CN104800159A - Ibuprofen microemulsion drug delivery system - Google Patents
Ibuprofen microemulsion drug delivery system Download PDFInfo
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Abstract
The invention provides an ibuprofen microemulsion drug delivery system which comprises a surfactant, a cosurfactant, water, oil and ibuprofen, wherein the oil is mixed oil of GTCC and glycerol trioleate, and the mass ratio of the GTCC to the glycerol trioleate is (6:1)-(1:6). The microemulsion drug delivery system is characterized by adopting the mixed oil as an oil phase. By virtue of the use of the mixed oil, the microemulsion area is remarkably expanded, the drug solubility is greatly increased, and as a result, the absolute use amount of the surfactant required for preparing the drug loading microemulsion is reduced in a double-effect manner, so that the toxic and side effects of the microemulsion caused by overhigh use amount of the surfactant are reduced; A rat pharmacokinetics result shows that the oral bioavailability of ibuprofen is remarkably improved by the optimized drug loading microemulsion containing less surfactant. Compared with other drug loading microemulsions wither higher content of surfactant, the optimized drug loading microemulsion containing less surfactant has the advantage that the influence of less use amount of the surfactant in the microemulsion on the capability of improvement of the oral bioavailability of drugs is avoided.
Description
Technical field
The present invention relates to a kind of ibuprofen microemulsion drug-supplying system and preparation method thereof.
Background technology
By the drug candidate with potential Development volue that high flux screening obtains, the monomer more than 40% is insoluble in water.These monomers are usually due to defect that slightly solubility is relevant, low or the dosage of such as oral administration biaavailability cannot be gone beyond, its drug research is died young (Lipinski too early, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 46 (1-3), 3-26).At art of pharmacy, a lot of method can improve the dissolubility of insoluble drug, and such as the crystal formation of salify, change medicine, adopts mixed solvent, cosolvent, solubilizing agent, form solid dispersion, clathrate etc.Or adopt Novel Drug Delivery Systems as micelle, liposome, microemulsion etc.Wherein, microemulsion relies on its thermodynamic stability, has good dissolubility to insoluble drug, and technique is simple and easy to the favor of the advantages such as industrialization extremely researcher.
Isotropic thermodynamic stable system that microemulsion (microemulsion, ME) is made up of by a certain percentage oil phase, aqueous phase, surfactant and cosurfactant.Because inside exists oleophylic, hydrophilic region simultaneously, microemulsion significantly can increase the dissolubility of insoluble drug, is widely used in improving drug solubility at field of medicaments.But there is an antinomy between formation of microemulsion and toxicity thereof, namely the formation of microemulsion needs a large amount of surfactants usually, the heavy dose of surfactant uses and will cause the generation of toxicity, thus greatly constrains the application of microemulsion.The toxicity such as hemolytic, histopathological response of surfactant constitutes the technology fort being difficult to go beyond together of microemulsion application.Therefore, minority microemulsion (or self-emulsifying microemulsion) product is only had to be ratified by food and medicine Surveillance Authority (Food and Drug Administration, FDA) at present.Such as, patent CN103690483A discloses praeruptorin A microemulsion and preparation method thereof.In that patent, microemulsion significantly improves the dissolubility (0.8%) of praeruptorin A, but in this prescription, the total amount of surfactant is up to 30%-50%, directly affects the clinical practice of praeruptorin A microemulsion.
Ibuprofen belongs to Biopharmaceutics Classification system II class (BCS class II) medicine, belongs to low-solubility, high osmosis medicine, and dissolving is the limiting factor that it absorbs.The ibuprofen microemulsion of current report, its surface-active contents is common higher.For patent documentation CN101904815 A, during this invention uses, carbochain triglyceride prepares as the oil phase of microemulsion the dissolubility (20 mg/ml) that microemulsion significantly can increase ibuprofen, in this microemulsion formulation, dosage of surfactant is up to 30 %-40 %, and dosage of surfactant is 15 ~ 20 times of medicine.
Summary of the invention
The object of the present invention is to provide a kind of ibuprofen microemulsion drug-supplying system, wherein the absolute dosage of surfactant is significantly reduced, and drug solubility and oral administration biaavailability significantly improve simultaneously.
