CN102058538B - Cycloartenyl ferulate solid dispersion and preparation thereof - Google Patents
Cycloartenyl ferulate solid dispersion and preparation thereof Download PDFInfo
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- CN102058538B CN102058538B CN2009102380911A CN200910238091A CN102058538B CN 102058538 B CN102058538 B CN 102058538B CN 2009102380911 A CN2009102380911 A CN 2009102380911A CN 200910238091 A CN200910238091 A CN 200910238091A CN 102058538 B CN102058538 B CN 102058538B
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Abstract
The invention discloses cycloartenyl ferulate solid dispersion, which comprises cycloartenyl ferulate and povidone serving as a carrier material. The invention further discloses a medicinal preparation and a preparation method of the solid dispersion. Experiments prove that the solid dispersion makes obvious technical progress in technical indexes such as dissolution rate, stability, water solubility, bioavailability and the like.
Description
Technical field
The invention discloses a kind of solid dispersion of cycloartenyl ferulate, comprise cycloartenyl ferulate and, belong to field of medicaments as the polyvidone of carrier.
Background technology
Oryzanol is a kind of natural mixture that the ferulic acid ester of the ferulic acid ester that is the main body with ring jackfruit alcohols and sterols is formed, and outward appearance is white or light yellow crystal powder.In the Testa oryzae oil oryzanol, ring jackfruit alcohols ferulic acid ester content is about 70-80%.The discovery that studies for a long period of time, oryzanol has multiple pharmacologically active, comprising: the absorption of blood fat reducing, cholesterol reducing, prevent lipid oxidation, angiocardiopathy preventing.In addition, research in recent years finds that also oryzanol can relax various health obstacles and the vegetative dystonie phenomenon of women after entering into the climacteric period, and improves the diencephalon functional disorder.
Oryzanol is soluble in chloroform, the acetone and other organic solvent, is difficult to water-solublely, and oral availability is very low, and a large amount of medicine of needs brings side effect and economic loss when causing that the patient is actual to take.In the prior art, the oryzanol preparation of using clinically is an injection, need inject at deep part of muscle during use, uses inconvenience, and intramuscular injection is simultaneously lumpd easily, brings big painful to patient.
In the prior art, had disclosedly to the solubilization studies of oryzanol raw material, all disclose oryzanol vegetable oil solubility preparation like Chinese patent CN123428, CN2007100156403 etc., improved bioavailability, clinical effectiveness is superior to general tablet.But because must intramuscular injection during oily solubility preparation clinical practice, the less patient suffering sense is more intense, and is prone to cause the muscle caking.Oily solubility preparation onset simultaneously is slow, needs about one month time remaining to carry out intramuscular injection, and this can have a strong impact on patient's live and work.One Chinese patent application CN2004100945568, CN100386082C etc. disclose surface active ingredients such as oryzanol and phospholipid are combined and have been prepared into the scheme of liposome, Emulsion etc.These technical schemes depend on surface active ingredient used in the scheme in fact to the raising of oryzanol dissolubility; When having improved the oryzanol dissolubility, also brought the side effect of surfactant itself, and injection is convenient not as oral formulations in clinical practice.
Existing oral formulations, as 200410012115.9 oryzanol disclosed capsule, wherein also contain the oiliness composition; 200610012341.6 disclose a kind of dispersible tablet, but it can not significantly improve the dissolution and the bioavailability of insoluble drug.Still unexposed in the prior art have an obvious oral formulations that improves the oryzanol dissolution.
Cycloartenyl ferulate is one of main component in the oryzanol.Compare with the oryzanol raw material, cycloartenyl ferulate monomer dissolubility is lower, and bioavailability is poorer.Still there is not research to relate to stripping and the biological utilisation problem of improving cycloartenyl ferulate in the prior art.It also is unforeseen that the solubilising scheme that will be used for the oryzanol raw material is used for the cycloartenyl ferulate effect.
