CN101543476A - A naringin solid dispersion and the preparation method, and the application thereof - Google Patents
A naringin solid dispersion and the preparation method, and the application thereof Download PDFInfo
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Abstract
The invention discloses a naringin solid dispersion, and the preparation method and the application thereof. The naringin solid dispersion contains naringin and vector material. The mass ratio of naringin and the vector material is 1:2 to 1:5. The vector material is any one of or any mixture of polyethylene glycol, polyvinyl pyrrolidone and poloxamer. The preparation method of the naringin solid dispersion is to get the naringin, the vector material and the other regular auxiliary materials by melting method, solvent method, solvent-melting method, spray drying method or freeze-drying method. The application of the naringin solid dispersion is to apply in preparing pharmaceutical preparations or healthfood. The invention of the naringin solid dispersion is to disperse naringin by solid dispersion technique, which improves the solubility in water and dissolution rate in vitro and at the same time enhances the bioavailability.
Description
Technical field
The present invention relates to a kind of naringin solid dispersion and its production and application.
Background technology
It is carrier that solid dispersion mainly adopts water miscible macromolecular material, also can according to circumstances add surfactant, uses fusion method, solvent method and solvent-fusion method, and insoluble drug is dispersed in the another kind of solid carrier with the imperfect crystal formation form.Not only can keep the height dispersibility of medicine in carrier, make medicine have good wettability, improve insoluble drug dissolution rate and dissolubility, promote drug absorption, can also be as the intermediate of rapid release or slow releasing preparation, enteric coated preparation.
Naringin is a kind of flavone compound, is one of main effective ingredient of Fructus Aurantii Immaturus, Fructus Aurantii, the multiple medical material of Exocarpium Citri Grandis.Modern pharmacological research proves, naringin has stronger biological activity at aspects such as blood fat reducing, calmness, antioxidation, antitumor, antifungal, atherosclerosis, spasmolytic, analgesia, relieving cough and resolving phlegm, blood sugar regulation, has been used to do bitters, stimulant, has also had aspect such as cholesterol reducing.Though naringin has pharmacotoxicological effect widely, water solublity is relatively poor, is difficult to dissolving in the body, has limited absorption process, has limited to it and has been applied to experimentation and clinical development.
Summary of the invention
The objective of the invention is water solublity at naringin in the prior art low, absorb relatively poor problem, a kind of obvious water miscible, naringin solid dispersion that bioavailability is higher that improves naringin is provided.
Another object of the present invention provides the preparation method of above-mentioned naringin solid dispersion.
Another object of the present invention provides the application of above-mentioned naringin solid dispersion in preparation medicine or health product.
The present invention is achieved through the following technical solutions above-mentioned purpose:
A kind of naringin solid dispersion, contain naringin and carrier material, naringin: the mass ratio of carrier material is 1:2～1:15; Described carrier material can be any one or several mixture among Polyethylene Glycol (PEG), polyvinylpyrrolidone (PVP) or the pool Luo Samu (Poloxamer).
Preferred PEG4000 of described Polyethylene Glycol or PEG6000; Preferred PVPK30 of described polyvinylpyrrolidone or PVP K90; Preferred Poloxamer 188 of described pool Luo Samu or Poloxamer 407.
Described naringin solid dispersion also is added with surfactant, and the addition of described surfactant is preferably one of naringin and carrier material gross weight 16 parts (1/16) to 1/3rd (1/3); The mixture of one or more in the preferred dodecyl sodium sulfate of described surfactant, pool Luo Samu or the glyceryl monostearate.
Naringin solid dispersion of the present invention adopts fusion method, solvent method, solvent-fusion method, spray drying method or freeze-drying preparation.
Described fusion method comprises the steps:
With carrier material or carrier material and surfactant mixtures and naringin mixing, heated and stirred is to fusion fully, also can be with behind carrier material or carrier material and the surfactant mixtures surfactant heating and melting, adding naringin again stirs molten, then with fused mass under vigorous stirring, stainless steel disc makes it be cooled to solid rapidly in the impouring ice-water bath, the solid that obtains placed exsiccator dry 1～5 day, or 10～48h in 25～70 ℃ of vacuum drying ovens, grind, cross 60～100 mesh sieves, promptly get naringin solid dispersion.
