CN109077993A - A kind of lacrimal sustained-release hydrogel implant and preparation method thereof - Google Patents
A kind of lacrimal sustained-release hydrogel implant and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of active agent preparations, more particularly to a kind of lacrimal sustained-release hydrogel implant, the implant includes polyethyleneglycol derivative hydrogel and active ingredient particle, the implant is using polyethyleneglycol derivative hydrogel as matrix, active ingredient particle is uniformly distributed, and the implant is prepared using tensilometer.The invention also discloses the preparation methods of the implant.By control hydrogel prescription and drawing parameter, implant large-scale production is realized.Gel can facilitate insertion lacrimal, realize noninvasive implantation, improve patient's compliance.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of lacrimal sustained-release hydrogel implant and its preparation side
Method.
Background technique
Many eye diseases, such as cataract, ocular infection inflammation, xerophthalmia, macular degeneration, retinopathy
The diseases such as change, ocular allergy result even in blindness if cannot timely and effectively treat.These eye diseases are treated,
Eye drops is one of important channel of ophthalmic remedy, but since cornea capsule accommodates amount of liquid only 20 μ L, and 1 dripping eyedrop volume is about
50~60 μ L, cornea tissue barrier and tear dilution in addition, eyedrops instill it is intraocular after uptake not as good as 10% (ophthalmically acceptable activity at
Divide the progress of preparation, food and drug, the 5th phase of volume 14 in 2012)；In addition, eye drops administration is frequently, general provision is given
3~4 times/d of medicine, but patient when using can up to 10~20 times/d, thus generate many side effects, there is also night administration is inconvenient
The drawbacks of.
Eye implant, which is meant, to be mixed and made into preparation for active constituent and high molecular material or is packed into micro device, and eye is implanted into
Behind portion, thus make active constituent slowly, the drug delivery system of sustained release.Compared with traditional eye drops, eye implant it is excellent
Point is can to increase the eye residence time, to extend active constituent action time；It can the drug release of slow or constant rate of speed；To medicament
Amount is accurate, and implantation active constituent will not be lost as eye drops with tear；It can be with precursor activated ingredient, penetrating agent, fine granule
Equal compatibilities, prescription and technique are convenient for optimization；It can achieve the purpose that target administration through non-cornea approach into human eye portion.Currently, eye
Implant has been successfully applied to the postoperative inflammatory reaction of cataract, cytomegalovirus retinitis, chronic uveitis etc.
Prevention and treatment and the treatment of many chronic ophthalmology diseases.
Hydrogel has hydrophilic radical as a kind of functional high molecule material, can be water-swellable but tool not soluble in water
There is the polymer of three-dimensional net structure.After hydrogel adsorbs water, internal structure contains a large amount of moisture and gel is made to become soft,
It is similar with bio-tissue, and good mechanical performance can be made it have by specific preparation method, it can be made
For human body implanting tissue material with reduce adverse reaction and rise certain supporting role (hydrogel medical domain application study into
Exhibition, New Chemical Materials, the 5th phase of volume 45 in 2017).Hydrogel has the advantage that 1. eye is stagnant as eye implant
Stay the time long；2. easily being received by patient without greasy feeling, patient compliance is good；3. highly-safe, toxicity is low, few irritating mistake
Quick property；4. good biocompatibility.
The implantation currently, eye implant need to perform the operation, there are certain foreign body sensations for some patientss, may after rubbing one's eyes
It can be subjected to displacement, to affect the treatment.Patent CN102395401B discloses a kind of tear stains implant of hydrogel matrix, the plant
Enter agent and do not need operation implantation, facilitates insertion into tear stains, and slow-release time is up to 1 month, is had a good application prospect.But due to
It is prepared using pulling method in silicone tube, there are silicone tube tensile property is poor, and in the drying process, both ends are easily broken off and are difficult to protect
Xerogel is bent after holding tensional state and silicone tube retraction, and bending xerogel is not easily taken out and cuts, and it is big that there are differences between batches
The problems such as, so that industrialization production is extremely difficult.
Therefore, a kind of good moldability is developed, tensile strength is suitable for, the method for the lacrimal implant of uniform content is very
It is necessary.
Summary of the invention
Present invention aims to overcome that problems of the prior art, provide a kind of lacrimal sustained-release hydrogel implant
And preparation method thereof, solve the difficulty in lacrimal implant industrialization preparation process, can industrialization continuous batch production
Lacrimal implant achieves unexpected effect.
