CN103202811B - Diflunisal solid dispersion and preparation method thereof - Google Patents
Diflunisal solid dispersion and preparation method thereof Download PDFInfo
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- CN103202811B CN103202811B CN201310095775.7A CN201310095775A CN103202811B CN 103202811 B CN103202811 B CN 103202811B CN 201310095775 A CN201310095775 A CN 201310095775A CN 103202811 B CN103202811 B CN 103202811B
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- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960000616 diflunisal Drugs 0.000 title claims abstract description 97
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000001125 extrusion Methods 0.000 claims abstract description 11
- 239000012943 hotmelt Substances 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 10
- 238000010298 pulverizing process Methods 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 55
- 239000012876 carrier material Substances 0.000 abstract description 19
- 229920000642 polymer Polymers 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract description 13
- 238000002844 melting Methods 0.000 abstract description 5
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 5
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 4
- 229920001577 copolymer Polymers 0.000 abstract description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract description 4
- MXRGSJAOLKBZLU-UHFFFAOYSA-N 3-ethenylazepan-2-one Chemical compound C=CC1CCCCNC1=O MXRGSJAOLKBZLU-UHFFFAOYSA-N 0.000 abstract 1
- 206010061623 Adverse drug reaction Diseases 0.000 abstract 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 abstract 1
- 229920001531 copovidone Polymers 0.000 abstract 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 42
- 238000001228 spectrum Methods 0.000 description 26
- 238000004090 dissolution Methods 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 22
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 21
- 229920003081 Povidone K 30 Polymers 0.000 description 20
- 239000000463 material Substances 0.000 description 16
- 238000000338 in vitro Methods 0.000 description 15
- 239000006069 physical mixture Substances 0.000 description 14
- 229960003943 hypromellose Drugs 0.000 description 12
- 239000000126 substance Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 6
- 230000005496 eutectics Effects 0.000 description 5
- 238000007500 overflow downdraw method Methods 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical class C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- -1 SOLUPLUS Polymers 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229950005770 hyprolose Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
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Abstract
The invention discloses a diflunisal solid dispersion and a preparation method thereof. The solid dispersion is composed of diflunisal as active components and high-polymer carrier materials. The high-polymer carrier materials are 40-90% of the diflunisal in total and selected from povidones, copovidones, and polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer or hydroxypropyl methylcellulose. The preparation method adopts a hot-melting extrusion method. The diflunisal solid dispersion obtained is higher in solubility and quick and high in dissolving, bioavailability of indissolvable drugs is improved, drug dosage is reduced, and adverse drug reaction is reduced.
Description
Technical field
The invention belongs to medical art, particularly relate to a kind of Diflunisal solid dispersion and preparation method thereof.
Background technology
Medicine dissolubility is in the solution the basic parameter preparing preparation, directly affects the absorption of medicine and affects the bioavailability of medicine.Along with the extensive use in new drug development of combinatorial chemistry and high flux screening, at present, the new discovery medicine of 35%-40% has a strong impact on it because of its low solubility or hypotonicity at gastrointestinal and effectively absorbs to have report to show, and may cause the result of lower bioavailability.Therefore, utilize preparation measure to improve the dissolubility of insoluble drug and dissolution rate, thus improve its bioavailability and clinical efficacy, one of ultimate challenge that the person that become Pharmaceutical study faces.
At present, make salt, solubilising, reduce oral absorption and bioavailability that particle diameter etc. is widely used in increasing insoluble drug, but these methods all have some limitations itself.For unrealistic neutral compound and some weak acid, weak base.Even if can obtain salt, in many situations, medicine may not increase in gastrointestinal stripping.Because these salt are converted into again corresponding acid or alkali separately after entering gastrointestinal tract.The solution made by interpolation organic solvent or surface active agent solubilization then reduces the compliance of patient and the safety of use, thus limits commercial applications.Comparatively conventional particle diameter reduces method and there is particle diameter minimizing limit and follow-up preparation difficult treatment, and hydrophobicity increases, and likely reassociate problems such as making the reduction of powder wettability.