Carrier material described in the fusion method is preferably moored Luo Samu 188, Macrogol 4000 or polyethylene glycol 6000; The preferred glyceryl monostearate of described surfactant, dodecyl sodium sulfate, pool Luo Samu 188.
Described solvent method comprises the steps:
With carrier material or carrier material and surfactant mixtures and naringin mixing, add organic solvent dissolution again, also can with carrier material or carrier material and surfactant mixtures with mix after naringin is dissolved in organic solvent respectively, adopt rotary evaporation to remove organic solvent behind the mixing, 10～48h in 25～70 ℃ of vacuum drying ovens, grind, cross 60～100 mesh sieves, promptly get naringin solid dispersion; Described organic solvent is dehydrated alcohol or 95% ethanol.
The preferred Macrogol 4000 of carrier material described in the solvent method, polyethylene glycol 6000 or polyvinylpyrrolidone K30; The preferred glyceryl monostearate of described surfactant, dodecyl sodium sulfate, pool Luo Samu 188.
Described solvent-fusion method comprises the steps:
Carrier material or carrier material and surfactant mixtures heated in 50～90 ℃ of water-baths make its fusion, add naringin with organic solvent dissolution, adopting rotary evaporation to remove behind the mixing desolvates, 10～48h in 25～70 ℃ of vacuum drying ovens, grind, cross 60～100 mesh sieves, promptly get naringin solid dispersion; Described organic solvent is dehydrated alcohol or 95% ethanol (95% is concentration of volume percent, down together).
The preferred Macrogol 4000 of carrier material described in solvent-fusion method, polyethylene glycol 6000 or polyvinylpyrrolidone K30, K90; The preferred glyceryl monostearate of described surfactant, dodecyl sodium sulfate, pool Luo Samu 188.
Described spray drying method comprises the steps:
With carrier material or carrier material and surfactant mixtures and naringin mixing, add organic solvent dissolution again, also can with carrier material or carrier material and surfactant mixtures with mix after naringin is dissolved in organic solvent respectively, add the adjuvant mixing again be insoluble to solvent behind the mixing, carry out spray drying then, cross 60～100 mesh sieves, get naringin solid dispersion; Organic solvent is dehydrated alcohol or 95% ethanol.
The preferred Macrogol 4000 of carrier material described in the spray drying method, polyethylene glycol 6000 or polyvinylpyrrolidone K30, K90; The preferred glyceryl monostearate of described surfactant, dodecyl sodium sulfate, pool Luo Samu 188; The described adjuvant that is insoluble to solvent is selected from hydroxypropyl cellulose, lactose or mannose.
Described freeze-drying comprises the steps:
After carrier material or carrier material and surfactant mixtures adding organic solvent stirring and dissolving, add naringin dissolving mixing, carry out lyophilization then, freeze-drying time is 24～48h, takes out, and grinds, cross 60～100 mesh sieves, get naringin solid dispersion; Described organic solvent is dehydrated alcohol or 95% ethanol.
Carrier material described in the freeze-drying is pool Luo Samu 188, Macrogol 4000 or polyethylene glycol 6000, polyvinylpyrrolidone K30, K90; Described surfactant is glyceryl monostearate, dodecyl sodium sulfate, pool Luo Samu 188.
The application of naringin solid dispersion of the present invention in useful in preparing drug formulations is the naringin solid dispersion that will make and conventional pharmaceutical necessities makes through conventional method; Can make suitable dosage form as required, as tablet, capsule, granule, pellet, oral liquid etc.; Usually use with oral way, also can adopt other administering modes.
The application of naringin solid dispersion of the present invention in the preparation health food is that the naringin solid dispersion that will make adopts conventional health food processing method to be prepared into health food.