Summary of the invention
It is a kind of technological means that solves dissolution and drug bioavailability that insoluble drug is made solid dispersion.In solid dispersion, the insoluble drug molecule is distributed in the high-molecular weight carrier material with amorphous form.To different drug, need screen the solid dispersion carrier material.Solid dispersion carrier material commonly used in the prior art comprises that cellulose, microcrystalline Cellulose, beta-schardinger dextrin-, alpha-cyclodextrin, Polyethylene Glycol etc. are multiple.
In inventor's early-stage Study; Obtained cycloartenyl ferulate through effectively the component in the oryzanol being separated; The research is open in the patent 200810114405.2 of applicant's earlier application, and this full patent texts can be used as the application's reference.After obtaining cycloartenyl ferulate the applicant to find that above-mentioned these carrier materials are used to prepare the effect that its dissolution of cycloartenyl ferulate solid dispersion improves unsatisfactory.
The applicant is through lot of experiments; Surprisingly find; Select for use polyvidone as carrier material to cycloartenyl ferulate; Compare with selecting other solid dispersion carrier material for use, prepared cycloartenyl ferulate solid dispersion has the effect unexpected, that dissolution significantly improves, and resulting solid dispersion good stability, bioavailability are high.
Based on above-mentioned discovery; The invention provides the cycloartenyl ferulate solid dispersion that a kind of stable, dissolution and bioavailability significantly improve; Comprise cycloartenyl ferulate and as the polyvidone of solid dispersion carrier material, the present invention also further provides and has contained the pharmaceutical preparation that above solid dispersion and other pharmacy can be accepted adjuvant.Simultaneously, the present invention also provides the said medicine corresponding preparation method.
Among the present invention; Described polyvidone can disperse cycloartenyl ferulate to make it to be dissolved in water or other solvent; Preferred polyvidone mean molecule quantity is 5000D-50000D, more preferably the mixture of one or more in 30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, the 30 POVIDONE K 30 BP/USP 90.
Among the present invention, cycloartenyl ferulate can be from the oryzanol raw material purification, also can be to adopt the chemical industry method synthetic.
In the present invention, the mass ratio of polyvidone and cycloartenyl ferulate is 1: 100-100: 1, be preferably 2: 1-40: and 1, most preferred is 4: 1-20: 1.
Among the present invention, in order further to improve the dissolution of cycloartenyl ferulate, can add synergist, suitable synergist can be:
Poloxamer in polyoxyethylene-polyoxypropylene copolymer, preferred poloxamer 188;
Vitamin and derivant thereof, preferred vitamin E, vitamin E polyethylene glycol succinic acid ester;
Lecithin comprises egg yolk lecithin, soybean phospholipid, preferably soya lecithin;
Polyalcohols comprises organic polyhydric alcohol liquid under the room temperature, preferred propylene glycol, glycerin, ethylene glycol or its mixture;
Tweens, preferred polysorbate40, polysorbate60, Tween 80, most preferably Tween 80;
Polyoxyl stearate, preferred polyoxyethylene stearate (40) ester;
Preferably, the synergist that is used for solid dispersion of the present invention is polyhydric alcohol and tween.
In containing the cycloartenyl ferulate solid dispersion of synergist, the mass ratio of cycloartenyl ferulate, polyvidone, synergist is 1: 2-20: 0.2-5.
On the other hand, the present invention also provides the method for preparing of cycloartenyl ferulate solid dispersion.
Solid dispersion of the present invention can adopt following method preparation:
Cycloartenyl ferulate, polyvidone are dissolved in the organic solvent, thereby organic solvent is reclaimed and the dry cycloartenyl ferulate solid dispersion that obtains.Wherein, used organic solvent can be any Organic substance that can dissolve cycloartenyl ferulate, polyvidone, for example alcohol, acetonitrile, oxolane, dichloromethane, chloroform, ethyl acetate, acetone or its any mixture.The actual needs of bound drug safety and preparation, the method for preparing of the present invention preferably organic solvent of usefulness are alcohol, ethyl acetate, acetone and/or its mixture.When using alcohol as organic solvent, the present invention preferably uses dehydrated alcohol, absolute methanol, ethanol water, methanol aqueous solution.In the above-mentioned course of dissolution, can heat in order to accelerate dissolution velocity, the temperature of heating is at 30-85 ℃.
