CN106560175A - Menthol-camphor eutectic mixture nano-emulsion in situ gel preparation - Google Patents
Menthol-camphor eutectic mixture nano-emulsion in situ gel preparation Download PDFInfo
- Publication number
- CN106560175A CN106560175A CN201510787922.6A CN201510787922A CN106560175A CN 106560175 A CN106560175 A CN 106560175A CN 201510787922 A CN201510787922 A CN 201510787922A CN 106560175 A CN106560175 A CN 106560175A
- Authority
- CN
- China
- Prior art keywords
- emulsion
- nano
- menthol
- camphor
- gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a nasal nano-emulsion in situ gel using a menthol-camphor eutectic mixture as an oil phase, and a preparation method thereof, wherein the preparation is prepared from an oil phase, an emulsifier, a co-emulsifier, a gelling agent, a thickener, water and the like, is a low-viscosity liquid having good fluidity in vitro, and is rapidly converted into the gel state after being mixed with blenna narium under a physiological condition (in nasal cavity). According to the present invention, with the menthol-camphor eutectic mixture nano-emulsion in situ gel preparation, the residence time of the drug in the nasal cavity part can be significantly prolonged, the drug absorption across nasal mucosa can be promoted, and the bioavailability can be increased; and the preparation has no obvious irritation and side effect on the nasal mucosa, and has advantages of stable and controllable quality, easy treatment effect improving, and patient medication compliance improving.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly it relates to nasal nanometer emulsion in-situ gel of a kind of menthol-camphor eutectic and preparation method thereof.
Background technology
Compound Menthol Nose Drop is a kind of common dosage forms for treating drying property and atrophic rhinitis, the menthol and camphor of the quality such as main active is, solvent is liquid paraffin.Menthol is selectively applied to the cold receptor of mucous membrane and produces creeping chill, because the transmitting of receptor is acted on, makes vessel retraction, and edema mitigates, so that the sense of discomfort of inflammation is eased.Camphor also plays the role of similar peppermint brain stimulation cold receptor, meanwhile, also with analgesia, antipruritic effect.
There is the record that menthol and camphor are made eutectic in prior art, but menthol and camphor are only made eutectic and are used as auxiliary material by it, usually as the carrier of local application.Because menthol and camphor form the change of the property such as microstructure after eutectic, it is unpredictable that whether menthol and camphor form eutectic also have the active function of menthol and/or camphor, therefore, still the menthol used as active component and camphor are made into eutectic without prior art in this area, on the contrary, this area all tends to avoid menthol and camphor from forming eutectic for the stability of preparation and the controllability of production process in production process.
Nano-emulsion, also known as microemulsion, is formed by water, oil, surfactant etc., particle diameter be nano level Thermodynamically stable, isotropism, transparent or semitransparent homogeneous dispersion system.But, nano-emulsion is nanoscale due to particulate, and the property stable in properties requirement of the auxiliary material and active component to composition is higher.And the property of menthol and camphor eutectic is not also by the state of the art all announcements, particularly its stability, stability more particularly in nano-emulsion is not yet understood by those skilled in the art, therefore, those skilled in the art be difficult to expect also will not using menthol and camphor eutectic as nano-emulsion oil phase.
Situ-gel, after in body gel, macromolecular material is referred to solution or semi-solid state administration, stimulates to external world in medicine-feeding part（The change such as the temperature of agents area, pH values, ionic species and concentration, illuminance）Response is produced, the reversible transition that dispersity or conformation occur, the semi-solid or solid pharmaceutical preparation of formation.A mucous membrane, schneiderian membrance, mucous membrane of mouth, rectal mucosa and drug administration by injection position etc. are widely used at present.But it is still rare in this area that nano-emulsion is made into situ-gel, particularly during gel is prepared, gel component very likely produces various interactions with active component or auxiliary material, so as to affect the stability of active component or preparation, therefore, the situation that nano-emulsion is prepared as situ-gel by this area is less, be more not based on menthol and camphor eutectic as oil phase nano-emulsion preparing situ-gel.
