CN102048702B - Bifendate nano crystal preparation and preparation method thereof - Google Patents
Bifendate nano crystal preparation and preparation method thereof Download PDFInfo
- Publication number
- CN102048702B CN102048702B CN2010105720119A CN201010572011A CN102048702B CN 102048702 B CN102048702 B CN 102048702B CN 2010105720119 A CN2010105720119 A CN 2010105720119A CN 201010572011 A CN201010572011 A CN 201010572011A CN 102048702 B CN102048702 B CN 102048702B
- Authority
- CN
- China
- Prior art keywords
- biphenyl
- dimethylesterate
- bifendate
- suspensoid
- nano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a bifendate nano crystal preparation, which comprises 200 weight parts of raw material of bifendate and 20 to 400 weight parts of auxiliary material of stabilizing agent. A preparation method comprises the following steps of: (1) dispersing the stabilizing agent serving as a dispersion medium in double distilled water to obtain a suspension A; (2) dispersing the bifendate in an organic solvent to obtain a coarse suspension B; (3) dispersing the coarse suspension B in the suspension A under the ultrasonic condition to obtain a suspension C; (4) homogenizing the suspension C by using a high pressure microfluidization nano dispersion instrument to obtain bifendate nano crystal suspension; and (5) performing freeze drying on the prepared bifendate nano crystal suspension, or adding a freeze drying protective agent and performing freeze drying to obtain the bifendate nano crystal preparation. The bifendate nano crystal preparation can be prepared into injection or oral preparations such as tablets, capsules and the like when applied.
Description
Technical field
The present invention relates to a kind of biphenyl dimethylesterate nano crystallization preparation and preparation method thereof
Background technology
Bifendate (Bifendate): being the intermediate of synthetic schisandrin C, is the hepatoprotective of efficient, the low toxicity with new structure of China initiative.Its chemistry is called 4,4 '-dimethoxy-5,6, and 5 ', 6 '-secondary first dioxy-2,2 '-dioctyl phthalate methyl ester biphenyl, molecular formula is: C
20H
18O
10, molecular weight is: 419.36.These article are a kind of white crystalline powder, and odorless, tasteless is water-soluble hardly, is slightly soluble in methanol and ethanol, are soluble in chloroform, dimethyl formamide season pyridine, are certain fat-soluble.
Clinical research shows that the main pharmacological of bifendate has: (1) has significant function for protecting liver and reducing enzyme activity: can obviously reduce serum glutamic pyruvic transminase (glutamic pyrumic transaminase; GPT) and glutamic oxaloacetic transaminase, GOT (glutamic Oxalictransaminase, GOT); (2) strengthen the function of detoxification of liver: the content of hepatomicrosome such as P-450 is significantly increased, and then strengthen the detoxification ability of liver; (3) the liver protecting is avoided the poisonous substance damage: alleviate the hepatic injury that is caused by chemical substances such as carbon tetrachloride, anticarcinogen, antitubercular agents; The effect of (4) anti-cell sudden change, necrosis.This poison of drug property is very low, and no teratogenesis tire, mutagenic action are a kind of relatively safe drugs, and cheap, easy for patients to accept, thereby have good research and application prospect.At present this medicine is clinical is used for the gpt activity rising person that chronic persistent hepatitis is followed, and also can be used for chemical toxicant, drug-induced gpt activity raises.
The almost water-fast character of bifendate makes the external stripping of its preparation poor, though in gastrointestinal tract, be not destroyed, the serious liver first-pass effect in oral back causes this medicine oral administration biaavailability low, generally has only 25%～30%.Bifendate get in the body back at liver rapidly by metabolic conversion, plasma half-life had only about 5 hours, 70% discharges from feces after 24 hours.Though only absorb about 25%, show the very strong GPT effect of falling, explain that its biological activity is very high, be one the researching value medicine to be arranged.The preparation that uses at present or study mainly contains Bifendate Tablet, Bifendate, bifendate drop pill, compound bifenox sheet, compound bifenox electuary, bifendate oral administration mixed suspension etc.; CN 200410070669.4 discloses a kind of bifendate oral disintegration tablet, CN 03145971.4 discloses a kind of bifendate slow releasing preparation; Because bifendate is water insoluble, so the low shortcoming of these preparation ubiquity bioavailability.CN 03146030.5 discloses a kind of biphenyl diester emulsion, CN 100998561A discloses a kind of bifendate intravenous injection emulsion, and liquid preparation stores and the transportation inconvenience, also causes medicine unstable easily.CN 200610038662.3 discloses a kind of bifendate solid dispersion, CN 200810234507.8 discloses a kind of self-emulsifying formulation of biphenyldicarboxylatand to improve its bioavailability and stability.