Solid dispersion refers to that medicine is dispersed in the system in solid carrier with molecule, amorphous or microcrystalline state high uniformity.From 1961, solid dispersion technology is first for since the dissolution rate that improves insoluble drug and oral administration biaavailability, many researcheres have carried out research extensively and profoundly to solid dispersion, prove that insoluble drug being made solid dispersion is one of method of the most application potential improving its dissolubility and dissolution rate further.The traditional preparation methods of solid dispersion comprises fusion method, solvent method, solvent-fusion method.In recent years, hot-melt extruded method enjoys the concern of domestic and international Pharmaceutical study person as a kind of novel method preparing solid dispersion.The method, by the singe screw heated piecemeal or double screw extruder, realizes the transmission conveying of material, shear-mixed and melt extruded.Relative to traditional preparation method, it is high that hot-melt extruded method has production efficiency, without the need to organic solvent, is suitable for the features such as suitability for industrialized production.But usually, preparation temperature need higher than the fusing point of the vitrification point of carrier and medicine.Therefore, for medicine and the carrier with higher melt, fusion method and hot-melt extruded method easily cause the thermal decomposition of medicine and carrier, thus limit the extensive use of the method.
Summary of the invention
Based on this, the object of this invention is to provide the Diflunisal solid dispersion that a kind of dissolution is high.
Concrete technical scheme is as follows:
A kind of Diflunisal solid dispersion, be prepared from by as the diflunisal of active component and polymer carrier, the mass percentage that described polymer carrier accounts for Diflunisal solid dispersion is 40-90%, and described polymer carrier is selected from polyvidone class, copolyvidone class, Polyethylene Glycol/caprolactam/vinyl acetate co-polymer (Soluplus) or hypromellose class.
Wherein in some embodiments, the mass percentage that described polymer carrier accounts for Diflunisal solid dispersion is 60-80%.
Wherein in some embodiments, described polymer carrier is selected from PVP K30, copolyvidone VA64, Soluplus or hypromellose E5.
Another object of the present invention is to provide the preparation method of above-mentioned Diflunisal solid dispersion.
Concrete technical scheme is as follows:
The preparation method of above-mentioned Diflunisal solid dispersion, comprises the steps:
To join in twin screw hot melt extruder after diflunisal and polymer carrier mixing, namely the mixture extruded by hot-melt extruded machine obtains described Diflunisal solid dispersion through pulverization process; Wherein the extrusion temperature of hot-melt extruded machine is 50-200 DEG C, and screw speed is that 50-300 turns/min.
Wherein in some embodiments, the extrusion temperature of described hot-melt extruded machine is 100-160 DEG C; Described screw speed is that 50-250 turns/min.
Principle of the present invention is:
The fusing point of medicine, namely under a certain pressure, pure material solid-state and liquid in balance time temperature, that is under this pressure and melting temperature, pure material be that solid-state chemical potential is equal with the chemical potential be in a liquid state.When between medicine and polymer, have certain interaction force, when medicine and polymer form homogeneous system, the chemical potential of medicine will reduce, then medicine fusing point is in the polymer by the fusing point lower than pure medicine.Namely when medicine and carrier possess certain interaction, hot-melt extruded or fusion method prepare the temperature of unformed solid dispersion can lower than the fusing point of medicine.
Diflunisal is slightly solubility NSAID (non-steroidal anti-inflammatory drug).Fusing point is 220 DEG C, and namely melting is decomposed medicine and contained hydroxyl, is the hydrogen-bond donor of high-quality, forms hydrogen bond with polymer supported physical ability.Medicine fusing point in the polymer, by the fusing point lower than pure medicine, therefore utilizes fusion method or hot-melt extruded legal system for the preparation temperature of the unformed solid dispersion of diflunisal lower than the fusing point of medicine.Avoid the fusion and decomposition of medicine in preparation process.
The present invention successfully utilizes hot-melt extruded method to prepare unformed Diflunisal solid dispersion under drug melting point, and this Diflunisal solid dispersion is prepared from by as the diflunisal of active component and polymer carrier.Described polymer carrier includes polyethylene glycols, poly(ethylene oxide)polymers class, polyvidone class, copolyvidone class, hypromellose class, hyprolose class, poloxamer class, Polyethylene Glycol/caprolactam/vinyl acetate co-polymer (Soluplus), especially strange class or ethyl cellulose type etc., and the present invention is by a large amount of creative experiments preferred polyvidone class in numerous polymer carriers, copolyvidone class, Soluplus or hypromellose class, this several macromolecule carrier preferred can make insoluble drug diflunisal eutectic solid dispersion dissolubility increase, dissolution rate is fast, dissolution is high, improve the bioavailability of insoluble drug, reduce dosage, reduce adverse effect.In addition the inventive method is without the need to an organic solvent, environmental friendliness, no solvent residue.