Additionally, although Compound Menthol Nose Drop has good therapeutic effect to drying property and atrophic rhinitis, original side's technique falls behind, and current administering mode still with the direct nasal-cavity administration of nasal drops form, is primarily present following deficiency：1）There are a large amount of atoleines in former preparation（98%）, have impact on the saturating mucosal absorption of menthol and camphor；2）A large amount of atoleines make medicine peak type shift and change in continuous mode in former preparation, largely disturb the assay of medicine.3）Former preparation is the strong liquid of mobility, and the holdup time is short in nasal cavity, causes bioavilability low and using the shortcoming of the patient's poor compliance for frequently causing, the development of the prescription is limited to a certain extent；4）Camphorae and menthue is volatile in former preparation, with unstable characteristic.Therefore, using menthol in prescription and the eutectic characteristic of camphor, the eutectic of the two is prepared into into nano-emulsion, and it is used as nasal drop further combined with situ-gel property, while the prescription dose of former preparation is maintained, have nano-emulsion particle diameter concurrently little, it is easy to mucosal absorption and gel preparation the characteristics of the nasal cavity holdup time is long, former preparation stored can not only be overcome unstable and the inaccurate shortcoming of assay, and can significantly extend holdup time and schneiderian membrance through performance of the medicine in nasal cavity local, so as to be conducive to improving bioavilability, improve curative effect, facilitate patient.
The content of the invention
Present invention aim at menthol-camphor eutectic is prepared into into nano-emulsion as oil phase, and combine in-situ gel preparation, a kind of nano-emulsion in-situ gel preparation for treating drying property and atrophic rhinitis is provided, to promoting the saturating mucosal absorption of medicine, and extend holdup time of the medicine in nasal cavity, so as to reduce administration number of times, curative effect and patient compliance are improved.
Present inventors have surprisingly discovered that, menthol and camphor are formed and have after eutectic more preferably mucosal absorption effect.Tested it is found that menthol-camphor by release in vitro and external in vitro mucous membrane thoroughly（1:1）The more former agent in vitro release of eutectic nano-emulsion and external in vitro mucous membrane effect thoroughly, 100
Can improve during min up to 3 times or more than 3 times.
The present inventor has now surprisingly been found that menthol and camphor formation eutectic can be used as the stable presence of oil phase in nano-emulsion.30 are centrifuged with the nano-emulsion that eutectic is prepared as oil phase under the conditions of 20000 rpm
Min, menthol and camphor form eutectic can be as oil phase stable existence, referring to Fig. 6 in nano-emulsion.
The present inventor more has now surprisingly been found that, menthol and camphor 3:1-1:1（By weight）Eutectic there is more preferably stability, be particularly suitable for application as the oil phase of nano-emulsion.Preferably, menthol-camphor is 7:It is most stable under the conditions of 3.
The present inventor also has now surprisingly been found that, stability is more preferably when menthol-camphor eutectic makes situ-gel as the nano-emulsion of oil phase, particularly compared with menthol-nano-emulsion of the camphor eutectic as oil phase, the present inventor through experimental example 2 be similar to experimental studies have found that, its stability improves more than 40%.Further, when the average grain diameter of nano-emulsion is about 135 nm, prepared situ-gel good stability specifically can be found in Fig. 7.
The present inventor have now surprisingly been found that emulsifying agent for Tween 80, assistant for emulsifying agent be glycerine, gel rubber material be deacetylated gellan gum, thickener be sodium alginate when prepared nano-emulsion in-situ gel, stability is more preferably.The present inventor through experimental example 2 be similar to experimental studies have found that, its stability is substantially better than the combination of other auxiliary materials.
Specifically, the present invention relates to following technical scheme：
A kind of nasal nanometer emulsion in-situ gel, it is characterized in that being made up of active component and auxiliary material, wherein active component is made up of menthol and camphor, and menthol and camphor form eutectic, oil phase of the eutectic as nano-emulsion, accessory package contains emulsifying agent, gel rubber material and water, and active component and auxiliary material are by weight：Eutectic 1-4 parts, emulsifying agent 1-10 parts, gel rubber material 0.4-23 parts, water 63-97.6 parts.
The weight ratio of the menthol and camphor is 3:1-1:1.
Preferably, the weight ratio of the menthol and camphor is 7:3.