Compared with prior art, the present invention has following beneficial effect:
Solid dispersion of the present invention is to adopt solid dispersions technique to disperse naringin, has improved its dissolubility and external dissolution rate in water, can improve and bioavailability simultaneously, makes naringin can absorb preferably at intestinal.By the dissolution in vitro test, the bioavailability test proves that naringin solid dispersion dissolution in vitro of the present invention is higher than the naringin conventional formulation in the body, and the single oral bioavailability is equivalent to 150% of ordinary preparation.
The specific embodiment
Below further specify technical scheme of the present invention by specific embodiment.
Embodiment 1 solid dispersion carrier material, ratio and preparation experiment
Present embodiment has been studied the influence to the solid dispersion preparation of naringin and carrier material proportioning, carrier material kind, preparation method.Study by following table 1 and table 2:
Table 1 factor and water-glass
Table 2 orthogonal test table
No. 1 test: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 1.2g PVPK30 is dissolved in the 100ml dehydrated alcohol, PVPK30 solution and naringin solution are mixed, vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, and promptly gets solid dispersion.
No. 2 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 1.2g PEG6000 and 3.6g lactose are added the 200ml water dissolution, mixed carrier material solution and naringin solution are mixed, carry out spray drying with electric heating mini spray exsiccator, intake air temperature is 70 ℃, application of sample speed is 25ml/min, promptly gets solid dispersion.
No. 3 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, 1.2g Poloxamer 188 heat in 80 ℃ of water-baths make its fusion then, add the naringin of usefulness organic solvent dissolution, vigorous stirring makes its uniform mixing, after continuing to be stirred to solvent and flinging to, pour into rapidly and place the ice bath stainless steel disc to make it be cooled to solid, in the freezing placement of refrigerator 6h,-20 ℃ of pre-freeze 4h, lyophilization 48h treats embrittlement afterwards, takes out, grind, promptly get solid dispersion.
No. 4 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then with 4.8g PVP K30 and 3.6g lactose 100ml anhydrous alcohol solution, mixed carrier material solution and naringin solution are mixed, carry out spray drying with electric heating mini spray exsiccator, intake air temperature is 70 ℃, application of sample speed is 25ml/min, promptly gets solid dispersion.
No. 5 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, 4.8g PEG6000 heat in 80 ℃ of water-baths make its fusion then, add the naringin of usefulness organic solvent dissolution, vigorous stirring makes its uniform mixing, after continuing to be stirred to solvent and flinging to, pour into rapidly and place the ice bath stainless steel disc to make it be cooled to solid, in the freezing placement of refrigerator 6h,-20 ℃ of pre-freeze 4h, lyophilization 48h treats embrittlement afterwards, takes out, grind, promptly get solid dispersion.
No. 6 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 4.8g Poloxamer 188 is heated in 80 ℃ of water-baths and make its fusion, add naringin with organic solvent dissolution, vigorous stirring makes its uniform mixing, after continuing to be stirred to solvent and flinging to, pours into rapidly and places the ice bath stainless steel disc to make it be cooled to solid, behind the freezing placement of refrigerator 6h, 48h in 25 ℃ of vacuum drying ovens grinds, and promptly gets solid dispersion.
No. 7 tests: 600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 9g PVPK30 is dissolved in the 100ml dehydrated alcohol, PVPK30 solution and naringin solution are mixed, vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent ,-20 ℃ of pre-freeze 4h, lyophilization 48h afterwards, take out, grind, promptly get solid dispersion.
No. 8 tests: 600mg naringin monomeric compound is dissolved in 20ml 95% ethanol, then 9g PEG6000 is dissolved in the 100ml dehydrated alcohol, carrier material solution and naringin solution are mixed, vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, pour into rapidly and place the ice bath stainless steel disc to make its cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, and promptly gets solid dispersion.
No. 9 tests: 600mg naringin monomeric compound is dissolved in 20ml 95% ethanol, then 9g Poloxamer 188 and 3.6g lactose sugar are added the 200ml water dissolution, mixed carrier material solution and naringin solution are mixed, carry out spray drying with electric heating mini spray exsiccator, intake air temperature is 70 ℃, application of sample speed is 25ml/min, promptly gets solid dispersion.
