CN109481419B - Rosiglitazone nano preparation and preparation method and application thereof - Google Patents
Rosiglitazone nano preparation and preparation method and application thereof Download PDFInfo
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention discloses application of a rosiglitazone nano preparation in treating vascular restenosis, and relates to a rosiglitazone composition which comprises rosiglitazone, polylactic acid-polyglycolic acid copolymer, lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, and a rosiglitazone nano preparation which is a nano particle formed by rosiglitazone, polylactic acid-polyglycolic acid copolymer, lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, wherein the nano preparation is of a spherical structure, and the particle size is between 250-300 nanometers. The rosiglitazone nanometer preparation can treat intravascular restenosis after implantation of intravascular rack effectively, lower the toxicity of rosiglitazone and raise biological safety.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a rosiglitazone nano preparation, a preparation method and application thereof.
Background
Cardiovascular and cerebrovascular diseases are currently one of the leading causes of death. Among them, stenosis or occlusion of blood vessels is a major cause of stroke. Currently, endovascular therapy and angioplasty are among the effective means of treating stenosis or occlusion of blood vessels, and can rapidly improve blood supply to the brain. However, restenosis or thrombosis of the blood vessel may occur after the implantation of the stent, and the conventional treatment scheme is to implant the stent again at the site of restenosis. The sandwich cake type treatment of the stent-in-stent undoubtedly leads to the defects of reduction of the area of the blood vessel cavity, occurrence of restenosis, formation of late thrombus and the like. Although the use of drug eluting stents has reduced the occurrence of intravascular restenosis at present, the use of drug eluting stents still remains expensive and does not completely prevent intravascular restenosis. Clinically, a treatment scheme with high efficiency, reasonable price and convenient use is needed. The method of clinical research of using nanometer preparation for treating vascular restenosis is to coat the medicine for resisting cell proliferation in the nanometer preparation, and after the nanometer preparation is applied to the narrow part, the medicine enters the inner membrane of the blood vessel via slow release or controlled release to play the role of resisting restenosis, and no implant (such as stent beam) is left in vivo, so that the nanometer preparation has many advantages and can be accepted by more patients later.
Rosiglitazone (Rosiglitazone) has the chemical name 5- {4- [2- (methyl-2-pyridinylamino) ethoxy ] benzyl } -2, 4-thiazolidinedione and the structure shown below:
rosiglitazone belongs to the thiazolidinediones insulin sensitizer. The hydrochloric acid salt preparation of rosiglitazone is commonly used clinically, is orally taken and is mainly used for treating diabetes.
The rosiglitazone is a ligand of a peroxisome proliferator-activated receptor gamma (PPAR gamma), and recent researches show that the medicine not only increases insulin sensitivity, but also has the effects of inhibiting proliferation and migration of vascular smooth muscle cells, resisting inflammation and the like, so that the rosiglitazone also has an application prospect in treating vascular restenosis. However, researches show that the traditional rosiglitazone oral preparation has the defects of low absorption utilization rate, low blood concentration at the position of angiostenosis, short duration of biological effect and the like. Meanwhile, patients with abnormal liver function and congestive heart failure cannot use the medicine due to systemic effects of rosiglitazone oral preparations, which cause side effects on other target organs, such as liver function damage, edema, anemia, etc. These factors all limit the use of rosiglitazone as a drug for the treatment of intravascular restenosis that occurs following intravascular stent implantation. A new preparation is clinically needed, so that the rosiglitazone can treat the intravascular restenosis after the intravascular stent is implanted, the acting site of the rosiglitazone is more accurate and limited, higher concentration can be continuously maintained at the focus site, and a continuous biological effect is generated. Thereby enlarging the application range and reducing the occurrence of side effects.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a rosiglitazone nano preparation, a preparation method and application thereof. The nanometer medicinal preparation can be used for treating restenosis.
In order to achieve the purpose, the invention adopts the following technical scheme:
a rosiglitazone nano preparation comprises nanoparticles formed by rosiglitazone, polylactic acid-polyglycolic acid copolymer, lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, and the nano preparation is of a microsphere structure, and the particle size is 250-300 nanometers.
