CN105708844A - Tobramycin and dexamethasone nanosuspension eye drop and preparation method thereof - Google Patents
Tobramycin and dexamethasone nanosuspension eye drop and preparation method thereof Download PDFInfo
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- CN105708844A CN105708844A CN201410737403.4A CN201410737403A CN105708844A CN 105708844 A CN105708844 A CN 105708844A CN 201410737403 A CN201410737403 A CN 201410737403A CN 105708844 A CN105708844 A CN 105708844A
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Abstract
The invention provides a tobramycin and dexamethasone nanosuspension eye drop, which is prepared from the following active pharmaceutical ingredients and auxiliary ingredients in percentage by weight: 0.1 percent w/v of dexamethasone, 0.3 percent w/v of tobramycin, 0.2 to 0.5 percent w/v of water-solubility macromeclecule polymers, 0.025 to 0.1 percent v/v of wetting agents, 0.3 to 0.6 percent w/v of osmotic pressure regulators, 1.0 to 1.5 percent v/v of pH regulators, 0.0025 to 0.01 percent w/v of metal ion complexing agents and 0.1 to 0.3 percent v/v of preservatives. The invention also provides a preparation method of the eye drop. The preparation method of the tobramycin and dexamethasone nanosuspension eye drop has the advantages that the process is simple and convenient; the repeatability is high; a degerming method is simple and effective; the auxiliary ingredients can be easily obtained; and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of tobramycin dexamethasone nanometer suspension eye drop.
Background technology
Tobramycin dexamethasone eye drop is glucocorticoid and antibiotic compound preparation, is usually used in treating the antibacterial to the ophthalmic inflammatory pathological changes of adrenocortical hormone sensitivity, ocular and infects and latent infection disease, can alleviate edema and inflammatory reaction；It is also applied for chronic anterior uveitis, chemical, radioactivity, Burn and foreign body penetrance corneal injury；The eye antibacterial common to some and pathogenic bacterial infection also have certain curative effect.
The former commodity " allusion quotation must be very " (TOBRADEX) by name grinding medicine of said preparation, are produced by Alcon Universal Ltd. of the U.S. (ALCON), and nineteen ninety-five enters China market.Owing to the size of suspendible eye drop is closely related with the comfort level of patient's eye drip, curative effect of medication and action time in the tissue etc., therefore, improve preparation technology, effectively reduce the particle diameter of dexamethasone in domestic similar eye drop, for promoting quality standard in the industry, the therapeutic effect improving domestic tobramycin dexamethasone eye drop is most important.In addition, the sterilizing of current tobramycin dexamethasone eye drop key component dexamethasone mainly adopts dry method sterilizing, irradiation sterilization, the Chinese invention patent " method for making of compound tobramycin suspension for eye " if: the patent No. is ZL97105772.9 namely disclose the use of 160 DEG C of xeothermic or 2-2.5 Megarad radiation orThe method that dexamethasone is carried out sterilizing by the irradiation under ultraviolet ray of wavelength, but there is sterilizing and not thoroughly or sterilizing installation had the defect of particular/special requirement in above-mentioned sterilization.
Summary of the invention
The technical scheme is that and provide a kind of new tobramycin dexamethasone nanometer suspension eye drop.The preparation method that another technical scheme of the present invention there is provided this eye drop.
The invention provides a kind of tobramycin dexamethasone nanometer suspension eye drop, it is characterised in that: this eye drop is prepared from by crude drug and the adjuvant of following percentage composition:
Dexamethasone 0.1%w/v, tobramycin 0.3%w/v, high molecular weight water soluble polymer 0.2～0.5%w/v, wetting agent 0.025～0.1%v/v, osmotic pressure regulator 0.3～0.6%w/v, pH adjusting agent 1.0～1.5%v/v, complexing of metal ion agent 0.0025～0.01%w/v, preservative 0.1～0.3%v/v.
Wherein, described high molecular weight water soluble polymer is: hypromellose (E50), hypromellose (15000cps), hypromellose (K100M), hypromellose (K100) hypromellose (E15), hypromellose (low replacement)；Described wetting agent is: Tween 80；Described osmotic pressure regulator is: sodium chloride；Described pH adjusting agent is: dilute hydrochloric acid, dilute sulfuric acid；Described complexing of metal ion agent is: disodium edetate；Described preservative is: benzalkonium bromide, benzalkonium chloride.
Wherein, described high molecular weight water soluble polymer is: hypromellose；Described wetting agent is: Tween 80；Described osmotic pressure regulator is: sodium chloride, sodium sulfate；Described pH adjusting agent is: dilute hydrochloric acid；Described complexing of metal ion agent is: disodium edetate；Described preservative is: benzalkonium bromide.
