 16.8mmol/L be diabetes set up, after 8 weeks, collect diabetes rat 24h urine, measuring urine protein, microalbuminuria occur, namely Diabetic nephropathy animal model is set up, it is randomly divided into diabetic nephropathy model group, hirudin group, hirudin phosphatide complexes group), often group 10.
2, Therapeutic Method: hirudin group (lumbar injection hirudin 2u/kg d), hirudin phosphatide complexes group (described in lumbar injection embodiment 3 hirudin phosphatide complexes 2u/kg d), blank group, model control group give normal saline lumbar injection 8 weeks, give normal diet and feed.
3, relevant curative effect index, biochemical indicator and detection method: observe body weight, blood glucose, twenty-four-hour urine amount, put method of exempting from and survey microdose urine protein, the dye pathological change of nephridial tissue of renal index (kidney weight and weight ratio), light Microscopic observation HE is shown in that Fig. 5, SABC detection nephridial tissue VEGF, TGF-β are expressed and seen Fig. 6, Fig. 7.
4, statistical method: experimental data adopts t inspection and variance analysis
5, result
5.1 each group rat blood sugar levels () compare, the no significant difference (P > 0.05) of each group, there is comparability.Dead 3 of model group rats, dead 3 of hirudin group, dead 2 of hirudin phosphatide complexes group, it is in modeling one week after, it is considered to traumatic infection blood glucose is too high to be caused.
Early diabetic nephropathy rat model body weight that STZ is induced by 5.2 hirudin phosphatide complexes and the impact (see table 2) of renal index (kidney weight/body weight)
The impact of early diabetic nephropathy rat body weight that STZ is induced by table 2 Hirudo phosphatide complexes and renal index ()
Note: compare with blank group, * P < 0.05;Compare with model group, #P < 0.05, ##P < 0.01.
The impact (see table 3) of the early diabetic nephropathy rat model renal function that STZ is induced by 5.3 hirudin phosphatide complexes
The impact (x ± s) of the early diabetic nephropathy rat model renal function that STZ is induced by table 3 hirudin phosphatide complexes
Note: compare with blank group, * P < 0.05;Compare with model group, #P < 0.05.
6, conclusion
This experiment finds, after hirudin phosphatide complexes intervenes the early diabetic nephropathy rat model of STZ induction, rat kidney hypertrophy index reduces, renal function index (blood urea nitrogen), 24h excretion quantity of urinary protein are substantially lower than matched group, pathological change alleviates, SABC shows can effectively reduce TGF-β 1, the VEGF expression in nephridial tissue, and curative effect is better than alone hirudin group, and prompting hirudin phosphatide complexes treatment early diabetic nephropathy can improve curative effect than the treatment of alone hirudin.
The above-mentioned detailed description this kind of hirudin phosphatide complexes and preparation method thereof carried out with application with reference to embodiment; it is illustrative rather than determinate; can according to restriction scope list several embodiments; therefore without departing from changing and modifications under present general inventive concept, should belong within protection scope of the present invention.
Claims (9)
1. a hirudin phosphatide complexes, it is characterised in that: being made up of hirudin and phospholipid, the mol ratio of described hirudin and phospholipid is calculated as 1:1 with mean molecule quantity, and described hirudin phosphatide complexes is prepared by following method:
(1) being dissolved in ethanol by hirudin, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is calculated as 1:5-30 by g/mL；
(2) phospholipid is dissolved with aprotic solvent, obtain the second solution, wherein, the amount ratio of described phospholipid and aprotic solvent is calculated as 1:10-200 by g/mL, and described aprotic solvent is the combination in any of any one or several any concentration in oxolane, chloroform, methanol, ether or dioxane；
(3) under stirring condition, the first solution and the second solution are sufficiently mixed, remove organic solvent, add Osmitrol, dissolve, filter, lyophilization and get final product.
2. the preparation method of the hirudin phosphatide complexes described in claim 1, it is characterised in that: specifically comprise the following steps that
(1) being dissolved in ethanol by hirudin, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is calculated as 1:5-30 by g/mL；
(2) phospholipid is dissolved with aprotic solvent, obtain the second solution, wherein, the amount ratio of described phospholipid and aprotic solvent is calculated as 1:10-200 by g/mL, and described aprotic solvent is the combination in any of any one or several any concentration in oxolane, chloroform, methanol, ether or dioxane；
(3) the first solution and the second solution being sufficiently mixed under stirring condition, wherein, the mol ratio of described hirudin and phospholipid is calculated as 1:1 with mean molecule quantity, removes organic solvent, adds Osmitrol, dissolves, and filters, lyophilization and get final product.
3. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: in described step (1), the volumetric concentration of ethanol is 70-90% (v/v).
4. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: in described step (3), the first solution and the second solution well-mixed response time are 5min-2h.
5. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: in described step (3), the consumption of Osmitrol is calculated as 5-20 times in gram of hirudin and phospholipid quality total value with milliliter.
6. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: in described step (3), in Osmitrol, the concentration of mannitol is calculated as 1-20% by g/mL.
7. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: described step (3) is filtered into the aseptic filtration that filtering accuracy is more than 0.22 μm.
8. the preparation method of hirudin phosphatide complexes according to claim 2, it is characterised in that: specifically comprise the following steps that
(1) being dissolved in by hirudin in 80% (v/v) ethanol, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is calculated as 1:15 by g/mL；
(2) being dissolved with chloroform by Ovum Gallus domesticus Flavus lecithin, obtain the second solution, wherein, the amount ratio of described Ovum Gallus domesticus Flavus lecithin and chloroform is calculated as 1:50 by g/mL；
(3) under stirring condition, second solution is dropped in the first solution, being heated to reflux, react 30min, heating in water bath is vaporized solvent, add 2% mannitol solution to redissolve, wherein, the consumption of Osmitrol is calculated as 5 times in gram of hirudin and phospholipid quality total value, 0.22 μm of filtering with microporous membrane with milliliter, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes.
9. the application in preparing the medicine for treating early diabetic nephropathy of the hirudin phosphatide complexes described in claim 1.
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| "水蛭素药物治疗尿微量白蛋白为主要表现的糖尿病肾病和高血压肾病的临床研究";李莹等;《临床合理用药》;20101130;第3卷(第22期);第6-7页 * |
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Effective date of registration: 20180703 Address after: 537300 Pingnan County Industrial Park in Guigang, the Guangxi Zhuang Autonomous Region (plot A) fifth buildings for migrant workers' entrepreneurship Park Patentee after: Guangxi Kang Yu biological Limited by Share Ltd Address before: 537000 sunrise room 8, 5 building, 1 Lian Sheng Road, Yuzhou District, Yulin, the Guangxi Zhuang Autonomous Region Patentee before: Guangxi Nan Bazai Science and Technology Ltd. |
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