Also comprising assistant for emulsifying agent 1-5 parts and thickener 0.1-1 parts in the auxiliary material.
The emulsifying agent is Tween 80, Triton X-100, D- α -One or more mixtures in vitamin E polyethylene glycol succinic acid ester, Emulsifier EL-60, PLURONICS F87, lecithin.
The assistant for emulsifying agent is one or more mixtures in absolute ethyl alcohol, n-butanol, polyglycerol ester, propane diols, ethylene glycol, glycerine, PEG400.
The gel rubber material is one or more in deacetylated gellan gum, Carbomer P974, shitosan and poloxamer188.
Thickener is one or more mixtures in Carbomer, sodium alginate, hydroxypropyl methyl cellulose, PVP, sodium carboxymethylcellulose, methylcellulose.
The average grain diameter of the nano-emulsion is less than or equal to 200 nm, PI
<0.25, pH is neutral.
The average grain diameter of the nano-emulsion is approximately equal to 135 nm.
The situ-gel is in vitro working fluid state, and gel of the viscosity more than 5 Pas is changed in nasal cavity.
More specifically, the purpose of the present invention is achieved by the following technical programs：
A kind of menthol-camphor eutectic nasal nanometer emulsion in-situ gel, its prescription component mass percent：Eutectic 1.0%-4.0%, emulsifying agent 1.0%-5.0%, assistant for emulsifying agent 0.1%-5%, gel rubber material 0.1%-2.0%, thickener 0.1%-1%, water surplus.
Above-mentioned menthol-camphor eutectic preparation method adopts polishing, and eutectic is in colourless transparent liquid, fragrant odour, and obtained nano-emulsion is have the translucent liquid of opalescence.
Mentioned emulsifier is Tween 80, Triton X-100, D-αOne or more mixtures in-vitamin E polyethylene glycol succinic acid ester, Emulsifier EL-60, PLURONICS F87, lecithin.
Above-mentioned assistant for emulsifying agent is that assistant for emulsifying agent is one or more mixtures in absolute ethyl alcohol, n-butanol, polyglycerol ester, propane diols, ethylene glycol, glycerine, PEG400.
Above-mentioned gel rubber material is one or more in deacetylated gellan gum, shitosan, PVP and poloxamer188；
Above-mentioned thickener is one or more mixtures in Carbomer, sodium alginate, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, methylcellulose.
The preparation method of above-mentioned eutectic nasal nanometer emulsion in-situ gel：Eutectic is taken as oil phase, oil phase and emulsifying agent and assistant for emulsifying agent are mixed；Water is gradually added in said mixture, vortex oscillation is uniform, makes nano-emulsion；Gel-type vehicle is added in a certain amount of water, gel solution is made；Nano-emulsion is added in gel solution, is well mixed, add water to full dose, the nasal nanometer emulsion in-situ gel of eutectic is obtained.
Nano-emulsion average grain diameter prepared by said method is less than 0.25 in 200 nm or so, PI.
The application of above-mentioned eutectic nasal nanometer emulsion in-situ gel, in collunarium form by nasal-cavity administration, fast transition is gel state to gel preparation after mixing with artificial nose liquid.
Beneficial effects of the present invention：
Present invention comprehensive utilization nano-emulsion and in-situ gel preparation technology, first make nano-emulsion by eutectic, are greatly enhanced the dispersiveness and stability of medicine, promote medicine to pass through mucosal absorption, and then are prepared into situ-gel liquid for collunarium.Situ-gel system is in vitro the fluid of low-viscosity, and the phase in version that solution-gel will occur in physiological conditions, so as to extend holdup time of the preparation in intranasal, be conducive to further improving drug absorption.
