CN106727308A - A kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof - Google Patents
A kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof Download PDFInfo
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract
The present invention provides a kind of dexamethasone lipid emulsion droplet ocular fluid, and described dexamethasone lipid emulsion droplet ocular fluid is oil-in-water submicron emulsion system, and the lipidic nanoparticles formed by lipid carrier and dexamethasone are coated with the grease in emulsion droplet.It is an object of the invention to provide a kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof, with the infiltration for increasing eye inner tissue's distribution, promoting to intraocular, and then the purpose of safely, effectively treatment intraocular and fundus oculi disease is reached.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof.
Background technology
Dexamethasone is the common drug that Macular lesion is particularly for treating intraocular inflammation, but by traditional eye drip
The therapeutic effect of administration is difficult to enter eye inner tissue by medicine, and abundance is few within the eye, treats intraocular or posterior segment disease
Effect it is not notable.
Therefore, intraocular or posterior segment the disease such as entophthamia such as iris, ciliary body, vitreous hemorrhage or macula retinae venereal disease
The treatment of the diseases such as change, clinic need to be using medications such as intravenous injection or intravitreal injection, conjunctival injections.
But intraocular injection is invasive, and need repeatedly to inject in therapeutic process, under may causing conjunctiva
Scab, adhesion;Injection process is easily stabbed cornea or is caused bleeding, and this undoubtedly increased the risk that entophthamia occurs, once hair
Raw entophthamia, it would be possible to cause the irreversible damage of patient's vision or even forfeiture, this is also the technology for perplexing those skilled in the art
Problem.
The content of the invention
The present invention provides a kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof, to increase eye inner tissue's distribution, promote
Forward to the infiltration of intraocular, and then reach the purpose of safely, effectively treatment intraocular and fundus oculi disease.
In order to solve the above-mentioned technical problem, the technical scheme that the present invention is provided is a kind of such, dexamethasone lipid breast
Eye drops, described dexamethasone lipid emulsion droplet ocular fluid is oil-in-water submicron emulsion system, be coated with the grease in emulsion droplet by
The lipidic nanoparticles that lipid carrier and dexamethasone are formed.
It should be noted that above-mentioned dexamethasone lipid emulsion droplet ocular fluid emulsion droplet average grain diameter is less than 200nm, particle diameter distribution
It is 173 ± 36nm, 90% particle diameter aggregate-value is less than or equal to 500nm.
It should be noted that above-mentioned dexamethasone lipid emulsion droplet ocular fluid component includes following percentage by weight:
It should be noted that above-mentioned lipid carrier be egg yolk lecithin, LIPOID E 80 (refined egg yolk lecithin, its
Middle phosphatidylcholine content is any one 80), in LIPOID S 75 (soybean lecithin), soybean lecithin, hydrogenated soya phosphatide
The mixture of kind or various arbitrary proportions.
It should be noted that above-mentioned grease is medicinal soybean oil, olive oil, injection soybean oil, caprylic/capric glycerine
The mixture of any one or more arbitrary proportion in three esters, medium chain triglyceride.
It should be noted that above-mentioned emulsifying agent is Emulsifier EL-60, the penta hydroxy group stearate of polyethylene glycol ten, gathers
The mixture of any one or more arbitrary proportion in oxygen ethylene hydrogenation castor oil, poloxamer, glycerine, propane diols.
It should be noted that above-mentioned isotonic regulator is any one in glycerine, sodium chloride, mannitol or many
Plant the mixture of arbitrary proportion;PH adjusting agent is using any one in hydrochloric acid, NaOH, phosphate, citrate or many
Plant the mixture of arbitrary proportion;The consumption of described pH adjusting agent is that the pH of the dexamethasone lipid emulsion droplet ocular fluid described in regulation is
5.5~8.
It should be noted that above-mentioned bacteriostatic agent is using any one in benzyl carbinol, sorbic acid or Phenoxyethanol or many
The mixture of arbitrary proportion is planted, the mass concentration of described bacteriostatic agent is 0.75%~1.5%.