Bifendate is as a kind of medicine of life-time service, and a kind of administration number of times of clinical needs is few, bioavailability is high, good stability, preparation simply help the preparation that the patient uses.
Nanocrystal (nanocrystals): in recent years by stable the increasing of quantity of the activity chemistry entity of screening such as combinatorial chemistry preparation, but major part is a hydrophobic compound.According to statistics, have 40% to be insoluble in water in the medicine that obtains through high flux screening at present, and this situation reach 60% in the medicine that obtains through direct synthesis technique.Insoluble drug usually is difficult to reach the bioavailability that the treatment disease requires after oral through traditional formulation method, or is difficult to process the preparation that supplies intravenously administrable, thus big limitations the application of medicine.The preparation work person has taked a lot of methods to solve this problem, as using mixed solvent, adopt inclusion technique, micronization or processing vein emulsion etc.Avoid the drawback of said method up to 1994 by the nanocrystal of reported first such as M ü ller, had clear superiority.
Nanocrystal is to utilize the Stabilization of surfactant, and drug particles is dispersed in the water, forms the stabilized nano colloidal dispersion through pulverizing or control the crystallize technology.The charge effect that the pure drug particles of nanoscale particle diameter relies on surfactant in the system is or/and stereoeffect stably is suspended in the solution, and the mean diameter of its Chinese medicine is less than 1 μ m, generally between 100～500nm.Nanocrystal can further be prepared as the pharmaceutical dosage form that is fit to oral, injection or other administration route, thereby improves the absorption and the bioavailability of medicine.And nanocrystal can improve the drug loading in the preparation, is particularly suitable for the oral and drug administration by injection of heavy dose, insoluble drug.In addition, owing to do not contain carrier and cosolvent in the prescription, the toxic and side effects of drug administration by injection is lower.
Deposition-high pressure homogenization method (high-pressure homogenization): the method for preparing of nanocrystal mainly contains grinding method, high pressure homogenization method, the sedimentation method, deposition-high pressure homogenization method, emulsion process and microemulsion method etc.
In sum, bifendate is processed nano crystallization preparation, expection can reach that toxic and side effects is little, system is stable, can increase purpose such as bioavailability of medicament.Do not see in the prior art relevant for the report of bifendate being processed nano crystallization preparation.Lack in the prior art under the situation of relevant report; Develop and a kind ofly have that good effect, good biocompatibility, bioavailability are high, system stablizes, is applicable to that the biphenyl dimethylesterate nano crystallization preparation of large-scale industrial production, low cost and other advantages and method for preparing are difficult points; Creative work need be paid, lot of test and conditional filtering need be carried out.
Summary of the invention
To above-mentioned prior art; Clinical practice limitation to the bifendate poorly water-soluble; The invention provides a kind of new architecture of bifendate: biphenyl dimethylesterate nano crystallization preparation, calcium preparation can increase the bioavailability of bifendate, and toxic and side effects is little, system stable.The present invention also provides the method for preparing of this biphenyl dimethylesterate nano crystallization preparation, and this method can adopt conventional process equipment, is fit to the extensive high benefit production of industry.
The present invention realizes through following technical scheme:
A kind of biphenyl dimethylesterate nano crystallization preparation comprises raw material and adjuvant, and raw material is a bifendate, and adjuvant is a stabilizing agent, and the weight portion of raw material and adjuvant is following: 200 parts of bifendate, 20～400 parts of stabilizing agents; Wherein, Said stabilizing agent comprises surfactant and the agent of macromolecule suspending; Surfactant is selected from one or more in fatty glyceride, polyol-based non-ionic surfactant, polyoxyethylene-type non-ionic surface active agent, poloxamer, the lecithin; The agent of macromolecule suspending is selected from one or more in arabic gum, hydroxypropyl cellulose, methylcellulose, polyvidone, carbopol, the glucosan, and the consumption mass ratio of surfactant and the agent of macromolecule suspending is 1: 4.