The eutectic nasal nanometer emulsion in-situ gel that the present invention is provided, in accordance with original side's usage still can rapidly there is phase in version in nasal cavity and gelation after the administration of collunarium form, but the administration of this preparation, prolongation medicine is in the schneiderian membrance holdup time, the bioavilability of medicine is increased, patient's compliance is good.Compare with common nasal drop with ordinary gel agent, the invention has the advantages that：（1）Directly nano-emulsion is prepared into as oil phase with menthol-camphor eutectic, its average grain diameter is 200
Below nm, and menthol, camphor are respectively provided with good mucosa penetration promotion functions, are conducive to passing through Nasal mucosa absorption；（2）Carry nano-emulsion in-situ gel system viscosity it is little, instill nasal cavity after can umklappen be gel, significantly extend in the nasal cavity holdup time, reduce usage frequency, increase patient's compliance, be easy to use；（3）And the side effect almost nonirritant to nasal cavity such as selected macromolecular material emulsifying agent and assistant for emulsifying agent；（4）This nasal drop storage-stable, uniform content under the conditions of normal temperature and 4 DEG C.
Further, it is emphasized that the present invention following marked improvement technically：1）The present invention greatly improves medicine and acts on through mucosal absorption while essentially identical content of dispersion is kept.2）Instant invention overcomes Compound Menthol Nose Drop（Former preparation）It is difficult that drug content is determined, and is vulnerable to the shortcoming of atoleine interference, can easily establish the method for determining medicine HPLC assays in nano-emulsion gel, have the advantages that test limit it is low, not by other materials interference.3）Instant invention overcomes former preparation volatile shortcoming in placement process, nano-emulsion attached gel technology, unstability that can be with effectively solving medicine in prescription.4）Instant invention overcomes former preparation is in physiological conditions（In nasal cavity）Be easy to run off, the deficiency of absorption difference, greatly improve holdup time of the medicine in nasal cavity, can effectively reduce administration frequency, improve the compliance of patient, its concrete effect may refer to Fig. 8.
The above-mentioned advantage of the present invention is further detailed below in conjunction with accompanying drawing and specific embodiment, however, it will be understood that following specific embodiments will not constitute the restriction intentional to the present invention, the scope of the present invention is defined by the claims.
Description of the drawings
Fig. 1 is the photo before and after the nano-emulsion in-situ gel of embodiment 5 mixes with artificial nose liquid.Wherein A is to add the preparation of embodiment 5 before artificial nose liquid, is working fluid state；B is to add the preparation of embodiment 5 after artificial nose liquid, and Jing measurements are gel of the viscosity more than 5 Pas.
Fig. 2 is that the grain size distribution of nano-emulsion obtained in embodiment 1 and TEM scheme.
Fig. 3 is the nano-emulsion in-situ gel of embodiment 1 and Compound Menthol Nose Drop（Former preparation group）In vitro mucous membrane releasing curve diagram.Wherein menthol-camphor（1:1）The in vitro mucous membrane effect thoroughly of the more former agent in vitro of eutectic nano-emulsion has at least up to 3 times of raising.
Fig. 4 is the nano-emulsion in-situ gel of embodiment 1 and Compound Menthol Nose Drop（Former preparation group）In-vitro release curves.Wherein menthol-camphor（1:1）The more former agent in vitro releasing effect of eutectic nano-emulsion has at least up to 5 times of raising.
Fig. 5 is the nano-emulsion in-situ gel of embodiment 1 and Compound Menthol Nose Drop（Former preparation group）Rat schneiderian membrance irritant experiment H＆E coloring pathological section figures.Wherein A is nano-emulsion group, and B figures are former preparation group, and knowable to figure, nano-emulsion in-situ gel has lower schneiderian membrance excitant.
Fig. 6 is the stability diagram after the nano-emulsion that the eutectic of embodiment 1 is oil phase preparation is centrifuged 30 min under the conditions of 20000 rpm.There it can be seen that the nano-emulsion prepared as oil phase with eutectic is centrifuged 30 under the conditions of 20000 rpm
Min, menthol and camphor form eutectic can be used as oil phase stable existence in nano-emulsion.
It is 465 with particle diameter prepared by identical auxiliary material that Fig. 7 is the nano-emulsion in-situ gel that the particle diameter of embodiment 7 is 135 nm
The nano-emulsion in-situ gel of nm is 5000 at 60 DEG C
Rpm is centrifuged the delamination figure after 30 min.Wherein A particle diameters are 135 nm, and B particle diameters are 465 nm.