Experimental result shows, uses different carriers material preparation solid dispersion nature difference bigger in the preparation process, and with the PVPK30 best results, Poloxamer 188 takes second place; The prepared sample of different proportion all meets solid dispersion and requires to be the existence of metamict crystals state, but each sample appearance characteristics significant difference, 1:2 ratio sample color sample is the yellowish orange powder, and is mobile relatively poor, easily bonding.1:8 and 1:15 ratio color sample are faint yellow fine powder, and be mobile good.Good and bad as follows: 1:15〉1:8〉1:2; But different preparation method gained same material solid dispersion volume propertys do not have marked difference.
The preparation of embodiment 2 naringin solid dispersions
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 1.2gPEG6000 and 600mg dodecyl sodium sulfate are dissolved in the 150ml dehydrated alcohol, mixed carrier material solution and naringin solution are mixed, and vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, cross 60 mesh sieves, promptly get solid dispersion.
The preparation of embodiment 3 naringin solid dispersions
600mg naringin monomeric compound is dissolved in the 20ml95% ethanol, then 1.8g PVP K30 and 600mg Poloxamer 188 are dissolved in the 150ml dehydrated alcohol, mixed carrier material solution and naringin solution are mixed, and vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, cross 80 mesh sieves, promptly get solid dispersion.
The preparation of embodiment 4 naringin solid dispersions
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 9.0g PVP K30 and 600mg glyceryl monostearate are dissolved in the 150ml dehydrated alcohol, mixed carrier material solution and naringin solution are mixed, and vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, cross 80 mesh sieves, promptly get solid dispersion.
The experimental result of embodiment 2～4 shows that surfactant can improve the sample preparation quality, simultaneously preparation efficiency is also had raising, and the amount that adds surfactant when being (1/16)～(1/3) effect preferable.
Embodiment 5
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 1.8g PVP K30 is dissolved in the 100ml dehydrated alcohol, PVPK30 solution and naringin solution are mixed, vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, and promptly gets solid dispersion.
Embodiment 6
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then 3.6gPoloxamer 188 is heated in 80 ℃ of water-baths and make its fusion, add naringin with organic solvent dissolution, vigorous stirring makes its uniform mixing, after continuing to be stirred to solvent and flinging to, pours into rapidly and places the ice bath stainless steel disc to make it be cooled to solid, behind the freezing placement of refrigerator 6h, 48h in 25 ℃ of vacuum drying ovens grinds, and promptly gets solid dispersion.
Embodiment 7
600mg naringin monomeric compound is dissolved in 20ml 95% ethanol, then 5.4g PVPK30 and 600mg glyceryl monostearate are dissolved in the 150ml dehydrated alcohol, mixed carrier material solution and naringin solution are mixed, and vigorous stirring makes mixing then, adopts rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, cross 80 mesh sieves, promptly get solid dispersion.
The mensuration of embodiment 8 solid dispersion dissolution in vitro
1 medicine, reagent and instrument
Reagent naringin (prepared in laboratory, lot number: 080202); Polyvinylpyrrolidone K30 (PVP K30, ISP); Pool Luo Samu 188 (ISP); Dehydrated alcohol (Tianjin Da Mao chemical reagent factory); Above reagent is analytical pure.
Instrument ZRS-8G intelligence digestion instrument (Radio Factory of Tianjin Univ.); TU-1901 dual-beam UV, visible light spectrophotometer (Beijing Puxi General Instrument Co., Ltd); HWS24 type thermostat water bath (Shanghai Yiheng Scientific Instruments Co., Ltd); BP-211D analytical balance (German Sartorius);
2. sample preparation methods
2.1 the solid dispersion of naringin and polyvinylpyrrolidone K30 (PVP K30) preparation
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, respectively 1.2g, 1.8g, 3.6g, 5.4g PVPK30 are dissolved in the 100ml dehydrated alcohol then, PVPK30 solution and naringin solution are mixed, vigorous stirring makes mixing then, adopt rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens, grind, promptly get solid dispersion PVPSD (1:2), PVPSD (1:3), PVPSD (1:6), PVPSD (1:9).
