CN108066315A - Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof - Google Patents
Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof Download PDFInfo
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- CN108066315A CN108066315A CN201610995593.9A CN201610995593A CN108066315A CN 108066315 A CN108066315 A CN 108066315A CN 201610995593 A CN201610995593 A CN 201610995593A CN 108066315 A CN108066315 A CN 108066315A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
Abstract
The invention discloses Puerarins and scutellarin lipid nano particle eye-drops preparations and preparation method thereof, are prepared as：(1) matrix material is taken, scutellarin adds ethyl alcohol to dissolve, and obtains the first oil phase；Distilled water is the first water phase；(2) lecithin and cholesterol are taken, adds in methanol/ethanol mixed liquor ultrasonic dissolution, solubilizer is added in, obtains the second oil phase；Puerarin, stabilizer, penetration enhancer and cationic materials are added in phosphate buffer and stirred to being completely dissolved again, obtain the second water phase；(3) the first oil phase is added in the first water phase, stirring obtains the first colostric fluid；Second oil phase is added in the second water phase, stirring obtains the second colostric fluid；(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, cooled down, obtain mixing colostrum liquid；(5) ultrasound to get.There is the preparation of the present invention huge film surface to accumulate, and Drug loading capacity is strong；With good biocompatibility.With higher bioadhesive.
Description
Technical field
The present invention relates to field of medicaments, and in particular to Puerarin and scutellarin lipid nano particle eye-drops preparations and its preparation
Method.
Background technology
Cataract is that muddiness occurs for crystalline lens in eyes, becomes opaque by transparent, light is hindered to enter intraocular, so as to shadow
Eyesight is rung.Initial stage muddiness is little to eyesight influence, then gradually aggravates, hence it is evident that affects vision and even blinds.Worldwide
Cataract is the primary cause of disease of blinding, and about 20,000,000 people are blinding due to cataract in the world now, separately have 100,000,000 it is white in
Barrier patient needs surgery recovery eyesight, and the half of blind person is at least accounted in most Africa and Asian countries, cataract.Modern medicine
Pharmacological research shows Puerarin and scutellarin is natural non-selective calcium ion channel blocker, have it is very strong it is anti-inflammatory,
Anti-oxidant, anti-fibrosis reduces intraocular pressure, immunosuppressive action.Inhibiting inflammation of eye section reaction, prevention cataract increases
Wide application prospect is shown in the eye disease such as natural disposition vitreoretinopathy, retinoblastoma.
As what the development of biopharmacy and ocular pharmacokinetics were studied deepens continuously, the experimental results show
Traditional eye-drops preparations such as eye drops applies eye agent, collyrium, eye ointment etc., there are drug dose loss is big, visual acuity is poor,
The problems such as bioavilability is low.Especially for the eye disease for needing long-term treatment, also it is difficult to reach long-acting mesh even if Reusability
, it is also possible to cause Ocular irritation and general toxic reaction using high concentration medicine.
The content of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of Puerarin and scutellarin lipid nano particle eye
Use preparation.
Second object of the present invention is to provide the preparation of a kind of Puerarin and scutellarin lipid nano particle eye-drops preparations
Method.
Technical scheme is summarized as follows:
The preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, includes the following steps：
(1) matrix material is taken, scutellarin adds in solvent absolute ethyl alcohol, is heated to 50-70 DEG C, dissolves under stiring, obtain
Homogeneous first oil phase；Distilled water is the first water phase；
(2) it is another to take lecithin and cholesterol, methanol/ethanol mixed liquor ultrasonic dissolution is added in, and solubilizer is added in, it obtains homogeneous
Second oil phase；Puerarin, stabilizer, penetration enhancer and cationic materials are added in into the phosphate-buffered that pH is 6.0-7.0 again
It is stirred in liquid to being completely dissolved, obtains the second water phase；
(3) the first oil phase is added in the first water phase, stirs 1-2h under 200-400rpm, obtain the first colostric fluid；Again will
Second oil phase is added in the second water phase, is stirred 1-2h under 200-400rpm, is obtained the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, mixed
Close colostric fluid；
(5) under conditions of power 300-450W, by mixing colostrum liquid ultrasound 3-10min to get Puerarin and oil lamp second
Plain lipid nano particle eye-drops preparations.