Solid dispersion of the present invention is not limited to only adopt method for preparing, and other method such as fusion method, fusion-solvent methods etc. that are used to prepare solid dispersion all can adopt suitable preparation parameter to be used to prepare solid dispersion of the present invention.
In above-mentioned method for preparing, the drying means that is adopted is unrestricted, and drying means of using always in the industry such as drying under reduced pressure, spray drying, constant pressure and dry all can be used for method for preparing of the present invention.For example, can the distillation of gained solution decompression be obtained the coprecipitate of paste, be dried pulverizing; Can directly collect the dried powder of solid dispersion with gained solution through the spray drying machine; Can then gained paste precipitate be pulverized at heating, drying organic solvent under the normal pressure and get final product.
Solid dispersion of the present invention can get into human body, normally oral or parenteral route through suitable route of administration.In order to carry out this type application, solid dispersion of the present invention can be prepared as acceptable any dosage form on the pharmaceutics through adding suitable pharmaceutic adjuvant.When being used to treat as active component, can be directly to perhaps directly the fill capsulae vacuus is oral with the simple cycloartenyl ferulate solid dispersion powder of patient.During cycloartenyl ferulate solid dispersion practical application usually of the present invention all is to occur with the medicine type that contains pharmaceutic adjuvant, therefore the invention provides the preparation of cycloartenyl ferulate solid dispersion.
But through suitable oral, the non-intestinal that is mixed with pharmaceutic adjuvant, the dosage form of topical can be tablet, capsule, pill, granule, suspensoid, powder, oral liquid, injectable or infusion solution or suspensoid, suppository etc.; Preferred dosage form is a peroral dosage form in practical application, is easy to the patient and uses.
Solid dispersion of the present invention can combine to be prepared into various peroral dosage forms with adjuvant; Like tablet, capsule, granule, drop pill etc.; The method of used preparation can be the conventional method of drug world; Tablet for example can be processed mixture tabletting system then through add suitable additive to cycloartenyl ferulate solid dispersion of the present invention; Capsule can add in the capsule shells through the granule that is processed into powder or specific standard to cycloartenyl ferulate solid dispersion adding pharmaceutic adjuvant of the present invention and process.Preferred dosage form is tablet and capsule, and these dosage forms can adopt routine techniques and conventional machine to prepare.
According to the difference of pharmaceutical dosage form, can randomly contain other suitable pharmaceutic adjuvant.Adaptable pharmaceutically common adjuvant includes but not limited to:
One or more pharmaceutically useful filleies include but not limited to sucrose, lactose, microcrystalline Cellulose, starch etc.;
One or more disintegrating agents include but not limited to polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose;
One or more lubricants include but not limited to magnesium stearate, colloidal silica;
The adjuvant (flavoring agent, coloring agent) that one or more are used to improve abnormal smells from the patient, impression includes but not limited to Herba Menthae, essence, beta-carotene;
One or more stabilizing agents, antioxidant include but not limited to butylated hydroxytoluene, alpha-tocopherol, propyl gallate, malonic acid, vitamin C, sodium sulfite, sodium sulfite, sodium pyrosulfite.
As required, can also add other suitable adjuvant in the preparation process.
In foregoing, said filler, disintegrating agent, lubricant, coloring agent, flavoring agent etc. belong to the pharmaceutics category, are that those skilled in the art are familiar with or should be familiar with.Used " the including but not limited to " of applicant be meant and comprise in the described concrete material one or several, but also can be well known to those skilled in the art, the material that plays the same purpose effect outside said.For example said disintegrating agent is except that polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, and those skilled in the art will be appreciated that like carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose and also can be used as disintegrating agent.