Accompanying drawing explanation
Fig. 1 is diflunisal Materials Powder X-ray diffracting spectrum in embodiment 1, diflunisal and Soluplus physical mixture x-ray diffractogram of powder spectrum, Soluplus Materials Powder X-ray diffracting spectrum, hot-melt extruded legal system are composed for the x-ray diffractogram of powder of solid dispersion;
Fig. 2 is diflunisal and be carrier material with Soluplus in embodiment 1, and hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
Fig. 3 is diflunisal Materials Powder X-ray diffracting spectrum in embodiment 2, diflunisal and copolyvidone VA64 physical mixture x-ray diffractogram of powder spectrum, copolyvidone VA64 Materials Powder X-ray diffracting spectrum, hot-melt extruded legal system are composed for the x-ray diffractogram of powder of solid dispersion;
Fig. 4 be in embodiment 2 diflunisal and with copolyvidone VA64 for carrier material, hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
Fig. 5 is diflunisal powder X ray diffracting spectrum in embodiment 3, diflunisal and copolyvidone VA64 physical mixture x-ray diffractogram of powder spectrum, copolyvidone VA64 Materials Powder X-ray diffracting spectrum, hot-melt extruded legal system are composed for the x-ray diffractogram of powder of solid dispersion;
Fig. 6 be in embodiment 3 diflunisal and with copolyvidone VA64 for carrier material, hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
The x-ray diffractogram of powder spectrum of the solid dispersion that Fig. 7 is the x-ray diffractogram of powder spectrum of diflunisal raw material in embodiment 4, the x-ray diffractogram of powder spectrum of diflunisal and PVP K30 physical mixture, the x-ray diffractogram of powder spectrum of PVP K30 raw material and hot-melt extruded method prepare;
Fig. 8 is diflunisal and be carrier material with PVP K30 in embodiment 4, and hot-melt extruded legal system is for the In Vitro Dissolution curve of eutectic solid dispersion;
Fig. 9 is diflunisal Materials Powder X-ray diffracting spectrum in embodiment 5, hypromellose E5 Materials Powder X-ray diffracting spectrum, diflunisal and hypromellose E5 physical mixture x-ray diffractogram of powder spectrum, hot-melt extruded legal system are composed for the x-ray diffractogram of powder of solid dispersion;
Figure 10 be in embodiment 5 diflunisal and with hypromellose E5 for carrier material, hot-melt extruded legal system is for the In Vitro Dissolution curve of solid dispersion.
Figure 11 is diflunisal Materials Powder X-ray diffracting spectrum in comparative example 1, Macrogol 2000 Materials Powder X-ray diffracting spectrum, diflunisal and Macrogol 2000 physical mixture x-ray diffractogram of powder spectrum, hot-melt extruded legal system is composed for the x-ray diffractogram of powder of solid dispersion;
Figure 12 is diflunisal and be carrier material with Macrogol 2000 in comparative example 1, and hot-melt extruded legal system is for the In Vitro Dissolution curve of solid dispersion.
Figure 13 is diflunisal Materials Powder X-ray diffracting spectrum in comparative example 2, polyethylene glycol 6000 Materials Powder X-ray diffracting spectrum, diflunisal and polyethylene glycol 6000 physical mixture x-ray diffractogram of powder spectrum, hot-melt extruded legal system is composed for the x-ray diffractogram of powder of solid dispersion;
Figure 14 is diflunisal and be carrier material with polyethylene glycol 6000 in comparative example 2, and hot-melt extruded legal system is for the In Vitro Dissolution curve of solid dispersion.
The x-ray diffractogram of powder spectrum that Figure 15 is diflunisal Materials Powder X-ray diffracting spectrum in comparative example 4, PVP K30 Materials Powder X-ray diffracting spectrum, diflunisal and PVP K30 physical mixture x-ray diffractogram of powder spectrum, spray drying method prepares solid dispersion;
Figure 16 is diflunisal and be carrier material with PVP K30 in comparative example 4, and spray drying method prepares the In Vitro Dissolution curve of solid dispersion.
Detailed description of the invention
The embodiment of the present invention is raw materials used as follows:
Diflunisal is commercially available prod;
PVP K30 purchased from American International Specialty Products company;
Copolyvidone VA64 is purchased from BASF Aktiengesellschaft;
Novel adjuvant Polyethylene Glycol/caprolactam/vinyl acetate co-polymer (Soluplus) is purchased from BASF Aktiengesellschaft;
The happy Kanggong department of hypromellose E5 purchased from American card.
Below in conjunction with embodiment, set forth the present invention further:
Embodiment 1:
A kind of Diflunisal solid dispersion of the present embodiment, be prepared from by as the diflunisal of active component and Soluplus, the mass percentage that Soluplus accounts for Diflunisal solid dispersion is 80%.