The technical solution of the present invention is as follows: a kind of lacrimal sustained-release hydrogel implant, the implant include matrix and work
Property ingredient, active constituent is distributed in matrix, the implant matrix include polyethyleneglycol derivative.
Further, the polyethyleneglycol derivative is the product carried out after base group modification to polyethylene glycol, described to repair
Decorations group is succinimdyl carbonate-SC, succinimide base glutarate-SG, succinimide acetic acid esters-SCM, amber
Propionates-SPA, succinimidyl succinate-SS, succinimide valerate-SVA, in succinimide-MAL
It is one or more.
Further, the matrix further includes three lysine acetates.
Further, implant diameter is 0.3-0.5mm, preferably 0.35-0.45mm；Length 3-7mm, preferably 4-
6mm；For diameter expansion to 0.8-2.0mm, preferably 1.0-1.5mm, length shortens 10-60%, preferably 20-40% after meeting water.
Further, the mass ratio of the polyethyleneglycol derivative and three lysine acetates is 25/1-35/1.
Further, the implant includes color developing agent, and the content of the color developing agent is 0.001-0.1% (w/w),
Preferably 0.01-0.05 (w/w).
The implant includes surfactant；The surfactant is selected from tween, sapn, povidone and pool Lip river
One of husky nurse is a variety of；The content of the surfactant is 0.01-1% (w/w), preferably 0.05-0.6% (w/w).
The active constituent of the implant is Loteprednol, prednisone acetate, prednisone, nepafenac, cyclosporine, indoles
One of Mei Xin, tacrolimus and dexamethasone are a variety of；The implant drugloading rate is 10-50%, sustained release activity
The number of days of ingredient is not less than 7 days.
Above-mentioned lacrimal sustained-release hydrogel implantation agent method is prepared the present invention also provides a kind of, the implant is using drawing
Stretch instrument preparation, comprising the following steps:
(1) by active constituent micronization processes, and by developer solution in borate buffer solution；
(2) add borate buffer solution to dissolve polyethyleneglycol derivative, add active constituent, form active constituent and matrix
Mixed liquor；
(3) three lysine acetates are dissolved in borate buffer solution, then add to the mixed liquor of the active constituent and matrix
In, it is uniformly mixed；
(4) in pressurization injection silicone tube, standing forms hydrogel；
(5) hydrogel is dry to constant weight, and then extraction is placed in high humidity environment；
(6) hydrogel is placed in tensilometer, and constant rate of speed stretches, and then through drying, cutting, is obtained dry hydrogel and is planted
Enter agent.
The implant of the invention used tensilometer rate of extension in production is 1-100mm/s, preferably 3-60mm/s,
Further preferably 5-50mm/s.
Color developing agent is further includeed in implant of the present invention, with position of the accurate judgement implant in lacrimal
It sets.
Further, the color developing agent be selected from it is any be suitable for it is nontoxic colored used in implanted medical device
Substance, such as one of FD&C BLUE#1, FD&C BLUE#2, eosin, fluorescein, methylenum careuleum and indocyanine green or a variety of.
Further, the content of the color developing agent is 0.001-0.1% (w/w), preferably 0.01-0.05 (w/w).
Surfactant is further includeed in implant of the invention, so that active ingredient particle divides in hydrogel
It dissipates uniform.
Further, the surfactant is selected from one of tween, sapn, povidone and poloxamer or more
Kind.
Further, the content of the surfactant is 0.01-1% (w/w), preferably 0.05-0.6% (w/w).
Implant drugloading rate of the invention is 10-50%, and the number of days of sustained release activity ingredient is not less than 7 days.
Implant of the invention, contained active constituent are Loteprednol, prednisone acetate, prednisone, nepafenac, ring spore
One of element, Indomethacin, tacrolimus and dexamethasone are a variety of.
Further, the active constituent micro powder granule average grain diameter is 1-20 μm, preferably 2-10 μm.
Wherein, the polyethyleneglycol derivative is the product after being modified using modification group polyethylene glycol, institute
State modification group be succinimdyl carbonate-SC, succinimide base glutarate-SG, succinimide acetic acid esters-SCM,
Succinimidyl propionate-SPA, succinimidyl succinate-SS, succinimide valerate-SVA, succinimide-
One of MAL or a variety of.