Fig. 8 is the nano-emulsion in-situ gel and Compound Menthol Nose Drop of embodiment 1（Former preparation group）Nasal cavity be detained comparing result.A is former preparation group in figure, and B is nano-emulsion in-situ gel group, and from small animal living body imaging experiment result, former preparation is 30 in rat nasal cavity
Substantially without retaining after min, and nano-emulsion in-situ gel is changed into rapidly the larger gel form of viscosity after instilling in rat nasal cavity, 240
Still there is more delay after min, show that the present invention can effectively extend holdup time of the medicine in nasal cavity.
Specific embodiment
Below in conjunction with accompanying drawing technical scheme is described further by embodiment：
Embodiment 1：
2.00 g eutectics are weighed as oil phase, 4.00 are added
G Tween-80s and 2.00
G glycerine is mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 0.50
G deacetylated gellan gums are added into 50 mL deionized waters, add 0.20 g sodium alginates, make gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML is obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 1, design parameter is shown in Table 1.
Embodiment 2：
1.00 g eutectics are weighed as oil phase, 5.00 are added
G Triton X-100s and 5.00 g propane diols are mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；22 g poloxamer188s are added into 50 mL deionized waters, 0.10 g sodium carboxymethylcelluloses are added, gel solution is made；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML is obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 2, design parameter is shown in Table 1.
Embodiment 3：
4.00 g eutectics are weighed as oil phase, 5.00 are added
G Emulsifier EL-60s and 5.00 g PEG400s are mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；0.4g Carbomer974s are added into 50 mL deionized waters, 0.10 g sodium carboxymethylcelluloses are added；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML, obtains final product.Measure nano-emulsion in above-mentioned system and be designated as sample 3, design parameter is shown in Table 1.
Embodiment 4：
2.50 g eutectics are weighed as oil phase, 1.00 are added
g D-α- vitamin E polyethylene glycol succinic acid ester and 3.00 g n-butanols are mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；3.00 g shitosans are placed into dissolving in 50 mL water, 0.50g polyvinylpyrrolidones are added, is stood overnight, obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100 mL, obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 4, design parameter is shown in Table 1.
Embodiment 5：
3.00 g eutectics are weighed as oil phase, 3.50 are added
G lecithin and 3.50 g ethylene glycol are mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 0.50 g deacetylated gellan gums in 50 mL water heating for dissolving, add 0.50
G sodium alginates, stand overnight, and obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML, obtains final product.Measure nano-emulsion in above-mentioned system and be designated as sample 5, design parameter is shown in Table 1.
Embodiment 6：
2.00 g eutectics are weighed as oil phase, 5.33 are added
G Tween 80s and 2.67
G ethanol is mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 20 g poloxamer188s in 50 mL water, 50 DEG C of heating for dissolving add 0.30 g polyvinylpyrrolidones, stand overnight, and obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100 mL, obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 6, design parameter is shown in Table 1.
Embodiment 7：
4.00 g eutectics are weighed as oil phase, 4.00 are added
The polyglycerol ester of g Emulsifier EL-60s 2.00 is mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；0.60 g Carbomers P974 is dissolved in 50 mL water, 1.00 g ethyl celluloses are added, is stood overnight, obtain final product gel solution；Nano-emulsion is added in above-mentioned solution, is well mixed, add water to 100
ML, obtains final product.Measure nano-emulsion in above-mentioned system and be designated as sample 7, design parameter is shown in Table 1.
Embodiment 8：
2.00 g eutectics are weighed as oil phase, 3.00 are added
G PLURONICS F87s and 2.00 g propane diols are mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 0.50 g deacetylated gellan gums in 50 mL water, 90 DEG C of heating for dissolving add 0.20 g sodium alginates, stand overnight, and obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML, obtains final product.Measure nano-emulsion in above-mentioned system and be designated as sample 8, design parameter is shown in Table 1.
Embodiment 9：
2.00 g eutectics are weighed as oil phase, 5.33 are added
G Tween 80s and 2.67
G propane diols is mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 20 g poloxamer188s in 50 mL water, 50 DEG C of heating for dissolving add 1.00 g sodium carboxymethylcelluloses, stand overnight, and obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100 mL, obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 9, design parameter is shown in Table 1.