2.2 naringin and the solid dispersion of mooring Luo Samu 188 preparations
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then respectively with 1.8g, 3.6g, 5.4g heating, Poloxamer 188 makes its fusion in 80 ℃ of water-baths, add naringin with organic solvent dissolution, vigorous stirring makes its uniform mixing, after continuing to be stirred to solvent and flinging to, pour into rapidly and place the ice bath stainless steel disc to make it be cooled to solid, behind the freezing placement of refrigerator 6h, 48h in 25 ℃ of vacuum drying ovens, grind, promptly get solid dispersion Poloxamer 188 SD (1:3), Poloxamer 188 SD (1:6), Poloxamer188 SD (1:9).
2.3 the solid dispersion of naringin, PVP K30 and surfactant preparation
600mg naringin monomeric compound is dissolved in the 20ml dehydrated alcohol, then with 1.8gpVPK30 and glyceryl monostearate (Glu), 1.8gPVPK30 and 600mg dodecyl sodium sulfate (SDS) 1.8g, PVPK30 and 188 3 combinations of pool Luo Samu are dissolved in the 150ml dehydrated alcohol respectively, mixed carrier material solution and naringin solution are mixed, vigorous stirring makes mixing then, adopt rotary evaporation to remove organic solvent, after thing to be mixed is the thickness state, rapid cooling curing, 48h in 25 ℃ of vacuum drying ovens grinds, cross 60 mesh sieves, promptly get solid dispersion PVP+Glu (1:3:1), PVP+SDS (1:3:1), PVP+Poloxamer188 (1:3:1).
The mensuration of 3 dissolution in vitro
3.1 the foundation of analytical method
Detect wavelength determination: take by weighing naringin respectively and carrier material is an amount of, be mixed with the solution of suitable concentration, and be blank, in 200～600nm scope, scan with this solution with methanol.The result shows that naringin has maximum absorption band at the 283nm place; And carrier material is all noiseless to the mensuration of naringin herein.Therefore, selected 283nm is as measuring wavelength.Standard curve: it is an amount of that precision takes by weighing naringin, is mixed with the solution of series concentration with methanol, measures trap in the 283nm place, with concentration (C) trap (A) carried out linear regression.
3.2 SD determination of dissolution rate method
Solid dispersion (SD) sample that get naringin 50mg, contains naringin 50mg carries out the dissolution test.3 parts of every group of sample parallel assays are undertaken by 2005 editions second methods of Chinese Pharmacopoeia.Dissolution medium is the distilled water of 900mL, and temperature is 37 ± 0.5 ℃, and rotating speed is 100 ± 1rpm.Respectively 3,6,9,12,15min sampling 5mL and mend the dissolution medium of equal volume, sample is through 0.8 μ m filtering with microporous membrane.Get subsequent filtrate dilution back and measure trap in the 283nm place, calculate the dissolution of naringin.
3.3 measurement result
Standard curve equation C=0.0301A+0.0127, R
2=0.9996, the range of linearity: 3.236～29.124 μ g/ml.
It is contrast with the naringin crude drug that the present invention adopts the dissolution in vitro experiment, measures naringin solid dispersion in external stripping situation, and the result shows that naringin solid dispersion is all right in external stripping.The results are shown in Table 3, table 4 and table 5:
Table 3 naringin-polyvinylpyrrolidone K30SD dissolution rate
Table 4 naringin-pool Luo Samu 188SD dissolution rate
Table 5 naringin-polyvinylpyrrolidone K30-surfactant SD dissolution rate
From the result shown in table 3～table 5 as can be seen, the external accumulative total of crude drug medicine 45min stripping percentage rate is 85.0%, solid dispersion of the present invention then can reach 90.4～100.1% of labelled amount in 3～15min, the dissolution of the solid dispersion of various ratios all is higher than raw material.As seen, solid dispersion system has increased the extracorporeal releasing speed of medicine, but along with SD carrier ratio increases, solubilization is not remarkable.Wherein with the solid dispersion of polyvinylpyrrolidone K30 preparation, dissolution rate improves particularly remarkable.