Further, the polyethyleneglycol derivative solution concentration is 5-40% (w/v)；Preferably 10-30% (w/v).
Further, the three lysine acetates solution concentration is 0.5-15% (w/v)；Preferably 1-5% (w/v).
Further, the mixed volume ratio of the polyethyleneglycol derivative solution and three lysine acetate solution is 1/
, preferably 2/5-5/2.
Further, in the step (5), high humidity environment humidity be 75%-92.5%RH, moisture absorption increase weight 10-100%,
The 20-60% it is preferred that moisture absorption is increased weight.
Further, in the step (6), implant draw ratio is 1-5 times, and preferably draw ratio is 2-4 times, is stretched
Gel diameter is 0.3-0.6 times of initial hydrogel diameter afterwards, and the length of implant is 3-7mm after cutting.
Prepared by batch of the present invention using tensilometer for hydrogel, by using suitable polyethyleneglycol derivative and three
The mass ratio of lysine acetate, polyethyleneglycol derivative solution compound concentration, three lysine acetate solution concentrations and with it is poly-
Ethylene glycol derivative solution mixed proportion, active constituent grain size of micropowder and suspension concentration, so that the hydrogel formed has properly
Mechanical strength, elasticity modulus 9-12Mpa；Compression strength is 2.5-4.5Mpa；Breaking strain is 6-8.
The invention has the benefit that
1, by hydrogel uniaxial direct tensile, it is poor to avoid water-setting gum forming caused by silicone tube pulling method, stretches easily broken
It splits, drawbacks, the process operability such as bending xerogel difficulty cutting are good；
2, the active constituent sustained release time can effectively be adjusted by changing active constituent micro mist average grain diameter；
3, implant rate of extension can be automatically controled, can continuous and stable production, product differences between batches are small；
4, implant draw efficiency is high, and production capacity is big, it can be achieved that batch production requirements；
Specific embodiment
The present invention provides a kind of lacrimal sustained-release hydrogel implants and preparation method thereof.One embodiment is implantation
Agent includes polyethyleneglycol derivative hydrogel and active ingredient particle, and wherein implant is using polyethyleneglycol derivative hydrogel as base
Matter, active ingredient particle are uniformly distributed, and implant is prepared using tensilometer.
In another embodiment, the matrix of implant further includes three lysine acetates.
In another embodiment, the mass ratio of polyethyleneglycol derivative and three lysine acetates is 25/1-35/1；It is excellent
It is selected as 28/1-33/1.
For implant, diameter 0.3-0.5mm, preferably 0.35-0.45mm；Length 3-7mm, preferably 4-6mm；It meets
For diameter expansion to 0.8-2.0mm, preferably 1.0-1.5mm, length shortens 10-60%, preferably 20-40% after water.
For tensilometer, rate of extension 1-100mm/s, preferably 3-60mm/s, further preferably 5-50mm/s.
In another embodiment, implant includes color developing agent, position of the accurate judgement implant in lacrimal；It is aobvious
Toner is selected from any various nontoxic colored substances being suitable for used in implanted medical device.The content of color developing agent is
0.001-0.1% (w/w), preferably 0.01-0.05 (w/w).
In another embodiment, implant includes surfactant；So that active ingredient particle is in aquogel system
Middle dispersion is uniform；Surfactant can be such as one of tween, sapn, povidone and poloxamer or a variety of；Surface is living
Property agent content be 0.01-1% (w/w), preferably 0.05-0.6% (w/w).
Active constituent contained by implant is Loteprednol, prednisone acetate, prednisone, nepafenac, cyclosporine, indoles beauty
One of pungent, tacrolimus and dexamethasone are a variety of；The implant drugloading rate be 10-50%, sustained release activity at
The number of days divided is not less than 7 days.
A kind of preparation method of lacrimal sustained-release hydrogel implant of the present invention, comprising the following steps:
(1) active raw materials are subjected to micronization processes, obtain active constituent micro mist, and developer solution is buffered in borax
Liquid；
(2) add borate buffer solution to dissolve polyethyleneglycol derivative, add the active constituent micro mist, stirring forms equal
One active constituent suspension；
(3) three lysine acetates are dissolved in borate buffer solution, then added in the active constituent suspension, stirring is mixed
It closes uniform；
(4) mixed suspension is poured into silicone tube, stands, forms hydrogel after being chemically crosslinked；
(5) hydrogel is dried under vacuum to constant weight, and then extraction is placed in high humidity environment, and moisture absorption increases weight and softens；
(6) hydrogel is placed in tensilometer after moisture absorption, and constant rate of speed stretches, and then through drying, cutting process, obtains drying
Hydrogel implant.