Embodiment 10：
2 g eutectics are weighed as oil phase, 1.00 g are added
Tween 80 and 2.00
G glycerine is mixed；20 mL water are gradually added in said mixture, are well mixed, make nano-emulsion；By 0.50
G deacetylated gellan gums dissolve under 90 DEG C of water bath conditions in 50 mL water, place to room temperature and add 0.20 g sodium alginates, and 4 DEG C overnight, obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML is obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 10, design parameter is shown in Table 1.
Embodiment 11：
3.00 g eutectics are weighed as oil phase, 1.20 are added
G Triton X-100s and 0.60 g glycerine are mixed；By 1.10
ML water is gradually added in said mixture, is well mixed, and makes nano-emulsion；0.60 g deacetylated gellan gums are dissolved under 90 DEG C of water bath conditions in 50 mL water, is placed to room temperature and is added 0.30 g sodium alginates, 4 DEG C overnight, obtain final product gel solution；Nano-emulsion is added in gel solution, is well mixed, add water to 100
ML is obtained final product.Measure nano-emulsion in above-mentioned system and be designated as sample 11, design parameter is shown in Table 1.
Experimental example 1
Eutectic is tested with the result of extraction or absorption effect contrast of non low eutectic thing
Release in vitro：With freshly prepared artificial nose liquid as dissolution medium, precision measures the compound menthol nano-emulsion coagulant liquid of 4.0 mL in bag filter, and bag filter is placed in conical flask with cover, 50 mL dissolution mediums of addition, the rpm of rotating speed 100,（35 ± 0.5）DEG C, sample in different time points successively, isopyknic dissolution medium is added, miillpore filter filtration, HPLC determines medicament contg.
Mucosal absorption experiment thoroughly：Using drug transdermal diffusion test instrument.Artificial nose liquid is added in reception tank（To reach medicine sink conditions, 5% Tween 80 and 5% glycerine are added）, mucous membrane is fixed between supply chamber and diffuser casing, put temperature（35 ± 0.5）DEG C water-bath constant temperature oscillator in balance, take on 2.5 mL situ-gel uniform fold mucous membranes, rotating speed is 300 rpm, is sampled from reception tank respectively at different time points, and per equal-volume artificial nose liquid is added after sub-sampling, filtering with microporous membrane, HPLC determines medicament contg.
As a result Fig. 3 and Fig. 4 is seen, by experimental result, menthol and camphor are formed and have after eutectic more preferably mucosal absorption effect.By release in vitro and the experiment of external in vitro mucous membrane thoroughly it is found that wherein menthol-camphor（1:1）The in vitro mucous membrane effect thoroughly of the more former agent in vitro of eutectic nano-emulsion has at least up to 3 times of raising；Menthol-camphor（1:1）The more former agent in vitro releasing effect of eutectic nano-emulsion has at least up to 5 times of raising.
Experimental example 2
Different ratio eutectic at 4 DEG C under the conditions of shelf-stability experiment
The menthol of different ratio-camphor eutectic is placed under the conditions of 4 DEG C, it is observed from being placed into the time required to starting crystallization, 2 are the results are shown in Table：
By above-mentioned experiment, menthol and camphor 3:1-1:1（By weight）Eutectic there is more preferably stability, be particularly suitable for application as the oil phase of nano-emulsion.Preferably, menthol-camphor is 7:It is most stable under the conditions of 3.
Experimental example 3
The present inventor is further investigated to the accelerated stability of the semi-finished product nano-emulsion in the sample 1-11 and embodiment 1 prepared by embodiment 1-11.
Each sample is sealed in vial, is placed in（40 ± 2）DEG C, relative humidity（75 ± 5）Under the conditions of %, the outward appearance for investigating each sample changes（Muddy, floating and sedimentation etc.）Time used, the results are shown in Table 3：
From the above it is found that when menthol-camphor eutectic makes situ-gel as the nano-emulsion of oil phase stability more preferably, particularly compared with menthol-nano-emulsion of the camphor eutectic as oil phase, its stability improves more than 40%.