The dynamic (dynamical) research of generation of embodiment 8 naringin solid dispersion rat body giving drugs into nose
1 medicine, reagent and instrument
Animal: SD rat (SPF level) is provided the quality certification number: SCXK Guangdong 2006-0015 by No.1 Military Medical Univ.'s Experimental Animal Center.
Instrument: DIONEX high performance liquid chromatograph (U.S. wears peace, ASI-100 automatic sampler, P680 quaternary gradient pump, UV D170U detector); Laboratory Centrifuges 3K18 (Sigma); The quick turbine mixer of XK96-13 (Zhejiang); HWS24 type thermostat water bath (Shanghai Yiheng Scientific Instruments Co., Ltd); BP-211D analytical balance (German Sartorius); Simplicity ultra-pure water system (U.S. Millipore).
Reagent: naringin (Sigma company, content〉95%); Naringin crude drug and solid dispersion (prepared in laboratory, lot number: 080202); Naringenin (Sigma company, content〉98%); Psoralen (Nat'l Pharmaceutical ﹠ Biological Products Control Institute, content〉98%); Beta-Glucuronidase (Sigma, tool sulfatase activity); Methanol (B﹠amp; G company, chromatographically pure); Glacial acetic acid (analytical pure); Deionized water (U.S. Millipore).
The mensuration of 2 naringenin blood drug level
2.1 the preparation of standard solution
Standard reserving solution: take by weighing 105 ℃ of each about 10mg of naringenin reference substance that are dried to constant weight, the accurate title, decide, and places the 100ml volumetric flask respectively, uses the dissolve with methanol standardize solution, is mixed with the mother solution that concentration is 100 μ g/ml; Accurate respectively absorption mother solution is an amount of, places the 10ml volumetric flask, and (concentration is followed successively by 50 μ g/ml to become serial gradient concentration naringenin reference substance solution with methanol dilution standardize solution, 25 μ g/ml, 12.5 μ g/ml, 6.25 μ g/ml, 3.125 μ g/ml), as standard reserving solution, standby.
Interior mark storing solution: take by weighing psoralen reference substance 5mg, the accurate title, decide, and places the 50ml volumetric flask, and methanol constant volume is mixed with the mother solution that concentration is 100 μ g/ml, and precision is drawn mother solution, adds the methanol dilution and make 10 μ g/ml concentration reference substance solution, and be standby.
2.2 testing conditions (chromatographic condition)
Chromatographic column: Dikma C18 post (5 μ m, 250mm * 4.6mm);
Mobile phase: methanol: water (glacial acetic acid is transferred pH3.0)=53:47;
Detect wavelength: 283nm, 324nm;
Flow velocity: 1.0ml/min; Column temperature: room temperature; Sampling volume: 50 μ l.
2.3 the processing method of plasma sample
Get plasma sample 100 μ l, put in the 1.5ml centrifuge tube, add 50 μ l enzyme (β-Pu Taotanggansuanmei, 1500units/ml, tool sulfatase activity), 37 ℃ of water-baths 2 hours are taken out, add inner mark solution 10 μ l, vortex 30sec mix homogeneously adds 190 μ l methanol extraction albumen, the centrifugal 12min of 15000rpm on the centrifuge, get supernatant, 50 μ l sample introductions.
3 analytical methods are investigated
3.1 chromatographic condition specificity
Blank plasma 100 μ l3 parts add the 100 μ g/ml naringins of 10 μ l, the 100 μ g/ml naringenins of 10 μ l, the 100 μ g/ml psoralen reference substances of 10 μ l respectively, and whether investigate has interference.
3.2 the standard curve and the range of linearity
Accurate six parts of the blank plasma solution of drawing, every part 100 μ l, add each 10 μ l of 10 μ l inner mark solutions and specified series concentration gradient naringin and naringenin mark product solution respectively, naringin and naringenin reference substance concentration are respectively in the blood plasma: 125ng/ml, 250ng/ml, 500ng/ml, 1 μ g/ml, 2 μ g/ml, 4 μ g/ml, 8 μ g/ml.Press the processing method item operation down of 2.2.3 sample.Each sample feeding 50 μ l.Carry out linear regression with naringin, naringenin and interior target peak area ratio and naringin, naringenin plasma concentration, promptly get the standard curve equation and the range of linearity.