The weight portion of said raw material and adjuvant is preferably following: 200 parts of bifendate, 20～400 parts of stabilizing agents; Further preferred, for: 200 parts of bifendate, 20～300 parts of stabilizing agents.
A kind of method for preparing of biphenyl dimethylesterate nano crystallization preparation may further comprise the steps:
(1) stabilizing agent is dispersed in the distilled water with as disperse medium, obtains suspensoid A;
(2) bifendate is dispersed in the organic solvent, obtains thick suspensoid B;
(3) be scattered under the thick suspensoid B ultrasonic sound condition that step (2) is made among the water disperse medium suspensoid A that step (1) makes, make suspensoid C;
(4) the suspensoid C that step (3) is made is through high pressure microjet nano-dispersed appearance homogenizing 1～20 time under the pressure of 4660psig～27960psig, biphenyl dimethylesterate nano crystallization suspension;
(5) the biphenyl dimethylesterate nano crystallization suspension lyophilization that step (4) is made, or add the freeze drying protectant postlyophilization, promptly get biphenyl dimethylesterate nano crystallization preparation.
In the said step (1), when stabilizing agent was dispersed in the distilled water, the two following with magnitude relation: per 0.2～20g stabilizing agent was dispersed in the 100ml water.
In the said step (2); When bifendate is dispersed in the organic solvent; The two following with magnitude relation: per 0.2～20g bifendate is dispersed in the step described in 1～10ml organic solvent (2), and organic solvent is selected from one or more in chloroform, acetone, ethanol, ethyl acetate, isopropyl alcohol, PEG400, the dimethyl sulfoxide.
In the said step (4), the concrete operations of homogenizing are: homogenizing 2 times respectively under the pressure of 6990psig and 11650psig, homogenizing 10 times under 23300psig pressure then.
In the said step (5), freeze drying protectant is selected from one or more in mannitol, sucrose, lactose, galactose, chitosan, the trehalose.
In the said step (5), the addition of freeze drying protectant is 1%～10% (w/v) of biphenyl dimethylesterate nano crystallization suspension, unit: g:ml.
Preferably, said method for preparing concrete steps are following:
(1) with the surfactant-dispersed of the macromolecule suspending agent of 0.05g and 0.2g in the 100ml distilled water with as disperse medium, obtain suspensoid A; Wherein, the agent of macromolecule suspending is polyvidone or hydroxypropyl cellulose, and surfactant is a lecithin;
(2) the 0.2g bifendate is dispersed in the 5ml organic solvent, obtains thick suspensoid B; Wherein, organic solvent is that dimethyl sulfoxide, acetone or volume ratio are acetone-PEG400 mixture of 1: 1;
(3) be scattered under the thick suspensoid B ultrasonic sound condition that step (2) is made among the water disperse medium suspensoid A that step (1) makes, make suspensoid C;
(4) the suspensoid C that step (3) is made distinguishes homogenizing 2 times through high pressure microjet nano-dispersed appearance under the pressure of 6990psig and 11650psig, homogenizing 10 times under 23300psig pressure then must biphenyl dimethylesterate nano crystallization suspension;
(5) in the biphenyl dimethylesterate nano crystallization suspendible liquid cooling that step (4) makes, add freeze drying protectant mannitol, addition is 5% of a biphenyl dimethylesterate nano crystallization suspension, unit: g:ml, and lyophilization promptly gets biphenyl dimethylesterate nano crystallization preparation.The method for preparing of biphenyl dimethylesterate nano crystallization preparation of the present invention; Adopt deposition-high pressure homogenization method; It is earlier medicine to be dissolved in the organic solvent; Join in the aqueous solution that contains surfactant at the organic solvent that is dissolved with medicine following of low temperature condition of stirring then, under the effect of high pressure microjet nano-dispersed appearance, make nanocrystal behind the ultrasonic reasonable time of low temperature.This law has combined the advantage of the sedimentation method and high pressure homogenization method, also is suitable for preparing the aseptic nanocrystal of injection.
The prepared biphenyl dimethylesterate nano crystallization preparation that obtains of the present invention can be processed injection and use when concrete the application, and toxic and side effects is little, and system is stable; Also can process oral formulations, like tablet, capsule etc.
