CN102641237B - 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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- CN102641237B CN102641237B CN 201210149414 CN201210149414A CN102641237B CN 102641237 B CN102641237 B CN 102641237B CN 201210149414 CN201210149414 CN 201210149414 CN 201210149414 A CN201210149414 A CN 201210149414A CN 102641237 B CN102641237 B CN 102641237B
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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-activited in situ gel preparation and preparation method thereof.
Background technology
Curcumin (curcumin, Cur) is from the Zingiberaceae Curcuma
Curcuma longa L.A kind of natural phenolic compound that extracts in plant has antiinflammatory, antioxidation, the multiple pharmacological effect such as antibiotic, can treat the multiple brain diseasess such as the cerebral tumor, Alzheimer, parkinson disease.Curcumin is used for the treatment of Alzheimer and has also entered 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 is problem demanding prompt solution to the brain diseases curative effect.
The via intranasal application administration is subject to 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 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.Abundant blood capillary enters blood circulation to medicine through the respiratory region, or enters blood circulation through the lamina propria of olfactory region, and then circulation strides across BBB and enters cerebral tissue.But because the scavenging action of nasal cavity cilium makes medicine shorten in the time of staying of nasal cavity, affect the absorption of medicine.Gellan gum as a kind of ion-sensitive gel-type vehicle, is the study hotspot in pharmaceutics field, 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 binding 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, is conducive to the absorption of medicine.
Summary of the invention
The objective of the invention is for overcoming above-mentioned the deficiencies in the prior art, a kind of nasal-cavity administration curcumin microemulsion ion-activited in situ gel preparation and preparation method thereof is provided.
For achieving the above object, the present invention adopts following technical proposals:
A kind of nasal-cavity administration curcumin microemulsion ion-activited in situ gel preparation, take curcumin as crude drug, adjuvant adopts surfactant, cosurfactant, oil phase, gellan gum solution, wherein the parts by weight of each component are as follows: 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%.
Described surfactant is selected from: Solutol HS15(Solutol HS15), the Labrasol(Labraso), Cremophor EL(castor oil polyoxyethylene 35 ethers), polyoxyethylene nonylphenol ether (condensation compound of alkyl phenol and epoxy ethane) or Tween80(Tween 80).
Described cosurfactant is selected from: 1,2-PD, ethanol, PEG400, Transcutol HP(TC
) or Plurol Oleique CC497(polyglycerol acrylate).
Described oil phase is selected from: ethyl oleate, Oleum Ricini, Capryol 90(Capryol 90), isopropyl myristate or Labrafil M1944 CS(oleic acid polyethyleneglycol glyceride).
Described gellan gum concentration of polymer solution is between 0.1%～1.0%.
Described nasal cavity administrated preparation is solution.
Described curcumin microemulsion ion-activited in situ gel nasal formulations, prepare by the following method: at first oil phase, surfactant, cosurfactant are vibrated or the ultrasonic power mixing with electromagnetic agitation, vortex, then add curcumin, abundant stirring and dissolving, be added dropwise to again gellan gum solution, continue stirring and namely obtain curcumin microemulsion ion-activited in situ gel nasal formulations.
In the present invention, the dissolubility for curcumin in water only has 11ng/ml, therefore it is prepared into microemulsion formulation, improves the dissolubility of medicine.For fear of blood brain barrier, medicine is entered the barrier action of brain, make curcumin enter cerebral tissue bring into play the treatment brain diseases effect, therefore 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-activited in situ gel agent is used for nasal-cavity administration and is conducive to promote medicine in the absorption of nasal mucosa less than 100nm.
After microemulsion ion-activited 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-activited in situ gel.
The specific embodiment
The present invention will be further elaborated below by instantiation, should be noted that following explanation is only in order to explain the present invention, its content not to be limited.
The specific embodiment:
Embodiment 1:
Take 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 stir and get final product.
Embodiment 2:
Take Capryol 90 0.8g, Solutol HS15,5.0 g, Transcuol HP 2.5g, electromagnetic agitation evenly after, be added dropwise to 0.5% gellan gum solution 3g, add curcumin 450mg, after stirring and get final product.