Specifically, this eye drop is prepared from by crude drug and the adjuvant of following percentage composition:
Dexamethasone 0.1%w/v, tobramycin 0.3%w/v, sodium chloride 0.4%w/v, hypromellose 0.4%w/v, disodium edetate 0.005%w/v, concentration be 5% benzalkonium bromide solution 0.2%v/v, Tween 80 0.05%v/v, sodium sulfate 1.0%w/v, dilute hydrochloric acid 1.5%v/v.
Wherein, the pH value of described eye drop is 6.0～6.5.
Present invention also offers a kind of method preparing described eye drop, it comprises the steps:
A, weigh other components except dexamethasone, dilute hydrochloric acid according to formula ratio, dissolved with water for injection, through 0.22 μm of filtering with microporous membrane, obtain settled solution A；
B, weighing dexamethasone according to formula ratio, the water for injection to prepare total amount 15% suspends, and adds dilute hydrochloric acid and regulates pH value to 3.0～4.0, high cut disperse emulsification technology is adopted to carry out emulsification pretreatment, prepare dexamethasone suspension, degerming through 0.22 μm of filtering with microporous membrane, obtain suspension B；
C, suspension B is proceeded in solution A, stirring, mix homogeneously, regulate pH value to 6.0～6.5, to obtain final product.
Wherein, the emulsification condition described in b step is: 1000r/min, 15min.
Wherein, in the suspension B described in b step, the mean diameter of dexamethasone microgranule is less than 120nm, and the dexamethasone diameter of particle of 80% is at below 100nm.
The present invention is directed to the deficiency of above-mentioned preparation method, studied by repetition test, it is proposed that a kind of new tobramycin dexamethasone nanometer suspension eye drop preparation method, solve the problems referred to above, greatly improve product quality and the therapeutic effect of said preparation kind.
The preparation method production technology of tobramycin dexamethasone nanometer suspension eye drop provided by the invention is easy, favorable reproducibility, and degerming method is simply effective, and adjuvant is easy to get, and is suitable for industrialized production.
The benefit of the present invention specifically includes that
1) dexamethasone is insoluble in water, and the particle diameter therefore preparing into suspendible eye drop is related to product quality and therapeutic effect, and the control of this active component size is the key of preparation technology.Comparing existing preparation method, the present invention can reduce the particle diameter of dexamethasone further, is effectively improved the bioavailability of this eye drop and extends the action time of medicine, significantly improving comfort level during patient's eye drip.
2) the preparation method mild condition of the present invention, easy and simple to handle, favorable reproducibility；Stable and reliable product quality, evident in efficacy.
3) present invention effectively reduces dexamethasone particle diameter, therefore it is degerming only with 0.22 μm of filtering with microporous membrane, avoid the current normally used dry method sterilizing of this component, the irradiation sterilization particular/special requirement to equipment, simplify sterilization process, while guaranteeing product quality, substantially increase production efficiency.
4) adopting product prepared by present invention process, because reducing the consumption of dexamethasone particle diameter and adjuvant, prove without eye zest through rabbit eye irritant experiment, result of the test is consistent with former triturate " allusion quotation must be very ", and eye uses comfortable safety.
5) proving through the rabbit test of pesticide effectiveness, the concentration that eye drop prepared by the employing present invention process more former triturate of concentration " allusion quotation must be very " in rabbit eyes portion organizes is organized in rabbit eyes portion is higher, illustrates that its drug effect is better than former triturate.
6) adopting the product prepared of present invention process, each side such as emphasis quality index, safety, effectiveness is superior to current similar formulation products.
Accompanying drawing explanation
Fig. 1 a. is former grinds group drug level
Fig. 1 b. self-control group drug level
Detailed description of the invention
It is further illustrated by the examples that follow the present invention, but following example are not construed as limiting the invention.