A preparation method of a rosiglitazone nano preparation comprises the following steps:
(1) dissolving rosiglitazone and polylactic acid-polyglycolic acid in an organic solvent;
(2) carrying out ultrasonic dispersion on lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 by using an organic solvent, then adding water, continuing ultrasonic dispersion, heating at 65 ℃ for 30 minutes, and then cooling to room temperature;
(3) dropwise adding the solution obtained in the step (1) into the solution obtained in the step (2), quickly stirring for 3 minutes after dropwise adding is finished, and then continuously and slowly stirring for 1.5-2 hours at room temperature to obtain rosiglitazone nano preparation suspension;
(4) and (4) centrifugally separating the nano preparation suspension obtained in the step (3) at 10000, and washing with deionized water for three times to obtain the solidified rosiglitazone nano preparation.
The rosiglitazone nano preparation is used for treating intravascular restenosis after intravascular stent implantation.
The rosiglitazone nano preparation can reduce the toxic and side effects of rosiglitazone, improve the concentration of rosiglitazone at the restenosis position of the blood vessel of the mounting bracket, and simultaneously has the slow release effect of the rosiglitazone at the restenosis lesion position. Improves the targeting property of the targeting peptide on the vascular restenosis part, and achieves the aim of targeted therapy of the vascular restenosis. According to the characteristic that the nano preparation can slowly release the medicine, the invention adopts polylactic acid-polyglycolic acid copolymer with good biocompatibility as a medicine carrier, utilizes lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 as stabilizers, and adopts a nano precipitation method to prepare rosiglitazone into the slow release nano preparation. The rosiglitazone nano preparation prepared by the invention has better clinical application prospect. The polylactic acid-polyglycolic acid copolymer (PLGA) is a degradable functional polymer organic compound, has good biocompatibility and is approved by the U.S. food and drug administration to be used as a drug carrier in human bodies.
Compared with the prior art, the invention has the following beneficial effects:
1. the targeted therapeutic method for vascular restenosis after cerebrovascular stent implantation is characterized in that lecithin and polyethylene glycol are covered on the outer layer of the rosiglitazone nano preparation, so that the nano preparation has the characteristics of high dispersibility and in-vivo long circulation, and the vascular stenosis part is often accompanied with inflammation, so that the vascular permeability is increased, and the rosiglitazone nano preparation can be passively targeted and gathered on the vascular stenosis part and can be used for targeted therapy.
2. Can reduce the toxic and side effects of rosiglitazone. The rosiglitazone nano preparation can be gathered at a lesion part with higher concentration, so that the gathering of the rosiglitazone nano preparation in other organs is reduced, meanwhile, the rosiglitazone nano preparation can slowly release the rosiglitazone, the effective drug concentration is maintained for a long time, the overhigh instantaneous blood drug concentration in a body is avoided, and the toxic and side effect of the rosiglitazone can be effectively reduced.
Drawings
FIG. 1 is a schematic diagram of the preparation of rosiglitazone of the present invention;
FIG. 2 is an electron microscope image of the present invention;
FIG. 3 is a graph showing the effect of rosiglitazone free drug and nano-formulation in treating rat carotid injury.
Detailed Description
The present invention will be described in further detail below by way of specific embodiments:
as shown in figure 1, the rosiglitazone nano preparation comprises nanoparticles formed by rosiglitazone, polylactic acid-polyglycolic acid copolymer, lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, and the nano preparation has a microsphere structure, wherein the particle size is 250-300 nanometers.
A preparation method of a rosiglitazone nano preparation comprises the following steps:
(1) dissolving rosiglitazone and polylactic acid-polyglycolic acid in an organic solvent;
(2) carrying out ultrasonic dispersion on lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 by using an organic solvent, then adding water, continuing ultrasonic dispersion, heating at 65 ℃ for 30 minutes, and then cooling to room temperature;
(3) dropwise adding the solution obtained in the step (1) into the solution obtained in the step (2), quickly stirring for 3 minutes after dropwise adding is finished, and then continuously and slowly stirring for 1.5-2 hours at room temperature to obtain rosiglitazone nano preparation suspension;
(4) and (4) carrying out centrifugal separation on the nano preparation suspension obtained in the step (3), and washing with deionized water for three times to obtain the solidified rosiglitazone nano preparation.
Calculated by mass percent, the rosiglitazone content is 5.3-6.25%, the polylactic acid-polyglycolic acid copolymer content is 59.2-64.9%, and the lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 content is 29.2-35.5%.
Wherein the ratio of rosiglitazone to polylactic acid-polyglycolic acid copolymer in the step (1) is 1: 10 to 12.
