CN105796552A - Simvastatin and ezetimibe compound nano solution and freeze-dried powder and preparation method of solution - Google Patents
Simvastatin and ezetimibe compound nano solution and freeze-dried powder and preparation method of solution Download PDFInfo
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Abstract
The invention discloses a simvastatin and ezetimibe compound nano solution and freeze-dried powder and a preparation method of the solution and belongs to the field of medicine preparations. The nano solution is characterized by being prepared from 5-20 parts of simvastatin, 5-15 parts of ezetimibe, 80-240 parts of a carrier material, 150-750 parts of surfactant and 15-35 parts of an organic solvent, the average particle size of the nano solution is 126 nm or below, and the polydispersity index (PDI) is 0.4 or below. The selected carrier material and the surfactant are good in biocompatibility and small in toxicity and are ideal auxiliary materials. The selected organic solvent can well volatilize and be well removed and is small in toxicity. The compound nano solution is prepared from simvastatin and ezetimibe, a freeze-drying protective agent is added, and the freeze-dried powder is prepared through the freeze-drying method, so that stability of the nano solution is improved, and water solubility and bioavailability are improved. 2800-4800 parts of the freeze-drying protective agent is added, the average particle size of the nano solution is 650 nm or below after the freeze-dried powder is redissolved, and the polydispersity index is 0.7 or below. In the preparation process, the organic solvent is effectively removed through the heating volatilization method, remaining of the organic solvent is avoided, and meanwhile the system is more stable.
Description
Technical field
The present invention relates to a kind of simvastatin Ezetimibe compound preparation, be specifically related to simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder and preparation method thereof, belong to technical field of medicine.
Background technology
Along with aged tendency of population and growth in the living standard, hyperlipidemia has become as one of important diseases of harm human health, the atherosclerosis that hyperlipidemia causes, and the cardiovascular and cerebrovascular disease such as the hypertension caused further, coronary heart disease becomes the main arch-criminal causing death, it was reported that on average within every 10 seconds, just there is a people to die from cardiovascular and cerebrovascular disease.
Clinical research shows that the rising of total cholesterol level can cause human atherosclerotic, epidemiological study also indicates that the level of cardiovascular and cerebrovascular disease sickness rate and mortality rate and T-CHOL is directly proportional, and in blood plasma, cholesterol is mainly derived from and is endogenously synthesized and intestinal absorption.
Statins is the blood lipid-lowering medicine of current most study, and substantial amounts of clinical trial and epidemiological study confirm that statins has effect for reducing blood fat and the preventive effect to coronary heart disease.Statins full name is 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, HMG-CoA reductase is the rate-limiting enzyme of synthetic cholesterol commitment, it is suppressed that this enzymatic activity, and the cholesterol of liver synthesis reduces, and plasma total cholesterol levels will reduce, thus effectively treating hyperlipemia, reduces the generation of cardiovascular and cerebrovascular disease.Simvastatin is clinical conventional a kind of statins, and its structure is as follows:
Ezetimibe is global first intestinal cholesterol absorption selectivity inhibitor, mainly acts on NPC on small intestinal mucosa1L1Transport protein, optionally suppresses the cholesterol in meals and bile across Intestinal transit, makes cholesterol store and reduces and low density lipoprotein receptor in rat liver synthesis increase, reduces low-density lipoprotein white level, and its structure is as follows:
Simvastatin and Ezetimibe belong to the medicine of low-solubility, high osmosis, and both single preparations of ephedrine (being mainly tablet) existing is relatively conventional, but medicine water solublity is bad, is unfavorable for absorbing, and is difficult to play synergism；Take as combined, then add and take number of times, make troubles for patient.The compound tablet of the existing simvastatin of existing market and Ezetimibe, because medicine is unstable, it is necessary to adding antioxidant, be unfavorable for long-term taking, and drug solubility is low, bioavailability is low；Both preparations are become compound recipe nanometer solution and prepares into lyophilized powder further, water solublity and stability can be improved, increase bioavailability, also synergism can be formed, reduce exogenous absorption on the one hand, reduce on the other hand and be endogenously synthesized, the powerful level reducing plasma cholesterol and very low density lipoprotein (VLDL).