A kind of preparation method of dexamethasone lipid emulsion droplet ocular fluid as described above, comprises the following steps:
Step 1:Dexamethasone and lipid carrier are dispersed in volatile organic solvent, being removed under reduced pressure volatile has
Machine solvent, forms the cellular film of dexamethasone lipid carrier, and is scattered in the oil phase formed in grease;
Step 2:By oil phase with have emulsifying agent water mix, emulsification pretreatment, obtain final product dexamethasone lipid emulsion droplet ocular fluid
Colostrum;
Step 3:Appropriate water is added in colostrum to dexamethasone lipid emulsion droplet ocular fluid, is obtained final product.
In the preparation method of above-mentioned dexamethasone lipid emulsion droplet ocular fluid, described step 3 for colostrum through pressure 500~
1200bar's is high-pressure homogeneous, and cycle-index is 3~15 times, and breast is even, obtains lipid breast;Obtained lipid breast filtering with microporous membrane,
Regulation pH, is eventually adding in bacteriostatic agent, borate buffer aqueous solution liquid, the phosphate-buffered aqueous solution or aqueous borate buffer solution
One or more, obtain final product lipid eye drops.
Preferably, step 3 be colostrum through the high-pressure homogeneous of 600~800bar of pressure, cycle-index is 5~10 times, and breast is even,
Obtain lipid breast;Obtained lipid breast filtering with microporous membrane, adjusts pH, is eventually adding recipe quantity bacteriostatic agent, borate buffer water-soluble
One kind in liquid liquid, the phosphate-buffered aqueous solution or aqueous borate buffer solution, obtains final product lipid eye drops.
In the preparation method of above-mentioned dexamethasone lipid emulsion droplet ocular fluid, described volatile organic solvent is by ethanol
With acetone composition, ethanol is 20 with the gross weight of acetone and the volume ratio of lipid carrier:1, the volume ratio 1 of ethanol and acetone:1~
1:3;
It should be noted that the volume ratio of the gross weight of ethanol and acetone and lipid carrier in actual applications and is not needed
It is strictly limited at 20:The gross weight of 1 this value, such as ethanol and acetone is 25g, and the volume of lipid carrier still can be real for 1ml
This programme is applied, ethanol is dexamethasone and egg yolk lecithin is effectively disperseed with the principle of the consumption of acetone.It is right
For those skilled in the art, its rational Application Range is all optional.
In the preparation method of above-mentioned dexamethasone lipid emulsion droplet ocular fluid, in described decompression process, reaction temperature is
40 DEG C, vacuum is -0.07~-0.08MPa.
It should be noted that in actual applications, temperature in decompression process for effect of the invention influence simultaneously
It is not conclusive, reaction temperature can typically be selected as room temperature or slightly above and below such as 20-40 DEG C of the temperature of room temperature is all
It is optional, is also not precluded from certainly and temperature higher.The temperature that depressurized in the present invention and decompression time are closely related, temperature
Degree is higher, and vacuum is closer to vacuum, and its decompression time is shorter, in actual mechanical process, controls rational temperature to make volatilization
Property solvent can be volatilized with the speed of stabilization, the too high caused solution bumping of temperature should be avoided.
Beneficial effects of the present invention:
The present invention is combined medicine with amphipathic phosphatide, can disperse to form independent nano-particle, with life
Thing adhesion.The oil phase in oil-in-water type Submicron Emulsion is contained, the microstructure similar to tear film can be formed, can be promoted
Enter medicine and pass through membranes barriers.Due to lipid nano particle and the unique structure of oil-in-water type Submicron Emulsion, can lentamente discharge
Go out the medicine of encapsulating, increase distribution that medicine organizes within the eye, the infiltration for promoting to intraocular, and then reach and safely, effectively treat
The purpose of intraocular and fundus oculi disease.
Therefore, by a kind of dexamethasone lipid emulsion droplet ocular fluid of present invention preparation compared with commercially available eye drops, within the eye
Holdup time is obviously prolonged, and each Tissue of intraocular is significantly improved, and can pass it through the medication amount increasing of intraocular barrier
Plus, it is not only advantageous for improving intraocular drug concentration, and intraocular or posterior segment disease can also be treated by eye drip mode.