The invention provides a kind of ibuprofen microemulsion drug-supplying system, it comprises surfactant, cosurfactant, water, oil and ibuprofen, wherein said oil is the miscella of pungent capric acid triglyceride and glycerol trioleate, mass ratio is 6:1-1:6, sad part in described pungent capric acid triglyceride and capric acid part are after forming methyl caprylate and methyl caprate respectively, and the methyl caprylate measured through gas chromatograph-mass spectrometer and the peak area ratio of methyl caprate are 55:45 ~ 95:5.。In a preferred embodiment, the mass ratio of described pungent capric acid triglyceride and glycerol trioleate is 2:1-1:2, is more preferably 1:1.In one embodiment, the peak area ratio of methyl caprylate and methyl caprate is 75:25.
In an embodiment of the invention, the content of described surfactant is 2-10 times of described determination of ibuprofen.Preferably, the content of surfactant is only 2 times of described determination of ibuprofen.
In an embodiment of the invention, Tween 80 and the polyoxyethylene castor oil of described surfactant to be mass ratio be 2:1-1:2.Preferably, the mass ratio of Tween 80 and polyoxyethylene castor oil is 1:1.
In an embodiment of the invention, described cosurfactant is selected from one or more in PEG400,1,2-PD, dehydrated alcohol.Preferably, described cosurfactant is PEG400.
In an embodiment of the invention, the mass ratio of described cosurfactant and surfactant is 1:1.
The present invention provides the preparation method of described ibuprofen microemulsion drug-supplying system on the other hand.Ibuprofen microemulsion drug-supplying system of the present invention is made by the microemulsion preparation method of routine.Common preparation method comprises: surfactant and the cosurfactant of getting recipe quantity, stir; Get the miscella of recipe quantity, fully mix with magnetic stirring apparatus, mix with total surfactant, then add the medicine (ibuprofen) of recipe quantity, stir and fully dissolve, slowly drip recipe quantity distilled water, obtain the microemulsion of clarification.
In this microemulsion system, use midchain oil (namely, pungent capric acid triglyceride (GTCC)) and unsaturated fatty acid ester is (namely, glycerol trioleate (Glycerol trioleate)) as miscella, Tween 80 (Tween 80) and polyoxyethylene castor oil (Cremophor EL) are as surfactant, and PEG400 (PEG 400) is as cosurfactant.
Compare with single oil phase, the use of miscella of the present invention significantly expands microemulsion region area on the one hand, and (MA is 28.4 %, MA30 12.0 %), significantly improve the dissolubility (about 60 mg/ml) of ibuprofen on the other hand, both comprehensive functions make the absolute dosage preparing surfactant needed for medicine carrying microemulsion significantly reduce (such as, more single oily prescription reduces six times).This means that, when drug loading is constant, the absolute dosage preparing the surfactant required for medicine carrying microemulsion reduces further.
Simultaneously, compared with single oil microemulsion, the use of miscella of the present invention obtains identical Oral Administration in Rats bioavailability, the ability that it improves drug oral bioavailability is not affected because dosage of surfactant is lower, thus can drug effect be given full play to, making ibuprofen microemulsion extensively enter clinical practice becomes possibility.
Accompanying drawing explanation
Fig. 1 is the block diagram of pseudo-ternary phase diagram and MA, the MA30 drawn under different oil phase prescription, and wherein Fig. 1 a is that pungent capric acid triglyceride (GTCC) are as oil phase; Fig. 1 b is that glycerol trioleate (Glycerol trioleate) is as oil phase; Fig. 1 c is that pungent capric acid triglyceride-glycerol trioleate (GTCC-Glycerol trioleate (1:1)) is as oil phase; Fig. 1 d is Fig. 1 a, 1b, 1c tri-block diagram of MA and MA30 of width pseudo-ternary phase diagram; Wherein S-Cos represents total surfactant (i.e. surfactant+cosurfactant).
Fig. 2 shows ibuprofen at pungent capric acid triglyceride (GTCC), ethyl oleate (ethyl oleate), Masine 35-1 (Maisine
tM35-1), the dissolubility in glycerol trioleate (Glycerol trioleate), isopropyl myristate (IPM), miscella (GTCC-Glycerol trioleate, 1:1,1:6,6:1).With single oil phase ratio, ibuprofen brings up to 258.5%-310.0% at the dissolubility of miscella.