Wherein the organic solvent in the step (1) comprises acetonitrile, dimethyl sulfoxide and N, N' -dimethylformamide.
Wherein the ratio of lecithin to distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 in the step (2) is 1: 1.5-2, and the ratio of the polylactic acid-polyglycolic acid copolymer to the lecithin is 6.6-5: 1.
Wherein the organic solvent in step (2) comprises ethanol.
Wherein the ratio of the organic solvent in the step (2) to the water in the step (2) is 1: 10-20.
The rosiglitazone nano preparation is used for treating intravascular restenosis after intravascular stent implantation.
The purpose of adding ethanol is to disperse the lecithin and cannot affect the subsequent nanoparticle formation and drug loading, so the ethanol dosage cannot be too large, and the ratio of ethanol to water is preferably 0.6: 15. As is clear to those skilled in the art, after dropping the acetonitrile solution containing rosiglitazone and polylactic acid-polyglycolic acid copolymer in the aqueous solution containing lecithin and distearoylphosphatidylethanolamine-polyethylene glycol 2000, the stirring speed is preferably such that the acetonitrile solution is sufficiently mixed with the aqueous solution because the purpose of the rapid stirring is to sufficiently mix the acetonitrile solution with the aqueous solution. The slow stirring is to prevent the nanoparticles from settling on the premise of not influencing the self-assembly of the nano-drug. The ratio of acetonitrile in the step (1) to water in the step (2) is 1: 15, the ratio of the organic solvent to the water is too low, the particle size of the formed nano-drug is too large, the ratio is too high, the nano-drug is difficult to form, and the yield of the nano-drug is low.
Example one
3mg of rosiglitazone and 30mg of polylactic acid-polyglycolic acid were weighed and dissolved in 1ml of acetonitrile to obtain a solution 1.6 mg of lecithin and 9mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000 were weighed, added to 0.6ml of ethanol and subjected to ultrasonic dissolution by an ultrasonic instrument for 3 minutes. Then 15ml of water was added and the ultrasonic dissolution was continued for 3.5 minutes. Then the mixture is put into a water bath at 65 ℃ and added for 30 minutes, and then the mixture is taken out and put at room temperature to obtain a solution 2. And dropwise adding the solution 1 into the solution 2, quickly stirring for 3 minutes after the dropwise adding is finished, then slowly stirring for 1.5 hours by using a magnetic stirrer, and obtaining the rosiglitazone nano preparation suspension after the stirring is finished. And (4) centrifuging the rosiglitazone nanometer direct suspension by using a centrifuge at 10000 revolutions, and discarding the supernatant. Measuring 45ml of deionized water, and washing the precipitate for three times to finally obtain the solidified rosiglitazone nano preparation.
Example two
3mg of rosiglitazone and 33mg of polylactic acid-polyglycolic acid were weighed and dissolved in 1.2ml of dimethyl sulfoxide to obtain a solution 1.5 mg of lecithin and 10mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000 were weighed, added to 0.8ml of an aqueous ethanol solution and subjected to ultrasonic dissolution by an ultrasonic instrument for 3.5 minutes. Then 20ml of water was added and the ultrasonic dissolution was continued for 3 minutes. Then the mixture is put into a water bath at 65 ℃ and added for 30 minutes, and then the mixture is taken out and put at room temperature to obtain a solution 2. And dropwise adding the solution 1 into the solution 2, quickly stirring for 3 minutes after the dropwise adding is finished, then slowly stirring for 2 hours by using a magnetic stirrer, and obtaining the rosiglitazone nano preparation suspension after the stirring is finished. And (4) centrifuging the rosiglitazone nanometer direct suspension by using a centrifuge at 10000 revolutions, and discarding the supernatant. 30ml of deionized water is measured, and the precipitate is washed for three times to finally obtain the solidified rosiglitazone nano preparation.