It will be appreciated by those skilled in the art that the process that the resulting solid dispersion preparation of the present invention is adopted is that pharmaceutical field is common.For example; Knowledge according to galenic pharmacy; Cycloartenyl ferulate solid dispersion of the present invention and its pharmaceutic adjuvant be dissolved in stir in the systems such as alcohol, aqueous solution or fully grind after go out to desolvate and dry; Thereby obtain the dry suspension or the powder of solid dispersion of the present invention, further tabletting is perhaps encapsulated then.This preparation technique is that the present technique field is known, and the technical scheme that those skilled in the art adopt on formulation method does not influence protection scope of the present invention.Specifically be prepared into any dosage form and adopt which type of preparation process according to concrete production requirement decision.
Cycloartenyl ferulate solid dispersion and preparation thereof that the present invention is obtained carry out dissolution in vitro test, accelerated stability test and solubility experiment; The result shows that the cycloartenyl ferulate solid dispersion that the present invention openly prepares can make cycloartenyl ferulate in polyvidone, reach very high dispersity; Improve the dissolution in vitro of cycloartenyl ferulate greatly, thereby improved its bioavailability.
The specific embodiment
Embodiment 1
With 4g cycloartenyl ferulate, 15g 30 POVIDONE K 30 BP/USP 30; Mixed grinding 20min; The gained abrasive flour joined in the 80ml ethanol stir 10min, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into 10ml; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 2
Measure the 150ml ethyl acetate, add fully vibration dissolving of 7g 30 POVIDONE K 30 BP/USP 90 therein.Add cycloartenyl ferulate 1g then; About 15 minutes of 70 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into 20ml; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 3
Measure 50ml ethanol, add 20g 30 POVIDONE K 30 BP/USP 30,1g propylene glycol, 1g cycloartenyl ferulate, 0.2g egg yolk lecithin therein, the abundant stirring and dissolving of heating in 50 ℃ of water-baths.Gained solution is poured Rotary Evaporators into, takes out drying in baking oven when being concentrated into 15ml, and the gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 4
10g cycloartenyl ferulate, 100g 30 POVIDONE K 30 BP/USP 90,5g glycerin are dissolved in 99% ethanol; Again solution is made the cycloartenyl ferulate solid dispersion with the spray drying device spray drying; Further drying is 2 hours under 60 ℃; Remove residual solvent, gained powder art is cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 5
Cycloartenyl ferulate 5g, 30 POVIDONE K 30 BP/USP 15 15g are dissolved in the acetone, again solution are made the cycloartenyl ferulate solid dispersion with the spray drying device spray drying, 60 ℃ were descended further dry 2 hours, and removed residual solvent.
Embodiment 6
Measure the ethanol of 100ml 95%; Adding propylene glycol 2ml, 30 POVIDONE K 30 BP/USP 30 8g fully vibrate and dissolve back adding cycloartenyl ferulate 1.5g; About 10 minutes of 75 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into 15ml; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 7
Measure the ethanol of 100ml 95%; Add 3ml glycerin, 28g 30 POVIDONE K 30 BP/USP 15 and fully add the 4g cycloartenyl ferulate in vibration dissolving back; About 10 minutes of 80 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into 18ml; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 8
Measure the ethanol of 200ml 95%; Add 3ml Tween 80,30g 30 POVIDONE K 30 BP/USP 32 and fully add the 5g cycloartenyl ferulate in vibration dissolving back; About 20 minutes of 70 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into 15ml; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 9
Get the ethanol of 100ml 95%; Add fully vibration dissolving adding 5g cycloartenyl ferulate of 2ml polysorbate60,20g 30 POVIDONE K 30 BP/USP 15; About 10 minutes of 80 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into the 15ml left and right sides; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 10
Measure the ethanol of 100ml 95%; Add 5ml propylene glycol, 50g 30 POVIDONE K 30 BP/USP 15 and fully add the 6g cycloartenyl ferulate in vibration dissolving back; About 10 minutes of 80 ℃ of following heated and stirred, gained solution is poured Rotary Evaporators into, takes out in baking oven dry when being concentrated into the 15ml left and right sides; The gained solid was pulverized 80 mesh sieves, promptly got cycloartenyl ferulate solid dispersion of the present invention.