Summary of the invention
Nanotechnology can produce administration nano-drug administration system for formulation art, change drug distribution and pharmacokinetics process, the medicine concentration at absorption site can be improved, improve the stability of medicine, strengthen drug absorption, raising curative effect of medication, reduction toxic and side effects, raising bioavailability etc..It is an object of the invention to provide a kind of simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder and preparation method thereof, in order to realize the purpose of the present invention, intend adopting the following technical scheme that
A kind of simvastatin Ezetimibe compound recipe nanometer solution of the present invention and lyophilized powder, it is characterised in that the supplementary material preparing nanometer formulation includes:
Simvastatin: 5～20 parts；
Ezetimibe: 5～15 parts；
Carrier material: 80～240 parts；
Surfactant: 150～750 parts；
Organic solvent: 15～35 parts；
Freeze drying protectant: 2800～4800 parts.
Described simvastatin Ezetimibe compound recipe nanometer solution mean diameter is at below 126nm, and polydispersity coefficient (PDI) is below 0.4；After described simvastatin Ezetimibe compound recipe nano freeze-dried powder redissolution, mean diameter is at below 650nm, and polydispersity coefficient is below 0.7.
In a preferred embodiment of the present invention, one or more the combination in glyceryl monostearate, lecithin, stearic acid, palmitic acid and chitosan of the described carrier material.As preferably, selected carrier material is lecithin, and its toxicity is little, and drug loading is big.
In a preferred embodiment of the present invention, described organic solvent is selected from ethyl acetate, acetone, ethanol.As preferably, selected organic solvent is ethanol, and simvastatin, Ezetimibe dissolubility in ethanol is big, and alcohol toxicity is little, be easily removed.
In a preferred embodiment of the present invention, described surfactant is selected from one or more in polysorbas20, polysorbate40, polysorbate60, Tween 80, castor oil hydrogenated, F68, as preferably, selected surfactant is F68, its hydrophilic is strong, toxicity is little, preparing nanometer solution particle diameter little, polydispersity coefficient is little.
In the preparation method of above-mentioned simvastatin Ezetimibe compound recipe nanometer solution, as preferably, the concrete preparation method of described simvastatin Ezetimibe compound recipe nanometer solution is as follows:
(1) simvastatin, Ezetimibe and carrier material are dissolved in organic solvent, stir or ultrasonic dissolution, obtain settled solution A.
(2) surfactant is dissolved in purified water, stirs or ultrasonic dissolution, obtain settled solution B.
(3) when stirring, solution A is dispersed in solution B, obtains mixed solution C, by solution C stirring or ultrasonic disperse, obtain emulsion D.
(4) volatilize removal organic solvent by solution D in 50～60 DEG C of water-baths, obtains simvastatin Ezetimibe compound recipe nanometer solution.
Another aspect of the present invention further relates to the lyophilized powder of simvastatin Ezetimibe compound recipe nanometer solution, it is characterised in that will add freeze drying protectant in above-mentioned simvastatin Ezetimibe compound recipe nanometer solution and makes lyophilized powder by cryodesiccated method.
In a preferred embodiment of the present invention, one or more the combination in mannitol, lactose, glucose, sorbitol of the described freeze drying protectant；As preferably, selected freeze drying protectant is mannitol.Lyophilized powder form obtained by selection mannitol is good, it is fast to redissolve；After redissolution, solution particle diameter is little, polydispersity coefficient is little.
In the preparation method of above-mentioned simvastatin Ezetimibe compound recipe nano freeze-dried powder; as preferably; described freezing dry process is particularly as follows: take simvastatin Ezetimibe compound recipe nanometer solution; adding freeze drying protectant, ultrasonic mix homogeneously, through 0.22um filtering with microporous membrane; filtrate loads lyophilizing bottle; being placed in freezer dryer, control its temperature and carry out precooling lower than-35 DEG C, the time maintains more than 6 hours.After precooling completes, control its vacuum at below 20Pa, carrying out heats up again dries, design temperature maintains 3 hours when-25 DEG C, design temperature maintains 5 hours when-15 DEG C, and design temperature maintains 2 hours when 0 DEG C, and design temperature maintains 4 hours when 10 DEG C, design temperature maintains 8 hours when 30 DEG C, obtains simvastatin Ezetimibe compound recipe nano freeze-dried powder after completing lyophilization.