EXAMPLE III
4mg of rosiglitazone and 45mg of polylactic acid-polyglycolic acid were weighed and dissolved in 1ml of N, N' -dimethylformamide to obtain a solution 1. 9mg of lecithin and 18mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000 were weighed, added to 1ml of an aqueous ethanol solution and subjected to ultrasonic dissolution by an ultrasonic instrument for 3 minutes. Then 18ml of water was added and the ultrasonic dissolution was continued for 3.5 minutes. Then the mixture is put into a water bath at 65 ℃ and added for 30 minutes, and then the mixture is taken out and put at room temperature to obtain a solution 2. And dropwise adding the solution 1 into the solution 2, quickly stirring for 3 minutes after the dropwise adding is finished, then slowly stirring for 1.8 hours by using a magnetic stirrer, and obtaining the rosiglitazone nano preparation suspension after the stirring is finished. And (4) centrifuging the rosiglitazone nanometer direct suspension by using a centrifuge at 10000 revolutions, and discarding the supernatant. Measuring 45ml of deionized water, and washing the precipitate for three times to finally obtain the solidified rosiglitazone nano preparation.
Example four
9mg of rosiglitazone and 100mg of polylactic acid-polyglycolic acid were weighed out and dissolved in 3ml of acetonitrile to obtain a solution 1. 18mg of lecithin and 27mg of distearoylphosphatidylethanolamine-polyethylene glycol 2000 were weighed, added to 1.8ml of an aqueous ethanol solution and subjected to ultrasonic dissolution by an ultrasonic instrument for 3.2 minutes. Then 45ml of water was added and the ultrasonic dissolution was continued for 3 minutes. Then the mixture is put into a water bath at 65 ℃ and added for 30 minutes, and then the mixture is taken out and put at room temperature to obtain a solution 2. And dropwise adding the solution 1 into the solution 2, quickly stirring for 3 minutes after the dropwise adding is finished, then slowly stirring for 1.6 hours by using a magnetic stirrer, and obtaining the rosiglitazone nano preparation suspension after the stirring is finished. And (4) centrifuging the rosiglitazone nanometer direct suspension by using a centrifuge at 10000 revolutions, and discarding the supernatant. Measuring 45ml of deionized water, and washing the precipitate for three times to finally obtain the solidified rosiglitazone nano preparation.
And (3) verification test:
particle size of
The invention adopts a particle size analyzer to characterize the rosiglitazone nano preparation in a laboratory. As shown in FIG. 2, the particle size of the rosiglitazone nano preparation is between 250 and 300 nanometers, the polymerization dispersion index is lower than 0.2, and the surface charge is between-3 ev and-5 ev. From the above-mentioned particle size analyzer analysis, it can be concluded that the nano-formulation has a nano-size and a polymeric dispersion index and a surface charge suitable for in vivo applications.
Second, animal in vivo experiment
As shown in fig. 3, in order to verify the effectiveness of the rosiglitazone nano preparation prepared by the present invention, a carotid artery injury model was established by balloon dilatation injury of SD rats, and the therapeutic effects of the rosiglitazone nano preparation and the rosiglitazone free drug were evaluated.
Carotid vascular images of normal SD rats (female). The inner wall of the tube cavity is smooth, the inner diameter of the tube cavity is larger, and abnormal hyperplastic tissues are not seen. After injury of carotid artery in SD rat, lumen diameter became small without any treatment, and abnormal proliferation in blood vessel was observed. After SD rats have carotid artery injury, after rosiglitazone free drug treatment, the inner diameter of the lumen is larger than that of an untreated group, but the inner wall of the lumen is not smooth, so that tissue hyperplasia of different degrees can be seen, and the condition of partial stenosis still exists. After SD rat carotid artery injury and treatment by rosiglitazone nanometer preparation, the inner diameter of the lumen is similar to that of a normal group, is obviously increased compared with a group without administration of a medicament, and is smooth compared with a group with administration of a common medicament form, and obvious abnormal hyperplasia is not seen in the lumen. Animal experiment results show that the rosiglitazone nano preparation can effectively treat angiostenosis, and the effect is superior to that of a rosiglitazone free medicament.
Third, acute toxicity test of animal
Selecting a mouse with the weight of 17-23 g, carrying out an experiment according to the following experiment conditions, and calculating the LD50 and the confidence interval of the rosiglitazone.
TABLE acute toxicity test of mice injected intravenously with rosiglitazone
Acute toxicity test of intragastric rosiglitazone in Epidimo mice
Acute toxicity test of intravenous rosiglitazone nano preparation for epitrices
Acute toxicity test of intragastric rosiglitazone nano preparation for mice in Tab.I.