Brief description of the drawings
Fig. 1 is the grain size distribution of embodiment 1;
Fig. 2 is the grain size distribution of embodiment 2;
Fig. 3 is the grain size distribution of embodiment 3;
Fig. 4 is the Zeta potential figure of embodiment 1;
Fig. 5 is the Zeta potential figure of embodiment 2;
Fig. 6 is the Zeta potential figure of embodiment 3;
Fig. 7 is the tissue examination figure of the blank of embodiment 1;
Fig. 8 is the tissue examination figure of the blank of embodiment 2;
Fig. 9 is the tissue examination figure of the blank of embodiment 3;
Figure 10 is the tissue examination figure of the blank of commercially available control group;
Figure 11 is the tissue examination figure by test preparation of embodiment 1;
Figure 12 is the tissue examination figure by test preparation of embodiment 2;
Figure 13 is the tissue examination figure by test preparation of embodiment 3;
Figure 14 is the tissue examination figure by test preparation of commercially available control group;
Figure 15 is the accumulative infiltration spirogram of the isolated cornea of embodiment 1-3 and commercially available control group;
Figure 16 is distribution map of each time point medicine of embodiment 1-3 and commercially available control group in cornea tissue;
Figure 17 is distribution map of each time point medicine of embodiment 1-3 and commercially available control group in scleral tissue;
Figure 18 is distribution map of each time point medicine of embodiment 1-3 and commercially available control group in vitreum tissue;
Figure 19 is distribution map of each time point medicine of embodiment 1-3 and commercially available control group in lens tissue;
Figure 20 is the pharmaceutical concentration-time curve figure of embodiment 1-3 and commercially available control group.
Specific embodiment
With reference to specific embodiment, technical scheme is described in further detail, but do not constitute it is right
Any limitation of the invention.
Embodiment 1
Preparation method:Take recipe quantity egg yolk lecithin PL-100M and dexamethasone is dissolved in ethanol and acetone (1:1, v/v)
Mixed solvent in, mixed solvent is 200g;40 DEG C of solvent removed by evaporation at reduced pressure form the mixture of medicine and phosphatide, and this is mixed
Compound forms oil phase in being dispersed to the medicinal soybean oil of recipe quantity, separately take recipe quantity PLURONICS F87 emulsifying agent be dissolved in it is suitable
In amount water, then the aqueous solution containing glycerine is mixed with oil phase, 800rpm emulsification pretreatment 10min, both obtain colostrum.Regulation high pressure
The secondary valve pressure of homogenizer is 200~300bar, and homogeneous 2min makes the more uniform of the distribution of particles for having refined, then adjusts one
Between 500~600bar of step valve, 10 homogeneous treatment are circulated, make material fully in valve element, valve seat and impact ring three composition
Produced in narrow regions it is similar it is quick-fried how the strong hole effect of effect, simultaneous material is narrow by valve element and valve base chamber
Stitch the high-speed impact effect of the shear action and impact ring shock generation for producing so that whole system obtains micronization, treats
After high pressure homogenization terminates, between regulation pH to 6.5~7.8, benzyl carbinol is added, lead to nitrogen, low capacity ampoule fusion sealing, 100 DEG C of streams
30~45min of logical steam sterilizing, obtains final product dexamethasone lipid emulsion droplet ocular fluid.
Embodiment 2
Preparation method:Take recipe quantity LIPOID E 80 and dexamethasone is dissolved in ethanol and acetone (1:3, v/v) mixing
In solvent, mixed solvent is 100g;40 DEG C of solvent removed by evaporation at reduced pressure form the mixture of medicine and phosphatide, by the mixture point
It is dissipated in the medicinal soybean oil of recipe quantity and forms oil phase, the Solutol HS15 emulsifying agents for separately taking recipe quantity is dissolved in suitable quantity of water
In, then the aqueous solution containing emulsifying agent is mixed with oil phase, 800rpm emulsification pretreatment 10min, both obtain colostrum.Regulation is high-pressure homogeneous
The secondary valve pressure of machine is 200~300bar, and homogeneous 2min makes the more uniform of the distribution of particles for having refined, then adjusts one-step valve
Between 500~600bar, 10 homogeneous treatment are circulated, make material fully in the narrow and small of valve element, valve seat and impact ring three composition
The strong hole effect of similar explosion effect is produced in region, simultaneous material is produced by the slit of valve element and valve base chamber
Raw shear action and impact ring clash into the high-speed impact effect for producing so that whole system obtains micronization, treats high pressure
After homogeneous end, between regulation pH to 6.5~7.8, sorbic acid is added, lead to nitrogen, low capacity ampoule fusion sealing, 100 DEG C of circulations are steamed
Vapour 30~45min of sterilizing, obtains final product dexamethasone lipid emulsion droplet ocular fluid.