Carrier material selected by the present invention, surfactant and freeze drying protectant good biocompatibility, toxicity is little, is comparatively ideal adjuvant.Selected organic solvent can volatilize removing preferably, and toxicity is little.Selected freeze drying protectant good water solubility, prepared lyophilized powder form is good, redissolves fast.The present invention is by making compound recipe nanometer solution by simvastatin Ezetimibe, and makes lyophilized powder so that it is stability and water solublity increase, and is beneficial to body and absorbs, improves bioavailability.
The present invention effectively eliminates organic solvent by heating volatility process in preparation process, it is to avoid the residual of organic solvent, makes the system more stable simultaneously.
In sum, the present invention compared with prior art, has the advantage that
1. the simvastatin Ezetimibe compound recipe nanometer solution system of the present invention is relatively stable and dispersion is big, will not precipitate out precipitation before lyophilization；Method used can organic solvent in effectively removing system, the simvastatin Ezetimibe compound recipe nanometer solution clear obtained, mean diameter is at below 126nm, and polydispersity coefficient is below 0.4.
2. the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present invention, after redissolution, solution still is able to keep drug particles particle diameter to realize nanoscale, thus still being able to make medicine be administered by nanosystems, add medicine water solublity, ensure the bioavailability of medicine, after redissolution, the particle diameter of drug in solution nanoparticle is at below 650nm, and polydispersity coefficient is below 0.7, and entrapment efficiency reaches more than 80%.
3. the preparation method of the simvastatin Ezetimibe compound recipe nanometer solution of the present invention and lyophilized powder, technical process is simple, adopts conventional equipment to realize, is conducive to industrialized production.The nanometer solution preparation method of the present invention and freeze-drying method coordinate the supplementary material selected, it is possible to the effective performance ensureing medicine, are further ensured that the lyophilized powder stable in properties obtained, and are beneficial to preservation and use.
4. the simvastatin Ezetimibe compound recipe nanometer solution of the present invention and lyophilized powder, first prepare into medicine nanoscale colloid aqueous solution, be then further prepared into lyophilized powder, is redissolved by lyophilized powder and re-use for aqueous solution during use.Compared with existing preparation, solve medicine poorly water-soluble, the defect that bioavailability is low；Prepared product is compound preparation, has played synergism preferably；Lyophilized powder is solid forms simultaneously, improves medicine stability, is beneficial to preservation；Prescription is avoided use antioxidant, improve drug safety.
Accompanying drawing explanation
Fig. 1 is the grain size distribution of the simvastatin Ezetimibe compound recipe nanometer solution that the embodiment of the present invention 1 obtains.
Fig. 2 is the grain size distribution of solution after the simvastatin Ezetimibe compound recipe nano freeze-dried powder that the embodiment of the present invention 1 obtains redissolves.
Fig. 3 is the grain size distribution of the simvastatin Ezetimibe compound recipe nanometer solution that the embodiment of the present invention 2 obtains.
Fig. 4 is the grain size distribution of solution after the simvastatin Ezetimibe compound recipe nano freeze-dried powder that the embodiment of the present invention 2 obtains redissolves.
Fig. 5 is the simvastatin Ezetimibe compound recipe nanometer solution outside drawing that the embodiment of the present invention 3 obtains.
Fig. 6 is the scanning electron microscope (SEM) photograph of the simvastatin Ezetimibe compound recipe nanometer solution that the embodiment of the present invention 1 obtains.
Fig. 7 is the simvastatin Ezetimibe compound recipe nano freeze-dried powder scanning electron microscope (SEM) photograph that the embodiment of the present invention 1 obtains.