Selecting 17-23 g of mice, and dividing 10 mice into one group, namely a control group, a nano preparation group and a common tablet group. Wherein the control group orally takes the solvent without rosiglitazone, the nano preparation group orally takes nano preparation with 7915.6 mu mol/Kg dose, and the common tablet group orally takes the common tablet with 7915.6 mu mol/Kg dose, and the results are as follows:
table five rat oral administration different dosage form rosiglitazone plasma biochemical index determination result
Comparison of table one with table three shows that the safety of the intravenous rosiglitazone nano preparation is higher than that of the intravenous rosiglitazone, and the LD50 of the intravenous rosiglitazone nano preparation is higher than that of the common intravenous rosiglitazone. The rosiglitazone nano preparation shows better safety when being injected into the vein, and reduces the toxicity of the rosiglitazone.
Comparing the second table with the fourth table, the safety of the oral rosiglitazone nano preparation is higher than that of the oral rosiglitazone common tablet, and the LD50 of the oral rosiglitazone nano preparation is higher than that of the oral rosiglitazone common tablet. The rosiglitazone nano preparation shows better safety when being taken orally, and reduces the toxicity of rosiglitazone.
Table five shows that the plasma biochemical index measurement results of mice orally taking the rosiglitazone nano preparation are closer to the control group, and each plasma biochemical index is closer to the normal value compared with the mice orally taking the rosiglitazone ordinary tablet. The toxicity of the large-dose oral rosiglitazone nano preparation on mice is relatively small compared with the toxicity of the common rosiglitazone tablet.
Therefore, the rosiglitazone nano preparation disclosed by the invention has the effect of treating the vascular restenosis, can effectively reduce the toxicity of rosiglitazone and improve the safety of rosiglitazone in treating the vascular restenosis.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (8)
1. A rosiglitazone nano-preparation is characterized in that: the nano preparation comprises nanoparticles formed by rosiglitazone, polylactic acid-polyglycolic acid copolymer, lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000, and has a microsphere structure, wherein the particle size is 250-300 nanometers;
wherein, calculated by mass percentage, the rosiglitazone content is 5.3-6.25%, the polylactic acid-polyglycolic acid copolymer content is 59.2-64.9%, and the lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 content is 29.2-35.5%.
2. A method for preparing rosiglitazone nano-formulation as described in claim 1, characterized by: the preparation method comprises the following steps:
(1) dissolving rosiglitazone and polylactic acid-polyglycolic acid in an organic solvent;
(2) carrying out ultrasonic dispersion on lecithin and distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 by using an organic solvent, then adding water, continuing ultrasonic dispersion, heating at 65 ℃ for 30 minutes, and then cooling to room temperature;
(3) dropwise adding the solution obtained in the step (1) into the solution obtained in the step (2), quickly stirring for 3 minutes after dropwise adding is finished, and then continuously and slowly stirring for 1.5-2 hours at room temperature to obtain rosiglitazone nano preparation suspension;
(4) and (4) carrying out centrifugal separation on the nano preparation suspension obtained in the step (3), and washing with deionized water for three times to obtain the solidified rosiglitazone nano preparation.
3. The method for preparing a rosiglitazone nano-formulation according to claim 2, wherein: wherein the ratio of rosiglitazone to polylactic acid-polyglycolic acid copolymer in the step (1) is 1: 10 to 12.
4. The method for preparing a rosiglitazone nano-formulation according to claim 3, wherein: wherein the organic solvent in the step (1) comprises acetonitrile, dimethyl sulfoxide and N, N' -dimethylformamide.
5. The method for preparing rosiglitazone nano-preparation according to claim 4, wherein: wherein the ratio of lecithin to distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 in the step (2) is 1: 1.5-2, and the ratio of the polylactic acid-polyglycolic acid copolymer to the lecithin is 6.6-5: 1.
6. The method for preparing a rosiglitazone nano-formulation according to claim 5, wherein: wherein the organic solvent in step (2) comprises ethanol.
7. The method for preparing a rosiglitazone nano-formulation according to claim 6, wherein: wherein the ratio of the organic solvent in the step (2) to the water in the step (2) is 1: 10-20.
8. The rosiglitazone nano-formulation according to claim 1, wherein: the rosiglitazone nano preparation is used for treating intravascular restenosis after intravascular stent implantation.
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| CN103221070A (en) * | 2010-08-30 | 2013-07-24 | 哈佛大学校长及研究员协会 | Shear controlled release for stenotic lesions and thrombolytic therapies |
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