The present invention to increase its curative effect and to expand clinical practice, has adopted suitable stabilizing agent and high pressure homogenization method to prepare the biphenyl dimethylesterate nano crystallization in order to improve bifendate oral administration biaavailability and preparation injection bifendate.Stabilizing agent used in the present invention and freeze drying protectant are the adjuvant of field of pharmaceutical preparations extensive use, no immunostimulating, and no physiology toxicity, non-responsiveness property has excellent biological compatibility.The present invention selects suitable homogenization pressure and stabilizer concentration and composition through process optimization and prescription screening, can prepare that size can be controlled, stability biphenyl dimethylesterate nano crystallization preferably.The biphenyl dimethylesterate nano crystallization suspension that method of the present invention prepares is observed under transmission electron microscope; It is thus clear that bifendate is spherical entity particle; Surfaces coated is covered with stabilizing agent; Kernel is the bifendate crude drug, and particle diameter can judge that according to the form and the size of particle said preparation is the biphenyl dimethylesterate nano crystallization between 20～1000nm.In addition, biphenyl dimethylesterate nano crystallization suspension is mixed the biphenyl dimethylesterate nano crystallization that makes after the lyophilization again with freeze drying protectant; With carrying out grain diameter measurement again after its redissolution; Particle diameter also can confirm the formation of nano crystallization preparation at 100～1000nm, and is as shown in Figure 1.
The present invention has overcome the defective that bifendate is insoluble in water; The prepared nanocrystal of the present invention can significantly improve the dissolution in vitro degree and the dissolution rate of bifendate; Carry out for being released under the sink condition of medicine of assurance, this paper studies the release behaviour in vitro of DDB-NSP dried frozen aquatic products and crude drug powder with the stirring arm method, and the dissolution data of gained DDB crude drug and DDB-NSP freeze-dried powder is made accumulative total stripping quantity-time graph; Can obviously see with bifendate process nanocrystalline after; Compare with crude drug and obviously to have improved it and dissolve in speed, see Fig. 3 (p＜0.05), like embodiment 1.
The preparation technology of biphenyl dimethylesterate nano crystallization preparation of the present invention is easy to amplify; Prescription is simple, with improving stability of drug after its lyophilization, reduces the administration volume; Making oral administration nanometer crystallization suspensoid helps the swallow crowd of difficulty such as child and old man and is suitable for; Increase bioavailability, reduce dosage, reduce toxic and side effects; Make the pain that the injection lyophilized powder helps reducing the toxicity that increases other complicated adjuvant and extreme pH, help being suitable for of emergency case patient with severe symptoms.
Description of drawings
Fig. 1: the transmission electron microscope photo of the nanocrystal that bifendate and stabilizing agent form.
Fig. 2: be the particle size distribution figure (title: particle size distribution (Size distribution (s)), abscissa: particle diameter (Diameter), vertical coordinate: percentage rate (%in class) of biphenyl dimethylesterate nano suspension.
The external stripping curve (n=3) of Fig. 3: DDB-NSP and crude drug.
The specific embodiment
Below in conjunction with embodiment the present invention is done detailed elaboration, but protection scope of the present invention is not limited to the embodiment of these concrete records.
Embodiment 1: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved in the 5ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 0.05g polyvidone (k30), 0.2g lecithin under stirring; Behind the ultrasonic 40min of low temperature; Again through high pressure microjet nano-dispersed appearance with the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension according to 5% (w/v, g/ml) ratio adds mannitol, is filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving; Put into ultra cold storage freezer rapidly; Under-80 ℃ of temperature freezing 24 hours, take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf, cover vacuum (-tight) housing; The open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.Adopt the stirring paddle method to carry out external dissolution test lyophilized powder and crude drug, the result sees Fig. 3, can obviously see with bifendate process nanocrystalline after, compare it with crude drug and dissolve in speed and obviously improved.
Get above-mentioned DDB-NSP freeze-dried powder redissolution back liquid and be diluted to certain multiple, transmission electron microscope is observed down, and is as shown in Figure 1; Particle size distribution figure is as shown in Figure 2, and particle diameter is in 60～340nm scope.