Detailed description of the invention
Below by specific embodiment and accompanying drawing, the present invention is illustrated, but the present invention is not limited to these embodiments.
Embodiment 1
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 10mg；
Ezetimibe: 10mg；
Lecithin: 160mg；
Ethanol: 25mL；
F68: 150mg；
Mannitol: 4000mg.
The simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment and lyophilized powder adopt following preparation method to obtain:
Simvastatin Ezetimibe compound recipe nanometer solution:
Join 10mg simvastatin, 10mg Ezetimibe, 160mg lecithin the ethanol of 25mL dissolves and obtain organic phase solution, can dissolve by stirring or ultrasonic acceleration；
Join 150mg F68 the purified water of 40mL is dissolved and obtain aqueous phase solution, can dissolve by stirring or ultrasonic acceleration；
Organic phase solution obtained above is added to aqueous phase solution, adopts stirring, Probe Ultrasonic Searching to disperse, prepare emulsion；Being stirred under the water bath condition of 55 DEG C by the emulsion obtained, heating volatilization removes the organic solvent ethanol in emulsion, obtains simvastatin Ezetimibe compound recipe nanometer solution；After measured, the particle diameter of the nanometer solution of gained is 58.55nm, and polydispersity coefficient is 0.186, and envelop rate is 92.17%.
4000mg mannitol is added in the above-mentioned simvastatin Ezetimibe compound recipe nanometer solution prepared, dissolve by stirring or ultrasonic acceleration, then the hydrophilic microporous filter membrane of 0.22 micron is used to be filtered, remove the large granular impurity in solution, to improve product quality, the filtrate obtained is loaded in lyophilizing bottle, then carries out lyophilization.Described lyophilization detailed process is: put in freezer dryer by this lyophilizing bottle, control temperature and carry out precooling 8 hours for-40 DEG C, after precooling completes, control its vacuum at below 20Pa, carrying out heats up again dries, design temperature maintains 3 hours when-25 DEG C, design temperature maintains 5 hours when-15 DEG C, design temperature maintains 2 hours when 0 DEG C, design temperature maintains 4 hours when 10 DEG C, design temperature maintains 8 hours when 30 DEG C, seals after completing lyophilization, obtains simvastatin Ezetimibe compound recipe nano freeze-dried powder.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 146.6nm, and polydispersity coefficient is 0.204, and envelop rate is 84.28%.
Embodiment 2
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 20mg；
Ezetimibe: 15mg；
Lecithin: 100mg；
Glyceryl monostearate: 140mg；
Ethanol: 15mL；
F68: 600mg；
Mannitol: 4800mg.
The simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment and lyophilized powder adopt following preparation method to obtain:
Simvastatin Ezetimibe compound recipe nanometer solution:
Join 5mg simvastatin, 15mg Ezetimibe, 100mg lecithin and 140mg glyceryl monostearate the ethanol of 15mL dissolves and obtain organic phase solution, can dissolve by stirring or ultrasonic acceleration；
Join 600mg F68 the purified water of 40mL is dissolved and obtain aqueous phase solution, can dissolve by stirring or ultrasonic acceleration；
Organic phase solution obtained above is added to aqueous phase solution, adopts stirring, Probe Ultrasonic Searching to disperse, prepare emulsion；Being stirred under the water bath condition of 50 DEG C by the emulsion obtained, heating volatilization removes the organic solvent ethanol in emulsion, obtains simvastatin Ezetimibe compound recipe nanometer solution；After measured, the particle diameter of the nanometer solution of gained is 126.0nm, and polydispersity coefficient is 0.394, and envelop rate is 88.46%.