Embodiment one:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weighing the hypromellose (E50) of recipe quantity, be dissolved in appropriate water for injection, 0.22 μm of filtering with microporous membrane is degerming, mixes with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
Embodiment two:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weigh the hypromellose (15000cps) of recipe quantity, be dissolved in appropriate water for injection, degerming with 0.22 μm of filtering with microporous membrane, mix with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
Embodiment three:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weighing the hypromellose (K100M) of recipe quantity, be dissolved in appropriate water for injection, 0.22 μm of filtering with microporous membrane is degerming, mixes with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
Embodiment four:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weighing the hypromellose (K100) of recipe quantity, be dissolved in appropriate water for injection, 0.22 μm of filtering with microporous membrane is degerming, mixes with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
Embodiment five:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weighing the hypromellose (E15) of recipe quantity, be dissolved in appropriate water for injection, 0.22 μm of filtering with microporous membrane is degerming, mixes with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
Embodiment six:
Prescription:
Preparation technology:
1) weighing the tobramycin of recipe quantity, sodium chloride, disodium edetate, be dissolved in appropriate water for injection, measure benzalkonium bromide solution, the Tween 80 solution above-mentioned solution of addition, stir, 0.22 μm of filtering with microporous membrane is degerming；Weighing the hypromellose (low replacement) of recipe quantity, be dissolved in appropriate water for injection, 0.22 μm of filtering with microporous membrane is degerming, mixes with above-mentioned solution, standby.
2) dexamethasone of recipe quantity is weighed, it is suspended in appropriate water for injection, add dilute hydrochloric acid and regulate pH value to 3.0～4.0, high-shearing dispersion emulsifying machine shears 15min (1000r/min), it is prepared into dexamethasone suspension (particle size range: 50～200nm), 0.22 μm of filtering with microporous membrane is degerming, standby.
3) by 2) liquid proceeds to 1) liquid, stir 15min, add dilute hydrochloric acid and regulate pH value to 6.0.
For proving the creativeness of the present invention, with the former eye drop TOBRADEX that grinds of ALCON for comparison, the product quality carried out and the contrast of curative effect of medication index are investigated, and experimental data is as follows:
Test example 1. eye drop formulation optimization of the present invention
Under the premise determining principal agent recipe quantity (tobramycin: 0.3%, dexamethasone 0.1%), kind and consumption to adjuvant used by the present invention are optimized screening, and the quality index (pH value, particle diameter, sedimentation volume ratio, osmotic pressure) of each test group product is carried out contrast investigation, experimental result is in Table 1a, table 1b.
Table 1a. prescription composition is investigated
Table 1b. prescription group sample quality Indexs measure
Note: particle diameter item " >=90% (μm) " represents: from little particle, the maximum particle diameter of the accumulation distributed areas containing all particles 90%.
Conclusion: by table 1a, table 1b result of the test it can be seen that prescription of the present invention is preferably: 2#.
The optimization of test example 2. eye drop emulsifying parameter of the present invention
Owing to the quality of product is affected bigger by preparation technology, when determining prescription composition and consumption, feature in conjunction with this preparation, the high spot reviews of the present invention emulsifying parameter impact on product quality: the rotating speed of mulser is being set on the basis of 1000r/min, emulsification times is optimized, and with particle diameter, settling volume for Testing index, product prepared by different condition carries out contrast and investigates, and result is in Table 2.
The contrast of table 2. emulsification condition is investigated
Conclusion: as shown in Table 2, the emulsifying parameter described in b step is preferably: 1000r/min, 15min.
Test example 3. product quality indicator (the tobramycin dexamethasone eye drop quality standard with reference to state approval)
Table 3. product quality comparing result
Conclusion: adopt the more former triturate of the product mean diameter prepared of present invention process to reduce half, target particle size is substantially better than and former grinds product.
Test example 4. Ocular irritation is tested
According to tobramycin dexamethasone eye drop description, select the big ear rabbit 20 of Japan, be divided into two groups (one groups: self-control, two groups: former grind), adopt and test with group rabbit consubstantiality right and left eyes self-contrast method.Rabbit left eye instills tobramycin dexamethasone eye drop, and right eye instills normal saline as comparison.
Dosage: 2 droplets/time (100 μ l).
Medication: administration in eye conjunctival sac, the face about 10 seconds of gently sleeping after administration.
Repeat administration: successive administration two weeks (14d), every day is sooner or later respectively administered once, before administration every time and after being administered for the last time 1,2,4,24,48 and 72h eye is checked.Record cornea, iris, conjunctiva and other degree of impairments observed.According to " Draize Ocular irritation test scores standard ": the irritant reaction score value of the cornea of every rabbit, iris and conjunctiva is added, i.e. the total mark of all animal subject Eye irritation reactions.By total mark divided by number of animals, i.e. the animal subject last score value to eye irritation, result is in Table 4.
Table 4. rabbit eyes zest comparing result
Conclusion: adopt present invention process prepare products obtained therefrom, to eye nonirritant, with former grind consistent.
Test example 5. Tissue is tested
According to tobramycin dexamethasone eye drop description, select the big ear rabbit 28 of Japan, be divided into two groups of (groups 1: self-control；Group 2: former grind), give rabbit eyes and instill tobramycin dexamethasone eye drop.