Fig. 3 shows the dissolubility of ibuprofen in different microemulsion formulation.Wherein ME-A is for containing 24% total surfactant, 6% single oil (pungent capric acid triglyceride) microemulsion; ME-B is for containing 24% total surfactant, 6% miscella (pungent capric acid triglyceride-glycerol trioleate (1:1)) microemulsion; ME-C is for containing 20% total surfactant, 12% miscella (pungent capric acid triglyceride-glycerol trioleate (1:1)) microemulsion; ME-X is for containing 20% total surfactant, 12% miscella (pungent capric acid triglyceride-glycerol trioleate (6:1)) microemulsion; ME-Y is for containing 20% total surfactant, 12% miscella (pungent capric acid triglyceride-glycerol trioleate (2:1)) microemulsion; ME-Z is for containing 20% total surfactant, 12% miscella (pungent capric acid triglyceride-glycerol trioleate (1:2)) microemulsion.
Fig. 4 shows the cumulative in vitro release profiles of ibuprofen in different microemulsion ME-A-Ibu (■), ME-B-Ibu (●), ME-C-Ibu (▲), ME-D-Ibu (▼), ME-E-Ibu () prescription at 37 DEG C.Under the ibuprofen of same amount, the dosage of surfactant of ME-E is minimum, but cumulative in vitro release profiles changes without significance.
Fig. 5 shows the mean blood plasma concentration-time graph (n=5) after the different microemulsion formulation of Oral Administration in Rats and ibuprofen suspension (25 mg/kg).ME-A-Ibu (■), ME-B-Ibu (●), ME-C-Ibu (▲), ME-D-Ibu (▼), ME-E-Ibu (), ibuprofen suspension (×).
Detailed description of the invention
The present invention adopts Biopharmaceutics Classification system II class (BCS class II) medicine ibuprofen as model drug, and the miscella adopting the pungent capric acid triglyceride of midchain oil and glycerol trioleate is oil phase, prepares microemulsion drug-supplying system.Research finds, this miscella can not only significantly expand microemulsion region area, and can significantly improve the dissolubility of ibuprofen.Compared with single oil microemulsion, the miscella microemulsion of optimization has suitable Oral Administration in Rats bioavailability, and its dosage of surfactant is only 1/6th in single oil microemulsion.Effect of the present invention is confirmed further below by way of experiment.All carry out under the condition of 25 DEG C in pseudo-ternary phase diagram of the present invention and the preparation of microemulsion drug-supplying system and the mensuration of ibuprofen dissolubility.Pungent capric acid triglyceride are the mixture of the ester that sad, capric acid and glycerine esterification are formed, can purchased from Chengdu Gracia chemical technology company limited (production code member: 1022224; Lot number: I4285).
the preparation of embodiment 1 microemulsion pseudo-ternary phase diagram
Take a certain amount of surfactant and cosurfactant, fully mix 1 hour with magnetic stirring apparatus, obtain total surfactant S-Cos.At 25 DEG C, take S-Cos 1.8 respectively, 1.6, 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2 g is in cillin bottle, add 0.2 respectively again, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, (oil phase of a is pungent capric acid triglyceride to 1.8 g oil phases, the oil phase of b is glycerol trioleate, the oil phase of c is pungent capric acid triglyceride-glycerol trioleate (1:1)), mixing, slowly distilled water is dripped under magnetic stirring in mixed liquor, with outward appearance " clear " for index, record adds the water yield, by oil, total surfactant, water is at the respective mass percent (w/w) of critical point, draw pseudo-ternary phase diagram, determine microemulsion region, represent with black region, the results are shown in Figure 1a, 1b and 1c.