Preferably：The ratio of each raw material is preferably：Matrix material 20-42mg, scutellarin 1mg, stabilizer 4-12mg,
Lecithin 1mg, cholesterol 1mg, solubilizer 1mL, Puerarin 1mg, penetration enhancer 0.1-0.5mg and cationic materials 12-
20mg。
Matrix material be preferably glyceryl monooleate, glyceryl monolinoleate, two glyceryl oleates, phosphatidyl-ethanolamine,
Two sub- oleoylphosphatidyl ethanolamines, 1-palmitoyl-2-oleoylphosphatidylcholine, dimyristoyl phosphatidyl choline, phytantriol
One or more of.
Stabilizer is preferably one or both of pluronic F127 and polyvinyl alcohol mixture.
Preferably, the volume ratio of methanol/ethanol is 1：1.
Solubilizer is preferably Tween 80, polyethylene glycol 400, one or more of glycerine.
Penetration enhancer be preferably Gelucire 44/14, Labrasol, Solutol HS 15, Transcutol P,
One or more of Transcutol HP mixture.
Cationic materials are preferably carboxymethyl chitosan, octadecyl carboxymethyl chitosan quaternary ammonium salt and hydroxypropyl chitosan
One or more of.
Puerarin and scutellarin lipid nano particle eye-drops preparations prepared by the above method.
Advantages of the present invention：
Advantages of the present invention：
(1) there is preparation of the invention huge film surface to accumulate, and Drug loading capacity is strong；Can simultaneously encapsulating hydrophilic, lipophilic
Property and amphipathic drug molecule, hydrophilic medicament are encapsulated in the water channel of nanoparticle, and lipophilic drugs are encapsulated in the fat of nanoparticle
In matter duplicature.
(2) Puerarin and scutellarin lipid nano particle eye have the microstructure similar with biomembrane, degradation in vivo
For glycerine and aliphatic acid, there is good biocompatibility.
(3) cationic materials prepared in material have higher bioadhesive, are suitable as local mucosal drug delivery system
The carrier of system.
(4) Puerarin and scutellarin lipid nano particle belong to self-stabilization dispersion, and the long-time stability of preparation are higher.
(5) administration number of times can be reduced, improves the compliance of patient medication.
(6) play an important role of to encapsulate and protect drug, increase solubility, improving stability and promote drug absorption.
(7) conventional method can be used to sterilize, preparation process is relatively easy.
Description of the drawings
Fig. 1 is Puerarin and scutellarin lipid nano particle particle size results figure.
Fig. 2 is that rhodamine B lipid nano particle preparation and rhodamine B solution are detained result figure in the eye of different time points.
Wherein Fig. 2 a are rhodamine B solution；Fig. 2 b be rhodamine B lipid nano particle preparation, M1：Anterior corneal surface, M2：Inner eye corner.
Fig. 3 is that (pH of Puerarin and scutellarin is 6.8 phosphorus for Puerarin lipid nano particle eye-drops preparations and drug solution
Acid buffering salting liquid) Drug-time curve in aqueous humor；
Fig. 4 is that (pH of Puerarin and scutellarin is 6.8 for scutellarin lipid nano particle eye-drops preparations and drug solution
Phosphate buffered saline solution) Drug-time curve in aqueous humor.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated.
Gelucire 44/14, Labrasol, Solutol HS 15, Transcutol P, Transcutol HP are by method
Gattefosse SAS groups of state sell.
Embodiment 1
The preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, includes the following steps：
(1) 32.0mg glyceryl monooleates are taken, 1mg scutellarins add in 1mL solvent absolute ethyl alcohols, are heated to 60 DEG C,
The lower dissolving of stirring, obtains homogeneous first oil phase；Distilled water is the first water phase；
(2) another to take 1mg lecithin and 1mg cholesterol, it is 1 to add in 1mL volume ratios:1 methanol/ethanol mixed liquor ultrasound is molten
Solution, and 1mL Tween 80s are added in, obtain homogeneous second oil phase；Again by 1mg Puerarins, 4.44mg pluronics F127,0.5mg
Gelucire 44/14 and 20mg octadecyls carboxymethyl chitosan quaternary ammonium salt are added in the phosphate buffer that 2mL pH are 6.8
Stirring obtains the second water phase to being completely dissolved；
(3) the first oil phase is added in the first water phase, stirs 2h under 400rpm, obtain the first colostric fluid；Again by the second oil
It is added in the second water phase, 2h is stirred under 400rpm, obtain the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, mixed
Close colostric fluid；
(5) under conditions of power 450W, by mixing colostrum liquid ultrasound 5s, 5s is spaced, ultrasound 5min is to get Puerarin altogether
With scutellarin lipid nano particle eye-drops preparations.