Embodiment 3
Preparation method:Take recipe quantity LIPOID S 75 and dexamethasone is dissolved in ethanol and acetone (1:2, v/v) mixing
In solvent, mixed solvent is 140g;40 DEG C of solvent removed by evaporation at reduced pressure form the mixture of medicine and phosphatide, by the mixture point
It is dissipated in the medicinal soybean oil of recipe quantity and forms oil phase, the Cremophor EL emulsifying agents for separately taking recipe quantity is dissolved in suitable quantity of water
In, then the aqueous solution containing emulsifying agent is mixed with oil phase, 800rpm emulsification pretreatment 10min, both obtain colostrum.Regulation is high-pressure homogeneous
The secondary valve pressure of machine is 200~300bar, and homogeneous 2min makes the more uniform of the distribution of particles for having refined, then adjusts one-step valve
Between 500~600bar, 10 homogeneous treatment are circulated, make material fully in the narrow and small of valve element, valve seat and impact ring three composition
Produced in region it is similar it is quick-fried how the strong hole effect of effect, simultaneous material produced by the slit of valve element and valve base chamber
Raw shear action and impact ring clash into the high-speed impact effect for producing so that whole system obtains micronization, treats high pressure
After homogeneous end, between regulation pH to 6.5~7.8, plus Phenoxyethanol, lead to nitrogen, low capacity ampoule fusion sealing, 100 DEG C of circulations are steamed
Vapour 30~45min of sterilizing, obtains final product dexamethasone lipid emulsion droplet ocular fluid.
Illustrated by following experiment the formulation characteristics of dexamethasone lipid emulsion droplet ocular fluid in the present invention, Ocular irritation and
Its enhanced characteristic of corneal permeability compared with conventional formulation.
1. particle diameter and current potential
Trial drug:Dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention;
Experimental technique:
Take dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention suitably to be diluted with deionized water in right amount, using granularity
Delsa Nano C laser particle analyzers are determined, and automatically adjust instrument luminous intensity in 10000ICP or so, and temperature control dissipates at 25 DEG C
Firing angle degree is 165 °, determines its particle diameter distribution and current potential intensity.
Test result:
The grain size distribution of embodiment 1-3 is shown in Fig. 1-Fig. 3;Wherein, in Fig. 1-Fig. 3, abscissa Diameter (nm) table
Show diameter (nm), ordinate (left side) Differential Intensity (%) is laser intensity;Ordinate (right side)
Cumulative Intensity (%) are accumulative intensity (%).
The Zeta potential figure of embodiment 1-3 is shown in Fig. 4-Fig. 6;Wherein, in Fig. 4-Fig. 6, abscissa (on) Frequency
(Hz) it is the frequency (Hz) of electric potential signal appearance;Ordinate Intensity is electric potential signal intensity;Abscissa (under) Zeta
Potential (mV) is current potential (mV).
