CN103908678A - Hirudin phospholipid complex and preparation method and application thereof - Google Patents
Hirudin phospholipid complex and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a hirudin phospholipid complex and a preparation method and an application thereof. The hirudin phospholipid complex is composed of hirudin and phospholipid, the molar ratio of the hirudin to the phospholipid is 1:1 (by average molecular weight). The preparation method comprises the following steps: (1) dissolving the hirudin in ethanol to obtain a first solution; (2) dissolving the phospholipid in an aprotic solvent to obtain a second solution; (3) fully mixing the first solution with the second solution under a stirring condition, removing the organic solvent, adding an mannitol aqueous solution, dissolving, drying and freeze-drying. The lipophilicity and stability of the hirudin phospholipid complex are greatly improved, the bioavailability in the renal tissue is obviously improved, and the hirudin phospholipid complex 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 a kind of hirudin complex and preparation method thereof and application.
Background technology
Hirudin is a kind of single-stranded loop peptide compounds extracting from Hirudo head, and molecular weight is 7000 dalton, is made up of 65 amino acid residues.Hirudin is the important effective ingredient of one containing in Hirudo, has very strong anticoagulation and antithrombotic acitivity.Along with the development of molecular biology and technique for gene engineering, be successfully synthesized with natural hirudin structure and the essentially identical lepirudin 023 ludon of pharmacologically active, promote the clinical practice of hirudin.For example; aspect treatment diabetes and complication; hirudin is improved effect (the Zhejiang College Of Traditional Chinese Medicine journal of type 2 diabetes mellitus insulin resistant; the 29th the 4th phase of volume in 2005); hirudin can reduce microalbumin in urine, improve high solidifying situation; diabetic nephropathy and hypertensive renal patient's kidney is had to good protective effect (clinical rational drug use, the 3rd the 22nd phase of volume in 2010).
Hirudin is water-soluble biological macromole, fat-soluble poor, is mainly distributed in extracellular fluid after entering in body, is difficult for seeing through blood brain barrier, and easily degraded, is not combined with plasma protein (Chinese herbal medicine, the 34th the 8th phase of volume in 2003).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 of hirudin in blood plasma, this patient to the long-term anticoagulant of needs brought very big inconvenience less than 1 hour.Adopting liposomal encapsulated hirudin is a kind of effective means (CHINA JOURNAL OF CHINESE MATERIA MEDICA, the 32nd the 9th phase of volume in 2007) of improving hirudin bioavailability, but due to the problem such as envelop rate, particle diameter, hirudin liposome is used for mucosal drug delivery approach at present.Therefore, research and develop a kind of target that truly has the hirudin pharmaceutical composition of curative effect, injectable administration, lasting medicine to become those skilled in the art's unremitting pursue.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of hirudin phosphatide complexes.
Another technical problem to be solved by this invention is to provide the preparation method of above-mentioned hirudin phosphatide complexes.
Another technical problem to be solved by this invention is to provide the application of above-mentioned hirudin phosphatide complexes.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A kind of hirudin phosphatide complexes, by hirudin and Lipid composition, the mol ratio of described hirudin and phospholipid is that 1:1(is in mean molecule quantity), described hirudin phosphatide complexes is prepared by following method:
(1) hirudin is dissolved in ethanol, obtains 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 or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, the first solution is fully mixed with the second solution, remove organic solvent, add Osmitrol, dissolve, filter lyophilization and get final product.
Above-mentioned hirudin phosphatide complexes, described hirudin can be the natural hirudin obtaining with the whole bag of tricks separation and Extraction, can be also the lepirudin 023 ludon synthetic with biotechnology.
Above-mentioned hirudin phosphatide complexes, described phospholipid can be the soybean phospholipid of injection, can be also 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.
A preparation method for hirudin phosphatide complexes, concrete steps are as follows:
(1) hirudin is dissolved in ethanol, obtains 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 or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, the first solution is fully mixed with the second solution, wherein, the mol ratio of described hirudin and phospholipid is that 1:1(is in mean molecule quantity), 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 boiling temperature of room temperature to the mixed liquor of hirudin solution and phospholipid solution, to realize reflux.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, in described step (3), the first solution and well-mixed response time of the second solution are 5min-2h.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, the method for removing organic solvent in described step (3) is distillation under vacuum or atmospheric distillation.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, the consumption (take mL) of Osmitrol is for hirudin and phospholipid quality summation are (in 5 times-20 times that g) are worth in described step (3).