Wherein, active constituent micro powder granule average grain diameter is 1-20 μm, preferably 2-10 μm.
In one embodiment, polyethyleneglycol derivative is the product adopted after carrying out base group modification to polyethylene glycol, modification
Group can be such as succinimdyl carbonate-SC, succinimide base glutarate-SG, succinimide acetic acid esters-
SCM, succinimidyl propionate-SPA, succinimidyl succinate-SS, succinimide valerate-SVA, maleic acid are sub-
One of amine-MAL or a variety of.
In another embodiment, polyethyleneglycol derivative solution concentration is 5-40% (w/v)；Preferably 10-30% (w/
v)；
In another embodiment, three lysine acetate solution concentrations are 0.5-15% (w/v)；Preferably 1-5% (w/
v)；
In another embodiment, polyethyleneglycol derivative solution and the mixed volume ratio of three lysine acetate solution are
, preferably 2/5-5/2.
In another embodiment, the implant diameter after drying is 0.3-0.6 times of initial hydrogel diameter, cutting length
Degree is 3-7mm.
Embodiment 1: the preparation of dexamethasone implant
(1) by dexamethasone flow of feed gas pulverization process, 3.2 μm of obtained micro mist average grain diameter, wherein 90% particle
Less than 5 μm；
(2) 4 arm polyethylene glycol succinimidyl propionate (PEG-SPA, molecular weight 10K) of 2000mg is added 20mL's
0.015M borate buffer solution, stirring and dissolving add the Tween 80 aqueous solution that 0.5mL concentration is 1mg/mL, then add 230mg
Active constituent micro mist, stirring form uniform suspension；
(3) tri- lysine acetate of 70mg is dissolved in the 0.015M borate buffer solution of 5mL, then adds to active constituent suspension
In liquid, it is uniformly mixed；
(4) mixed suspension is injected in silicone tube, stands, forms hydrogel after being chemically crosslinked；
(5) hydrogel is dried under vacuum to constant weight, and 92.5%RH high humidity environment moisture absorption weight gain 30% is subsequently placed in after extraction；
(6) hydrogel draws 2 times, and control rate of extension is 50mm/s, dry, is then cut into the implant of 5.0mm long.
Embodiment 2: the preparation of cyclosporine implant
(1) by cyclosporine flow of feed gas pulverization process, 5.5 μm of obtained micro mist average grain diameter, wherein 90% particle is small
In 10 μm；
(2) by 8 arm polyethylene glycol succinimide base glutarate (molecular weight 15K) of 3000mg plus the 0.005M of 15mL
Borate buffer solution, stirring and dissolving add the PVP K30 aqueous solution that 1mL concentration is 0.7mg/mL, it is living then to add 175mg
Property ingredient micro mist, stirring form uniform suspension；
(3) tri- lysine acetate of 100mg is dissolved in the 0.005M borate buffer solution of 10mL, it is mixed then to add to active constituent
In suspension, it is uniformly mixed；
(4) mixed suspension is injected in silicone tube, stands, forms hydrogel after being chemically crosslinked；
(5) hydrogel is dried under vacuum to constant weight, and 92.5%RH high humidity environment moisture absorption weight gain 40% is subsequently placed in after extraction；
(6) hydrogel draws 4 times, and control rate of extension is 10mm/s, dry, is then cut into the implant of 4.0mm long.
Embodiment 3: the preparation of prednisone acetate implant
(1) by prednisone acetate flow of feed gas pulverization process, 12 μm of obtained micro mist average grain diameter, wherein 90% particle
Less than 20 μm；
(2) the 0.03M borax of 8 arm polyethylene glycol succinimidyl propionate (molecular weight 20K) of 1150mg plus 22mL is slow
Fliud flushing, stirring and dissolving add the span 40 aqueous solution that 1mL concentration is 0.8mg/mL, it is micro- then to add 300mg active constituent
Powder, stirring form uniform suspension；
(3) tri- lysine acetate of 35mg is dissolved in the 0.03M borate buffer solution of 3mL, then adds to active constituent suspension
In liquid, it is uniformly mixed；
(4) mixed suspension is injected in silicone tube, stands, forms hydrogel after being chemically crosslinked；
(5) hydrogel is dried under vacuum to constant weight, and 92.5%RH high humidity environment moisture absorption weight gain 40% is subsequently placed in after extraction；
(6) hydrogel draws 3 times, and control rate of extension is 5mm/s, dry, is then cut into the implant of 3.0mm long.