Puerarin and scutellarin lipid nano particle eye-drops preparations prepared by Example 1 measures grain by particle size determination instrument
Footpath is distributed, average grain diameter 181nm.See Fig. 1.
Embodiment 2
The preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, includes the following steps：
(1) take 15mg glyceryl monolinoleates, bis- glyceryl oleates of 15mg, 1mg scutellarins add in 0.67mL solvents without
Water-ethanol is heated to 50 DEG C, dissolves under stiring, obtains homogeneous first oil phase；Distilled water is the first water phase；
(2) another to take 1mg lecithin and 1mg cholesterol, it is 1 to add in 1mL volume ratios:1 methanol/ethanol mixed liquor ultrasound is molten
Solution, and 1mL glycerine is added in, obtain homogeneous second oil phase；Again by 1mg Puerarins, 4.44mg pluronics F127,0.3mg
Labrasol and 20mg hydroxypropyl chitosans add in 2mL pH to be stirred in 7.0 phosphate buffers to being completely dissolved, and obtain the
Two water phases；
(3) the first oil phase is added in the first water phase, stirs 1h at 200 rpm, obtain the first colostric fluid；Again by the second oil
It is added in the second water phase, stirs 1h at 200 rpm, obtain the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, mixed
Close colostric fluid；
(5) under conditions of power 300W, by mixing colostrum liquid ultrasound 5s, 5s is spaced, ultrasound 3min is to get Puerarin altogether
With scutellarin lipid nano particle eye-drops preparations.
Embodiment 3
The preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, includes the following steps：
(1) the sub- oleoylphosphatidyl ethanolamine of 10mg phosphatidyl-ethanolamines, 20mg bis-, 12mg 1- palmityl -2- oleoyl phosphorus are taken
Phosphatidylcholine, 1mg scutellarins add in 1.66mL solvent absolute ethyl alcohols, are heated to 60 DEG C, dissolve under stiring, obtain homogeneous first
Oil phase；Distilled water is the first water phase；
(2) another to take 1mg lecithin and 1mg cholesterol, it is 1 to add in 1mL volume ratios:1 methanol/ethanol mixed liquor ultrasound is molten
Solution, and 1mL polyethylene glycol 400s are added in, obtain homogeneous second oil phase；Again by 1mg Puerarins, 12mg pluronics F127,0.2mg
Solutol HS 15 and 20mg carboxymethyl chitosans are added in the phosphate buffer that pH is 6.0 and stirred to being completely dissolved, and are obtained
Second water phase；
(3) the first oil phase is added in the first water phase, stirs 2h at 200 rpm, obtain the first colostric fluid；Again by the second oil
It is added in the second water phase, stirs 2h at 200 rpm, obtain the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, mixed
Close colostric fluid；
(5) under conditions of power 400W, by mixing colostrum liquid ultrasound 5s, 5s is spaced, ultrasound 10min is to get pueraria lobata altogether
Element and scutellarin lipid nano particle eye-drops preparations.
Embodiment 4
The preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, includes the following steps：
(1) 10mg dimyristoyl phosphatidyl cholines, 10mg phytantriols, 1mg scutellarins is taken to add in 0.83mL solvents
Absolute ethyl alcohol is heated to 70 DEG C, dissolves under stiring, obtains homogeneous oil phase；Distilled water is the first water phase；
(2) another to take 1mg lecithin and 1mg cholesterol, it is 1 to add in 1mL volume ratios:1 methanol/ethanol mixed liquor ultrasound is molten
Solution, and 0.5mL Tween 80s and 0.5mL polyethylene glycol 400s are added in, obtain homogeneous second oil phase；Again by 1mg Puerarins, 2mg Pu Langni
Gram F127,2mg polyvinyl alcohol, (mass ratio of Transcutol P and Transcutol HP are 1 to 0.1mg penetration enhancers:1),
6mg octadecyls carboxymethyl chitosan quaternary ammonium salt, 6mg hydroxypropyl chitosans are added in the phosphate buffer that 2mL pH are 7.0
Stirring obtains the second water phase to being completely dissolved；
(3) the first oil phase is added in the first water phase, stirs 1h under 400rpm, obtain the first colostric fluid；Again by the second oil
It is added in the second water phase, 1h is stirred under 400rpm, obtain the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, mixed
Close colostric fluid；
(5) under conditions of power 400W, by mixing colostrum liquid ultrasound 5s, 5s is spaced, ultrasound 10min is to get pueraria lobata altogether
Element and scutellarin lipid nano particle eye-drops preparations.