4800mg mannitol is added in the above-mentioned simvastatin Ezetimibe compound recipe nanometer solution prepared, dissolve by stirring or ultrasonic acceleration, then the hydrophilic microporous filter membrane of 0.22 micron is used to be filtered, remove the large granular impurity in solution, to improve product quality, the filtrate obtained is loaded in lyophilizing bottle, then carries out lyophilization.Described lyophilization detailed process is: put in freezer dryer by this lyophilizing bottle, control temperature and carry out precooling 8 hours for-40 DEG C, after precooling completes, control its vacuum at below 20Pa, carrying out heats up again dries, design temperature maintains 3 hours when-25 DEG C, design temperature maintains 5 hours when-15 DEG C, design temperature maintains 2 hours when 0 DEG C, design temperature maintains 4 hours when 10 DEG C, design temperature maintains 8 hours when 30 DEG C, seals after completing lyophilization, obtains simvastatin Ezetimibe compound recipe nano freeze-dried powder.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 568.6nm, and polydispersity coefficient is 0.684, and envelop rate is 80.12%.
Embodiment 3
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 5mg；
Ezetimibe: 5mg；
Glyceryl monostearate: 80mg；
Ethyl acetate: 35mL；
Polysorbas20: 750mg；
Mannitol: 2800mg.
The simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment and lyophilized powder adopt following preparation method to obtain:
Simvastatin Ezetimibe compound recipe nanometer solution:
Join 5mg simvastatin, 5mg Ezetimibe, 80mg glyceryl monostearate the ethyl acetate of 35mL is dissolved and obtain organic phase solution, can dissolve by stirring or ultrasonic acceleration；
Join 750mg polysorbas20 the purified water of 40mL is dissolved and obtain aqueous phase solution, can dissolve by stirring or ultrasonic acceleration；
Organic phase solution obtained above is added to aqueous phase solution, adopts stirring, Probe Ultrasonic Searching to disperse, prepare emulsion；Being stirred under the water bath condition of 60 DEG C by the emulsion obtained, heating volatilization removes the organic solvent ethanol in emulsion, obtains simvastatin Ezetimibe compound recipe nanometer solution；After measured, the particle diameter of the nanometer solution of gained is 68.50nm, and polydispersity coefficient is 0.177, and envelop rate is 91.25%.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present embodiment is consistent with the method in embodiment 1, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 335.2nm, and polydispersity coefficient is 0.557, and envelop rate is 83.95%.
Embodiment 4
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 17mg；
Ezetimibe: 8mg；
Stearic acid: 40mg；
Lecithin: 120mg；
Acetone: 30mL；
Polysorbate40: 200mg；
Castor oil hydrogenated: 300mg；
Lactose: 3500mg；
Sorbitol: 1000mg.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment is consistent with the method in embodiment 1, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.After measured, the particle diameter of the nanometer solution of gained is 102.5nm, and polydispersity coefficient is 0.351, and envelop rate is 89.72%.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present embodiment is consistent with the method in embodiment 1, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 648.9nm, and polydispersity coefficient is 0.694, and envelop rate is 81.34%.
Embodiment 5
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 8mg；
Ezetimibe: 12mg；
Palmitic acid: 20mg；
Lecithin: 200mg；
Ethyl acetate: 20mL；
Polysorbate60: 50mg；
Tween 80: 400mg；
Glucose: 2000mg；
Mannitol: 1200mg.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment is consistent with the method in embodiment 1, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.After measured, the particle diameter of the nanometer solution of gained is 166.1nm, and polydispersity coefficient is 0.164, and envelop rate is 94.36%.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present embodiment is consistent with the method in embodiment 1, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 544.5nm, and polydispersity coefficient is 0.656, and envelop rate is 85.72%.
Embodiment 6
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 10mg；
Ezetimibe: 5mg；
Chitosan: 10mg；
Lecithin: 120mg；
Ethanol: 20mL；
Polysorbate60: 70mg；
F68: 330mg；
Glucose: 1200mg；
Lactose: 1800mg.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment is consistent with the method in embodiment 2, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.After measured, the particle diameter of the nanometer solution of gained is 120.1nm, and polydispersity coefficient is 0.183, and envelop rate is 93.86%.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present embodiment is consistent with the method in embodiment 2, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 429.5nm, and polydispersity coefficient is 0.597, and envelop rate is 82.18%.