Embodiment 2: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 2.5g bifendate is dissolved in the 5ml dimethyl sulfoxide; Stirring down at low temperature, injection 100ml contains 5g polyvidone k30), the aqueous solution of 1g lecithin; Behind the ultrasonic 40min of low temperature; Again through high pressure microjet nano-dispersed appearance with the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension according to 5% (w/v, g/ml) ratio adds mannitol, is filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving; Put into ultra cold storage freezer rapidly; Under-80 ℃ of temperature freezing 24 hours, take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf, cover vacuum (-tight) housing; The open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 3: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 5g bifendate is dissolved in the 5ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 2.5g hydroxypropyl cellulose, 2g lecithin under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 4: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 2g bifendate is dissolved in the 10ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 1g hydroxypropyl cellulose, 2g poloxamer under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 5: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved in the 1ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 2g hydroxypropyl cellulose, 2g poloxamer under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 6: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 2.5g bifendate is dissolved in the 6ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 3g hydroxypropyl cellulose, 2g poloxamer under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 7: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 5g bifendate is dissolved in the 10ml dimethyl sulfoxide;, low temperature injects the aqueous solution that 100ml contains 2.5g polyvidone (k30), 5g lecithin under stirring; Behind the ultrasonic 40min of low temperature; Again through high pressure microjet nano-dispersed appearance with the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension according to 5% (w/v, g/ml) ratio adds mannitol, is filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving; Put into ultra cold storage freezer rapidly; Under-80 ℃ of temperature freezing 24 hours, take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf, cover vacuum (-tight) housing; The open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 8: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved in the 5ml dimethyl sulfoxide; Under low temperature stirs, inject 100ml and contain 0.25 polyvidone (k30), 0.5g polyoxyethylene castor oil aqueous solution; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 9: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved in the 5ml acetone;, low temperature injects the aqueous solution aqueous solution that 100ml contains 0.05g polyvidone (k30), 0.2g lecithin under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 10: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved among 5ml acetone-PEG400 (1: 1);, low temperature injects the aqueous solution aqueous solution that 100ml contains 0.05g polyvidone (k30), 0.2g lecithin under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Embodiment 11: preparation biphenyl dimethylesterate nano crystallization preparation
Taking by weighing the 0.2g bifendate is dissolved in the 5ml acetone;, low temperature injects the aqueous solution that 100ml contains 0.05g hydroxypropyl cellulose, 0.20g lecithin under stirring; Behind the ultrasonic 40min of low temperature; With the pressure of 6990psig, 11650psig homogenizing 2 times respectively, homogenizing 10 times under 23300psig pressure promptly gets biphenyl dimethylesterate nano crystallization suspension then.
Get above-mentioned suspension and add mannitol according to 5% (w/v) ratio; Be filled to cillin bottle according to 2mL/ bottle branch after the stirring and dissolving, put into ultra cold storage freezer rapidly, under-80 ℃ of temperature freezing 24 hours; Take out again and put into temperature rapidly and reduce on-50 ℃ the freeze dryer shelf; Cover vacuum (-tight) housing, open vacuum switch pump, lyophilizing 48 hours.Lyophilizing finishes the back and takes out back pressurization aluminum cap packaging, promptly gets the biphenyl dimethylesterate nano crystallization.
Claims (9)
1. biphenyl dimethylesterate nano crystallization preparation, it is characterized in that: comprise raw material and adjuvant, raw material is a bifendate, and adjuvant is a stabilizing agent, and the weight portion of raw material and adjuvant is following: 200 parts of bifendate, 20～400 parts of stabilizing agents; Wherein, Said stabilizing agent comprises surfactant and the agent of macromolecule suspending; Surfactant is selected from one or more in fatty glyceride, polyol-based non-ionic surfactant, polyoxyethylene-type non-ionic surface active agent, poloxamer, the lecithin; The agent of macromolecule suspending is selected from one or more in arabic gum, hydroxypropyl cellulose, methylcellulose, polyvidone, carbopol, the glucosan, and the consumption mass ratio of surfactant and the agent of macromolecule suspending is 1: 4;
Obtain through following method for preparing:
(1) stabilizing agent is dispersed in the distilled water, obtains suspensoid A;
(2) bifendate is dispersed in the organic solvent, obtains thick suspensoid B;
(3) be scattered under the thick suspensoid B ultrasonic sound condition that step (2) is made among the suspensoid A that step (1) makes, make suspensoid C;
(4) the suspensoid C that step (3) is made is through high pressure microjet nano-dispersed appearance homogenizing 1～20 time under the pressure of 4660psig～27960psig, biphenyl dimethylesterate nano crystallization suspension;
(5) the biphenyl dimethylesterate nano crystallization suspension lyophilization that step (4) is made, or add the freeze drying protectant postlyophilization, promptly get biphenyl dimethylesterate nano crystallization preparation.