Embodiment 5
The release in vitro of Puerarin and scutellarin lipid nano particle eye-drops preparations is investigated
The Puerarin and scutellarin lipid nano particle eye-drops preparations that Example 1 is prepared are investigated.This experiment
The dissolution medium pH used investigates Puerarin using film dialysis and scutellarin lipid is received for 6.8 phosphate buffered saline solution
The release behaviour in vitro of grain of rice eye-drops preparations.
Specific experiment step is：
Precision weighs Puerarin 3.25mg, scutellarin 4.88mg, and it is molten to add in the phosphate buffered saline solution that appropriate pH is 6.8
Xie Hou is settled to 10mL, for Puerarin and the mixed solution of scutellarin, abbreviation drug solution.
Accurate measurement 2.0mL Puerarins and scutellarin lipid liquid crystal nanoparticle eye-drops preparations and drug solution are placed in respectively
In bag filter, both ends are clamped with bag filter, are placed in the beaker of the dissolution medium containing 60mL, and setting magnetic stirring apparatus rotating speed is
200rpm, temperature are 34 ± 0.5 DEG C.1mL is sampled respectively at 0.5,1,1.5,2,3,4,5,7,9,12h, while it is same to add isothermal
The dissolution medium of volume.Release amount of medicine is measured with HPLC methods, each sample carries out parallel laboratory test three times.
Cumulative release amount (Qn) and cumulative release percentage (F%) acquired respectively by formula (1) and formula (2)：
Q in formulanFor the cumulative release amount at each time point；F% is the cumulative release percentage at each time point；T (min) is to take
Sample time point；CnFor the actual measurement drug concentration of n-th of sampling time point；V0For dissolution medium total volume；ViFor every sub-sampling body
Product；CiDrug concentration is surveyed for i-th of sampling time point；C0For total drug concentration.
Puerarin release in vitro fitting result is shown in Table 1.Scutellarin release in vitro fitting result is shown in Table 2.
1 Puerarin release in vitro fitting result of table
2 scutellarin release in vitro fitting result of table
By the release data of the Puerarin of embodiment 1 and scutellarin lipid nano particle eye-drops preparations carry out zero level, level-one,
Higuchi diffusion equations are fitted and carry out regression analysis, the related coefficient of more each regression equation.In the fit equation of gained with
The R value highests of Higuchi equations and Ritger-Peppas equations, illustrate Puerarin and the ophthalmically acceptable system of scutellarin lipid nano particle
Agent has slow releasing function.
Embodiment 6
Puerarin and the Corneal trauma of scutellarin lipid nano particle eye-drops preparations prepared by embodiment 1 is investigated
Rabbit auricular vein injection air is lethal.Eyeball is after death taken out rapidly, and it is more to remove sclera, iris, crystalline lens etc.
Remaining tissue, isolates cornea.Fresh in vitro cornea is fixed between the supply pool and reception tank of Franz diffusion cells, makes epithelium
Level is to supply pool, and endodermis is towards reception tank.Puerarin and scutellarin lipid liquid crystal nanometer are separately added into supply pool
Grain eye-drops preparations and drug solution 1.0mL.Supply pool is sealed, prevents from evaporating；The phosphoric acid that pH is 6.8 is filled in reception tank to delay
Rush salting liquid bubble removing side by side.Package unit is placed in transdermal diffusion experiment instrument, and water bath with thermostatic control temperature is (34 ± 0.5) DEG C.It is real
After testing beginning, 40 after timing, 80,120,180,240min sample 4.5mL from reception tank, while supplement isometric
Synthermal phosphate buffered saline solution, sample take subsequent filtrate to carry out HPLC measure after 0.45 μm of filtering with microporous membrane.
In vitro evaluation parameter is acquired by the following formula (3)：
WhereinFor linear slope (μ g/min), 60 be the ratio point with the second, and A is cornea area, C0For initial drug
Concentration (μ g/mL).