Microemulsion region area accounts for microemulsion region when the percentage ratio (percentage of microemulsion area, MA) of pseudo-ternary phase diagram triangle area and total surfactant consumption are less than 30 % and accounts for the percentage ratio (MA30) of pseudo-ternary phase diagram triangle area.According to pseudo-ternary phase diagram, obtain concrete numerical value by computer computed in software, draw block diagram, the results are shown in Figure 1d.Visible, all obvious MA and MA30 than single oil microemulsion of MA and MA30 of miscella microemulsion is large.
the foundation of embodiment 2 ibuprofen HPLC content assaying method
Chromatographic condition: chromatographic column is GraceSmart C18 (250 × 4.6 mm, 5 μm), and mobile phase is methanol-pH3.0 phosphate buffer (60:40), flow velocity 1 mL/min, sample size 20 μ L, determined wavelength λ=220 nm, column temperature 35
oc.
The foundation of standard curve: take methanol as solvent, compound concentration is the ibuprofen serial solution of 40,20,10,5,2.5,1.2,0.6 μ g/mL, presses the sample introduction analysis respectively of fixed chromatographic condition, makes standard curve with ibuprofen peak area to concentration.Known, ibuprofen within the scope of 0.6-40 μ g/mL, peak area and concentration linear dependence good (A=57.103C-5.6333, R
2=0.9997).
the dissolubility of embodiment 3 ibuprofen in water
Get distilled water 2 mL in cillin bottle, parallel 3 parts, adding appropriate excessive ibuprofen to there is precipitation, vortex 3 ~ 5 min, promoting distilled water dissolved substance, sealing.Be placed in 25
oin C water bath with thermostatic control shaking table, 100 rpm balance 72 h.Centrifugal 5 min of 15000 rpm, get supernatant, and with methanol after suitably diluting, HPLC method measures medicament contg, namely obtains the dissolubility of ibuprofen in water and is about 0.07 mg/mL.
the dissolubility of embodiment 4 ibuprofen in different oil phase
Get oily 2 mL in cillin bottle, parallel 3 parts, adding appropriate excessive ibuprofen to there is precipitation, vortex 3 ~ 5 min, promoting oil phase dissolved substance, sealing.Be placed in 25
oCin water bath with thermostatic control shaking table, 100 rpm balance 72 h.Centrifugal 5 min of 15000 rpm, get supernatant, and with methanol after suitably diluting, HPLC method measures medicament contg, obtains the dissolubility of ibuprofen in different oil phase.Result is (pungent capric acid triglyceride: 96.15 mg/mL as shown in Figure 2; Glycerol trioleate: 115.30 mg/mL; Pungent capric acid triglyceride-glycerol trioleate (1:1): 298.07 mg/mL; Pungent capric acid triglyceride-glycerol trioleate (6:1): 285.30 mg/mL; Pungent capric acid triglyceride-glycerol trioleate (1:6): 270.15 mg/mL).
the preparation of embodiment 5 microemulsion system
At 25 DEG C, take surfactant and the cosurfactant of recipe quantity according to table 1, fully mix with magnetic stirring apparatus, obtain total surfactant.Separately get recipe quantity oil phase, mix homogeneously, obtain miscella.Miscella mixes with total surfactant again, under agitation slowly drips prescription water gaging, obtains blank microemulsion ME-A, ME-B, ME-C, ME-F, ME-G, ME-H, ME-I, ME-J, ME-X, ME-Y, ME-Z.
The prescription composition of table 1 microemulsion
Note: total surfactant: Tween 80-polyoxyethylene castor oil-PEG400 (1:1:2)
Wherein bracket [] represents that sad part in described pungent capric acid triglyceride and capric acid part are after forming methyl caprylate and methyl caprate respectively, the methyl caprylate measured through gas chromatography combined with mass spectrometry (GC-MS) instrument and the peak area ratio of methyl caprate
.determine that the program of described peak area ratio is as follows: get 1 sample and add 2 mL 2% potassium hydroxide methanol solutions in 60 DEG C of water-bath 15 min, n-hexane extraction supernatant, with 10 mL water washings, get organic over anhydrous sodium sulfate sample introduction.