Test example 1: the implant In Vitro Dissolution comprising different average grain diameter active ingredient particles
What it is with implant made from embodiment 1, and according to the preparation of embodiment 1 includes that average grain diameter distinguishes 2.0 μm, 3.2 μ
M, 4.5 μm of dexamethasone implant carries out In Vitro Dissolution test respectively, and using paddle board method, using water 900ml as solvent, revolving speed is
50 turns per minute, sample time: 1,2,4,6,8,10,13,16,20,25,30 day, solution 3ml is taken, while it is same to supplement same volume
The water of temperature, samples taken after filtering, are measured with HPLC method, calculate Cumulative release amount, the results are shown in Table 2.
Table 1 includes the implant dissolution results of different-grain diameter Dexamethasone particles
As seen from the results in Table 1, the size of active ingredient particle is affected to the In Vitro Dissolution of implant, and partial size is bigger,
The sustained release time is longer.And it can also be seen that implant prepared by the present invention, active ingredient delivery rate are normal from table 1
In zero-order release, uniform blood level can provide during medication.
Influence of the mass ratio of 2 polyethyleneglycol derivative of test example and three lysine acetates to implant performance
According to the method for embodiment 1, only change the mass ratio of PEG-SPA: three lysine acetates, mass ratio is respectively
10:1,20:1,30:1,35:1,40:1 and 50:1.Remaining is the same as embodiment 1.
Using the machine of the prepared implant of the PEG-SPA and three lysine acetates of Texture instrument test different quality ratio
Tool intensity, while degradation time of the implant in physiological saline is measured, test result is shown in Table 2.
The mechanical performance and degradation time of the implant of the polyethylene glycol and three lysine acetates of 2 different quality ratio of table
From Table 2, it can be seen that being gradually increased with PEG-SPA and three lysine acetate mass ratioes, implant
Mechanical strength appearance first increases the trend reduced afterwards, and PEG-SPA and three lysine acetate mass ratioes are excessive or too small all unfavorable
In the mechanical strength of prepared implant or the raising of degradation time.When PEG-SPA and three lysine acetate mass ratioes are
When 25:1-35:1, implant has excellent mechanical strength and degradation time, guarantees that active constituent keeps it that should have in 30 days
Mechanical strength, continual and steady discharge active component.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to
The scope of the patents of the invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention
In the range of scheme.
Claims (10)
1. a kind of lacrimal sustained-release hydrogel implant, which is characterized in that the implant includes matrix and active constituent, will be lived
Property component distributing in matrix, the implant matrix include polyethyleneglycol derivative.
2. implant according to claim 1, which is characterized in that the polyethyleneglycol derivative be to polyethylene glycol into
Product after row base group modification, the modification group be succinimdyl carbonate-SC, succinimide base glutarate-SG,
Succinimide acetic acid esters-SCM, succinimidyl propionate-SPA, succinimidyl succinate-SS, succinimide penta
One of acid esters-SVA, succinimide-MAL or a variety of.
3. implant according to claim 1, which is characterized in that the matrix further includes three lysine acetates.
4. implant according to claim 1-3, which is characterized in that implant diameter is 0.3-0.5mm, preferably
For 0.35-0.45mm；Length 3-7mm, preferably 4-6mm；Diameter expansion is to 0.8-2.0mm, preferably 1.0- after meeting water
1.5mm, length shorten 10-60%, preferably 20-40%.
5. implant according to claim 1-3, which is characterized in that the implant includes color developing agent,
The content of the color developing agent is 0.001-0.1% (w/w), preferably 0.01-0.05 (w/w).
The implant includes surfactant；The surfactant is selected from tween, sapn, povidone and poloxamer
One of or it is a variety of；The content of the surfactant is 0.01-1% (w/w), preferably 0.05-0.6% (w/w).