The maintenance of in vitro rabbit corneal physiological activity is most important to stable experiment, and cornea slaking velue is in-vitro evaluation substance
To the important indicator of the tissue irritation, normal cornea slaking velue be 76%~80%, more than 83%, you can judge cornea by
Damage to a certain extent, therefore can judge that Puerarin and scutellarin lipid liquid crystal nanoparticle eye-drops preparations are diagonal by slaking velue
The irritation of film.It is careful to remove scleral tissue, claim the pupil region that dispersive medium is exposed to after experiment in vitro to its quality, be denoted as
mb；Claim its quality again after 60 DEG C of dry 12h, be denoted as ma.(4) calculate cornea slaking velue as follows:
Isolated cornea slaking velue the results are shown in Table 3, the results showed that the HL% of various preparations is respectively less than 83%, illustrates various preparations
Isolated cornea is not caused to damage.
3 isolated cornea slaking velue (n=3) of table
Isolated cornea is shown in Table 4 through parameter.
4 isolated cornea of table penetrates parameter
Isolated cornea penetrate the experimental results showed that, compared with drug solution, the Papp of Puerarin adds 2.01 in preparation
Times, the Papp of scutellarin adds 1.23 times, and lipid nano particle can significantly improve Puerarin and the cornea of scutellarin is saturating
The property crossed.
Embodiment 7
The residence time of Puerarin and scutellarin lipid nano particle eye-drops preparations is investigated
The Puerarin of embodiment 1 and scutellarin equivalent are replaced with into rhodamine B and prepare rhodamine B lipid nano particle with method
Preparation carries out small animal living body imaging, and by rhodamine B 3.25mg, it is molten that 4.88mg is dissolved in the phosphate-buffered salt that 10mLpH is 7.0
The anelasticity (325 μ g/mL, 488 μ g/mL) that rhodamine B solution investigates prescription as control is made in liquid.
Every rabbit cornea, iris and conjunctiva situation are first observed and recorded before experiment, has lesion or inflammation person, is rejected not
With.During experiment, every lagophthalmos accurately instills 20 μ L of sample with micro sample adding appliance, and all samples are all carefully instilled in conjunctival sac, greatly
The centre position of about interior outer canthus, and double eyelid 30s are gently closed after being added dropwise, then rabbit auricular vein injects 10% hydration chlorine
Aldehyde 5mL anaesthetizes sb. generally and carries out imaging in 0,10,30,60,90,120,180min different time points.
The results are shown in Figure 2, shows that lipid nano particle is obviously prolonged in the residence time of eye.
Embodiment 8
The pharmacokinetics of Puerarin and scutellarin lipid nano particle eye-drops preparations is investigated
(1) implantation of microdialysis probe
Ofloxacin eye drops are given once daily twice in three days in operation consent, to prevent the inflammation of eye section that may occur.Operation consent
After 0.5 and 4h, rabbit auricular vein injection 100Ukg-1Heparin sodium, to prevent from due to inflammatory reaction fiber in anterior chamber being caused to be given birth to
Into.Ocular injection 0.4ml lidocaine anesthesias, eyelid is strutted with eye speculum, starts to perform the operation.With 10#Syringe needle is at canthus position angle
Connectivity puncture is done at film edge, pumps syringe needle, adjusting the position of probe makes dialysis window be totally immersed into aqueous humor, probe both ends difference
It is fixed in inner eye corner and the tail of the eye.Ofloxacin eyedrops is instilled at wound to be prevented from infecting.By a convalescence and antiphlogistic
The clean phase of water heals after wound after anterior chamber fills, starts interior medicine dynamics experiment completely.
(2) pharmacokinetics experiment in rabbit aqueous humor
Using the phosphate buffered saline solution that pH is 6.8 as perfusion liquid, flow rate set is 3.0 μ Lmin-1, after rinsing 0.5h,
200 μ L drug solutions, Puerarin and scutellarin lipid nano particle eye-drops preparations are respectively dropped into conjunctival sac, starts simultaneously at collection
Sample collects sample in initial 1h per 10min, then collects sample every 20min, all samples are directly into efficient liquid phase
It measures.
