CN103110586B - Method for preparing farrerol solid dispersion - Google Patents
Method for preparing farrerol solid dispersion Download PDFInfo
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- CN103110586B CN103110586B CN201310017221.5A CN201310017221A CN103110586B CN 103110586 B CN103110586 B CN 103110586B CN 201310017221 A CN201310017221 A CN 201310017221A CN 103110586 B CN103110586 B CN 103110586B
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Abstract
The invention discloses a method for preparing a farrerol solid dispersion, and the method relates to the technical field of pharmaceutical preparations and is used for solving the problems of low dissolution rate, incomplete dissolution and low bioavailability of farrerol. The method comprises the following steps of: dissolving the farrerol and a carrier material into a medicinal organic solvent according to a mass ratio of (1:1)-(1:12) so as to form a transparent solution; heating the organic solvent in a water bath of 50-80 DEG C, vaporizing the organic solvent to be sticky and then quickly putting the organic solvent in a refrigerator of -20 DEG C to be solidified for 3-5 hours; taking the solidified organic solvent out, and grinding the solidified organic solvent into small particles of 20 meshes; putting the small particles in a vacuum drying oven for 12-24 hours so as to thoroughly remove the residual organic solvent; taking the small particles out, finely grinding and screening the small particles through a screen of 80 meshes and putting the small particles in a drying device to be kept in dark places. In a process of preparing the solid dispersion, the farrerol is uniformly dispersed into the water-soluble carrier, so that the water solubility, dissolution rate, bioavailability and therapeutic effect of the farrerol are improved.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, be specifically related to a kind of preparation method of farrerol solid dispersion.
Background technology
Farrerol has another name called farrerol, is light yellow crystalline powder, and odorless is tasteless, fusing point 229-231 ℃.English name: Farrerol, chemical name: 5,7-dihydroxy-2-(4-hydroxy phenyl)-6,8-dimethyl-2,3-dihydrobenzopyrans-4-ketone, molecular formula: C
17h
16o
5, molecular weight: 300.10, there is the following chemical structure:
, belong to flavanone kind composition, be a kind of compound with the effect of eliminating the phlegm extracting from Folium Rhododendri Daurici and other Rhododendron in Lushan Botanical Gardens at first, now can synthetic.
Farrerol can directly act on respiratory mucosa, promotes ciliary movement, strengthens the function of trachea, bronchus mechanical removal foreign body, make expectorant inner acidic glycoprotein fibrous fracture, sialic acid content declines, and makes expectorant viscosity degradation, sputum is thinning, is easy to expectoration, makes amount of expectoration reduce gradually simultaneously.In addition, farrerol oozes out and has certain inhibitory action skin scald inflammation, shows as skin graft edema degree and alleviates, and dyestuff oozes out minimizing, and its action intensity increases with the increase of dosage.
But farrerol almost insoluble (be dissolved in ethanol, ether, be soluble in acetone) in water, belongs to insoluble drug, farrerol is mainly with the form administration of oral tablet at present, and its dissolution rate is low, and stripping is incomplete, causes its bioavailability low.For the medicine of poorly water-soluble, dissolution affects the principal element of its degree of absorption often, yet, also do not have any good way to improve the dissolution of farrerol at present.
In order to accelerate the dissolution rate of farrerol, increase operation rate, the present invention has researched and developed a kind of solid dispersion of farrerol, the problem existing to solve above-mentioned prior art.
Summary of the invention
The present invention is low in order to solve farrerol dissolution rate, and stripping is incomplete, the problem that bioavailability is low, and a kind of preparation method of farrerol solid dispersion is provided.