The polydispersity index (PDI) of embodiment 1-3 is shown in Table -1:
The polydispersity index of the embodiment of table -1 1-3
Project | Embodiment 1 | Embodiment 2 | Embodiment 3 |
PDI | 0.103±0.012 | 0.176±0.27 | 0.119±0.017 |
2. excitant evaluation
Trial drug:Dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention, embodiment 1, embodiment 2, embodiment 3 and city
Sell eye drops (Containing dexamethasone, TOB compound preparation) control group, each dosage is 100 μ l;
Experimental animal:Cleaning grade NZw 12, male and female half and half, 2.5~3.5kg of body weight is (big purchased from southern medical courses in general
Learn Experimental Animal Center);
Animal feeding environment:20 DEG C, RT30%~70%, artificial light rays, 12 hours daylight, 12 hours dark;
Experimental animal quality certification number:NO.44002100003592;
Experimental technique:Using consubstantiality Self-control method, 0.1mL trial drugs instillation conjunctiva of right eye is intracapsular, and left eye is instilled
Lactated Ringer's parenteral solution is used as control.Make eyes passively 5~10s of closure after administration.Three times a day, successive administration 7 days, observation is every
Before secondary administration and last time be administered after (1,2,4,24,48 and 72h) when cornea, iris, the physiological conditions of conjunctiva, according to
Draize experiment tables are scored, and are calculated each group and are received test preparation score.After excitant evaluation last dose observation terminates, ear edge is quiet
Arteries and veins injection air puts to death rabbit, takes respectively to group and tested group of eyeball, and after fixing 48h with 4% paraformaldehyde solution, paraffin is cut
Piece, HE (hematoxylin-eosin) dyeing, neutral gum mounting amplifies suitable multiple and checks respectively for control group and tested under microscope
Group iris, cornea, the tissue such as retina, observation basal cell and epithelial cell form, eosinocyte, neutrophil cell and
The tissue morphology of mast cell, it is impregnated with without change.
Experimental result:During administration and after last dose, visually observe rabbit cornea and had no without muddiness, iris and conjunctiva
The anomalies such as redness, hyperemia.Eyeball tissue is cut into slices as shown in Fig. 7-Figure 14, compared with control group, exposed to different preparations
Tissue is not significantly changed.Tested group of epithelial cell form of basis of microscopic observation is normal, lymphoid tissue, leucocyte in matrix
Normally, there are not the phenomenons such as morphologic change, neutrophil cell infiltration.
3. isolated cornea permeability is evaluated
Trial drug:Dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention, embodiment 1, embodiment 2, embodiment 3 and city
Eye drops control group is sold, each dosage is 100 μ l;
Evaluation method:Using the vertical diffusion cells of improved Franz, diffusing opening diameter 8mm, effective diffusion area is
0.5024cm2, reception pool volume is 6mL.Fresh in vitro cornea is carefully fixed on the supply pool and reception tank of Franz diffusion cells
Between, make epithelial layer towards supply pool.Reception medium is filled in reception tank, precision pipettes sample in supply pool, and film seal is prevented
Only moisture evaporation.Diffusion cell is placed on percutaneous dispersion test instrument, adjusts 34 ± 1 DEG C of temperature, and rotating speed is 200rpm, is taken in time point
Sample 2ml, HPLC measure, calculates the transmission parameter of dexamethasone.
Experimental result:Be fitted for Q and time of penetration t as shown in figure -15 by different time points isolated cornea Percutaneous permeability Q
Equation, calculates apparent permeability coefficients.As shown in table -2, the apparent permeability coefficients of dexamethasone lipid emulsion droplet ocular fluid in embodiment
PappThere is significant difference (P < 0.05) compared with solution control group, lipid eye drops can produce significant rush for dexamethasone
The effect of oozing.
The isolated cornea of table -2 passes through parameter
4. ocular tissue's distribution research
Trial drug:Dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention, embodiment 1, embodiment 2, embodiment 3 and city
Eye drops control group is sold, each dosage is 100 μ l.
Administration design:Rabbit is randomly divided into 3 groups, and every group 5, every group gives different preparations.12h starts to prohibit before experiment
Food, but normal water.During administration, rabbit eyelid is strutted respectively and is respectively dropped into trial drug in images of left and right eyes using micro syringe
100 μ l, force rabbit catacleisis to make drug distribution uniform in about 15 seconds.
Sample collection:After behind 0.75,1.5,3,6 and 9h time points, eyeball is won, filter is rinsed and used with lactated Ringer's solution
Paper suck dry moisture, isolated cornea, sclera, vitreum and crystalline lens, precise weighing determines each time point medicine using Re-HPLC
Concentration.
Experimental result:Square preparation is shown in Figure 16~Figure 19 in the distribution situation that eye is respectively organized at difference.The eye of embodiment
Tissue distribution amount is substantially higher than commercially available eye drops.
Due to the addition of biocompatible phospholipids, the permeability of insoluble drug dexamethasone is changed, with commercially available eye drip
Liquid phase can improve the abundance that medicine is distributed in part tissue of eye than lipid breast, be that its treatment posterior segment disease lays the foundation.