Embodiment 3:
Take 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 stir and get final product.
Embodiment 4:
Take 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 stir and get final product.
Get above-mentioned micro emulsion gel liquid appropriate, distilled water suitably dilutes, dip mentioned solution with the special-purpose copper mesh of transmission electron microscope, 2% phosphotungstic acid carries out negative staining, then be placed under transmission electron microscope and observe, result as shown in Figure 1, the preparation particle is spherical in shape or class is spherical, particle diameter in 30～100nm scope, favorable dispersibility.
Test example 1: according to embodiment 4 preparation curcumin microemulsion ion-activited in situ gel preparations, carry out the rat pharmacokinetic studies:
The preparation of injection: get the curcumin raw material appropriate, add the mixed solvent of N,N-dimethylacetamide, PEG400 and 5% glucose injection (15%:40%:45%), mix homogeneously 0.22 μ m filtration sterilization is standby.
Get 10 healthy Wistar male rats and be divided into two groups, 5 every group.Fasting 12h before administration can freely drink water.Before experiment, the nasal-cavity administration group is with rat anesthesia, and the injection group is not anaesthetized.The rat of nasal-cavity administration is placed in the container that contains ether, makes its incoming call etherization.After rat anesthesia, use the microsyringe nasal-cavity administration; The administration of injection group tail vein injection.Then 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 is placed in the EP pipe that contains heparin, and the centrifugal 15min of 4000rm gets blood plasma to be measured in-20 ℃ of Refrigerator stores.The rat plasma sample carries out ethyl acetate and methyl alcohol mixed liquor extracts, and methanol redissolves to be processed, and HPLC carries out medicine assay.
Experimental result: the absolute bioavailability of curcumin microemulsion ion-activited in situ gel preparation nasal-cavity administration reaches 55.82%, and the absolute bioavailability of curcumin Oral Administration in Rats only has 4.13% left and right, obviously improve the absorption of medicine, improved the bioavailability of curcumin.
Test example 2: according to embodiment 4 preparation curcumin microemulsion ion-activited in situ gel preparations, carry out large raticide cerebral tissue distribution research:
Get 30 healthy Wistar male rats and be divided into two groups, 15 every group.Fasting 12h before administration can free drinking water.Before experiment, the nasal-cavity administration group is with rat anesthesia, and the injection group is not anaesthetized.The rat of nasal-cavity administration is placed in the container that contains ether, makes its incoming call etherization.After rat anesthesia, in-situ gel preparation is splashed into nasal cavity; The administration of injection group tail vein injection.Then respectively in different time points (0.083,0.5,1,3,5h), the blood sampling of subclavian vein hole is placed in the EP pipe that contains heparin, and the centrifugal 15min of 4000rpm gets blood plasma to be measured in-20 ℃ of Refrigerator stores.Open immediately simultaneously the rat cranial cavity, take out cerebral tissue, the normal saline rinsing, the filter paper suck dry moisture, precise weighing is placed in-20 ℃ of refrigerators to be measured.Rat plasma sample and murine brain sample carry out respectively sample treatment, and HPLC carries out medicine assay.
Result: under same dose, the AUC that curcumin microemulsion ion-activited 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 to have significantly improved the dose that curcumin enters brain, be of value to the treatment of brain diseases.
Claims (1)
1. curcumin microemulsion ion-activited in situ gel preparation, it is characterized in that: obtain by following preparation method: take Capryol 90 0.6g, Solutol HS15 3.5g, Transcuol HP 3.5g, after electromagnetic agitation is even, add curcumin 400mg, after stirring, be added dropwise to 0.3% gellan gum solution 4g, continue stir and get final product.
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| 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 |
| PL3225112T3 (en) | 2016-04-01 | 2022-01-03 | Trioptotec Gmbh | Photosensitiser dispersion and use of the same |
| 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 |
| CN111494316B (en) * | 2020-04-14 | 2021-05-18 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| 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 |
| 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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