Embodiment 11
| The cycloartenyl ferulate solid dispersion of embodiment 6 | 9g |
| Microcrystalline Cellulose | 10g |
| Polyvinylpolypyrrolidone | 3g |
| Magnesium stearate | 0.2g |
It is subsequent use that the cycloartenyl ferulate solid dispersion of embodiment 6, microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate are crossed 80 mesh sieves respectively.Take by weighing cycloartenyl ferulate solid dispersion, microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate mix homogeneously according to above table, tabletting promptly gets tablet of the present invention, totally 100.
Embodiment 12
| The cycloartenyl ferulate solid dispersion of embodiment 8 | 16g |
| Starch | 80g |
| Magnesium stearate | 2g |
| 5% starch slurry | In right amount |
With the cycloartenyl ferulate solid dispersion and the starch uniform mixing of the embodiment of the invention 8, add an amount of granulation of 5% starch slurry, drying again, add the magnesium stearate mixing, then gained is joined in the capsule totally 200.
Embodiment 13
| The cycloartenyl ferulate solid dispersion of embodiment 4 | 15g |
| Microcrystalline Cellulose | 10g |
| Lactose | 30g |
| Magnesium stearate | 8g |
With the cycloartenyl ferulate solid dispersion of the embodiment of the invention 4 and microcrystalline Cellulose, lactose uniform mixing, granulate with dehydrated alcohol, drying adds the magnesium stearate mixing then, the direct bag distribution packaging of granule, totally 130 bags.
Embodiment 14
| The cycloartenyl ferulate solid dispersion of embodiment 10 | 3g |
| Cetomacrogol 1000 | 50g |
The cycloartenyl ferulate solid dispersion of the embodiment of the invention 10 is mixed with cetomacrogol 1000; Be heated to 80 ℃, mix up the drop pill machine, it is splashed in the dimethylsilane; Promptly get cycloartenyl ferulate solid dispersion drop pill of the present invention, totally 30.
Embodiment 15
| The cycloartenyl ferulate solid dispersion of embodiment 6 | 15g |
| Microcrystalline Cellulose | 20g |
| Low-substituted hydroxypropyl cellulose | 3g |
| Magnesium stearate | 0.2g |
It is subsequent use that the cycloartenyl ferulate solid dispersion of embodiment 6, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate are crossed 80 mesh sieves respectively.Take by weighing cycloartenyl ferulate solid dispersion, microcrystalline Cellulose, polyvinylpolypyrrolidone, magnesium stearate mix homogeneously according to above table, tabletting promptly gets tablet of the present invention, totally 500.
The comparative example 1
Measure the 150ml ethyl acetate, fully vibrate it is dissolved fully to wherein adding the 7g microcrystalline Cellulose.Adding 1g cycloartenyl ferulate, extremely dissolving was abundant in about 15 minutes for 70 ℃ of following heated and stirred, and gained solution is poured Rotary Evaporators into, takes out drying in baking oven when adopting distilling under reduced pressure to be concentrated into 20ml, and dry gained solid was pulverized 80 mesh sieves, promptly gets.
The comparative example 2
Measure the 150ml ethyl acetate, it is dissolved fully to wherein adding the 188 abundant vibrations of 7g poloxamer.Adding 1g cycloartenyl ferulate, extremely dissolving was abundant in about 15 minutes for 60 ℃ of following heated and stirred, and gained solution is poured Rotary Evaporators into, takes out drying in baking oven when adopting distilling under reduced pressure to be concentrated into 20ml, and dry gained solid was pulverized 80 mesh sieves, promptly gets.
The comparative example 3
Measure the 150ml ethyl acetate, fully vibrate it is dissolved fully to wherein adding the 7g polyethylene glycol 6000.Adding 1g cycloartenyl ferulate, extremely dissolving was abundant in about 20 minutes for 65 ℃ of following heated and stirred, and gained solution is poured Rotary Evaporators into, takes out drying in baking oven when adopting distilling under reduced pressure to be concentrated into 20ml, and dry gained solid was pulverized 80 mesh sieves, promptly gets.
The comparative example 4
With 1g cycloartenyl ferulate, 7g 30 POVIDONE K 30 BP/USP 30, mix and stir, cycloartenyl ferulate polyvidone common mixt.