And emulsifying agent is Tween 80, assistant for emulsifying agent is glycerine, gel rubber material is deacetylated gellan gum, the nano-emulsion in-situ gel that thickener is prepared when being sodium alginate, and stability is more preferably.
Claims (10)
1. a kind of nasal nanometer emulsion in-situ gel, it is characterized in that being made up of active component and auxiliary material, wherein active component is made up of menthol and camphor, and menthol and camphor form eutectic, oil phase of the eutectic as nano-emulsion, accessory package contains emulsifying agent, gel rubber material and water, and active component and auxiliary material are by weight：Eutectic 1-4 parts, emulsifying agent 1-10 parts, gel rubber material 0.4-23 parts, water 63-97.6 parts.
2. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that the weight ratio of the menthol and camphor is 3:1-1:1, preferred weight ratio is 7:3.
3. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that also comprising assistant for emulsifying agent 1-5 parts and thickener 0.1-1 parts in the auxiliary material.
4. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that the emulsifying agent is Tween 80, Triton X-100, D- α-One or more in vitamin E polyethylene glycol succinic acid ester, Emulsifier EL-60, PLURONICS F87, lecithin.
5. nasal nanometer emulsion in-situ gel according to claim 3, it is characterised in that：The assistant for emulsifying agent is one or more in absolute ethyl alcohol, n-butanol, polyglycerol ester, propane diols, ethylene glycol, glycerine, PEG400.
6. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that：The gel rubber material is one or more in deacetylated gellan gum, Carbomer P974, shitosan and poloxamer188.
7. nasal nanometer emulsion in-situ gel according to claim 3, it is characterised in that：Thickener is one or more in Carbomer, sodium alginate, hydroxypropyl methyl cellulose, PVP, sodium carboxymethylcellulose, methylcellulose.
8. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that the average grain diameter of the nano-emulsion is less than or equal to 200
Nm, polydispersity index（Polydispersity
Index, PI）<0.25, pH is neutral.
9. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that the average grain diameter of the nano-emulsion is approximately equal to 135
nm。
10. nasal nanometer emulsion in-situ gel according to claim 1, it is characterised in that the situ-gel is in vitro working fluid state, and gel state of the viscosity more than 5 Pas is rapidly converted in nasal cavity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510787922.6A CN106560175B (en) | 2015-11-17 | 2015-11-17 | Menthol-camphor eutectic nanoemulsion in-situ gel preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510787922.6A CN106560175B (en) | 2015-11-17 | 2015-11-17 | Menthol-camphor eutectic nanoemulsion in-situ gel preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106560175A true CN106560175A (en) | 2017-04-12 |
| CN106560175B CN106560175B (en) | 2020-07-14 |
Family
ID=58485453
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510787922.6A Expired - Fee Related CN106560175B (en) | 2015-11-17 | 2015-11-17 | Menthol-camphor eutectic nanoemulsion in-situ gel preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106560175B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110684129A (en) * | 2019-09-10 | 2020-01-14 | 北京理工大学 | Sodium alginate green preparation method based on choline eutectic solvent |
| CN111494316A (en) * | 2020-04-14 | 2020-08-07 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN116036095A (en) * | 2022-09-30 | 2023-05-02 | 华润三九医药股份有限公司 | Preparation method of compound dexamethasone acetate emulsifiable paste |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101524325A (en) * | 2009-04-03 | 2009-09-09 | 龚志成 | Compound menthol microemulsion and preparation for nose |
| CN104800446A (en) * | 2015-05-20 | 2015-07-29 | 宁夏医科大学 | Haheilili-extract nano-emulsion in-situ gel preparation and preparation method thereof |
| CN104997724A (en) * | 2014-04-22 | 2015-10-28 | 北京大学 | Nasal in situ gel delivery system, preparation and applications thereof |
-
2015
- 2015-11-17 CN CN201510787922.6A patent/CN106560175B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101524325A (en) * | 2009-04-03 | 2009-09-09 | 龚志成 | Compound menthol microemulsion and preparation for nose |
