CN102641237A - Curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration and preparation method thereof - Google Patents
Curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration and preparation method thereof Download PDFInfo
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- CN102641237A CN102641237A CN2012101494141A CN201210149414A CN102641237A CN 102641237 A CN102641237 A CN 102641237A CN 2012101494141 A CN2012101494141 A CN 2012101494141A CN 201210149414 A CN201210149414 A CN 201210149414A CN 102641237 A CN102641237 A CN 102641237A
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Abstract
The invention discloses a curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration, which uses curcumin as a raw medicine and adopts a surfactant, a cosurfactant, an oil phase and a gellan gum solution. According to the portions by weight, the preparation comprises 0.5-8 portions of curcumin, 4-25.6 portions of oil phase, 17-46.4 portions of surfactant, 17-46.4 portions of cosurfactant and 20-50 portions of gellan gum solution, wherein the mass concentration of the gellan gum solution is 0.1%-1.0%. The preparation method comprises the following steps of: firstly, uniformly mixing the oil phase, the surfactant and the cosurfactant in a mode of electromagnetic stirring, vortex oscillation or ultrasound; secondly, adding the curcumin, and fully stirring the mixture to be dissolved; thirdly, dropwise adding the gellan gum solution; and finally, continuously stirring the mixture to obtain the curcumin microemulsion ion sensitive in situ gel preparation for intranasal administration. After intranasal administration of the microemulsion ion sensitive in situ gel preparation disclosed by the invention, the medicine can reach brain targeted sites through a direct nose-brain path and a systemic circulation path, so that the curcumin has a treatment effect on brain tissues.
Description
Technical field
The present invention relates to a kind of nasal-cavity administration curcumin microemulsion ion-sensitive in-situ gel preparation and preparation method thereof.
Background technology
(curcumin is from the Zingiberaceae Curcuma Cur) to curcumin
Curcuma longa L.A kind of natural phenolic compound that extracts in the plant has antiinflammatory, antioxidation, multiple pharmacological effect such as antibiotic, can treat multiple brain diseasess such as the cerebral tumor, Alzheimer, parkinson disease.Curcumin is used to treat Alzheimer and has also got into the clinical research stage; Because the curcumin water solubility is poor; Oral administration biaavailability is extremely low by only 1%, and therefore, improving the dissolubility of curcumin and promoting drug absorption, improve the brain diseases curative effect is problem demanding prompt solution.
The via intranasal application administration receives transport of drug to the method for brain the attention of researcher day by day.At the olfactory region of the nasal cavity nervi olfactory that distributing, the sieve aperture that distributing on the SM sieve shape hone lamella, nervi olfactory arrive the olfactory bulb of brain through sieve aperture.Medicine can directly arrive cerebral tissue by nasal cavity through olfactory neural pathway and nervi trigeminus path.The medicine blood capillary abundant through the respiratory region gets into blood circulation, or gets into blood circulation through the lamina propria of olfactory region, and circulation strides across BBB and gets into cerebral tissue then.But, influence the absorption of medicine because the scavenging action of nasal cavity cilium makes medicine shorten in the time of staying of nasal cavity.Gellan gum is the pharmaceutics hot research fields as a kind of ion-sensitive gel-type vehicle, has obtained drugs approved by FDA with the timolol maleate eye of gellan gum substrate with gelling soln.Gellan gum situ-gel preparation is simple, can with the ions bind of agents area such as nasal cavity or eye, form the semi-solid preparation of toughness, strong to the mucosal tissue affinity, the holdup time is long, helps the absorption of medicine.
Summary of the invention
The objective of the invention is for overcoming the deficiency of above-mentioned prior art, a kind of nasal-cavity administration curcumin microemulsion ion-sensitive in-situ gel preparation and preparation method thereof is provided.
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
A kind of nasal-cavity administration curcumin microemulsion ion-sensitive in-situ gel preparation is to be crude drug with the curcumin, and adjuvant adopts surfactant, cosurfactant, oil phase, gellan gum solution; Wherein the parts by weight of each component are following: 0.5～8 part of curcumin; Oil phase: 4～25.6 parts, surfactant: 17～46.4 parts, 17～46.4 parts of cosurfactants; Gellan gum solution: 20～50 parts, the concentration of gellan gum solution is 0.1%～1.0%.