The present invention is achieved through the following technical solutions:
A preparation method for farrerol solid dispersion, comprises the following steps:
The farrerol and the carrier material that by mass ratio, are 1:1-1:12 are dissolved in medicinal organic solvent, form clear solution, 50-80 ℃ of heating in water bath, while evaporating organic solvent to sticky shape, be placed in rapidly-20 ℃ of refrigerators and solidify 3-5 h, take out, be ground into 20 object granules, in vacuum drying oven, place 12-24 h thoroughly to remove residual organic solvent, take out, porphyrize, crosses 80 mesh sieves, puts exsiccator and keeps in Dark Place.
Further, the preferred 1:6-1:10 of the mass ratio of described farrerol and carrier material, more preferably 1:10.
Described carrier material is hydrophilic high molecular material, is included as PEG4000, PEG6000, PVP K30 (PVPK30), moors husky nurse 188(Poloxemer188).
Described organic solvent is dehydrated alcohol, acetone, 95% ethanol, ethyl acetate and methanol.
The present invention also can be achieved through the following technical solutions:
A preparation method for farrerol solid dispersion, comprises the following steps:
Get farrerol and carrier material that mass ratio is 1:1-1:12, first by carrier material in 40-80 ℃ of heating in water bath, after the complete melting of carrier, add farrerol, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 3-5 h, take out, be ground into 20 object granules, in vacuum drying oven, place 12-24 h thoroughly to remove residual organic solvent, take out, porphyrize, crosses 80 mesh sieves, puts exsiccator and keeps in Dark Place.
Further, the preferred 1:3-1:10 of the mass ratio of described farrerol and carrier material, more preferably 1:10.
Further, described carrier material is hydrophilic high molecular material, is included as PEG4000, PEG6000, PVP K30 (PVPK30), moors husky nurse 188(Poloxemer188), preferred PEG6000.
The present invention can also be achieved through the following technical solutions:
A preparation method for farrerol solid dispersion, comprises the following steps:
Get farrerol and carrier material that mass ratio is 1:1-1:12, farrerol is dissolved in to medicinal organic solvent, carrier material, in 40-80 ℃ of heating in water bath, is added to the organic solvent that is dissolved with farrerol after the complete melting of carrier material, stir, be placed on ice-water bath, then vigorous stirring is placed in curing material-20 ℃ of refrigerator 3-5 h till solidifying extremely completely, taking-up is put and in vacuum drying oven, is placed 12-24 h, after embrittlement, pulverize, cross 80 mesh sieves, put exsiccator and keep in Dark Place.
Further, the preferred 1:1-1:10 of the mass ratio of described farrerol and carrier material, more preferably 1:10.
Further, described carrier material is hydrophilic high molecular material, is included as PEG4000, PEG6000, PVP K30 (PVPK30), moors husky nurse 188(Poloxemer188), preferred Poloxemer188.
Described organic solvent comprises dehydrated alcohol, acetone, 95% ethanol, ethyl acetate and methanol, and wherein preferred organic solvent is dehydrated alcohol.
Farrerol solid dispersion dissolution determination result of the present invention shows: compare with farrerol crude drug, dissolution rate and the degree of farrerol solid dispersion are all significantly improved, as shown in Figure 1.
The farrerol solid dispersion made to the present invention carries out dsc analysis, result demonstration, and farrerol crude drug has the endothermic peak of the last one near 217 ℃, the fusing point peak that this peak is farrerol.In farrerol solid dispersion, the endothermic peak of farrerol disappears, and shows that farrerol exists with unformed state in solid dispersion, as shown in Figure 2.
The present invention has also carried out Pharmacokinetics in Rat research to prepared farrerol solid dispersion, and result shows: give respectively rat oral gavage farrerol crude drug and farrerol solid dispersion (50 mgkg
-1) after, comparing with crude drug group, Cmax and the AUC of farrerol solid dispersion group is significantly increased (P < 0.05), as shown in Figure 3.
The present invention, in preparing the process of solid dispersion, is dispersed in water-solubility carrier farrerol, thereby improves the water solublity of farrerol, improves dissolution rate and the bioavailability of farrerol, improves the therapeutical effect of farrerol.