6. implant according to claim 1-3, which is characterized in that the active constituent of the implant replaces for chlorine
Sprinkle one of promise, prednisone acetate, prednisone, nepafenac, cyclosporine, Indomethacin, tacrolimus and dexamethasone or
It is a variety of；The implant drugloading rate is 10-50%, and the number of days of sustained release activity ingredient is not less than 7 days.
7. a kind of prepare the implantation agent method of lacrimal sustained-release hydrogel described in claim 1-6, the implant is using stretching
Instrument preparation, comprising the following steps:
(1) by active constituent micronization processes, and by developer solution in borate buffer solution；
(2) add borate buffer solution to dissolve polyethyleneglycol derivative, add active constituent, form the mixed of active constituent and matrix
Close liquid；
(3) three lysine acetates are dissolved in borate buffer solution, then added in the active constituent and the mixed liquor of matrix, mixed
It closes uniform；
(4) in pressurization injection silicone tube, standing forms hydrogel；
(5) hydrogel is dry to constant weight, and then extraction is placed in high humidity environment；
(6) hydrogel is placed in tensilometer, and constant rate of speed stretches, and then through drying, cutting, obtains dry hydrogel implantation
Agent.
8. preparation method according to claim 6, which is characterized in that the active constituent average grain diameter is 1-20 μm,
Preferably 2-10 μm.
9. preparation method according to claim 6, which is characterized in that the polyethyleneglycol derivative solution concentration is 5-
40% (w/v)；Preferably 10-30% (w/v)；The three lysine acetates solution concentration is 0.5-15% (w/v)；Preferably
1-5% (w/v)；The mixed volume ratio of the polyethyleneglycol derivative solution and three lysine acetate solution is 1/10-10/1,
Preferably 2/5-5/2.
10. preparation method according to claim 6, which is characterized in that the gel moisture absorption weight gain 10-50%, preferably
For 20-40%, it is 1-5 times that the gel, which stretches the gel draw ratio,；Preferably 2-4 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811010645.8A CN109077993B (en) | 2018-08-31 | 2018-08-31 | Lacrimal duct slow-release hydrogel implant and preparation method thereof |
Applications Claiming Priority (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110639066A (en) * | 2019-09-27 | 2020-01-03 | 北京诺康达医药科技股份有限公司 | Degradable lacrimal duct suppository and preparation method and application thereof |
| CN111773178A (en) * | 2020-06-08 | 2020-10-16 | 北京诺康达医药科技股份有限公司 | Hydrogel lacrimal passage suppository and preparation method thereof |
| CN113171463A (en) * | 2021-03-31 | 2021-07-27 | 北京诺康达医药科技股份有限公司 | In-situ drug-loaded hydrogel and preparation method and application thereof |
| WO2023221978A1 (en) * | 2022-05-17 | 2023-11-23 | 北京诺康达医药科技股份有限公司 | Polylysine salt, preparation method therefor, and purification method therefor |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110639066A (en) * | 2019-09-27 | 2020-01-03 | 北京诺康达医药科技股份有限公司 | Degradable lacrimal duct suppository and preparation method and application thereof |
| CN110639066B (en) * | 2019-09-27 | 2020-10-20 | 北京诺康达医药科技股份有限公司 | Degradable lacrimal duct suppository and preparation method and application thereof |
| WO2021056775A1 (en) * | 2019-09-27 | 2021-04-01 | 北京诺康达医药科技股份有限公司 | Degradable tear duct plug, preparation method therefor and application thereof |
| CN111773178A (en) * | 2020-06-08 | 2020-10-16 | 北京诺康达医药科技股份有限公司 | Hydrogel lacrimal passage suppository and preparation method thereof |
| CN111773178B (en) * | 2020-06-08 | 2022-11-25 | 北京诺康达医药科技股份有限公司 | Hydrogel lacrimal passage suppository and preparation method thereof |
| CN113171463A (en) * | 2021-03-31 | 2021-07-27 | 北京诺康达医药科技股份有限公司 | In-situ drug-loaded hydrogel and preparation method and application thereof |
| WO2022206882A1 (en) * | 2021-03-31 | 2022-10-06 | 北京诺康达医药科技股份有限公司 | In-situ drug-loaded hydrogel, preparation method therefor and use thereof |
| WO2023221978A1 (en) * | 2022-05-17 | 2023-11-23 | 北京诺康达医药科技股份有限公司 | Polylysine salt, preparation method therefor, and purification method therefor |
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| CN109077993B (en) | 2021-03-16 |
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