Said surfactant is selected from: Solutol HS15 (polyglycol distearate 15), Labrasol (sad capric acid polyethyleneglycol glyceride), Cremophor EL (castor oil polyoxyethylene 35 ethers), polyoxyethylene nonylphenol ether (alkyl phenol and ethylene oxide condensate) or Tween80 (Tween 80).
Said cosurfactant is selected from: 1, and 2-propylene glycol, ethanol, PEG400, Transcutol HP (TC
) or Plurol Oleique CC497 (polyglycerol acrylate).
Said oil phase is selected from: ethyl oleate, Oleum Ricini, Capryol 90 (Capryol 90), isopropyl myristate or Labrafil M1944 CS (oleic acid polyethyleneglycol glyceride).
Said gellan gum solution quality concentration is between 0.1%～1.0%.
Said nasal cavity administrated prepn is a solution.
Said curcumin microemulsion ion-sensitive situ-gel nasal formulations; Prepare through following method: at first oil phase, surfactant, cosurfactant are vibrated or the ultrasonic power mixing with electromagnetic agitation, vortex; Add curcumin then; Fully stirring and dissolving is added dropwise to gellan gum solution again, continues to stir promptly to obtain curcumin microemulsion ion-sensitive situ-gel nasal formulations.
Among the present invention, have only 11ng/ml,, improve the dissolubility of medicine so it is prepared into microemulsion formulation to the dissolubility of curcumin in water.To the barrier action that medicine gets into brain, make that curcumin more gets into the effect that cerebral tissue are brought into play the treatment brain diseases for fear of blood brain barrier, thus with it as nasal formulations.In the preparation of the present invention's preparation, the medicament contg of curcumin can reach 40～80mg/ml, has significantly improved the dissolubility of curcumin.The particle diameter of this microemulsion ion-sensitive in-situ gel is used for nasal-cavity administration and helps promoting the absorption of medicine at nasal mucosa less than 100nm.
Behind the microemulsion ion-sensitive in-situ gel nasal-cavity administration of the present invention, but medicine per nasal-brain direct path and systemic circulation path two paths arrive the brain targeting moiety, make curcumin bring into play therapeutical effect at cerebral tissue.
Description of drawings
Fig. 1: the transmission electron microscope picture (120,000 *) of curcumin microemulsion ion-sensitive situ-gel.
The specific embodiment
Through instantiation the present invention is further set forth below, should be noted that following explanation only is in order to explain the present invention, its content not to be limited.
The specific embodiment:
Embodiment 1:
Take by weighing Capryol 90 0.7g, Cremophor EL 4.0 g, Transcuol HP 2.5g, electromagnetic agitation evenly after, add curcumin 600mg, after stirring, be added dropwise to and contain 0.3% gellan gum solution 3g, continue to stir and promptly get.
Embodiment 2:
Take by weighing Capryol 90 0.8g, Solutol HS15,5.0 g, Transcuol HP 2.5g after electromagnetic agitation is even, is added dropwise to 0.5% gellan gum solution 3g, adds curcumin 450mg, promptly gets after stirring.
Embodiment 3:
Take by weighing Capryol 90 0.5g, Solutol HS15 3.5 g, Transcuol HP 2.2g after electromagnetic agitation is even, adds curcumin 500mg, after stirring, is added dropwise to 0.3% gellan gum solution 3.5g, continues to stir promptly to get.
Embodiment 4:
Take by weighing Capryol 90 0.6g, Solutol HS15 3.5g, Transcuol HP 3.5g after electromagnetic agitation is even, adds curcumin 400mg, after stirring, is added dropwise to 0.3% gellan gum solution 4g, continues to stir promptly to get.
It is an amount of to get above-mentioned micro emulsion gel liquid, and distilled water suitably dilutes, and dips in the special-purpose copper mesh of transmission electron microscope and gets above-mentioned solution; 2% phosphotungstic acid carries out negative staining; Place then under the transmission electron microscope and observe, the result is as shown in Figure 1, the spherical in shape or type sphere of preparation particle; Particle diameter in 30～100nm scope, favorable dispersibility.
Test Example 1:, carry out the rat pharmacokinetic studies according to embodiment 4 preparation curcumin microemulsion ion-sensitive in-situ gel preparations:
The preparation of injection: it is an amount of to get the curcumin raw material, adds the mixed solvent of DMAC N,N, PEG400 and 5% glucose injection (15%:40%:45%), and mix homogeneously 0.22 μ m filtration sterilization is subsequent use.