3.3 precision test
Get preparation gained naringin and naringenin height under standard curve and the range of linearity item, in, (concentration is respectively 0.125 μ g/ml to low three concentration samples, 1 μ g/ml, 6 μ g/ml), by 4.2 operations down, use Liquid Detection 5 times continuously, calculate RSD%, be instrument precision.
3.4 stability test
Get preparation gained naringin, naringenin height under standard curve and the range of linearity item, in, low three concentration samples (concentration is respectively 0.125 μ g/ml, 1 μ g/ml, 6 μ g/ml), by 4.2 operations down, placing 0h respectively, 2h, 4h, 8h measures behind the 12h, calculates RSD%, promptly.
3.5 recovery test
Get 12 parts of blank plasma solution, (high, normal, basic concentration is respectively 0.125 μ g/ml to every part 100 μ l, 1 μ g/ml, 4 parts of 6 μ g/ml operation repetitives), add inner mark solution 10 μ l and prescribed concentration naringenin, naringin standard solution 10 μ l, press operation under the 2.2.3 item, detect with liquid phase, calculate with the ratio of the chromatographic peak area of respective concentration sample before the medicine chromatographic peak area behind the methanol extraction albumen and the methanol extraction albumen high, in, the response rate of low 3 concentration.
3.6 lowest detectable limit test
The low concentration sample solution dilution is become certain concentration, carry out Liquid Detection, require concentration (peak height) 10 times for noise.With concentration is that the sample of 250ng/ml dilutes 10 times respectively, and 5 times, concentration is respectively 25ng/ml, 50ng/ml, sample introduction 50 μ l.
The medication design and the blood specimen collection of the experiment of 4 pharmacokineticss
Adopt single-dose, 16 of SD rats, body weight is 250 ± 20g, is divided into 2 groups at random.Experiment fasting the previous day 12h freely drinks water, and gavages naringin raw material and naringin solid dispersion (being equivalent to crude drug 135mg/kg) respectively, in preset time point (0.5,1,1.5,2,3,4,5,6,7,8,12,24h) the rat eye socket is got blood 0.5ml, put 1.5mL in the plastic centrifuge tube that heparin is handled, the centrifugal 10min of 3000rpm/min; Get supernatant blood plasma, put-20 ℃ of preservations in the refrigerator, to be analyzed.Operate by " 2.2.3 " sample treatment, measure.The result is abscissa with the administration time, is that vertical coordinate is drawn drug-time curve with the blood drug level of naringenin.
5 experimental results
5.1 method specificity
Under above-mentioned mobile phase and chromatographic condition, naringenin and interior mark separate well with the endogenous material in the blood plasma, and the free from admixture peak disturbs.
5.2 the standard curve and the range of linearity
Naringenin is good in 125～8000ng/ml concentration range internal linear scope, and regression equation is
Y＝2.034X-0.3223，R2＝0.9935。
5.3 precision test
Precision is tested the RSD value of high, medium and low concentration precision all less than 15%, and effect is better, meets the biological sample analysis requirement.
5.4 stability test
RSD value in the high, medium and low stability of concentration 12h of stability test is all less than 10%, and effect is better, meets the biological sample analysis requirement.
5.5 recovery test
The response rate of the high, medium and low concentration of recovery test is between 99% to 115%, and RSD is in 10%, and effect is better, meets the biological sample analysis requirement.
5.6 lowest detectable limit test
The minimum 2.5ng that quantitatively is limited to, minimum quantitative concentrations is 50ng/ml.