5. medicine Annual distribution in aqueous humor
Trial drug:Dexamethasone lipid emulsion droplet ocular fluid disclosed by the invention, embodiment 1, embodiment 2, embodiment 3 and city
Eye drops control group is sold, each dosage is 100 μ l.
Administration design:Using ceratocentesis, rabbit is randomly divided into 3 groups, and every group 3, every group gives different preparations.It is real
Preceding 12h is tested to be fasted, but normal water.During administration, rabbit eyelid is strutted respectively and uses micro syringe to distinguish in images of left and right eyes
The μ l of trial drug 100 are instilled, forces rabbit catacleisis to make drug distribution uniform in about 15 seconds.
Sample collection:After behind 0.75,1.5,3,6 and 9h time points, the μ L of aqueous humor 100 are extracted, when determining each using Re-HPLC
Between put drug concentration.
Pharmacokinetic parameters are calculated using statistics moments method, such as pharmaceutical concentration-time curve in -20 aqueous humors of figure can be seen that
After eye drop administration, due to medicine into need before aqueous humor the dexamethasone passed through in cornea, therefore aqueous humor have a non-vein to
The absorption process of medicine approach, the time up to Cmax is relatively slow.Result shows, the peak of lipid emulsion droplet ocular fluid group in embodiment
Concentration is significantly higher than commercially available eye drops control group, and lipid emulsion droplet ocular fluid prepared by the present invention is conducive to dexamethasone suction within the eye
Receive.
The present invention has advantages below compared with conventional method:
1. the present invention is combined medicine with amphipathic phosphatide, can disperse to form independent nano-particle, is had
Bioadhesive.The oil phase in oil-in-water type Submicron Emulsion is contained, the microstructure similar to tear film can be formed, can
Medicine is promoted to pass through membranes barriers.Due to lipid nano particle and the unique structure of oil-in-water type Submicron Emulsion, can lentamente release
The medicine of encapsulating is released, increases the distribution that medicine is organized within the eye, the infiltration for promoting to intraocular, and then reached and safely, effectively control
Treat the purpose of intraocular and fundus oculi disease.
2. it is detained within the eye compared with commercially available eye drops by a kind of dexamethasone lipid emulsion droplet ocular fluid of present invention preparation
Time is obviously prolonged, and each Tissue of intraocular is significantly improved, and can pass it through the medication amount increase of intraocular barrier, no
Only it is beneficial to improve intraocular drug concentration, and intraocular or posterior segment disease can also be treated by eye drip mode
3. the present invention is used using the dexamethasone lipid emulsion droplet ocular fluid that film dispersion-high-pressure homogeneous technique is prepared
Laser particle size method measures average grain diameter less than 200nm, and between 173 ± 36nm, D90 is less than 500nm, system to particle size distribution range
Emulsion droplet surface institute is negatively charged, and zeta potential value is in-(50 ± 10) mV, and system stability is good.
It is above-described be only presently preferred embodiments of the present invention, it is all made in the range of the spirit and principles in the present invention appoint
What modification, equivalent and improvement etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of dexamethasone lipid emulsion droplet ocular fluid, it is characterised in that described dexamethasone lipid emulsion droplet ocular fluid is oil-in-water
Submicron emulsion system, is coated with the lipidic nanoparticles formed by lipid carrier and dexamethasone in the grease in emulsion droplet.
2. dexamethasone lipid emulsion droplet ocular fluid according to claim 1, it is characterised in that described dexamethasone lipid breast
Eye drops emulsion droplet average grain diameter is less than 200nm, and particle diameter distribution is 173 ± 36nm, and 90% particle diameter aggregate-value is less than or equal to 500nm.
3. dexamethasone lipid emulsion droplet ocular fluid according to claim 1 and 2, it is characterised in that described dexamethasone fat
Matter emulsion droplet ocular fluid component includes following percentage by weight:
4. dexamethasone lipid emulsion droplet ocular fluid according to claim 3, it is characterised in that described lipid carrier is yolk
Any one or more any ratio in lecithin, LIPOID E 80, LIPOID S 75, soybean lecithin, hydrogenated soya phosphatide
The mixture of example.