| CN104997724A (en) * | 2014-04-22 | 2015-10-28 | 北京大学 | Nasal in situ gel delivery system, preparation and applications thereof |
| CN104800446A (en) * | 2015-05-20 | 2015-07-29 | 宁夏医科大学 | Haheilili-extract nano-emulsion in-situ gel preparation and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| BISWAJIT BISWAL ET AL.: ""Formulation and Evaluation of Microemulsion Based Topical Hydrogel Containing Lornoxicam"", 《JOURNAL OF APPLIED PHARMACEUTICAL SCIENCE》 * |
| WENPING WANG ET AL.: ""Microemulsions based on paeonol-menthol eutectic mixture for enhanced transdermal delivery: formulation development and in vitro evaluation"", 《ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY》 * |
| 刘晨等: ""复方薄荷脑微乳原位凝胶剂的评价"", 《中成药》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110684129A (en) * | 2019-09-10 | 2020-01-14 | 北京理工大学 | Sodium alginate green preparation method based on choline eutectic solvent |
| CN111494316A (en) * | 2020-04-14 | 2020-08-07 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN111494316B (en) * | 2020-04-14 | 2021-05-18 | 山东大学 | Preparation method and application of disulfiram-loaded nano-emulsion in-situ gel |
| CN116036095A (en) * | 2022-09-30 | 2023-05-02 | 华润三九医药股份有限公司 | Preparation method of compound dexamethasone acetate emulsifiable paste |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106560175B (en) | 2020-07-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hao et al. | Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery | |
| FI119498B (en) | Compositions for the treatment of hemorrhoids and method of use | |
| JP3903061B2 (en) | Nanoparticles containing drug, method for producing the same, and preparation for parenteral administration comprising the nanoparticles | |
| Wang et al. | Nano-in-Nano dendrimer gel particles for efficient topical delivery of antiglaucoma drugs into the eye | |
| FR2814074A1 (en) | NEW TOPICAL ESTRO-PROGESTIVE COMPOSITIONS WITH SYSTEMIC EFFECT | |
| EP3160444A1 (en) | A pharmaceutical oil-in-water nano-emulsion | |
| WO2014108076A1 (en) | Gel composition of insoluble drug and preparation method therefor | |
| JP2019501215A (en) | Local film forming spray | |
| JP6207291B2 (en) | Composition for external use | |
| TW201540303A (en) | Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them | |
| CN106560175A (en) | Menthol-camphor eutectic mixture nano-emulsion in situ gel preparation | |
| Dudhipala et al. | Colloidal lipid nanodispersion enriched hydrogel of antifungal agent for management of fungal infections: comparative in-vitro, ex-vivo and in-vivo evaluation for oral and topical application | |
| CN107080745A (en) | A kind of oral instant membrane for carrying lutein albumin nano granular and preparation method thereof | |
| CN104491867A (en) | Preparation method of novel administration system with medicine-carrying montmorillonite wrapped by chitosan | |
| CN114983927A (en) | Temperature-sensitive instant gel system and preparation method and application thereof | |
| EP2745839B1 (en) | Pharmaceutical composition in the form of an oral suspension including a flavonoid fraction and xanthan gum | |
| JPH0768130B2 (en) | Micronized drug | |
| CN109646422A (en) | A kind of preparation method of the ophthalmic administration system of polyacrylic resin package load medicine montmorillonite | |
| JPS6218526B2 (en) | ||
| JP2016222611A (en) | Composition for external preparation | |
| CN114028324A (en) | Rhynchophylline temperature-sensitive gel nasal administration preparation and preparation method thereof | |
| Tavano | Liposomal gels in enhancing skin delivery of drugs | |
| CN106361727A (en) | Bilobalide-PVA nanoparticle and preparation method thereof | |
| KR100979347B1 (en) | Antifungal composition | |
| TW202015700A (en) | Nasal composition comprising fluticasone furoate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Wang Wenping Inventor after: Liu Chen Inventor after: Yang Weijing Inventor after: Su Hong Inventor after: Hu Jin Inventor after: Zhang Qiuju Inventor after: Zhang Licheng Inventor before: Wang Wenping Inventor before: Liu Chen Inventor before: Su Hong Inventor before: Hu Jin Inventor before: Zhang Qiuju Inventor before: Zhang Licheng |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200714 Termination date: 20211117 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |