CN107982219A - Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations and preparation method - Google Patents
Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations and preparation method Download PDFInfo
- Publication number
- CN107982219A CN107982219A CN201711242276.0A CN201711242276A CN107982219A CN 107982219 A CN107982219 A CN 107982219A CN 201711242276 A CN201711242276 A CN 201711242276A CN 107982219 A CN107982219 A CN 107982219A
- Authority
- CN
- China
- Prior art keywords
- pilocarpine hydrochloride
- liposomes
- solution
- preparation
- flexible nano
- 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
Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations and preparation method, preparation method is：(1) lecithin and cholesterol are placed in chloroform, it is ultrasonic to obtain suspension；Pilocarpine hydrochloride and penetration enhancer are dissolved in methanol and obtain solution one；(2) suspension and solution one are mixed, removes organic solvent, form uniform lipid membrane；(3) softener is dissolved in pure water and obtains solution two, lipid membrane is dissolved in solution two, obtains mixing colostrum liquid；(4) by mixing colostrum liquid ultrasound, warm bath, obtains pilocarpine hydrochloride flexible nano-liposomes preparation；(5) cationic materials are dissolved in pure water and obtain solution three, stirred pilocarpine hydrochloride flexible nano-liposomes preparation, solution three is instilled, stirred, obtain eye-drops preparations of the present invention；There is the preparation of the present invention huge film surface to accumulate, the adhesiveness of height, increase the permeability of medicine.Good biocompatibility and relatively low Ocular irritation.
Description
Technical field
The present invention relates to field of medicaments, and in particular to cation modified pilocarpine hydrochloride flexible nano-liposomes eye
With preparation and preparation method.
Background technology
Glaucoma is that the slow of retinal ganglial cells and optic nerve axons carries out sexual involution, if be not diagnosed or not
Through treatment, then it may cause irreversible blindness.Glaucoma is world's second largest blindness reason, accounts for 12.3% all to blind.
Modern research shows that pilocarpine hydrochloride has the obvious effect for reducing intraocular pressure, controlling inflammation, primary green grass or young crops can be treated
Light eye, including open-angle and angle-closure glaucoma, are the fiest-tire medications of clinical treatment glaucoma.
The common formulations of pilocarpine hydrochloride are eye drops, and this formulation has the eye holdup time short, and cornea passes through
The shortcomings of property is poor.
The progress of medicine delivery is intended to improve by increasing medicine retention time on anterior corneal surface and Corneal trauma
Bioavilability.
In order to extend the action time of pilocarpine hydrochloride, there is an urgent need for a kind of cornea transmission for increasing pilocarpine hydrochloride
Property and bioavilability, reduce medicine frequency of use, reduce Ocular irritation new preparation.
The content of the invention
It is soft the purpose of the present invention is overcoming the deficiencies of the prior art and provide a kind of cation modified pilocarpine hydrochloride
Property nano liposomes eye-drops preparations.
Second object of the present invention is to provide a kind of cation modified pilocarpine hydrochloride flexible nano-liposomes
The preparation method of eye-drops preparations.
Technical scheme is summarized as follows:
The preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, including following step
Suddenly：
(1) lecithin and cholesterol are placed in chloroform, ultrasonic 3-5min, obtains suspension；By pilocarpine hydrochloride and
Penetration enhancer, which is dissolved in methanol, obtains solution one；
(2) suspension and solution one are mixed, organic solvent is removed in 35-50 DEG C of rotary evaporation, until container
Uniform lipid membrane is formed on bottom；
(3) softener is dissolved in pure water and obtains solution two, the lipid membrane is dissolved in solution two, obtain mixing just
Lotion；
(4) under conditions of power 100-200W, by mixing colostrum liquid ultrasound 10-60min, 25-60 DEG C of warm bath 0.5-2h,
Obtain pilocarpine hydrochloride flexible nano-liposomes preparation；
(5) cationic materials are dissolved in pure water and obtain solution three, using rotating speed as 200-400rpm under the conditions of stirring described in
Pilocarpine hydrochloride flexible nano-liposomes preparation, the pilocarpine hydrochloride flexible nano is added dropwise to by the solution three
In Liposomal formulation, 0.5-2h is stirred, that is, obtains the cation modified ophthalmically acceptable system of pilocarpine hydrochloride flexible nano-liposomes
Agent.
The lecithin, cholesterol, pilocarpine hydrochloride, penetration enhancer, the quality of softener and cationic materials
Than for：400:20:(5-25):(0.1-0.5):(12-25):(12-20)；
The ratio of the lecithin and chloroform is 40mg:1-3mL.
Penetration enhancer is preferably Gelucire 44/14 (Gelucire 44/14 PEG-32), Labrasol
(Labraso PEG-8) and Transcutol P (diethylene glycol monoethyl ether), Transcutol HP
One or more of mixtures in (diethylene glycol monoethyl ether).
Softener is preferably deoxysodium cholate, sodium taurocholate, one or more of mixtures in ethanol and propane diols.
Cationic materials are preferably N- trimethyl chitins (quaternization degree >=60%), carboxymethyl chitosan (substitution value
>=80%), hydroxypropyl chitosan (substitution value >=80%) and carboxymethyl chitosan octadecyl quaternary ammonium salt (substitution value >=90%)
In one or more of mixtures.
Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations prepared by the above method.
Advantages of the present invention：
(1) there is preparation of the invention huge film surface to accumulate, and the adhesiveness of height, can change physical and chemical properties of drugs, increase
The permeability of dosing thing.
(2) medicine that energy sustained release is encapsulated, has long-acting slow-release effect, the supersession rate of medicine is reduced, so as to drop
Low administration frequency, improves the compliance of patient medication.
(3) preparation Ocular irritation of the invention is weak, improves the security of preparation, is adapted to long-time service.
(4) pilocarpine hydrochloride flexible nano-liposomes belong to self-stabilization dispersion, the long-time stability of preparation compared with
It is high.
(5) conventional method can be used to sterilize, preparation process is relatively easy.
Brief description of the drawings
Fig. 1 is cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations particle size results figure.
Fig. 2 is the histotomy with the cornea (a, b) of the rabbit of hematoxylin eosin staining, conjunctiva (c, d) and iris (e, f)
Result figure.In figure, EP：Epithelial cell, ST：Basal cell.Wherein a, c, e be added dropwise phosphate buffer solution, b, d, f be added dropwise sun from
The pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of son modification.
Fig. 3 is cation modified rhodamine B flexible nano-liposomes preparation and rhodamine B solution in different time points
Eye is detained result figure.Wherein a is rhodamine B solution；B is rhodamine B flexible nano-liposomes preparation, 1：Eye, 2：Interior eye
Angle and nasolacrimal duct area.
Fig. 4 is cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations (being preparation in figure) and salt
Sour Pilocarpus jaborandi aqueous slkali (pH of pilocarpine hydrochloride is 6.8 phosphate buffered saline solution, is solution in figure), in tear
Drug-time curve.
Embodiment
With reference to specific embodiment, the present invention is further illustrated.
Embodiment 1
The preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, including following step
Suddenly：
(1) 400mg lecithin and 20mg cholesterol are placed in 20mL chloroforms, ultrasonic 4min, obtains suspension；By 20mg salt
Sour pilocarpinum and 0.5mgGelucire 44/14 (Gelucire 44/14 PEG-32), which are dissolved in 10mL methanol, to be obtained
Solution one；
(2) suspension and solution one are mixed, organic solvent is removed in 40 DEG C of rotary evaporations, until the bottom of container is formed
Uniform lipid membrane；
(3) 25mg deoxysodium cholate is dissolved in pure water and obtains solution two, the lipid membrane is dissolved in solution two, is obtained
To mixing colostrum liquid；
(4) under conditions of power 150W, by mixing colostrum liquid ultrasound 60min, 60 DEG C of warm bath 0.5h, obtain hydrochloric acid comospore
Graveoline flexible nano-liposomes preparation；
(5) 20mgN- trimethyl chitins (quaternization degree >=60%) are dissolved in pure water and obtain solution three, with rotating speed
To stir the pilocarpine hydrochloride flexible nano-liposomes preparation under the conditions of 300rpm, the solution three is added dropwise to described
In pilocarpine hydrochloride flexible nano-liposomes preparation, 1h is stirred, it is flexible to obtain cation modified pilocarpine hydrochloride
Nano liposomes eye-drops preparations.
Cation modified pilocarpine hydrochloride flexible nano-liposomes preparation prepared by Example 1 is surveyed by particle diameter
Determine instrument measure particle diameter distribution, average grain diameter 123nm.See Fig. 1.
Embodiment 2
The preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, including following step
Suddenly：
(1) 400mg lecithin and 20mg cholesterol are placed in 20mL chloroforms, ultrasonic 3min, obtains suspension；By 10mg salt
Sour pilocarpinum and 0.3mgLabrasol (Labraso PEG-8), which are dissolved in 10mL methanol, obtains solution
One；
(2) suspension and solution one are mixed, organic solvent is removed in 45 DEG C of rotary evaporations, until the bottom of container is formed
Uniform lipid membrane；
(3) 25mg sodium taurocholates are dissolved in pure water and obtain solution two, the lipid membrane is dissolved in solution two, is mixed
Close colostric fluid；
(4) under conditions of power 200W, by mixing colostrum liquid ultrasound 10min, 25 DEG C of warm bath 2h, obtain hydrochloric acid comospore rue
Fragrant alkali flexible nano-liposomes preparation；
(5) 20mg hydroxypropyl chitosans (substitution value >=80%) are dissolved in pure water and obtain solution three, using rotating speed as
The pilocarpine hydrochloride flexible nano-liposomes preparation is stirred under the conditions of 300rpm, the solution three is added dropwise to the salt
In sour pilocarpinum flexible nano-liposomes preparation, 1h is stirred, cation modified pilocarpine hydrochloride flexibility is obtained and receives
Mizhi plastid eye-drops preparations.
After testing, average grain diameter 135nm.
Embodiment 3
The preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, including following step
Suddenly：
(1) 400mg lecithin and 20mg cholesterol are placed in 10mL chloroforms, ultrasonic 4min, obtains suspension；By 5mg salt
Sour pilocarpinum and 0.1mgTranscutol HP (diethylene glycol monoethyl ether), which is dissolved in 10mL methanol, obtains solution one；
(2) suspension and solution one are mixed, organic solvent is removed in 35 DEG C of rotary evaporations, until the bottom of container is formed
Uniform lipid membrane；
(3) by 12mg1,2 propane diols, which are dissolved in pure water, obtains solution two, and the lipid membrane is dissolved in solution two, is obtained
To mixing colostrum liquid；
(4) under conditions of power 100W, by mixing colostrum liquid ultrasound 50min, 30 DEG C of warm bath 1h, obtain hydrochloric acid comospore rue
Fragrant alkali flexible nano-liposomes preparation；
(5) 15mg carboxymethyl chitosans (substitution value >=80%) are dissolved in pure water and obtain solution three, using rotating speed as
The pilocarpine hydrochloride flexible nano-liposomes preparation is stirred under the conditions of 200rpm, the solution three is added dropwise to the salt
In sour pilocarpinum flexible nano-liposomes preparation, 2h is stirred, cation modified pilocarpine hydrochloride flexibility is obtained and receives
Mizhi plastid eye-drops preparations.
After testing, average grain diameter 129nm.
Embodiment 4
The preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, including following step
Suddenly：
(1) 400mg lecithin and 20mg cholesterol are placed in 30mL chloroforms, ultrasonic 5min, obtains suspension；By 25mg salt
Sour pilocarpinum, 0.5mg penetration enhancers (mass ratio 1：1 Gelucire 44/14 and Transcutol P (diethyl two
Alcohol list ethylether)) it is dissolved in 10mL methanol obtaining solution one；
(2) suspension and solution one are mixed, organic solvent is removed in 50 DEG C of rotary evaporations, until the bottom of container is formed
Uniform lipid membrane；
(3) by 20mg softeners (volume ratio 1：1 ethanol and 1,2-PD) solution two is dissolved in pure water obtaining, by institute
State lipid membrane to be dissolved in solution two, obtain mixing colostrum liquid；
(4) under conditions of power 150W, by mixing colostrum liquid ultrasound 30min, 30 DEG C of warm bath 1h, obtain hydrochloric acid comospore rue
Fragrant alkali flexible nano-liposomes preparation；
(5) by 6mg carboxymethyl chitosan octadecyls quaternary ammonium salt (substitution value >=90% and the (substitution of 6mg hydroxypropyl chitosans
Degree >=80%) be dissolved in pure water and obtain solution three, using rotating speed as 400rpm under the conditions of stir the pilocarpine hydrochloride flexibility
Nano liposome preparations, the solution three is added dropwise in the pilocarpine hydrochloride flexible nano-liposomes preparation, stirring
0.5h, obtains cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations.
After testing, average grain diameter 120nm.
Embodiment 5
The release in vitro of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations is investigated
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations that Example 1 is prepared into
Row is investigated.The dissolution medium that this experiment uses is investigated cation using film dialysis and is repaiied for the phosphate buffer solution of pH 6.8
The release in vitro of the pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of decorations.
Specific experiment step is：
(1) precision weighs pilocarpine hydrochloride 2mg, fixed after adding the phosphate buffered saline solution dissolving that appropriate pH is 6.8
Hold to 10mL, be Akarpine.
(2) it is accurate respectively to measure the cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of 2.0mL
It is placed in Akarpine in bag filter, both ends are clamped with bag filter, and bag filter is immersed the fresh preparations of 60mL
Phosphate buffer in, it be 200rpm to set magnetic stirring apparatus rotating speed, and temperature is 34 ± 0.5 DEG C.Respectively at 0.25,0.5,1,
2,4,6,8,10 and 12h samples 1mL, while adds the dissolution medium of the same volume of isothermal.Release amount of medicine is measured with HPLC methods,
Each sample parallel laboratory test is three times.
(3) Cumulative release amount (Qn) and cumulative release percentage (F%) are tried to achieve by formula (1) and formula (2) respectively：
Wherein QnIt is the cumulative release amount of each time point；F% is the cumulative release percentage of each time point；C1It is
The drug concentration of one point in time measurement；V0It is the cumulative volume of dissolution medium；CiIt is the medicine in ith sample point in time measurement
Concentration；C0It is total drug concentration.
Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations release in vitro fitting result is shown in Table
1。
Fitting result is discharged outside the cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of table 1
By the release data of the cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of embodiment 1
Carry out zero level, level-one, Higuchi diffusion equations to be fitted and carry out regression analysis, the related coefficient of more each regression equation.Gained
Fit equation in the R value highests of Higuchi equations and Ritger-Peppas equations, illustrate cation modified hydrochloric acid hair
Fruit graveoline flexible nano-liposomes eye-drops preparations has slow releasing function.
Embodiment 6
The security of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations is investigated
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations that Example 1 is prepared into
Row is investigated.Cation modified pilocarpine hydrochloride flexibility is investigated using the Draize experiments of improvement and tissue slice experiment to receive
The security of Mizhi plastid eye-drops preparations.
Specific experiment step is：
(1) the Draize experiments of improvement：Conjunctival sac is added dropwise 100 μ L embodiments 1 and is prepared into daily under the right eye of every rabbit
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations arrived, continues 7 days, and corresponding left eye is daily
Same amount of phosphate buffer solution (pH 6.8) is added dropwise as control.0.5 after last time completion of dropwise addition, 1,2,3,6,
12,24,32 and 48 observe every rabbit eyes when small.Stimulus index (Iirr) is calculated and assessed in each observation.
(2) tissue slice experiment：After the completion of eye irritation Journal of Sex Research, all rabbits intravenous injection air is lethal.Then,
It is immediately disconnected its cornea, iris and conjunctiva and is separately fixed in 4% formaldehyde.The section of 5 μ m thicks is cut from paraffin mass, is used in combination
H and E (H＆E) dyes.With light microscope (BX51W1, Olympus Optical Co., Ltd, Tokyo,
Japan histological examination) is carried out, to check the change of epithelial cell and basal cell.
(3) pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations cation modified in the Draize experiments of improvement
The stimulus index (Iirr) of corneal, iris and conjunctiva is respectively 0,0,0.The epithelium (EP) of rabbit cornea, conjunctiva and iris and
Matrix (ST) structure is as shown in Figure 2.Compared with control group, cation modified pilocarpine hydrochloride flexible nano-liposomes eye
Without significant difference in being organized with preparation group three.The result shows that cornea structure and integrality are unaffected.
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of embodiment 2,3,4 substitutes this reality
Apply the cation modified pilocarpine hydrochloride flexible nano-liposomes of example, the results showed that, cornea structure and integrality from
Influence.
Embodiment 7
The holdup time of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations is investigated
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations that Example 1 is prepared into
Row is investigated.Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations is investigated using small animal imaging method
Intraocular retention performance.
Specific experiment step is：
(1) the pilocarpine hydrochloride equivalent of embodiment 1 is replaced with into rhodamine B, cation modified sieve is prepared with method
Red bright B flexible nano-liposomes preparation；Rhodamine B 2mg is dissolved in the phosphate buffered saline solution that 10mL pH are 6.8 and is made
Rhodamine B solution is as control.Small animal living body imaging is carried out, investigates the retention performance of prescription.
(2) first observed before testing and record the situation of every rabbit eyeball, existing lesion or inflammation person, rejecting do not have to.
Before imaging, with chloraldurate (injection 2.5mLkg-1) through auricular vein injecting anesthetic.Accurately the cation of 20 μ L is repaiied
The rhodamine B flexible nano-liposomes preparation of decorations is directly injected into conjunctiva of right eye capsule, and left eye is used as control (rhodamine B solution).Hand
Dynamic closure eyelid 10s makes medicine in cornea distribution.And imaging is carried out at 0,30,90,150min.
The results are shown in Figure 3, shows cation modified rhodamine B flexible nano-liposomes preparation in the delay of eye
Between be obviously prolonged.
Embodiment 8
The pharmacokinetics of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations is investigated
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations that Example 1 is prepared into
Row is investigated.The cation modified ophthalmically acceptable system of pilocarpine hydrochloride flexible nano-liposomes is investigated using the tear bar experiment of improvement
The bioavilability of agent.
Specific experiment step is：
(1) the cation modified ophthalmically acceptable system of pilocarpine hydrochloride flexible nano-liposomes that Example 1 is prepared
Agent 100mL, instills conjunctival sac under every rabbit right eye, and the left eye of every rabbit receives the pilocarpine hydrochloride of same volume
Solution is compared.Eyes are turned off manually 10 seconds, then collect ocular fluid samples 0.25,0.5,0.75,1,3,6,9,12h.
(2) being lightly inserted into dry filter paper bar (40mm × 5mm) in the lower eyelid of rabbit keeps 10s to collect sample.
Each tear bar is weighed, and calculates the tear amount of collection.
(3) band is put into centrifuge tube, 1mL methanol is added into pipe, hydrochloric acid is extracted from band by being vortexed 90 seconds
Pilocarpinum, is then centrifuged pipe 10 minutes with 10000rpm.Pilocarpine hydrochloride in supernatant is measured by HPLC
Concentration, each sample parallel laboratory test is three times.
(4) research calculates pharmacokinetic parameters using non-compartment model, and pilocarpine hydrochloride the results are shown in Table 2.
Pharmacokinetic parameters after 2 pilocarpine hydrochloride local administration of table
Tmax, peak time；Cmax, the Cmax of pilocarpine hydrochloride；AUC, area under the curve；T1/2, half-life period；
MRT, mean residence time
*：Relative to PN solution, P<0.05；**：Relative to PN solution, P<0.01
The AUC of cation modified pilocarpine hydrochloride flexible nano-liposomes is 4.55 times of contrast solution in table 2.
It is molten in aqueous humor to show that cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations can improve medicine
Xie Du, so as to improve bioavilability.Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations and salt
The Drug-time curve of sour Pilocarpus jaborandi aqueous slkali is shown in Fig. 4.
The cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations of embodiment 2,3,4 substitutes this reality
The cation modified pilocarpine hydrochloride flexible nano-liposomes of example are applied, its effect is similar to the result of the present embodiment.
Claims (5)
1. the preparation method of cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations, it is characterised in that bag
Include following steps：
(1) lecithin and cholesterol are placed in chloroform, ultrasonic 3-5min, obtains suspension；By pilocarpine hydrochloride and infiltration
Accelerating agent, which is dissolved in methanol, obtains solution one；
(2) suspension and solution one are mixed, organic solvent is removed in 35-50 DEG C of rotary evaporation, until the bottom of container
Form uniform lipid membrane；
(3) softener is dissolved in pure water and obtains solution two, the lipid membrane is dissolved in solution two, obtains mixing colostrum
Liquid；
(4) under conditions of power 100-200W, by mixing colostrum liquid ultrasound 10-60min, 25-60 DEG C of warm bath 0.5-2h, obtains
Pilocarpine hydrochloride flexible nano-liposomes preparation；
(5) cationic materials are dissolved in pure water and obtain solution three, using rotating speed as 200-400rpm under the conditions of stir the hydrochloric acid
Pilocarpinum flexible nano-liposomes preparation, the pilocarpine hydrochloride flexible nano lipid is added dropwise to by the solution three
In body preparation, 0.5-2h is stirred, obtains cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations；
The lecithin, cholesterol, pilocarpine hydrochloride, penetration enhancer, the mass ratio of softener and cationic materials are：
400:20:(5-25):(0.1-0.5):(12-25):(12-20)；
The ratio of the lecithin and chloroform is 40mg:1-3mL.
2. according to the method described in claim 1, it is characterized in that the penetration enhancer for Gelucire 44/14,
At least one of Labrasol, Transcutol P and Transcutol HP.
3. according to the method described in claim 1, it is characterized in that the softener is deoxysodium cholate, sodium taurocholate, ethanol and third
At least one of glycol.
4. according to the method described in claim 1, it is characterized in that the cationic materials are N- trimethyl chitins, carboxymethyl shell
Glycan, at least one of hydroxypropyl chitosan and carboxymethyl chitosan octadecyl quaternary ammonium salt.
5. cation modified pilocarpine hydrochloride flexible nano-liposomes prepared by the method for one of claim 1-4 are ophthalmically acceptable
Preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711242276.0A CN107982219B (en) | 2017-11-30 | 2017-11-30 | Cation-modified pilocarpine hydrochloride flexible nano-liposome ophthalmic preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711242276.0A CN107982219B (en) | 2017-11-30 | 2017-11-30 | Cation-modified pilocarpine hydrochloride flexible nano-liposome ophthalmic preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107982219A true CN107982219A (en) | 2018-05-04 |
| CN107982219B CN107982219B (en) | 2020-09-15 |
Family
ID=62034889
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711242276.0A Active CN107982219B (en) | 2017-11-30 | 2017-11-30 | Cation-modified pilocarpine hydrochloride flexible nano-liposome ophthalmic preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107982219B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051654A (en) * | 2019-04-19 | 2019-07-26 | 天津中医药大学 | The ophthalmically acceptable lipid nano particle preparation of baicalein and preparation method thereof of N- trimethyl chitin modification |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390834A (en) * | 2008-10-01 | 2009-03-25 | 山东省眼科研究所 | Eye amphotericin B flexible liposome |
| WO2011098578A2 (en) * | 2010-02-12 | 2011-08-18 | Bioneer A/S | Liposome system for ocular administration |
| CN102274175A (en) * | 2011-07-01 | 2011-12-14 | 中国人民解放军第二军医大学 | Nano lipid cubic crystal preparation, its preparation method and application |
| EP2526923A1 (en) * | 2009-11-27 | 2012-11-28 | Shenyang Xingqi Pharmaceutical Co., Ltd. | Ophthalmic gel of gatifloxacin and preparation method thereof |
| CN105726484A (en) * | 2016-02-25 | 2016-07-06 | 天津中医药大学 | Tetrandrine liquid crystal nanoparticle preparation for eyes and preparation method thereof |
-
2017
- 2017-11-30 CN CN201711242276.0A patent/CN107982219B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390834A (en) * | 2008-10-01 | 2009-03-25 | 山东省眼科研究所 | Eye amphotericin B flexible liposome |
| EP2526923A1 (en) * | 2009-11-27 | 2012-11-28 | Shenyang Xingqi Pharmaceutical Co., Ltd. | Ophthalmic gel of gatifloxacin and preparation method thereof |
| WO2011098578A2 (en) * | 2010-02-12 | 2011-08-18 | Bioneer A/S | Liposome system for ocular administration |
| CN102274175A (en) * | 2011-07-01 | 2011-12-14 | 中国人民解放军第二军医大学 | Nano lipid cubic crystal preparation, its preparation method and application |
| CN105726484A (en) * | 2016-02-25 | 2016-07-06 | 天津中医药大学 | Tetrandrine liquid crystal nanoparticle preparation for eyes and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| 何文等: "阳离子脂质体原位凝胶离体眼球滞留特性及生物相容性 ", 《中国医院药学杂志》 * |
| 何文等: "阳离子脂质体原位凝胶离体眼球滞留特性及生物相容性", 《中国医院药学杂志》 * |
| 吴艳丽等: "眼用葛根素柔性脂质体温敏凝胶剂的制备及其性质考察", 《中成药》 * |
| 黄云等: "毛果芸香碱脂质体的制备及其质量评价 ", 《中国医院药学杂志》 * |
| 黄云等: "毛果芸香碱脂质体的制备及其质量评价", 《中国医院药学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051654A (en) * | 2019-04-19 | 2019-07-26 | 天津中医药大学 | The ophthalmically acceptable lipid nano particle preparation of baicalein and preparation method thereof of N- trimethyl chitin modification |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107982219B (en) | 2020-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Li et al. | Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma | |
| Yu et al. | Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate | |
| CN110664757B (en) | Nanocrystalline eye drop, preparation method and application thereof | |
| CN105726484B (en) | A kind of tetrandrine liquid crystal nanoparticle eye-drops preparations and preparation method thereof | |
| CN105431138A (en) | Ophthalmic composition, method for preparing the same, and use of the same | |
| JP7504125B2 (en) | Cationized hyaluronic acid modified niosome vesicles and their production and use | |
| CN102210645B (en) | Lutein ophthalmic nanocapsule in-situ gel preparation and preparation method thereof | |
| CN108295072A (en) | Nintedanib prevents the purposes of eye disease | |
| CN109260146A (en) | Ophthalmic solution sodium in situ forming eye type gel eyedrop and preparation method | |
| Gupta et al. | Formulation and evaluation of brinzolamide encapsulated niosomal in-situ gel for sustained reduction of IOP in rabbits | |
| EP3536352A1 (en) | Keratoconjunctival cover sheet and method for producing keratoconjunctival cover sheet | |
| Meshram et al. | Ocular in Situ gels: Development, evaluation and advancements | |
| CN105012235B (en) | A kind of ophthalmically acceptable antimycotic nano micellar solution containing terbinafine HCl | |
| Zhu et al. | Chondroitin sulfate and L-Cysteine conjugate modified cationic nanostructured lipid carriers: Pre-corneal retention, permeability, and related studies for dry eye treatment | |
| CN107982219A (en) | Cation modified pilocarpine hydrochloride flexible nano-liposomes eye-drops preparations and preparation method | |
| CN102648894B (en) | Eye-purposed in-vivo gel preparation prepared from pH (Potential Of Hydrogen) sensitive type baicalin | |
| CN109985024A (en) | Tetrandrine lipid nano particle eye-drops preparations and preparation method thereof | |
| Gupta et al. | Enhancement of anti-glaucoma potential by novel ocular drug delivery system | |
| Chen et al. | Characterization of stimuli-responsive and cross-linked nanohydrogels for applications in ophthalmiatrics therapy | |
| CN108066315A (en) | Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof | |
| CN110151703A (en) | Ophthalmically acceptable gel with liquid crystal structure preparation of pilocarpine nitrate and preparation method thereof | |
| CN113786380A (en) | Pilocarpine nitrate ophthalmic gel and preparation method thereof | |
| CN104721130B (en) | A kind of brinzolamide inclusion compound eye-drops preparations and preparation method thereof | |
| CN115487139B (en) | Puerarin gellan gum ionic in-situ gel eye drops and preparation method thereof | |
| Iyer et al. | Development and Characterization of Moxifloxacin Hydrochloride Cubogel for Enhanced Ocular Drug Delivery. |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |