CN107362143B - Nifedipine proliposome and preparation method thereof - Google Patents
Nifedipine proliposome and preparation method thereof Download PDFInfo
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- CN107362143B CN107362143B CN201710547026.1A CN201710547026A CN107362143B CN 107362143 B CN107362143 B CN 107362143B CN 201710547026 A CN201710547026 A CN 201710547026A CN 107362143 B CN107362143 B CN 107362143B
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- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
The invention discloses a nifedipine proliposome and also provides a novel PEI-STA polymer which has a synergistic effect with DSPE-PEG2000 to improve the absorption effect of the nifedipine proliposome in intestinal tracts; compared with nifedipine bulk drug, the invention obviously improves the solubility of the drug by more than 50 times, improves the light stability by 2.53 times, and is convenient for storage and transportation. Pharmacokinetic experiments of the nifedipine proliposome prove that the bioavailability of the nifedipine is improved by 10.2 times, the solubility, the stability and the bioavailability of the nifedipine can be improved, the clearing time of the nifedipine in a body can be prolonged, and the administration frequency is reduced. Is a medicine for treating hypertension with wide application prospect.
Description
The technical field is as follows:
the invention discloses a nifedipine proliposome and also provides a preparation process of the medicament, belonging to the technical field of medical pharmacy.
Technical background:
nifedipine is faint yellow crystalline powder, is odorless and tasteless, and is a calcium channel blocker for treating hypertension; however, nifedipine has poor water solubility, low oral bioavailability, significant liver first-pass effect, short in vivo clearance period, high administration frequency, obvious individual difference, and fluctuation of plasma drug concentration is accompanied by side effects of different degrees, so that users feel dizzy when taking nifedipine for the first few times. Common side effects include headache, fatigue, cough, shortness of breath, lethargy, bradycardia, etc., which can lead to rapid blood pressure drop, loss of consciousness, cerebral ischemic infarction, myocardial infarction, complete cardiac obstruction, even death in severe cases. In addition, nifedipine is easy to decompose when exposed to ultraviolet light, and can be decomposed into nitroso derivatives and nitro derivatives, which are not beneficial to use and storage.
Nifedipine has two main obstacles in the absorption of the intestinal tract (1), a hydrophilic mucus layer exists in the intestinal tract, nifedipine is a hydrophobic medicament, is difficult to penetrate through a mucus layer barrier in the intestinal tract and is difficult to be absorbed by the intestinal tract (2), if nifedipine is prepared into a common liposome preparation, although nifedipine can penetrate through the mucus layer, the capability of penetrating through a small intestinal epithelial cell barrier is weak, and the capability of improving the bioavailability of nifedipine is limited.
The invention content is as follows:
the invention discloses a nifedipine proliposome which can improve the solubility, stability and bioavailability of nifedipine, prolong the clearing time of nifedipine in vivo and reduce the administration frequency.
The invention also discloses a preparation method of the nifedipine proliposome drug, which can improve the bioavailability of nifedipine and give full play to the drug effect, reduce side effects and prolong the action time. Is a medicine for treating hypertension with wide application prospect.
The invention discloses a nifedipine proliposome which is characterized by being prepared from the following raw materials in parts by weight:
2-10 parts of HSPC, 0.2-3 parts of sodium deoxycholate, 2-8 parts of nifedipine, 0.2-5 parts of polyethyleneimine-linked stearic acid (PEI-STA), 1-7 parts of DSPE-PEG2000, 4-20 parts of a spray drying protective agent and the balance of preparation auxiliary materials.
The preparation method of the nifedipine proliposome comprises the following steps:
1) synthesis of polyethyleneimine-linked stearic acid (PEI-STA):
1-8 parts of polyethyleneimine with the molecular weight of 600-70000 and 0.6-18 parts of stearic acid are dissolved in 40-200 parts of dichloromethane and subjected to condensation reaction under the catalytic action of 1-14 parts of EDCI and 0.5-10 parts of NHS;
the polyethyleneimine-stearic acid has the following structure:
wherein R ═ COCH3(CH2)16 or H;
linking 1-4 molecules of stearic acid-COCH 3(CH2)16 per polyethyleneimine polymeric unit;
2) weighing HSPC, sodium deoxycholate, nifedipine, polyethylene imine-connected stearic acid and DSPE-PEG2000 in proportion, dissolving in 3000 parts of methanol in 300-.
The polyethyleneimine is a polyamino water-soluble high polymer material, and is colorless or light yellow viscous liquid; according to the invention, hydrophobic stearic acid modified polyethyleneimine is adopted and is modified into an amphiphilic material, so that the amphiphilic stearic acid modified polyethyleneimine and a liposome membrane material can be fused together to construct a nifedipine precursor liposome, and the cationic property of PEI-STA can enhance the capability of the liposome for penetrating through epithelial cells of small intestine and improve the bioavailability of nifedipine.
In addition, DSPE-PEG2000 in the liposome formulation enhances the hydrophilicity of the liposome and improves the ability of the liposome to penetrate the mucus layer barrier in the intestinal tract. The invention discloses a DSPE-PEG2000 in a nifedipine precursor liposome drug formula and a synthesized new material PEI-STA synergistic effect, which enhances the oral bioavailability of nifedipine.
The following experiments show that the nifedipine proliposome medicament disclosed by the invention can improve the solubility, stability and bioavailability of nifedipine, reduce side effects, prolong the clearing time of nifedipine in vivo and reduce the administration frequency.
Solubility: the nifedipine proliposome medicine prepared by adopting the materials with optimized prescription amount has the encapsulating rate of 94.21 percent. After the nifedipine proliposome is redissolved, the solubility of the nifedipine in water at 25 ℃ can reach 10mg/mL which is far higher than 200ug/mL of the nifedipine bulk drug.
Light stability: sealing 1mg/mL nifedipine proliposome and nifedipine bulk drug (dissolved in 10% ethanol, 10% tween 80 and 80% physiological saline), placing in an optical box with 4500LX illumination intensity for 10 days, and determining the light stability of the drug. The results are shown in Table 1.
TABLE 1 photostability of nifedipine proliposomes and nifedipine drug substances of the invention
In vitro release: adopting artificial intestinal fluid and gastric juice to simulate the release condition of the nifedipine proliposome and the raw material in the gastrointestinal tract in vitro, placing 9.6mg of the nifedipine proliposome and the raw material in a pretreated dialysis bag (with the molecular weight cutoff of 8000 + 12,000Da), sealing two ends of the dialysis bag, placing the dialysis bag into 200mL of dissolution medium with the temperature of 37 +/-0.5 ℃, rotating at the speed of 350r/min, taking 5mL of corresponding dissolution medium at fixed time points, immediately adding the same volume of release medium, selecting the time points as 0.083, 0.167, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 48h, measuring the content of nifedipine at different time points, calculating the cumulative release degree at each time point, and drawing a release curve based on the time points, as shown in figure 1. The nifedipine proliposome is relatively stable in the stomach and has a sustained release effect in the intestinal tract.
The pharmacokinetics research of the nifedipine proliposome in the rat body comprises the following steps:
30 rats were randomly divided into 6 groups, and the oral administration dose was 6mg/kg, and the administration groups were the nifedipine proliposome of the present invention prepared in example 2, the nifedipine proliposome not containing DSPE-PEG2000, the nifedipine proliposome not containing PEI-STA, the nifedipine proliposome not containing DSPE-PEG2000 and PEI-STA, the nifedipine bulk drug, and the nifedipine proliposome containing DSPE-PEG2000 and polyethyleneimine, respectively. Two groups of rats were bled at the canthus at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36h after administration, and were placed in a centrifuge tube treated with heparin sodium to centrifuge and take plasma, 10 μ L of 0.02mg/mL internal standard nimodipine solution was added, 10 μ L of 1mol/L sodium hydroxide was added, vortex mixing was performed for 1min, 600 μ L of diethyl ether-trichloromethane (5: 1) was added, vortex mixing was performed for 10min, 10,000rpm was performed, centrifugation was performed for 10min, the upper organic phase was placed in another tube, blow-dried at 40 ℃ under nitrogen flow, and the residue was redissolved with 200 μ L of acetonitrile-water (1:1), and the content of nifedipine was determined by hplc, see fig. 2.
And (4) conclusion: the pharmacokinetic results are shown in fig. 2, the area under the curve (AUC) of rats dosed with nifedipine proliposome without DSPE-PEG2000 and PEI-STA was 1.51 times that of the nifedipine bulk drug group; the AUC of the nifedipine proliposome prepared by the invention is 10.20 times of that of the nifedipine bulk drug; the AUC of the nifedipine proliposome without the DSPE-PEG2000 is 2.28 times of that of the nifedipine bulk drug administration; the AUC of the nifedipine proliposome without PEI-STA is 2.21 times of that of the nifedipine bulk drug administration. The elimination half-life period of the nifedipine bulk drug is 1.39h, and the elimination half-life period of the nifedipine proliposome is 6.30 h.
The AUC of the nifedipine proliposome containing DSPE-PEG2000 and polyethyleneimine is only 2.86 times of that of the nifedipine bulk drug to be administered.
In conclusion, the DSPE-PEG2000 and PEI-STA provided by the invention have a synergistic interaction effect in preparation of the nifedipine proliposome, and intestinal absorption of the nifedipine proliposome is greatly promoted. Compared with the synthesized novel material PEI-STA, the unmodified polyethyleneimine does not have the function of improving the bioavailability of nifedipine by the synergistic effect of DSPE-PEG 2000.
The nifedipine precursor liposome can improve the bioavailability of nifedipine, prolong the elimination half-life period and stabilize the blood concentration.
The nifedipine proliposome medicament disclosed by the invention improves the contact area between the medicament and intestinal epithelial cells by increasing the solubility of nifedipine so as to improve the absorption efficiency, and in addition, the nifedipine proliposome is slowly released in the stomach to form a colloid structure, so that the gastric emptying is delayed, the residence time is improved, and the phenomenon is favorable for improving the bioavailability, prolonging the half-life period and stabilizing the concentration of plasma medicaments.
The invention has the beneficial effects that:
provides a new PEI-STA polymer which has a synergistic effect with DSPE-PEG2000 to improve the absorption effect of the nifedipine proliposome in intestinal tracts; compared with nifedipine bulk drug, the invention obviously improves the solubility of the drug by more than 50 times, improves the light stability by 2.53 times, and is convenient for storage and transportation. The pharmacokinetic experiment of the nifedipine precursor liposome proves that the bioavailability of the nifedipine is improved by 10.2 times.
Drawings
FIG. 1 shows the cumulative release rate of nifedipine proliposome and raw materials in artificial intestinal juice and gastric juice;
figure 2 time course of nifedipine proliposomes in rats.
The specific implementation mode is as follows:
the present invention is further illustrated by the following examples, which do not limit the present invention in any way, and any modifications or changes that can be easily made by a person skilled in the art to the present invention will fall within the scope of the claims of the present invention without departing from the technical solution of the present invention.
Example 1:
1 g of polyethyleneimine with the molecular weight of 600, 0.6 g of stearic acid, 1 g of EDCI as a reaction catalyst, 0.5 g of NHS as a reaction solvent and 40 ml of dichloromethane as a reaction solvent, synthesizing polyethyleneimine linked stearic acid (PEI-STA),
2 g of HSPC, 0.2 g of sodium deoxycholate, 2 g of nifedipine, 0.2 g of polyethylene imine-connected stearic acid and 1 g of DSPE-PEG2000, which are dissolved in 300 ml of methanol, are subjected to ultrasonic treatment until the mixture is completely dissolved to form a lipid phase, the lipid phase is quickly injected into 3000 ml of phosphate buffer to form a liposome, 4 g of mannitol serving as a spray drying protective agent is added for ultrasonic dissolution, and spray drying is carried out to obtain the nifedipine precursor liposome.
Example 2:
8 g of polyethyleneimine with the molecular weight of 70000, 18 g of stearic acid, 14 g of EDCI as a reaction catalyst, 10 g of NHS as a reaction solvent and 200ml of dichloromethane as a reaction solvent, synthesizing polyethyleneimine linked stearic acid (PEI-STA),
10 g of HSPC, 3 g of sodium deoxycholate, 8 g of nifedipine, 5 g of polyethylene imine-connected stearic acid and 7 g of DSPE-PEG2000, which are dissolved in 3000 ml of methanol, are subjected to ultrasonic treatment until the mixture is completely dissolved to form a lipid phase, the lipid phase is quickly injected into 15000 ml of phosphoric acid buffer solution to form a liposome, 20 g of mannitol serving as a spray drying protective agent is added for ultrasonic dissolution, and spray drying is carried out to obtain the nifedipine precursor liposome.