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, in described step (3), being filtered into filtering accuracy is aseptic filtration more than 0.22 μ m.
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, lyophilization is that to dewater be the lyophilization of object in described step (3).
Preferably, the preparation method of above-mentioned hirudin phosphatide complexes, concrete steps are as follows:
(1) hirudin is dissolved in to 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 or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, the second solution is dropped in the first solution, reflux, reaction 30min, heating in water bath is waved loose solvent, add 2% mannitol solution to redissolve, wherein, the consumption of Osmitrol (take mL) as hirudin and phospholipid quality summation (in g) 5 times, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes.
The application of above-mentioned hirudin phosphatide complexes aspect the medicine for the preparation for the treatment of early diabetic nephropathy.
Above-mentioned hirudin phosphatide complexes redissolves with water for injection, is made into finite concentration, can be used for the treatment of early diabetic nephropathy.
The invention has the beneficial effects as follows:
Above-mentioned hirudin phosphatide complexes, to be prepared from by specific method, phospholipid is the basic composition material of cell membrane, strong with the affinity of cell membrane, when hirudin and lecithin form after phosphatide complexes with specific consumption and specific complex method, the biomacromolecule forming by molecular separating force, lipotropy and the stability of hirudin are improved greatly, phospholipid can promote hirudin better from blood transfer to each organ-tissue as pharmaceutical carrier, enter cell, after intravenous administration, the bioavailability of hirudin in nephridial tissue obviously improves, to improving early diabetic nephropathy patient's renal function, there is important clinical value, its preparation method is simple, is applicable to the needs that large-scale industrial is produced.
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 curve when hirudin medicine 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 that diabetic nephropathy is organized the section of VEGF SABC.
The specific embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further described.
Embodiment 1
Take 0.7g hirudin, be dissolved in 3.5mL90% ethanol.Separately get 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, reflux, reaction 2h, removal of solvent under reduced pressure, adds 4mL20% Osmitrol to redissolve, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtains off-white color hirudin phosphatide complexes 1.02g, yield 64%.
Embodiment 2
Take 2g hirudin, be dissolved in 60mL70% ethanol.Separately get 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, reflux, reaction 5min, removal of solvent under reduced pressure, adds 44.6mL1% mannitol solution to redissolve, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes 2.42g, yield 90%.
Embodiment 3
Take 1.2g hirudin, be dissolved in 18mL80% ethanol.Separately get 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, reflux, reaction 30min, heating in water bath is waved loose solvent, adds 6.7mL2% mannitol solution to redissolve, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes 1.37g, yield 93%.
Embodiment 4
Take 1.4g lepirudin 023 ludon, be dissolved in 14mL85% ethanol.Separately get 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 waved loose solvent, add 15.6mL4% mannitol solution to redissolve, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtain off-white color lepirudin 023 ludon phosphatide complexes 2.13g, yield 84%.
Embodiment 5
Take 4.2g lepirudin 023 ludon, be dissolved in 80mL75% ethanol.Separately get 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 μ m filtering with microporous membrane, filtrate lyophilization, obtain off-white color lepirudin 023 ludon phosphatide complexes 7.58g, yield 65%.
Embodiment 6
Get respectively 0.1g hirudin, 0.1 soybean phospholipid and be equivalent to hirudin phosphatide complexes described in the embodiment 3 of 0.1g hirudin, with appropriate potassium bromide mixed pressuring plate, be 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 known, 1439cm
-1to be obviously better than by force peak in hirudin strong at the peak of carbon nitrogen stretching vibration peak in complex, and peak broadens, may increase because the electric inductive effect of strong suction of the quaternary nitrogen in phosphatidylcholine structure in phospholipid causes the conjugated electrons number on original C-N key, thereby cause the absorption of C-N key to strengthen, and cause the absworption peak blue shift (3cm of C-N key
-1), explanation thus, hirudin Phosphatidylcholine Complex forms, meanwhile, due to the amide Ⅰ (1629cm in hirudin albumen
-1) and amide II band (1558cm
-1) at the peak of compound front and back, strong and peak position does not all change, and shows the one-level α-helixstructure of hirudin albumen and remains all not destroyed with disulfide bond, the hydrogen bond of stable space conformation, shows that the activity of hirudin should be uninfluenced after compound.