Experimental example 1 accelerated stability test
Place 40 ℃, the calorstat of 75% relative humidity to preserve six months in the solid dispersion of the embodiment of the invention 6,11 preparation and tablet thereof, respectively 0 month, January, February, March, June its dissolution of sampling and measuring and content.
High-efficient liquid phase chromatogram condition: use octadecylsilane chemically bonded silica to be filler; Mobile phase A is methanol-oxolane (10: 23), and Mobile phase B is acetonitrile-water (55: 15), and flow velocity is 1.0ml/min, gradient elution; Column temperature is 45 ℃; The detection wavelength is 325nm.
According to two appendix VD of Chinese Pharmacopoeia version in 2005, get an amount of sample (being equivalent to contain cycloartenyl ferulate 10mg), the accurate title, decide; Porphyrize is put in the 100ml measuring bottle, adds that mobile phase is ultrasonic to be made dissolving and be diluted to scale; Shake up; Filter, precision is measured filtrating 10 μ l and is injected chromatograph of liquid, the record chromatogram; Other gets cycloartenyl ferulate reference substance 10mg, and accurate the title decides, and puts in the 100ml measuring bottle, adds the dissolving of mobile phase A liquid and is diluted to scale.By the content of external standard method with the calculated by peak area cycloartenyl ferulate.
According to 2005 editions two appendix XC second subtraction units of Chinese Pharmacopoeia, be solvent with water 500ml, precision takes by weighing an amount of sample (being equivalent to contain cycloartenyl ferulate 10mg).Take a sample when operating in 45min, with its dissolution of high effective liquid chromatography for measuring in accordance with the law.
The gained data are following table
Table 1 solid dispersion stability of the present invention and dissolution are investigated
Can find out that from table 1 solid dispersion of the present invention and tablet thereof are under the accelerated test condition, dissolution and content do not have to change basically, have explained that cycloartenyl ferulate solid dispersion of the present invention and tablet stability thereof are good.
Experimental example 2 solubility tests test
Solid dispersion of the present invention has not only improved the dissolution of cycloartenyl ferulate greatly, has also improved its water solublity.
Get an amount of cycloartenyl ferulate solid dispersion; Make it to form saturated solution in right amount with purified water; Filter with the 0.45um filter membrane; Dilution back is with spectrophotometric determination 320 place's traps, by the absorptance (ECM 1%) of cycloartenyl ferulate thus be the dissolubility that the concentration of 250 calculating saturated solutions obtains cycloartenyl ferulate in the cycloartenyl ferulate solid dispersion.
At normal temperatures and pressures, the dissolubility of cycloartenyl ferulate in water is less than 1mg/ml.
Cycloartenyl ferulate solid dispersion of the present invention is at cycloartenyl ferulate: the dissolubility of cycloartenyl ferulate is greater than 5mg/ml during 30 POVIDONE K 30 BP/USP 30 (1: 2).
Cycloartenyl ferulate solid dispersion of the present invention is at cycloartenyl ferulate: the dissolubility of cycloartenyl ferulate is greater than 6mg/ml during 30 POVIDONE K 30 BP/USP 30 (1: 3).
Cycloartenyl ferulate solid dispersion of the present invention is at cycloartenyl ferulate: the dissolubility of cycloartenyl ferulate is greater than 8mg/ml during 30 POVIDONE K 30 BP/USP 30 (1: 5).
Visible by above-mentioned data, cycloartenyl ferulate solid dispersion of the present invention has remarkable effect to improving the cycloartenyl ferulate dissolubility.
Experimental example 4 different carriers materials, method for preparing dissolution contrast test
According to 2005 editions two appendix XC second subtraction units of Chinese Pharmacopoeia, be solvent with water 500ml, precision takes by weighing an amount of sample (being equivalent to contain cycloartenyl ferulate 10mg).Take a sample when operating in 45min, with its dissolution of high effective liquid chromatography for measuring in accordance with the law.