Get 2g diflunisal, 8gSoluplus, mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 160 ° of C, and start screw rod after reaching preset temperature, screw speed 150 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains Diflunisal solid dispersion powder.
The solid dispersion powder X-ray diffraction (Fig. 1) that the present embodiment prepares shows medicine and is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result display medicament contg and related substance have no significant change, and meet Chinese Pharmacopoeia pertinent regulations.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and significantly improves (Fig. 2).
Embodiment 2:
A kind of Diflunisal solid dispersion of the present embodiment, be prepared from by as the diflunisal of active component and copolyvidone VA64, the mass percentage that copolyvidone VA64 accounts for Diflunisal solid dispersion is 70%.
Get 3g diflunisal, 7g copolyvidone VA64 (PVPVA64), mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 100 ° of C, and start screw rod after reaching preset temperature, screw speed 50 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains Diflunisal solid dispersion powder.
The present embodiment obtains powder X-ray diffraction (Fig. 3) and shows medicine and be dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result display medicament contg and related substance have no significant change, and meet Chinese Pharmacopoeia pertinent regulations.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and significantly improves (Fig. 4).
Embodiment 3:
A kind of Diflunisal solid dispersion of the present embodiment, be prepared from by as the diflunisal of active component and copolyvidone VA64, the mass percentage that copolyvidone VA64 accounts for Diflunisal solid dispersion is 70%.
Get 3g diflunisal, 7g copolyvidone VA64 (PVPVA64), mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 140 ° of C, and start screw rod after reaching preset temperature, screw speed 250 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains medicine solid dispersion powder.
The present embodiment prepares solid dispersion powder X-ray diffraction (Fig. 5) and shows medicine and be dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result display medicament contg and related substance have no significant change, and meet Chinese Pharmacopoeia pertinent regulations.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and significantly improves (Fig. 6).
Embodiment 4:
A kind of Diflunisal solid dispersion of the present embodiment, be prepared from by as the diflunisal of active component and PVP K30 (K30), the mass percentage that PVP K30 (K30) accounts for Diflunisal solid dispersion is 60%.
Get 4g diflunisal, 6g PVP K30 (K30), mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 160 ° of C, and start screw rod after reaching preset temperature, screw speed 150 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains medicine solid dispersion powder.
Embodiment 5:
A kind of Diflunisal solid dispersion of the present embodiment, be prepared from by as the diflunisal of active component and hypromellose E5, the mass percentage that hypromellose E5 accounts for Diflunisal solid dispersion is 70%.
Get 3g diflunisal, 7g hypromellose E5 (HPMCE5), mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 160 ° of C, and start screw rod after reaching preset temperature, screw speed 150 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains medicine solid dispersion powder.
The solid dispersion powder X-ray diffraction (Fig. 7) that the embodiment of the present invention prepares shows medicine and is dispersed in carrier material with amorphous or molecular state.High performance liquid chromatography testing result display medicament contg and related substance have no significant change, and meet Chinese Pharmacopoeia pertinent regulations.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and significantly improves (Fig. 8).
Comparative example 1:
A kind of Diflunisal solid dispersion of this comparative example, be prepared from by as the diflunisal of active component and Macrogol 2000, the mass percentage that carrier material accounts for Diflunisal solid dispersion is 80%.
Embodiment 1 same procedure is adopted to prepare Diflunisal solid dispersion powder.
The solid dispersion powder X-ray diffraction (Fig. 9) that this comparative example prepares shows medicine and shows that the medicine of this solid dispersion adds up stripping percentage rate and improves limited (Figure 10) with microcrystalline dispersion In Vitro Dissolution experimental result in carrier material.
Comparative example 2:
A kind of Diflunisal solid dispersion of this comparative example, be prepared from by as the diflunisal of active component and polyethylene glycol 6000, the mass percentage that carrier material accounts for Diflunisal solid dispersion is 70%.
Embodiment 1 same procedure is adopted to prepare Diflunisal solid dispersion powder.
The solid dispersion powder X-ray diffraction (Figure 11) that this comparative example prepares shows medicine with microcrystalline dispersion in carrier material.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and increases.(Figure 12).
Comparative example 3
A kind of Diflunisal solid dispersion of this comparative example, be prepared from by as the diflunisal of active component and PVP K30, the mass percentage that PVP K30 accounts for Diflunisal solid dispersion is 90%.