Example 3:
4 g of polyethyleneimine with the molecular weight of 8000, 12 g of stearic acid, 10 g of EDCI as a reaction catalyst, 8 g of NHS as a reaction solvent and 100 ml of dichloromethane as a reaction solvent, synthesizing polyethyleneimine linked stearic acid (PEI-STA),
5 g of HSPC, 1 g of sodium deoxycholate, 4 g of nifedipine, 2 g of polyethylene imine-connected stearic acid and 3 g of DSPE-PEG2000, which are dissolved in 1000 ml of methanol, are subjected to ultrasonic treatment until the mixture is completely dissolved to form a lipid phase, the lipid phase is quickly injected into 10000 ml of phosphate buffer solution to form a liposome, 10 g of mannitol serving as a spray drying protective agent is added for ultrasonic dissolution, and spray drying is carried out to obtain the nifedipine precursor liposome.
Clinical efficacy experiment:
in the clinical test, 240 patients with essential hypertension who meet the conditions after clinical examination screening are randomly divided into two groups (a control group and an experimental group) by adopting a double-blind method, and the patients in the control group take 15mg of nifedipine every time and take 2 times every day; the patients in the experimental group took the nifedipine proliposome (containing 5mg of nifedipine) of examples 1 to 3 1 time per day. After 1 week of continuous administration, systolic pressure and diastolic pressure of two groups of patients were measured, and adverse reactions of the patients during the treatment period were counted, and the results are shown in tables 2 and 3.
TABLE 2 therapeutic Effect of nifedipine proliposomes with nifedipine
Compared with the control group, the patient has no statistical difference in diastolic pressure and systolic pressure in the experimental group before treatment (P > 0.05). After one week of treatment, the blood pressure of the patients was significantly reduced compared to the control group. Represents P <0.01 after treatment of experimental group compared to control group.
TABLE 3 adverse reactions of nifedipine proliposome with nifedipine
Compared with the bulk drug, the nifedipine proliposome has higher bioavailability, so the antihypertensive effect can be improved on the basis of reducing the administration dosage, and the nifedipine proliposome has long elimination half-life period and stable blood concentration, and can reduce the side effect caused by multiple times of high-dose administration.
Claims (1)
1. The nifedipine proliposome is characterized by being prepared from the following raw materials in parts by weight:
2-10 parts of HSPC, 0.2-3 parts of sodium deoxycholate, 2-8 parts of nifedipine, 0.2-5 parts of polyethyleneimine-linked stearic acid, 1-7 parts of DSPE-PEG2000, 4-20 parts of spray drying protective agent and the balance of preparation auxiliary materials;
the preparation method of the nifedipine proliposome comprises the following steps:
1) synthesis of polyethyleneimine-linked stearic acid:
1-8 parts of polyethyleneimine with the molecular weight of 600-70000 and 0.6-18 parts of stearic acid are dissolved in 40-200 parts of dichloromethane and subjected to condensation reaction under the catalytic action of 1-14 parts of EDCI and 0.5-10 parts of NHS;
2) weighing HSPC, sodium deoxycholate, nifedipine, polyethylene imine-connected stearic acid and DSPE-PEG2000 in proportion, dissolving in 3000 parts of methanol in 300-.
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Non-Patent Citations (3)
| Title |
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| Novel Cationic Microbubble Coated with Stearic Acid Modified Polyethylenimine to Enhance DNA Loading and Gene Delivery by Ultrasound;Qiaofeng Jin等;《PLOS ONE》;20130926;第8卷(第9期);第1-10页，尤其是摘要，第2页右栏第2段 * |
| Oleic acid derivative of polyethylenimine-functionalized proliposomes for enhancing oral bioavailability of extract of Ginkgo biloba;Bin Zheng等;《Drug Delivery》;20151203;第23卷(第4期);第1194-1203页，尤其是摘要，第1195页右栏第3段 * |
| 硝苯地平脂质体的制备工艺优化;刘一方;《科学中国人》;20160731;第50页，左栏倒数第3段 * |
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