Embodiment 7
Simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, this nanometer formulation includes the weight of following component:
Simvastatin: 15mg；
Ezetimibe: 10mg；
Lecithin: 200mg；
Ethyl acetate: 15mL；
Castor oil hydrogenated: 120mg；
F68: 130mg；
Lactose: 3000mg.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nanometer solution of the present embodiment is consistent with the method in embodiment 2, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.After measured, the particle diameter of the nanometer solution of gained is 79.2nm, and polydispersity coefficient is 0.230, and envelop rate is 92.24%.
The concrete preparation method of the simvastatin Ezetimibe compound recipe nano freeze-dried powder of the present embodiment is consistent with the method in embodiment 2, differs only in and adopts supplementary material used in the present embodiment and consumption, repeats no more here.The white round pie of obtained freeze-drying powder, mode of appearance is good, without atrophy and cavitation, by with lyophilizing before the purified water of equivalent add in lyophilizing bottle, treat that it dissolves naturally, redissolve, the solution particle diameter that redissolves is 576.5nm, and polydispersity coefficient is 0.492, and envelop rate is 84.48%.
Randomly select the simvastatin Ezetimibe compound recipe nanometer solution obtained in above-described embodiment and nano freeze-dried powder uses laser nano analyzer to carry out particle diameter test, wherein, the test of described nano freeze-dried powder particle diameter is that the compound recipe nano freeze-dried powder present invention obtained adds purified water, after it dissolves naturally, its solution is tested.Concrete test result is as follows, Fig. 1 is the grain size distribution of the simvastatin Ezetimibe compound recipe nanometer solution that embodiments of the invention 1 obtain, Fig. 2 is the grain size distribution of solution after the simvastatin Ezetimibe compound recipe nano freeze-dried powder that embodiments of the invention 1 obtain redissolves, Fig. 3 is the grain size distribution of the simvastatin Ezetimibe compound recipe nanometer solution that embodiments of the invention 2 obtain, and Fig. 4 is the grain size distribution of solution after the simvastatin Ezetimibe compound recipe nano freeze-dried powder that embodiments of the invention 2 obtain redissolves.As can be seen from the figure, prepared nanometer solution particle diameter and polydispersity coefficient are all less, particle diameter and the polydispersity coefficient of prepared lyophilized powder redissolution solution increase to some extent, but still in nanometer level, nanometer solution and the lyophilized powder redissolution equal clear of solution (Fig. 5 is the simvastatin Ezetimibe compound recipe nanometer solution outward appearance prepared by embodiment 3).By the enforcement of the present invention, the water solublity of medicine is improved, and prepares into lyophilized powder and still is able to ensure that medicine realizes a nanometer effect for administration while improving stability.
Fig. 6 is the Electronic Speculum figure of solution after the simvastatin Ezetimibe compound recipe nano freeze-dried powder obtained in embodiment 1 redissolves；The solution dilution 20 times that Example 1 lyophilized powder redissolves, drips on the glass sheet, dyes with the Sodium phosphotungstate solution of 2%, take a small amount of on silicon chip with glass capillary, under room temperature, natural volatile dry, is then placed under scanning electron microscope and observes nanoparticle form, obtain corresponding Electronic Speculum figure；It can be seen that form comparatively rounding, size are uniform, spherical for class.Fig. 7 is the Electronic Speculum figure of the simvastatin Ezetimibe compound recipe nano freeze-dried powder obtained in embodiment 1；Lyophilized powder is spread on silicon chip, be placed under scanning electron microscope and observe its form；It can be seen that form is loose porous, it is beneficial to dissolving and preserves.
The above is the preferred embodiments of the present invention; it should be pointed out that, for those skilled in the art, under the premise without departing from principle of the present invention; can also making some improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention.Technical staff for general domain, any apparent change under the premise without departing substantially from true spirit, it done, all by composition to infringement of patent right of the present invention, corresponding legal responsibility will be undertaken.
Claims (8)
1. a simvastatin Ezetimibe compound recipe nanometer solution and lyophilized powder, it is characterised in that the supplementary material preparing nanometer formulation includes:
Simvastatin: 5～20 parts；Ezetimibe: 5～15 parts；Carrier material: 80～240 parts；Surfactant: 150～750 parts；Organic solvent: 15～35 parts；Freeze drying protectant: 2800～4800 parts.