Get 10 healthy Wistar male rats and be divided into two groups, 5 every group.Fasting 12h before the administration can freely drink water.Before the experiment, the nasal-cavity administration group is with rat anesthesia, and injection groups is not anaesthetized.The rat of nasal-cavity administration places the container that contains ether, makes its incoming call etherization.After treating rat anesthesia, use the microsyringe nasal-cavity administration; The administration of injection groups tail vein injection.Respectively in different time points (0.083,0.25,0.5,0.75,1,1.5,2,3,5,8,12h), the blood sampling of subclavian vein hole places the EP pipe that contains heparin then, and the centrifugal 15min of 4000rm gets blood plasma and preserves to be measured in-20 ℃ of refrigerators.The rat plasma sample carries out ethyl acetate and methyl alcohol mixed liquor extracts, and methanol redissolves to be handled, and HPLC carries out medicine assay.
Experimental result: the absolute bioavailability of curcumin microemulsion ion-sensitive in-situ gel preparation nasal-cavity administration reaches 55.82%; And the oral absolute bioavailability of curcumin rat only has about 4.13%; Obviously improve the absorption of medicine, improved the bioavailability of curcumin.
Test Example 2:, carry out rat medicine cerebral tissue distribution research according to embodiment 4 preparation curcumin microemulsion ion-sensitive in-situ gel preparations:
Get 30 healthy Wistar male rats and be divided into two groups, 15 every group.Fasting 12h before the administration can free drinking water.Before the experiment, the nasal-cavity administration group is with rat anesthesia, and injection groups is not anaesthetized.The rat of nasal-cavity administration places the container that contains ether, makes its incoming call etherization.After treating rat anesthesia, in-situ gel preparation is splashed into nasal cavity; The administration of injection groups tail vein injection.Respectively in different time points (0.083,0.5,1,3,5h), the blood sampling of subclavian vein hole places the EP pipe that contains heparin then, and the centrifugal 15min of 4000rpm gets blood plasma and preserves to be measured in-20 ℃ of refrigerators.Open simultaneously the rat cranial cavity immediately, take out cerebral tissue, the normal saline rinsing, the filter paper suck dry moisture, precision is weighed, and places-20 ℃ of refrigerators to be measured.Rat plasma sample and murine brain sample carry out sample treatment respectively, and HPLC carries out medicine assay.
Result: under the same dose; The AUC that curcumin microemulsion ion-sensitive in-situ gel preparation nasal-cavity administration arrives brain is 568 mg/L*h; The AUC of injection drug administration by injection is 183 mg/L*h, and this in-situ gel preparation nasal-cavity administration is 3 times of injection drug administration by injection AUC, brain targeting index ([AUC
Brain/ AUC
Blood]
I.n./ [AUC
Brain/ AUC
Blood]
I.v.) be 6.17, show the dose that has significantly improved curcumin entering brain, be of value to the treatment of brain diseases.
Claims (6)
1. curcumin microemulsion ion-sensitive in-situ gel preparation is characterized in that: with the curcumin crude drug, and accessory package oil scraper phase, surfactant, cosurfactant and gellan gum solution; The parts by weight of each component are following: 0.5～8 part of curcumin; Oil phase: 4～25.6 parts, surfactant: 17～46.4 parts, 17～46.4 parts of cosurfactants; Gellan gum solution: 20～50 parts, the mass concentration of gellan gum solution is 0.1%～1.0%.
2. curcumin microemulsion ion-sensitive in-situ gel preparation according to claim 1, it is characterized in that: the particle diameter of said preparation is in 20～100nm scope.
3. curcumin microemulsion ion-sensitive in-situ gel preparation according to claim 1, it is characterized in that: said oil phase is selected from: ethyl oleate, Oleum Ricini, Capryol 90, isopropyl myristate or Labrafil M1944 CS.
4. curcumin microemulsion ion-sensitive in-situ gel preparation according to claim 1, it is characterized in that: said surfactant is selected from Transcutol HS15, Labrasol, Cremophor EL, polyoxyethylene nonylphenol ether or Tween80.
5. curcumin microemulsion ion-sensitive in-situ gel preparation according to claim 1, it is characterized in that: said cosurfactant is selected from 1,2-propylene glycol, ethanol, PEG400, Transcutol HP or Plurol Oleique CC497.