Accompanying drawing explanation
Fig. 1 is the In Vitro Dissolution curve chart of farrerol solid dispersion of the present invention and farrerol crude drug;
Fig. 2 is for take the DSC curve chart of the farrerol solid dispersion that PVPK30 is carrier material;
Fig. 3 is rat oral gavage (50 mgkg
-1) give the blood drug level-time plot after farrerol solid dispersion and farrerol crude drug.
The specific embodiment
Embodiment 1:
Take 1.0024 g farrerol and 6.0096 gPVPK30, add 80 ml95% dissolve with ethanols, stir, until farrerol and PVPK30 are all dissolved in 95% ethanol and form clear solution, 65 ℃ of heating in water bath, while evaporating 95% ethanol to sticky shape, be placed in rapidly-20 ℃ of refrigerators and solidify 4 h, take out, be ground into 20 object granules, in vacuum drying oven, place 24 h thoroughly to remove 95% residual ethanol, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 2:
Take 1.0024 g farrerol and 8.0152 g PEG4000, add 60 ml acetone solutions, stir, until farrerol and PEG4000 are all dissolved in acetone and form clear solution, 60 ℃ of heating in water bath, while evaporating acetone to sticky shape, be placed in rapidly-20 ℃ of refrigerators and solidify 3 h, take out, be ground into 20 object granules, in vacuum drying oven, place 18 h thoroughly to remove residual acetone, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 3:
Take 1.0024 g farrerol and 12.0096 g Poloxemer188, add acetic acid ethyl dissolution, stir, until farrerol and Poloxemer188 all dissolve formation clear solution, 75 ℃ of heating in water bath, evaporation of acetic acid ethyl ester when the sticky shape, is placed in rapidly-20 ℃ of refrigerators and solidifies 5 h, takes out, be ground into 20 object granules, in vacuum drying oven, place 12 h thoroughly to remove residual ethyl acetate, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 4:
Take 1.0024 g farrerol and 1.0013 gPVPK30, add acetic acid ethyl dissolution, stir, until farrerol and PVPK30 all dissolve formation clear solution, 80 ℃ of heating in water bath, evaporation of acetic acid ethyl ester when the sticky shape, is placed in rapidly-20 ℃ of refrigerators and solidifies 4 h, takes out, be ground into 20 object granules, in vacuum drying oven, place 20 h thoroughly to remove residual ethyl acetate, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 5:
Take 1.0014 g farrerol and 10.0132 gPVPK30, add 100 ml anhydrous alcohol solutions, stir, until farrerol and PVPK30 are all dissolved in dehydrated alcohol and form clear solution, 70 ℃ of heating in water bath, while evaporating dehydrated alcohol to sticky shape, be placed in rapidly-20 ℃ of refrigerators and solidify 4 h, take out, be ground into 20 object granules, in vacuum drying oven, place 24 h thoroughly to remove residual dehydrated alcohol, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 6:
Take 1.0015 g farrerol and 3.0043 gPEG6000, PEG6000, in 40 ℃ of heating in water bath, is added to farrerol after the complete melting of PEG6000, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 5 h, take out, be ground into 20 object granules, in vacuum drying oven, place 12 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 7:
Take 1.0015 g farrerol and 1.0023 g PEG4000, PEG4000, in 80 ℃ of heating in water bath, is added to farrerol after the complete melting of PEG4000, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 3 h, take out, be ground into 20 object granules, in vacuum drying oven, place 16 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 8:
Take 1.0015 g farrerol and 12.0048 g Poloxemer188, by Poloxemer188 in 60 ℃ of heating in water bath, after the complete melting of Poloxemer188, add farrerol, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, and then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 3 h, takes out, be ground into 20 object granules, in vacuum drying oven, place 24 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 9
Take 1.0015 g farrerol and 6.0085 gPEG6000, PEG6000, in 70 ℃ of heating in water bath, is added to farrerol after the complete melting of PEG6000, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 4 h, take out, be ground into 20 object granules, in vacuum drying oven, place 24 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 10:
Take 1.0015 g farrerol and 10.0146 gPEG6000, PEG6000, in 70 ℃ of heating in water bath, is added to farrerol after the complete melting of PEG6000, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 5 h, take out, be ground into 20 object granules, in vacuum drying oven, place 12 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 11:
Take 1.0015 g farrerol and 10.0146 g PVPK30, PVPK30, in 70 ℃ of heating in water bath, is added to farrerol after the complete melting of PVPK30, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 3 h, take out, be ground into 20 object granules, in vacuum drying oven, place 24 h, take out porphyrize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 12:
Take 1.0018 g farrerol and 3.0048 gPoloxemer 188, Poxoxemer188 is heated in 70 ℃ of water-baths, treat complete melting, add with 60 ml acetic acid ethyl dissolutions farrerol completely, stir, be placed on ice-water bath, till vigorous stirring is solidified extremely completely.Then curing material is placed in to-20 ℃ of refrigerator 4 h, takes out to put in vacuum drying oven and place 24 h thoroughly to remove residual ethyl acetate, after embrittlement, pulverize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 13:
Take 1.0018 g farrerol and 6.0088 g PVPK30, PVPK30 is heated in 40 ℃ of water-baths, treat complete melting, add with 120 ml dissolve with methanol farrerol completely, stir, be placed on ice-water bath, vigorous stirring is to till solidifying completely.Then curing material is placed in to-20 ℃ of refrigerator 3 h, takes out to put in vacuum drying oven and place 18 h thoroughly to remove residual methanol, after embrittlement, pulverize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 14:
Take 1.0018 g farrerol and 10.0165 gPoloxemer188, Poloxemer188 is heated in 80 ℃ of water-baths, treat complete melting, add with 100 ml anhydrous alcohol solutions farrerol completely, stir, be placed on ice-water bath, till vigorous stirring is solidified extremely completely.Then curing material is placed in to-20 ℃ of refrigerator 5 h, takes out to put in vacuum drying oven and place 12 h thoroughly to remove residual dehydrated alcohol, after embrittlement, pulverize, cross 80 mesh sieves, obtain pale yellow powder, be farrerol solid dispersion, put exsiccator and keep in Dark Place.
Embodiment 15: solubility test
Get respectively the farrerol solid dispersion of excessive farrerol crude drug, different proportion and put into tool plug conical flask, add 10 mL deionized waters, be placed in 37 ℃ of waters bath with thermostatic control and vibrate after 72 h, precision measures 5 mL saturated aqueous solutions in 5000 rmin
-1centrifugal 15 min, get supernatant after the filtering with microporous membrane of 0.45 μ m, get subsequent filtrate and measure absorbance under 296 nm wavelength, calculate the dissolubility of different samples in 37 ℃ of water.Result shows: compare with farrerol crude drug, the dissolubility of farrerol solid dispersion in water significantly improves, and along with carrier ratio increases, dissolubility also increases gradually, and take PVPK30 during as carrier material dissolubility increase maximum.
Embodiment 16: dissolution determination
With reference to bis-appendix XC dissolution determinations of version < < Pharmacopoeia of People's Republic of China > > in 2010 the second method, measure the dissolution of the made solid dispersion of embodiment 1-14.Rotating speed is 100 rmin
-1, temperature is (37 ± 0. 5) ℃, dissolution medium is that 900 mL boil degassed 15 min and let cool the distilled water to room temperature, take the made solid dispersion of embodiment 1-14 appropriate, be placed in respectively the cup that dissolution medium is housed, respectively at 0,5,10,15,20,30,45, during 60,90 min, sample 5.0 mL, supplement the fresh dissolution medium of synthermal same volume simultaneously, sample filters through the microporous filter membrane of 0.45 μ m, gets subsequent filtrate as test sample.It is appropriate that another precision takes farrerol reference substance, and with anhydrous alcohol solution, making concentration is 1.0 mgmL
-1reference substance solution, precision measures in right amount, the titer of series concentration is made in adding distil water dilution, with ultraviolet visible spectrophotometry, at 296 nm wavelength places, measure absorbance, take concentration as abscissa, absorbance is vertical coordinate, with absorbance, concentration is carried out to linear regression, obtains equation of linear regression; Be measured in the same method test sample, measurement result substitution standard curve calculating concentration, and be converted into cumulative release percentage rate, take time t(min) be abscissa, cumulative release percentage rate (%) is that vertical coordinate is drawn stripping curve.Result as shown in Figure 1.