Instrument title: gas chromatograph-mass spectrometer (GC-MS)
Producer: THERMOL FINNIGAN
Model: TRACE DSQ
Pillar: DB-5MS
Injector temperature: 230 DEG C
Sampling volume: 1mL
Column oven temperature: 190 DEG C (constant temperature keeps 34 min)
Ion source temperature: 230 DEG C
The solvent delay time: 3 min
Split ratio: 30:1
Gas phase-mass spectrum junction temperature: 230 DEG C.
the dissolubility of embodiment 6 ibuprofen in different microemulsion formulation
Get each 2 mL of the blank microemulsion of ME-A, ME-B, ME-C, ME-X, ME-Y, ME-Z in cillin bottle, parallel 3 parts, add appropriate excess drug respectively, until there is precipitation, vortex 3 ~ 5min, promote medicine dissolution, sealing.Be placed in 25 DEG C of water bath with thermostatic control shaking tables again, 100 rpm balance 24 h.Centrifugal 5 min of 15000 rpm, get supernatant, and after methanol dilution, HPLC method measures medicament contg.The dissolubility of ibuprofen in different microemulsion formulation (ME-A:15.30 mg/mL as shown in Figure 3; ME-B:31.71 mg/mL; ME-C:59.59 mg/mL; ME-X:55.25 mg/mL; ME-Y:57.95 mg/mL; ME-Z:56.25 mg/mL).
the ibuprofen microemulsion release experiment in vitro of the different prescription of embodiment 7
According to table 2, the surfactant taking recipe quantity adds cosurfactant, fully mixes 1 hour, obtain total surfactant with magnetic stirring apparatus.Get recipe quantity oil phase mix homogeneously, obtain miscella.At 25 DEG C, miscella is mixed with total surfactant, then adds recipe quantity ibuprofen, stir and fully dissolve, under agitation slowly drip recipe quantity distilled water, obtain ibuprofen microemulsion ME-A-Ibu, ME-B-Ibu, ME-C-Ibu, ME-D-Ibu, ME-E-Ibu of clarification.
Get each 1mL of each microemulsion formulation and be placed in bag filter (MW=3500kDa), it is placed in respectively the PBS solution of 50mL; It is placed in isothermal vibration device respectively, water-bath 37
oCconcussion, 100 rpm, and draw 1mL release medium respectively at 0.5,1,1.5,2,3,4,5,6,8,16,24 h, and supplement release medium in time, HPLC method measures medicament contg, and draws cumulative in vitro release profiles, as shown in Figure 4.
The prescription composition of table 2 ibuprofen microemulsion
Note:
After sad part in a pungent capric acid triglyceride and capric acid part form methyl caprylate and methyl caprate respectively, the methyl caprylate measured through gas chromatography combined with mass spectrometry (GC-MS) instrument and the peak area ratio of methyl caprate are 55:45 ~ 95:5
B total surfactant: Tween 80-polyoxyethylene castor oil-PEG400 (1:1:2)
The consumption of the Tween 80 in c medicine carrying microemulsion corresponding to every 10 mg ibuprofen.
the bioavailability experiment of ibuprofen microemulsion in rat body of the different prescription of embodiment 8
Take ibuprofen suspension as reference, oral administration gavage ibuprofen suspension and each microemulsion prepared by embodiment 7 respectively, investigate ibuprofen miscella microemulsion, single oil microemulsion to the raising of ibuprofen biological utilisation, investigate the difference of miscella and single oil microemulsion bioavailability, and dosage of surfactant declines whether affect the raising of drug bioavailability.
Get male SD rat 30, body weight 200 ± 20 g, is divided into 6 groups at random, often organizes 5 animals.By the dosage of ibuprofen 25 mg/kg, to SD Oral Administration in Rats gavage square preparation everywhere.Before administration, water is can't help in 12 h fasting, 4 h ad libs after administration, and blood sample collection process all freers drinking-water, and supplements normal saline 3 times.
Blood is got respectively at 5,10,20,30,45,60,90,120,240,360,480 min blood taking needles after oral administration gavage administration.Get blood plasma 50 μ L and add 50 μ L acetonitriles, then add interior mark naproxen solution 150 μ L, vortex 30 s of 788.8 ng/mL, 15 DEG C of 13000 centrifugal 10 min of rpm.Get supernatant blood plasma 100 μ L and add 900 μ L distilled water, 15 DEG C of 13000 centrifugal 10 min of rpm, gets supernatant, to process and measure by LC-MS/MS method to sample.Result of calculation is depicted as mean blood plasma concentration-time graph as shown in Figure 5.Relevant pharmacokinetic parameter is as shown in table 3.