6. the method for preparing of each described curcumin microemulsion ion-sensitive in-situ gel preparation in the claim 1～5; It is characterized in that: at first oil phase, surfactant, cosurfactant are vibrated or the ultrasonic power mixing with electromagnetic agitation, vortex; Add curcumin then; Fully stirring and dissolving is added dropwise to gellan gum solution again, continues to stir promptly to obtain curcumin microemulsion ion-sensitive situ-gel nasal formulations.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105343003A (en) * | 2015-11-16 | 2016-02-24 | 南京中医药大学 | Nasal dry powder inhalation for treating Alzheimer's disease and preparation method thereof |
| CN106822044A (en) * | 2017-03-15 | 2017-06-13 | 山东师范大学 | Curcumin sustained release aggregation and the preparation method of a kind of chitosan-containing |
| CN109152358A (en) * | 2016-04-01 | 2019-01-04 | 雷根斯堡大学 | Photosensitive agent dispersion and application thereof |
| CN109172517A (en) * | 2018-10-25 | 2019-01-11 | 山东师范大学 | A kind of preparation method of the microemulsion hydrogel as apiolin carrier with pH response |
| CN111494316A (en) * | 2020-04-14 | 2020-08-07 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN112206206A (en) * | 2020-10-15 | 2021-01-12 | 复旦大学附属中山医院青浦分院 | Preparation method and application of curcumin microemulsion gel for vaginal administration |
| CN113786382A (en) * | 2021-11-04 | 2021-12-14 | 浙江得恩德制药股份有限公司 | Terbinafine hydrochloride gel and preparation method thereof |
| CN117159445A (en) * | 2023-01-28 | 2023-12-05 | 济宁医学院 | Preparation method and application of curcumin nanoemulsion temperature-sensitive hydrogel |
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Cited By (15)
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| CN105343003A (en) * | 2015-11-16 | 2016-02-24 | 南京中医药大学 | Nasal dry powder inhalation for treating Alzheimer's disease and preparation method thereof |
| CN105343003B (en) * | 2015-11-16 | 2018-09-04 | 南京中医药大学 | Powder nose inhalant and preparation method thereof for treating alzheimer disease |
| CN109152358A (en) * | 2016-04-01 | 2019-01-04 | 雷根斯堡大学 | Photosensitive agent dispersion and application thereof |
| EP3225112B1 (en) | 2016-04-01 | 2021-08-18 | TriOptoTec GmbH | Photosensitiser dispersion and use of the same |
| CN106822044A (en) * | 2017-03-15 | 2017-06-13 | 山东师范大学 | Curcumin sustained release aggregation and the preparation method of a kind of chitosan-containing |
| CN106822044B (en) * | 2017-03-15 | 2019-09-24 | 山东师范大学 | A kind of the curcumin sustained release aggregation and preparation method of chitosan-containing |
| CN109172517B (en) * | 2018-10-25 | 2021-08-17 | 山东师范大学 | Preparation method of microemulsion hydrogel with pH response as apigenin carrier |
| CN109172517A (en) * | 2018-10-25 | 2019-01-11 | 山东师范大学 | A kind of preparation method of the microemulsion hydrogel as apiolin carrier with pH response |
| CN111494316B (en) * | 2020-04-14 | 2021-05-18 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN111494316A (en) * | 2020-04-14 | 2020-08-07 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN112206206A (en) * | 2020-10-15 | 2021-01-12 | 复旦大学附属中山医院青浦分院 | Preparation method and application of curcumin microemulsion gel for vaginal administration |
| CN112206206B (en) * | 2020-10-15 | 2023-02-10 | 复旦大学附属中山医院青浦分院 | Preparation method and application of curcumin microemulsion gel for vaginal administration |
| CN113786382A (en) * | 2021-11-04 | 2021-12-14 | 浙江得恩德制药股份有限公司 | Terbinafine hydrochloride gel and preparation method thereof |
| CN113786382B (en) * | 2021-11-04 | 2024-05-28 | 浙江得恩德制药股份有限公司 | Terbinafine hydrochloride gel and preparation method thereof |
| CN117159445A (en) * | 2023-01-28 | 2023-12-05 | 济宁医学院 | Preparation method and application of curcumin nanoemulsion temperature-sensitive hydrogel |
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