5. dexamethasone lipid emulsion droplet ocular fluid according to claim 3, it is characterised in that described grease is medicinal soybean
Any one or more any ratio in oil, olive oil, injection soybean oil, caprylic/capric triglyceride, medium chain triglyceride
The mixture of example.
6. dexamethasone lipid emulsion droplet ocular fluid according to claim 3, it is characterised in that described emulsifying agent is polyoxy second
In alkene castor oil, the penta hydroxy group stearate of polyethylene glycol ten, Crodaret, poloxamer, glycerine, propane diols
Any one or more arbitrary proportion mixture;
Described isotonic regulator is the mixing of any one or more arbitrary proportion in glycerine, sodium chloride, mannitol
Thing;PH adjusting agent uses the mixing of any one or more arbitrary proportion in hydrochloric acid, NaOH, phosphate, citrate
Thing;The consumption of described pH adjusting agent is that the pH of the dexamethasone lipid emulsion droplet ocular fluid that can adjust described is 5.5~8;
Described bacteriostatic agent uses the mixing of any one or more arbitrary proportion in benzyl carbinol, sorbic acid or Phenoxyethanol
Thing, the mass concentration of described bacteriostatic agent is 0.75%~1.5%.
7. a kind of preparation method of dexamethasone lipid emulsion droplet ocular fluid as claimed in claim 3, it is characterised in that including following
Step:
Step 1:Dexamethasone and lipid carrier are dispersed in volatile organic solvent, are removed under reduced pressure volatile organic molten
Agent, forms the cellular film of dexamethasone lipid carrier, and is scattered in the oil phase formed in grease;
Step 2:By oil phase with have emulsifying agent water mix, emulsification pretreatment, obtain final product dexamethasone lipid emulsion droplet ocular fluid just
Breast;
Step 3:Appropriate water is added in colostrum to dexamethasone lipid emulsion droplet ocular fluid, is obtained final product.
8. the preparation method of dexamethasone lipid emulsion droplet ocular fluid according to claim 7, it is characterised in that step 3 is first
Through the high-pressure homogeneous of 500~1200bar of pressure, cycle-index is 3~15 times to breast, and breast is even, obtains lipid breast;Obtained lipid breast is used
Filtering with microporous membrane, adjusts pH, is eventually adding bacteriostatic agent, buffer, obtains final product lipid eye drops.
9. the preparation method of dexamethasone lipid emulsion droplet ocular fluid according to claim 8, it is characterised in that step 3 is first
Through the high-pressure homogeneous of 600~800bar of pressure, cycle-index is 5~10 times to breast, and breast is even, obtains lipid breast;Obtained lipid breast is used
Filtering with microporous membrane, adjusts pH, is eventually adding recipe quantity bacteriostatic agent, buffer, obtains final product lipid eye drops.
10. the preparation method of dexamethasone lipid emulsion droplet ocular fluid according to claim 7, it is characterised in that:Described waves
The organic solvent of hair property is made up of ethanol and acetone, and ethanol is 20 with the gross weight of acetone and the volume ratio of lipid carrier:1, second
The volume ratio 1 of alcohol and acetone:1~1:3;
In described decompression process, reaction temperature is 40 DEG C, and vacuum is -0.07~-0.08MPa.
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CN111249442A (en) * | 2019-10-09 | 2020-06-09 | 沈阳药科大学 | Lipid nanocapsule eye drops and preparation method thereof |
CN112823784A (en) * | 2019-11-20 | 2021-05-21 | 湖北远大天天明制药有限公司 | Prenoxinate sodium eye drops and solution for ocular administration |
CN116077669A (en) * | 2022-12-15 | 2023-05-09 | 中南大学湘雅医院 | Glucocorticoid nano-lipid carrier for treating arthralgia, preparation method and application thereof |
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CN112823784A (en) * | 2019-11-20 | 2021-05-21 | 湖北远大天天明制药有限公司 | Prenoxinate sodium eye drops and solution for ocular administration |
CN112823784B (en) * | 2019-11-20 | 2022-09-16 | 湖北远大天天明制药有限公司 | Prenoxinate sodium eye drops and solution for ocular administration |
CN116077669A (en) * | 2022-12-15 | 2023-05-09 | 中南大学湘雅医院 | Glucocorticoid nano-lipid carrier for treating arthralgia, preparation method and application thereof |
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