Embodiment 7
Take respectively the hirudin phosphatide complexes that is equivalent to 10mg hirudin described in about 10mg hirudin and embodiment 3, be dissolved in pH6.86 phosphate buffer, be placed in 50,55,60,65 ℃ of waters bath with thermostatic control, in sampling in 60,120,180,240 minutes, with extremely approximately 50 μ g/mL of isopropanol, according to the concentration change of hirudin in solution under following high-efficient liquid phase chromatogram condition mensuration different temperatures, the half-life that calculates hirudin according to classical constant temperature acceleration laboratory method Arrhenius equation is 0.96h, and the half-life of hirudin phosphatide complexes is 16.62 hours.After compound with phospholipid, the half-life of hirudin has increased by 17 times.
Chromatographic condition: chromatographic column Kromasil C18 (250 × 4.6mm, 5 μ m), mobile phase: acetonitrile-methanol-water-formic acid (20:55:24:1), 30 ℃ of column temperatures, flow velocity lmL/min, detects wavelength 276nm.
Embodiment 8
8 of healthy male Wistar rats, are divided into 2 groups, 4 every group at random.After rat fasting 12h, chloral hydrate anesthesia, along skin before longitudinal incision kidney under the rib of left side, the about 1cm of otch, pushes 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) that is full of heparin, keep the about 1mm of needle gage kidney epidermis, dialysis solution is ultra-pure water, and flow velocity is 200 μ L/h.After balance 1h, tail vein injection administration: 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 is measured hirudin content with ELISA method.By the hirudin content in the renal tissue dialysis solution recording, with PK Solver2.0 software processes, while obtaining medicine, as shown in Figure 4, pharmacokinetic parameter is as shown in table 1 for curve.
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 of kidney of rats portion (t
1/2) be 2.3 times of hirudin, the relative bioavailability (F of complex
rel) being better than hirudin, complex apparent volume of distribution (V) has increased by 2 times, and the compound hirudin that makes of prompting phospholipid has certain targeting feature.
Embodiment 9
The efficacy experiment of early diabetic nephropathy rat model
1, grouping and modeling method: 40 of healthy male Wistar rats, randomly draw 10 for Normal group, all the other 30 rats underwent left side nephrectomys, tail vein injection STZ (streptozotocin) 30mg/kg after 1 week, blood glucose value >16.8mmol/L is that diabetes are set up, after 8 weeks, collect diabetes rat 24h urine, measure urine protein, occur microalbuminuria, Diabetic nephropathy animal model is set up, be divided at random diabetic nephropathy model group, hirudin group, hirudin phosphatide complexes group), 10 every group.
2, Therapeutic Method: hirudin group (lumbar injection hirudin 2u/kgd), hirudin phosphatide complexes group (hirudin phosphatide complexes 2u/kgd described in lumbar injection embodiment 3), blank group, model control group give equivalent 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 the method for exempting from and survey the pathological change of microdose urine protein, renal index (kidney heavy and weight ratio), light Microscopic observation HE dyeing nephridial tissue and see that Fig. 5, SABC detect nephridial tissue VEGF, TGF-β and express and see Fig. 6, Fig. 7.
4, statistical method: experimental data adopts t check and variance analysis
5, result
5.1 each group rat blood sugar levels (
) relatively, the difference not statistically significant (P>0.05) of each group, has comparability.3 of model group rats deaths, dead 3 of hirudin group, dead 2 of hirudin phosphatide complexes group, was after modeling in one week, considered too high the causing of traumatic infection blood glucose.
The early diabetic nephropathy rat model body weight that 5.2 hirudin phosphatide complexes are induced STZ and the impact (in table 2) of renal index (kidney weight/body weight)
The early diabetic nephropathy rat body weight of table 2 Hirudo phosphatide complexes on STZ induction and the impact of renal index (
)
Note: with the comparison of blank group, * P<0.05; With model group comparison, #P<0.05, ##P<0.01.