2. nanometer solution according to claim 1, one or more the combination in glyceryl monostearate, lecithin, stearic acid, palmitic acid and chitosan of the described carrier material；As preferably, selected carrier material is lecithin.
3. nanometer solution according to claim 1, described organic solvent is selected from ethyl acetate, acetone, ethanol；As preferably, selected organic solvent is ethanol.
4. nanometer solution according to claim 1, one or more the combination in polysorbas20, polysorbate40, polysorbate60, Tween 80, castor oil hydrogenated, F68 of the described surfactant, as preferably, selected surfactant is F68.
5. the nanometer solution according to Claims 1 to 4 any one, described nanometer solution is prepared via a method which to obtain:
(1) simvastatin, Ezetimibe and carrier material are dissolved in organic solvent, stir or ultrasonic dissolution, obtain settled solution A；
(2) surfactant is dissolved in purified water, stirs or ultrasonic dissolution, obtain settled solution B；
(3) when stirring, solution A is dispersed in solution B, obtains mixed solution C, by solution C stirring or ultrasonic disperse, obtain emulsion D；
(4) volatilize removal organic solvent by solution D in 50～60 DEG C of water-baths, obtains simvastatin Ezetimibe compound recipe nanometer solution.
6. simvastatin Ezetimibe compound recipe nano freeze-dried powder according to claim 1, it is characterised in that the simvastatin Ezetimibe compound recipe nanometer solution described in Claims 1 to 5 any one is added freeze drying protectant and makes lyophilized powder by cryodesiccated method.
7. lyophilized powder according to claim 6, one or more the combination in mannitol, lactose, glucose, sorbitol of the described freeze drying protectant；As preferably, selected freeze drying protectant is mannitol.
8. lyophilized powder according to claim 6; described lyophilized powder is prepared via a method which to obtain: take simvastatin Ezetimibe compound recipe nanometer solution; add freeze drying protectant; ultrasonic mix homogeneously; through 0.22um filtering with microporous membrane, filtrate loads lyophilizing bottle, is placed in freezer dryer; controlling its temperature and carry out precooling lower than-35 DEG C, the time maintains more than 6 hours；After precooling completes, control its vacuum at below 20Pa, carrying out heats up again dries, design temperature maintains 3 hours when-25 DEG C, design temperature maintains 5 hours when-15 DEG C, and design temperature maintains 2 hours when 0 DEG C, and design temperature maintains 4 hours when 10 DEG C, design temperature maintains 8 hours when 30 DEG C, obtains simvastatin Ezetimibe compound recipe nano freeze-dried powder after completing lyophilization.
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| CN108096199A (en) * | 2018-01-15 | 2018-06-01 | 常州市第四制药厂有限公司 | A kind of injection omeprazole sodium and preparation method |
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| CN102266323A (en) * | 2011-08-04 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Composition of ezetimibe and simvastatin and preparation method thereof |
| CN103070836A (en) * | 2013-02-02 | 2013-05-01 | 台州职业技术学院 | Ciclesonide nanometer freeze-dried powder and preparation method thereof |
| CN103110594A (en) * | 2013-02-02 | 2013-05-22 | 台州职业技术学院 | Atorvastatin calcium nano freeze-dried powder and preparation method thereof |
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| CN102266323A (en) * | 2011-08-04 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Composition of ezetimibe and simvastatin and preparation method thereof |
| CN103070836A (en) * | 2013-02-02 | 2013-05-01 | 台州职业技术学院 | Ciclesonide nanometer freeze-dried powder and preparation method thereof |
| CN103110594A (en) * | 2013-02-02 | 2013-05-22 | 台州职业技术学院 | Atorvastatin calcium nano freeze-dried powder and preparation method thereof |
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| CN108096199A (en) * | 2018-01-15 | 2018-06-01 | 常州市第四制药厂有限公司 | A kind of injection omeprazole sodium and preparation method |
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