High-efficient liquid phase chromatogram condition: use octadecylsilane chemically bonded silica to be filler; Mobile phase A is methanol-oxolane (10: 23), and Mobile phase B is acetonitrile-water (55: 15), and flow velocity is 1.0ml/min, gradient elution; Column temperature is 45 ℃; The detection wavelength is 325nm.
Measure embodiment 2, comparative example 1, comparative example 2, comparative example 3, comparative example 4 dissolution at room temperature respectively, be labeled as sample 1, sample 2, sample 3, sample 4, sample 5 respectively.
| Sample number | 45min dissolution (%) |
| Sample 1 | 91.2 |
| Sample 2 | 37.3 |
| Sample 3 | 39.5 |
| Sample 4 | 41.7 |
| Sample 5 | 1.4 |
Visible by above-mentioned data, compare with other carrier materials commonly used of solid dispersion, use the dissolution that polyvidone can very significantly improve cycloartenyl ferulate.
The mensuration of experimental example 5 bioavailability
Get the tablet of the embodiment of the invention 11 preparations.
Get 10 mices, give tablet of the present invention, every dosage 10mg.
Under no feed situation, put into the oral cavity of mice with the dosage of 10mg, it is swallowed.Make with extra care purified water 20ml.Before administration, after the administration 0,0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h draws blood respectively and measure the cycloartenyl ferulate content in the blood.
Testing result shows that solid dispersion tablet bioavailability of the present invention is good, is 60%.
Claims (14)
1. cycloartenyl ferulate solid dispersion comprises cycloartenyl ferulate and as the polyvidone of solid dispersion carrier, said polyvidone is a 30 POVIDONE K 30 BP/USP 30.
2. according to the cycloartenyl ferulate solid dispersion of claim 1, the mass ratio of polyvidone and cycloartenyl ferulate is 2: 1～20: 1.
3. according to the cycloartenyl ferulate solid dispersion of claim 1, the mass ratio of polyvidone and cycloartenyl ferulate is 4: 1～10: 1.
4. according to the cycloartenyl ferulate solid dispersion of one of claim 1-3; Also comprise synergist, said synergist is selected from one or more the mixture in polyhydric alcohol, poloxamer, vitamin E, lecithin, polyoxyl stearate, the tween.
5. according to the cycloartenyl ferulate solid dispersion of claim 4, the mass ratio of cycloartenyl ferulate, polyvidone, synergist is 1: 2～20: 0.2～5.
6. according to the cycloartenyl ferulate solid dispersion of claim 4, said polyhydric alcohol is one or more the mixture in ethylene glycol, propylene glycol, the glycerin.
7. according to the cycloartenyl ferulate solid dispersion of claim 4, said tween is one or more the mixture in polysorbate40, polysorbate60, the Tween 80.
8. a method for preparing the cycloartenyl ferulate solid dispersion of above-mentioned arbitrary claim comprises being dissolved in cycloartenyl ferulate, polyvidone in the organic solvent, reclaims organic solvent and exsiccant step.
9. according to Claim 8 method, said organic solvent are selected from one or more the mixture in alcohol, ethyl acetate, the acetone.
10. according to the method for claim 9, said alcohol is ethanol or ethanol water.
11. according to the method for claim 9, said alcohol is methanol or methanol aqueous solution.
12. a pharmaceutical preparation contains the cycloartenyl ferulate solid dispersion of claim 1.
13. according to the preparation of claim 12, it is an oral formulations.
14. according to the preparation of claim 13, said peroral dosage form is capsule, tablet, granule, powder or drop pill.
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| CN102125566B (en) * | 2011-01-11 | 2013-05-22 | 北京世纪博康医药科技有限公司 | Pharmaceutical composition comprising cycloartenyl ferulate |
| CN111529494B (en) * | 2020-06-28 | 2021-04-09 | 江西谷物源食品有限公司 | Oryzanol micelle compound solid dispersion and preparation method thereof |
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| Title |
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| 凌健斌 等.谷维素及其在功能性食品中的应用.《粮食与饲料工业》.2000,(第5期),35-37. * |
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| CN102058538A (en) | 2011-05-18 |
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