The impact (in table 3) of the early diabetic nephropathy rat model renal function of 5.3 hirudin phosphatide complexes on STZ induction
The impact of the early diabetic nephropathy rat model renal function of table 3 hirudin phosphatide complexes on STZ induction (x ± s)
Note: with the comparison of blank group, * P<0.05; With model group comparison, #P<0.05.
6, conclusion
This experiment is found, hirudin phosphatide complexes is intervened after the early diabetic nephropathy rat model of STZ induction, the loose index of rat kidney reduces, renal function index (blood urea nitrogen), 24h excretion quantity of urinary protein are all significantly 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, prompting hirudin phosphatide complexes treatment early diabetic nephropathy can improve curative effect than alone hirudin treatment.
Above-mentioned detailed description of this kind of hirudin phosphatide complexes and preparation method thereof and application being carried out with reference to embodiment; illustrative rather than determinate; can list several embodiment according to institute's limited range; therefore in the variation and the modification that do not depart under general plotting of the present invention, within should belonging to protection scope of the present invention.
Claims (9)
1. a hirudin phosphatide complexes, is characterized in that: by hirudin and Lipid composition, the mol ratio of described hirudin and phospholipid is counted 1:1 with mean molecule quantity, and described hirudin phosphatide complexes is prepared by following method:
(1) hirudin is dissolved in ethanol, obtains the first solution, wherein, the amount ratio of described hirudin and ethanol is counted 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 counted 1:10-200 by g/mL, and described aprotic solvent is the combination in any of any or several any concentration in oxolane, chloroform, methanol, ether or dioxane;
(3) under stirring condition, the first solution is fully mixed with the second solution, remove organic solvent, add Osmitrol, dissolve, filter lyophilization and get final product.
2. the preparation method of hirudin phosphatide complexes claimed in claim 1, is characterized in that: concrete steps are as follows:
(1) hirudin is dissolved in ethanol, obtains the first solution, wherein, the amount ratio of described hirudin and ethanol is counted 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 counted 1:10-200 by g/mL, and described aprotic solvent is the combination in any of any or several any concentration in oxolane, chloroform, methanol, ether or dioxane:
(3) under stirring condition, the first solution is fully mixed with the second solution, wherein, the mol ratio of described hirudin and phospholipid is counted 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, is characterized 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, is characterized in that: in described step (3), the first solution and well-mixed response time of the second solution are 5min-2h.
5. the preparation method of hirudin phosphatide complexes according to claim 2, is characterized in that: in described step (3) consumption of Osmitrol in milliliter count hirudin and phospholipid quality total value with gram 5-20 doubly.
6. the preparation method of hirudin phosphatide complexes according to claim 2, is characterized in that: in described step (3), in Osmitrol, the concentration of mannitol is counted 1-20% by g/mL.
7. the preparation method of hirudin phosphatide complexes according to claim 2, is characterized in that: in described step (3), being filtered into filtering accuracy is aseptic filtration more than 0.22 μ m.
8. the preparation method of hirudin phosphatide complexes according to claim 2, is characterized in that: concrete steps are as follows:
(1) hirudin is dissolved in to 80%(v/v) in ethanol, obtain the first solution, wherein, the amount ratio of described hirudin and ethanol is counted 1:15 by 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 counted 1:50 by g/mL;
(3) under stirring condition, the second solution is dropped in the first solution, reflux, reaction 30min, heating in water bath is waved loose solvent, add 2% mannitol solution to redissolve, wherein, the consumption of Osmitrol in milliliter count hirudin and phospholipid quality total value with gram 5 times, 0.22 μ m filtering with microporous membrane, filtrate lyophilization, obtains light yellow hirudin phosphatide complexes.
9. the application of hirudin phosphatide complexes claimed in claim 1 aspect the medicine for the preparation for the treatment of early diabetic nephropathy.
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| CN101088524A (en) * | 2006-06-12 | 2007-12-19 | 大百汇生物科技（深圳）有限公司 | Phosphatide composition of active skull cap components and its prepn process and prepn |
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| CN101088524A (en) * | 2006-06-12 | 2007-12-19 | 大百汇生物科技（深圳）有限公司 | Phosphatide composition of active skull cap components and its prepn process and prepn |
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| Title |
|---|
| 李莹等: ""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"", 《临床合理用药》, vol. 3, no. 22, 30 November 2010 (2010-11-30), pages 6 - 7 * |
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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. |