Get 5g diflunisal, 5g PVP K30 (PVPK30), mix homogeneously.The extrusion temperature of setting twin screw hot melt extruder is 160 ° of C, and start screw rod after reaching preset temperature, screw speed 150 turns/min, the physical mixture made joins in extruder, and mixture is that strip is extruded through screw rod; The bar of hot-melt extruded is crossed 80 mesh sieves after pulverization process, obtains Diflunisal solid dispersion powder.
Comparative example 4
A kind of Diflunisal solid dispersion of this comparative example, be prepared from by as the diflunisal of active component and PVP K30, the mass percentage that PVP K30 accounts for Diflunisal solid dispersion is 70%.
Get 0.9g diflunisal, 2.1g PVP K30 (PVPK30), is dissolved in 100mL dehydrated alcohol.Spraying dry is used to prepare solid dispersion.Controlling inlet temperature is 65 DEG C, and throughput is 0.7m
3/ min, atomizing pressure is 200kpa, and liquid supply speed is 5ml/min, collects the Diflunisal solid dispersion powder that namely 80 mesh sieves obtain this comparative example.
Solid dispersion powder X-ray diffraction (Figure 13) display that this comparative example prepares is dispersed in carrier material with amorphous or molecular state.In Vitro Dissolution experimental result shows that the medicine of this solid dispersion adds up stripping percentage rate and increases (Figure 14).
Contrast test
1, Dissolution Rate Testing
Above-described embodiment 1-5 and comparative example 1-4 prepares the Dissolution Rate Testing comparative result of Diflunisal solid dispersion as following table:
Can find out according to upper table experimental data: embodiment stripping is better than comparative example.This is because the hydroxyl/carboxyl of diflunisal can form hydrogen bond with the carbonyl of carrier (copolyvidone VA64, PVP K30, SOLUPLUS, hypromellose E5)/hydroxyl.Utilizing intermolecular interaction that medicine is dissolved at lower than the temperature of drug melting point enters in polymer melt, is dissociated into molecular state, is prepared into amorphous solid dispersion by hot-melt extruded, while effectively improving stripping, ensure chemical stability.And the degraded that comparative example 3 causes medicine because drug loading is too high in the process of preparation, although its stripping is suitable with embodiment, its content obviously declines after testing, requires (90%) lower than Chinese Pharmacopoeia.Spraying dry is the method preparing solid dispersion comparatively commonly used, also there is industrial prospect, but its shortcoming needs at substantial organic solvent and energy, and yield is lower, in body series, yield is only 30%, under identical prescription use also comparatively hot-melt extruded obtain solid dispersion difference.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (2)
1. a Diflunisal solid dispersion, is characterized in that, be prepared from by as the diflunisal of active component and copolyvidone VA64, the mass percentage that copolyvidone VA64 accounts for Diflunisal solid dispersion is 70%;
Its preparation method comprises the steps: to join in twin screw hot melt extruder after diflunisal and copolyvidone VA64 mixing, and namely the mixture extruded by hot-melt extruded machine obtains described Diflunisal solid dispersion through pulverization process; Wherein the extrusion temperature of hot-melt extruded machine is 100-160 DEG C, and screw speed is that 50-250 turns/min.
2. the preparation method of Diflunisal solid dispersion described in claim 1, is characterized in that, comprises the steps:
To join in twin screw hot melt extruder after diflunisal and copolyvidone VA64 mixing, namely the mixture extruded by hot-melt extruded machine obtains described Diflunisal solid dispersion through pulverization process; Wherein the extrusion temperature of hot-melt extruded machine is 100-160 DEG C, and screw speed is that 50-250 turns/min.
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| CN105126110B (en) * | 2015-07-29 | 2018-04-06 | 中山大学 | Solid dispersions of Itraconazole and its preparation method and application |
| CN109758432A (en) * | 2017-11-09 | 2019-05-17 | 郑州泰丰制药有限公司 | A kind of Diflunisal enteric coatel tablets and preparation method thereof |
| CN108186407B (en) * | 2018-02-24 | 2019-09-20 | 珀莱雅化妆品股份有限公司 | A kind of preparation method for the solid dispersions having effects that whitening is anti-ageing |
| CN113842367A (en) * | 2021-09-30 | 2021-12-28 | 上海研健和科技合伙企业(有限合伙) | Cannabidiol premix and preparation method thereof |
| CN116262110A (en) * | 2021-12-13 | 2023-06-16 | 苏州旺山旺水生物医药有限公司 | Pharmaceutical composition of oral deuterated nucleoside or pharmaceutically acceptable salt thereof, preparation method and application |
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