2. the method for preparing of the described a kind of biphenyl dimethylesterate nano crystallization preparation of claim 1 is characterized in that, may further comprise the steps:
(1) stabilizing agent is dispersed in the distilled water, obtains suspensoid A;
(2) bifendate is dispersed in the organic solvent, obtains thick suspensoid B;
(3) be scattered under the thick suspensoid B ultrasonic sound condition that step (2) is made among the suspensoid A that step (1) makes, make suspensoid C;
(4) the suspensoid C that step (3) is made is through high pressure microjet nano-dispersed appearance homogenizing 1～20 time under the pressure of 4660psig～27960psig, biphenyl dimethylesterate nano crystallization suspension;
(5) the biphenyl dimethylesterate nano crystallization suspension lyophilization that step (4) is made, or add the freeze drying protectant postlyophilization, promptly get biphenyl dimethylesterate nano crystallization preparation.
3. method for preparing according to claim 2 is characterized in that: in the said step (1), when stabilizing agent was dispersed in the distilled water, the two following with magnitude relation: per 0.2～20g stabilizing agent was dispersed in the 100ml water.
4. method for preparing according to claim 3 is characterized in that: in the said step (2), when bifendate was dispersed in the organic solvent, the two following with magnitude relation: per 0.2～20g bifendate was dispersed in 1～10ml organic solvent.
5. method for preparing according to claim 2 is characterized in that: in the said step (2), organic solvent is selected from one or more in chloroform, acetone, ethanol, ethyl acetate, isopropyl alcohol, PEG400, the dimethyl sulfoxide.
6. method for preparing according to claim 2 is characterized in that: in the said step (4), the concrete operations of homogenizing are: homogenizing 2 times respectively under the pressure of 6990psig and 11650psig, homogenizing 10 times under 23300psig pressure then.
7. method for preparing according to claim 2 is characterized in that: in the said step (5), freeze drying protectant is selected from one or more in mannitol, sucrose, lactose, galactose, chitosan, the trehalose.
8. method for preparing according to claim 2 is characterized in that: in the said step (5), the addition of freeze drying protectant is 1%～10% of a biphenyl dimethylesterate nano crystallization suspension, unit: g:ml.
9. method for preparing according to claim 2, it is characterized in that: concrete steps are following:
(1) with the surfactant-dispersed of the macromolecule suspending agent of 0.05g and 0.2g in the 100ml distilled water, obtain suspensoid A; Wherein, the agent of macromolecule suspending is polyvidone or hydroxypropyl cellulose, and surfactant is a lecithin;
(2) the 0.2g bifendate is dispersed in the 5ml organic solvent, obtains thick suspensoid B; Wherein, organic solvent is that dimethyl sulfoxide, acetone or volume ratio are acetone-PEG400 mixture of 1: 1;
(3) be scattered under the thick suspensoid B ultrasonic sound condition that step (2) is made among the suspensoid A that step (1) makes, make suspensoid C;
(4) the suspensoid C that step (3) is made distinguishes homogenizing 2 times through high pressure microjet nano-dispersed appearance under the pressure of 6990psig and 11650psig, homogenizing 10 times under 23300psig pressure then must biphenyl dimethylesterate nano crystallization suspension;
(5) in the biphenyl dimethylesterate nano crystallization suspendible liquid cooling that step (4) makes, add freeze drying protectant mannitol, addition is 5% of a biphenyl dimethylesterate nano crystallization suspension, unit: g:ml, and lyophilization promptly gets biphenyl dimethylesterate nano crystallization preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105720119A CN102048702B (en) | 2010-12-03 | 2010-12-03 | Bifendate nano crystal preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105720119A CN102048702B (en) | 2010-12-03 | 2010-12-03 | Bifendate nano crystal preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102048702A CN102048702A (en) | 2011-05-11 |
| CN102048702B true CN102048702B (en) | 2012-05-23 |
Family
ID=43953726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105720119A Expired - Fee Related CN102048702B (en) | 2010-12-03 | 2010-12-03 | Bifendate nano crystal preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102048702B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102846554B (en) * | 2012-09-28 | 2014-11-26 | 山东大学 | H2 nanocrystal preparation and preparation method thereof |