(3) research calculates pharmacokinetic parameters using non-compartment model, and Puerarin the results are shown in Table 5.Scutellarin the results are shown in Table
6。
Pharmacokinetic parameters after 5 Puerarin local administration of table
Pharmacokinetic parameters after 6 scutellarin local administration of table
The C of Puerarin and scutellarin lipid nano particle in table 5maxFor 1.69 times of Puerarin solution；AUC is Puerarin
2.33 times of solution；T1/2For 3.62 times of Puerarin solution；The C of Puerarin and scutellarin lipid nano particle in table 6maxFor lamp
1.12 times of small cup B prime solution；AUC is 2.32 times of scutellarin solution；T1/2For 4.23 times of scutellarin solution；Show Pueraria lobota
Root element and scutellarin lipid nano particle eye-drops preparations can improve solubility of the drug in aqueous humor, so as to improve biological utilisation
Degree.Drug-time curve of the Puerarin in aqueous humor in Puerarin and scutellarin lipid nano particle eye-drops preparations and drug solution is shown in
Fig. 3.
Medicine of the scutellarin in aqueous humor in Puerarin and scutellarin lipid nano particle eye-drops preparations and drug solution
When curve see Fig. 4.
It is demonstrated experimentally that Puerarin and the external of scutellarin lipid nano particle eye-drops preparations prepared by embodiment 2,3,4 are released
Put investigation, Corneal trauma is investigated, the residence time is investigated and pharmacokinetics is investigated, the Puerarin and lamp prepared with embodiment 1
Small cup B prime lipid nano particle eye-drops preparations effect is similar.
Claims (9)
1. the preparation method of Puerarin and scutellarin lipid nano particle eye-drops preparations, it is characterised in that include the following steps：
(1) matrix material is taken, scutellarin adds in solvent absolute ethyl alcohol, is heated to 50-70 DEG C, dissolves under stiring, obtain homogeneous
First oil phase；Distilled water is the first water phase；
(2) it is another to take lecithin and cholesterol, methanol/ethanol mixed liquor ultrasonic dissolution is added in, and solubilizer is added in, obtain homogeneous second
Oil phase；Puerarin, stabilizer, penetration enhancer and cationic materials are added in the phosphate buffer that pH is 6.0-7.0 again
Stirring obtains the second water phase to being completely dissolved；
(3) the first oil phase is added in the first water phase, stirs 1-2h under 200-400rpm, obtain the first colostric fluid；Again by second
Oil phase is added in the second water phase, is stirred 1-2h under 200-400rpm, is obtained the second colostric fluid；
(4) the first colostric fluid is added dropwise in the second colostric fluid under stiring, stirred evenly, is cooled to room temperature, obtain mixing just
Lotion；
(5) under conditions of power 300-450W, by mixing colostrum liquid ultrasound 3-10min to get Puerarin and scutellarin fat
Matter nanoparticle eye-drops preparations.
2. according to the method described in claim 1, it is characterized in that the matrix material 20-42mg, scutellarin 1mg in proportion,
Lecithin 1mg, cholesterol 1mg, solubilizer 1mL, Puerarin 1mg, stabilizer 4-12mg, penetration enhancer 0.1-0.5mg and sun
Ionic material 12-20mg.
3. method according to claim 1 or 2, it is characterized in that the matrix material is glyceryl monooleate, glycerine Dan Ya
Oleate, two glyceryl oleates, phosphatidyl-ethanolamine, two sub- oleoylphosphatidyl ethanolamines, 1- palmityl -2- oleoylphosphatidyl courages
One or more of alkali, dimyristoyl phosphatidyl choline, phytantriol.
4. method according to claim 1 or 2, it is characterized in that the volume ratio of the methanol/ethanol is 1：1.
5. method according to claim 1 or 2, it is characterized in that the solubilizer is Tween 80, polyethylene glycol 400, glycerine
One or more of.
6. method according to claim 1 or 2, it is characterized in that the stabilizer is in pluronic F127 and polyvinyl alcohol
One or two kinds of mixtures.
7. method according to claim 1 or 2, it is characterized in that the penetration enhancer be Gelucire 44/14,
One or more of Labrasol, Solutol HS 15, Transcutol P, Transcutol HP mixture.
8. method according to claim 1 or 2, it is characterized in that the cationic materials are carboxymethyl chitosan, octadecane
One or more of base carboxymethyl chitosan quaternary ammonium salt and hydroxypropyl chitosan.
9. Puerarin and scutellarin lipid nano particle eye-drops preparations prepared by the method for one of claim 1-8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610995593.9A CN108066315A (en) | 2016-11-11 | 2016-11-11 | Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof |
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| CN111450044A (en) * | 2020-04-30 | 2020-07-28 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
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| CN111450044A (en) * | 2020-04-30 | 2020-07-28 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
| CN111450044B (en) * | 2020-04-30 | 2021-06-25 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
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