The relevant pharmacokinetic parameter of the different microemulsion formulation of table 3 Oral Administration in Rats
Note: compare with ibuprofen suspension group,
*p<0.05;
*p<0.01.
The present invention passes through formulation optimization, select miscella microemulsion prepared by medium chain saturated oils and long-chain unsaturated oils, compared with single oil microemulsion, the dosage of surfactant of ibuprofen miscella microemulsion is only 1/6th of single oil, is only 2 times of ibuprofen when dosage of surfactant is optimum.
Oral Administration in Rats bioavailability result shows, although miscella microemulsion differs 10 times with single oil microemulsion surfactant absolute dosage, oral administration biaavailability is suitable.To sum up, the present invention adopts miscella, not only expand microemulsion region area, and improve the dissolubility of medicine simultaneously, thus significantly reduce the absolute dosage of the surfactant prepared needed for medicine carrying microemulsion, reduce the toxic and side effects of the microemulsion caused greatly due to dosage of surfactant, for microemulsion industrialization provides possible approach.
Claims (9)
1. an ibuprofen microemulsion drug-supplying system, comprise surfactant, cosurfactant, water, oil and ibuprofen, it is characterized in that, described oil is the miscella of pungent capric acid triglyceride and glycerol trioleate, mass ratio is 6:1-1:6, sad part in wherein said pungent capric acid triglyceride and capric acid part are after forming methyl caprylate and methyl caprate respectively, and the methyl caprylate measured through gas chromatograph-mass spectrometer and the peak area ratio of methyl caprate are 55:45 ~ 95:5.
2. ibuprofen microemulsion drug-supplying system according to claim 1, is characterized in that, the mass ratio of described pungent capric acid triglyceride and glycerol trioleate is 1:1.
3. ibuprofen microemulsion drug-supplying system according to claim 1 and 2, is characterized in that, the peak area ratio of described methyl caprylate and methyl caprate is 75:25.
4. ibuprofen microemulsion drug-supplying system according to claim 1, is characterized in that, the content of described surfactant is 2-10 times of described determination of ibuprofen.
5. ibuprofen microemulsion drug-supplying system according to claim 1, is characterized in that, Tween 80 and the polyoxyethylene castor oil of described surfactant to be mass ratio be 2:1-1:2.
6. ibuprofen microemulsion drug-supplying system according to claim 5, is characterized in that, the mass ratio of Tween 80 and polyoxyethylene castor oil is 1:1.
7. ibuprofen microemulsion drug-supplying system according to claim 1, is characterized in that, described cosurfactant be selected from PEG400,1,2-PD, dehydrated alcohol one or more.
8. ibuprofen microemulsion drug-supplying system according to claim 7, is characterized in that, described cosurfactant is PEG400.
9. ibuprofen microemulsion drug-supplying system according to claim 1, is characterized in that, the mass ratio of described cosurfactant and surfactant is 1:1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992008445A1 (en) * | 1990-11-13 | 1992-05-29 | Affinity Biotech, Inc. | Non-aqueous microemulsion for drug delivery |
| CN101904815A (en) * | 2009-06-03 | 2010-12-08 | 河北奥星集团药业有限公司 | Ibuprofen microemulsion preparation and preparation method |
-
2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992008445A1 (en) * | 1990-11-13 | 1992-05-29 | Affinity Biotech, Inc. | Non-aqueous microemulsion for drug delivery |
| CN101904815A (en) * | 2009-06-03 | 2010-12-08 | 河北奥星集团药业有限公司 | Ibuprofen microemulsion preparation and preparation method |
Non-Patent Citations (3)
| Title |
|---|
| XIUHUA YOU ET AL.: "Optimizing surfactant content to improve oral bioavailability of ibuprofen in microemulsions: Just enough or more than enough?", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| YIZHEN CHEN ET AL.: "Optimized mixed oils remarkab...enhancing drug solubility", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 陈华兵等: "布洛芬微乳的制备及其透皮吸收研究", 《中国药学杂志》 * |
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