5.7 sample determination
The analytical method of adopt setting up is used for detecting the concentration of the naringenin in the rat plasma, and specificity is strong, and sensitivity is higher, and experimental result sees Table 6, shown in the table 7.The oral back of naringin ordinary preparation and solid dispersion naringenin blood medicine peak time is about 6h, and blood medicine peak value is respectively 8102.54 ± 2076.31ngml
-1And 11722.66 ± 2192.30ngml
-1, bioavailability is respectively 31785.20 ± 3722.81nghml
-1And 47730.35 ± 6717.76nghml
-1Learn that by experimental result solid dispersion has improved the oral absorption and the bioavailability of naringin.The oral administration biaavailability of medicine is determined that by multiple reason one of them is exactly that medicine is difficult to dissolving and limits its absorption.Naringin solid dispersion reaches the purpose that improves bioavailability by dissolubility and the dissolution that improves naringin.
Plasma sample measurement result (n=8) after the administration of table 6 rat oral gavage
The main pharmacokinetic parameter of table 7
Claims (10)
1. naringin solid dispersion, it is characterized in that containing naringin and carrier material, naringin: the mass ratio of carrier material is 1:2～1:15; Described carrier material is selected from any one or several mixture among Polyethylene Glycol, polyvinylpyrrolidone or the pool Luo Samu.
2. naringin solid dispersion as claimed in claim 1 is characterized in that also being added with in the described naringin solid dispersion surfactant, and the addition of described surfactant is 1/16～1/3 of naringin and a carrier material gross weight; Described surfactant is selected from one or more the mixture of pool in Luo Samu 188, dodecyl sodium sulfate or the glyceryl monostearate.
3. naringin solid dispersion as claimed in claim 1 is characterized in that described Polyethylene Glycol is PEG4000 or PEG6000; Described polyvinylpyrrolidone is PVP K30 or PVP K90; Described pool Luo Samu is Poloxamer188 or Poloxamer407.
4. the preparation method of claim 1 or 2 described naringin solid dispersions is characterized in that naringin and carrier material and other conventional adjuvants are prepared by fusion method, solvent method, solvent-fusion method, spray drying method or freeze-drying.
5. preparation method as claimed in claim 4, it is characterized in that described fusion method is: with carrier material or carrier material and surfactant mixtures and naringin mixing, heated and stirred is to fusion fully, or with behind carrier material or carrier material and the surfactant mixtures surfactant heating and melting, adding naringin again stirs molten, then with fused mass under vigorous stirring, be cooled to solid in the container in the impouring ice-water bath rapidly, the solid that obtains promptly gets naringin solid dispersion after placing drying.
6. preparation method as claimed in claim 4, it is characterized in that described solvent method is: with carrier material or carrier material and surfactant mixtures and naringin mixing, add organic solvent dissolution again, or with carrier material or carrier material and surfactant mixtures with mix after naringin is dissolved in organic solvent respectively, adopt rotary evaporation to remove organic solvent behind the mixing, again through being drying to obtain naringin solid dispersion; Described organic solvent is dehydrated alcohol or 95% ethanol.
7. preparation method as claimed in claim 4, it is characterized in that described solvent-fusion method is: carrier material or carrier material and surfactant mixtures are heated make its fusion in 50～90 ℃ of water-baths, add naringin with organic solvent dissolution, adopt rotary evaporation to remove behind the mixing and desolvate, again through being drying to obtain naringin solid dispersion; Described organic solvent is dehydrated alcohol or 95% ethanol.
8. preparation method as claimed in claim 4, it is characterized in that described spray drying method is: with carrier material or carrier material and surfactant mixtures and naringin mixing, add organic solvent dissolution again, or with carrier material or carrier material and surfactant mixtures with mix after naringin is dissolved in organic solvent respectively, add the adjuvant mixing again be insoluble to solvent behind the mixing, carry out then promptly getting naringin solid dispersion after the spray drying; Organic solvent is dehydrated alcohol or 95% ethanol; The described adjuvant that is insoluble to solvent is selected from hydroxypropyl cellulose, lactose or mannose.
9. preparation method as claimed in claim 4, it is characterized in that described freeze-drying is: after carrier material or carrier material and surfactant mixtures adding organic solvent stirring and dissolving, add naringin dissolving mixing, carry out then promptly getting naringin solid dispersion after the lyophilization; Described organic solvent is dehydrated alcohol or 95% ethanol.
10. the application of the described naringin solid dispersion of claim 1 in useful in preparing drug formulations or health food.
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