| CN102895185B (en) * | 2012-11-05 | 2015-03-25 | 西安德天药业股份有限公司 | Bifendate rapid-release pellet and preparation method and application thereof |
| CN105796492B (en) * | 2016-04-07 | 2019-07-02 | 中山大学 | Razaxaban nano suspension and preparation method thereof |
| CN113069433B (en) * | 2021-04-16 | 2022-08-02 | 北京中医药大学 | Euphorbia lathyris element nanometer preparation and preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL160570A0 (en) * | 2001-09-26 | 2004-07-25 | Baxter Int | Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal |
| US20060003012A9 (en) * | 2001-09-26 | 2006-01-05 | Sean Brynjelsen | Preparation of submicron solid particle suspensions by sonication of multiphase systems |
| GB0216700D0 (en) * | 2002-07-18 | 2002-08-28 | Astrazeneca Ab | Process |
| KR20100052262A (en) * | 2008-11-10 | 2010-05-19 | (주)아모레퍼시픽 | Process for preparing powder comprising nanoparticles of sparingly soluble drug, powder prepared by same process and pharmaceutical composition comprising same powder |
-
2010
- 2010-12-03 CN CN2010105720119A patent/CN102048702B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Lei Gao 等.Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system.《Journal of Nanoparticle Research》.2008,第10卷(第5期),845-862. * |
| Lei Gao 等.Preparation and characterization of an oridonin nanosuspension for solubility and dissolution velocity enhancement.《Drug Development and Industrial Pharmacy》.2007,第33卷(第12期),1332-1339. * |
| 张熹 等.纳米结晶在难溶性药物口服给药中的应用.《中国医药工业杂志》.2009,第40卷(第11期),1-10. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102048702A (en) | 2011-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2334991T3 (en) | FARMACO MICROPARTICLES. | |
| CA2295588C (en) | Nanocrystalline formulations of human immunodeficiency virus (hiv) protease inhibitors using cellulosic surface stabilizers and methods of making such formulations | |
| CA2371912A1 (en) | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof | |
| JP2008280352A (en) | Composition improved in solubility and oral absorbability | |
| CN105902496A (en) | A treating method for a nanometer suspension solidification process | |
| CN102824356A (en) | Baicalin nano crystal suspension, nano crystal dry powder and methods for preparing baicalin nano crystal suspension and nano crystal dry powder | |
| CN102228430B (en) | Nano suspension of silybin-phospholipid complex and preparation method thereof | |
| CN102048702B (en) | Bifendate nano crystal preparation and preparation method thereof | |
| CN104398477A (en) | Usnic acid nanometer suspension, and preparation method and use thereof | |
| CN104523606B (en) | The method that self-assembly method prepares gossypol and its derivative pluronic nano-particle | |
| CN101961320A (en) | Budesonide nano crystallizing preparation and preparation method thereof | |
| Han et al. | In vitro and in vivo evaluation of core–shell mesoporous silica as a promising water-insoluble drug delivery system: Improving the dissolution rate and bioavailability of celecoxib with needle-like crystallinity | |
| Vadlamudi et al. | Disparate practical way of doing solubility enhancement study to improve the bioavailability of poorly soluble drugs | |
| CN101955505B (en) | Immune suppressor and composition thereof | |
| CN102579737B (en) | Dragon blood nano medicament crystallized preparation and preparation method thereof | |
| CN110251487B (en) | Preparation method and application of alcohol soluble protein nanoparticles for improving drug-loading rate and oral bioavailability of docetaxel | |
| CN102579373B (en) | Amoitone B nano crystallization preparation and preparation method thereof | |
| CN103263385B (en) | A kind of celecoxib long-acing nano injection and preparation method thereof | |
| CN102772365B (en) | 4-(4-(3-trifluoromethyl)benzamido-phenoxy)-2-(methyl-ammonia-formoxyl)pyridine nano suspension as well as preparation method and application thereof | |
| CN102293753A (en) | Coenzyme Q10 nanosuspension freeze-dried composition and preparation method and application thereof | |
| CN102133177B (en) | Plagiochin nanocrystal preparation and preparation method thereof | |
| CN102846554B (en) | H2 nanocrystal preparation and preparation method thereof | |
| CN101721461A (en) | High dispersion preparation of rabdosia rubescens total terpenoid extract | |
| CN109833483B (en) | Preparation of small molecular chaperone-based sorafenib nano-drug | |
| CN111557914A (en) | Pharmaceutical composition containing ereoxib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120523 Termination date: 20121203 |