Result shows: compare with farrerol crude drug, dissolution rate and the degree of farrerol solid dispersion are all significantly increased, wherein take PVPK30 during as carrier material effect best, when medicine and PVPK30 weight ratio are 1:10, farrerol solid dispersion preparation in 45 min has reached more than 85%.
Embodiment 17:DSC analyzes
The empty aluminum pincers of take are reference substance, and another aluminum pincers are put into approximately 5 mg samples, 10 ℃ of min of programming rate
-1, 40～250 ℃ of sweep limitss, carry out DSC analysis to farrerol crude drug and solid dispersion thereof respectively.Result shows: crude drug has a feature endothermic peak near 217 ℃, in physical mixture, the feature endothermic peak of farrerol still exists, in farrerol solid dispersion, its feature endothermic peak disappears, and shows that farrerol exists with unformed state in solid dispersion, and result as shown in Figure 2.
Embodiment 18: rat in vivo test
According to above-mentioned result of study, choose farrerol and carrier PVPK30(1:10 in mass ratio) solid dispersion prepared is tested medicine, carries out absorption test in rat body.Get 12 of SD rats, male and female half and half, body weight 180-220 g, is divided into two groups at random, 6 every group, take farrerol crude drug as control drug, by 50 mgkg
-1dosage gastric infusion, respectively at 1,3,5,10,15,20,30,40,50,60,90,120, the time point of 180,240min is from rat eye socket venous plexus blood sample collection, and blood sample after treatment, is measured the blood drug level of farrerol through HPLC method, and result DAS software processes is calculated pharmacokinetic parameter.Take the time as abscissa, and blood drug level is vertical coordinate, draws blood drug level-time graph, and result as shown in Figure 3.
Claims (1)
1. a preparation method for farrerol solid dispersion, is characterized in that, comprises the following steps: get farrerol and carrier material that mass ratio is 1:10, described carrier material is PVP K30; First by carrier material in 40-80 ℃ of heating in water bath, after the complete melting of carrier, add farrerol, stir, be placed in rapidly on ice-water bath, rapid stirring makes to solidify, and then solidfied material is placed in to-20 ℃ of refrigerators and continues to solidify 3-5 h, takes out, be ground into 20 object granules, in vacuum drying oven, place 12-24 h, take out porphyrize, cross 80 mesh sieves, get product.
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|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716135A (en) * | 2010-01-08 | 2010-06-02 | 山西医科大学 | Soy isoflavone solid dispersion suppository and preparation method thereof |
| CN102389416A (en) * | 2011-10-10 | 2012-03-28 | 山西医科大学 | Application of farrerol, derivative thereof and pharmaceutically-acceptable salts of farrerol and derivative to medicine for treating heart cerebrovascular disease caused by vasoconstriction |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716135A (en) * | 2010-01-08 | 2010-06-02 | 山西医科大学 | Soy isoflavone solid dispersion suppository and preparation method thereof |
| CN102389416A (en) * | 2011-10-10 | 2012-03-28 | 山西医科大学 | Application of farrerol, derivative thereof and pharmaceutically-acceptable salts of farrerol and derivative to medicine for treating heart cerebrovascular disease caused by vasoconstriction |
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