Dosage: 2 droplets/time/only (100 μ l).
Medication: administration in eye conjunctival sac, the face about 10 seconds of gently sleeping after administration.
Sample extraction after administration: after giving rabbit tobramycin dexamethasone eye drop medicine, 0.5h after administration, 1h, 1.5h, 2h, 3h, 4h, 6h respectively takes 2 tested rabbit, put to death, operation separates the vitreous body of rabbit eyes, iris, sclera, retina and choroid, in tissue homogenate and vitreous body, medicine is extracted with dichloromethane, separate organic facies, extract 3 times, merge organic facies, and on 70 DEG C of thermostat water baths, dry up with nitrogen, the 40% aqueous acetonitrile solution of residue 0.2ml, HPLC-MS/MS detection is adopted to analyze, distiller’s yeast line chart during drafting, result is shown in Fig. 1 a, Fig. 1 b.
Conclusion: by Fig. 1 a, Fig. 1 b it can be seen that adopt improvement technique to prepare products obtained therefrom with former triturate in rabbit eyes, the amount of contained dexamethasone is basically identical；The dose of different periods compares display, and the release trend of product prepared by the present invention is more mild, and action effect is more preferably.
Test example 6. Sterility testing
With reference to Chinese Pharmacopoeia version annex Ⅺ H sterile detection method in 2010, with staphylococcus aureus for positive control, investigating new product is aseptic, testing result is in Table 5.
Table 5. sterility test result
Conclusion: product is aseptic meets regulation, illustrates the degerming mode (being improved to: filtration sterilization) that patent of the present invention is improved by high-temperature heat sterilization, also can guarantee that product is aseptic while reducing production capacity, further illustrates the advance improving technique.
In order to overcome dexamethasone because dissolubility is poor, under wet heat condition, crystal formation easily changes and causes the deficiency that this component sterilizing methods is limited, present invention improves over the formula of this eye drop, adopt high cut disperse emulsification technology, by optimizing shear parameter, the mean diameter of dexamethasone is controlled at below 120nm by success, simplify the technique in the past needing tobramycin, dexamethasone are respectively adopted different sterilizing methods, the aseptic of this product can be realized only with heat sterilization technique, enormously simplify production technology.Comparing former triturate, the particle diameter of this invention product substantially reduces, and zest is less, and the biological more former triturate of curative effect has further raising.
Compare and former grind eye drop TOBRADEX, present invention optimizes pharmaceutical formulation, select the hypromellose that price is more cheap to replace hydroxyethyl cellulose as suspending agent, and reduce its consumption as far as possible, while guaranteeing clinical therapeutic efficacy, improve the safety of eye drop；By improving preparation technology, effectively reduce the particle diameter of dexamethasone in tobramycin dexamethasone eye drop, improve curative effect and the comfort level of said preparation, avoid the defect that above-mentioned sterilization process exists, provide a kind of simple to operate, be prone to commercial production and the production technology of the tobramycin dexamethasone nanometer suspension eye drop of constant product quality.
Claims (7)
1. a tobramycin dexamethasone nanometer suspension eye drop, it is characterised in that: this eye drop is prepared from by crude drug and the adjuvant of following percentage composition:
Dexamethasone 0.1%w/v, tobramycin 0.3%w/v, high molecular weight water soluble polymer 0.2～0.5%w/v, wetting agent 0.025～0.1%v/v, osmotic pressure regulator 0.3～0.6%w/v, pH adjusting agent 1.0～1.5%v/v, complexing of metal ion agent 0.0025～0.01%w/v, preservative 0.1～0.3%v/v.
Wherein, described high molecular weight water soluble polymer is: hypromellose (E50), hypromellose (15000cps), hypromellose (K100M), hypromellose (K100) hypromellose (E15) or hypromellose (low replacement)；Described wetting agent is: Tween 80；Described osmotic pressure regulator is: sodium chloride, sodium sulfate；Described pH adjusting agent is: dilute hydrochloric acid, dilute sulfuric acid；Described complexing of metal ion agent is: disodium edetate；Described preservative is: benzalkonium bromide, benzalkonium chloride.
2. eye drop according to claim 1, it is characterised in that: described high molecular weight water soluble polymer is: hypromellose；Described wetting agent is: Tween 80；Described osmotic pressure regulator is: sodium chloride；Described pH adjusting agent is: dilute hydrochloric acid；Described complexing of metal ion agent is: disodium edetate；Described preservative is: benzalkonium bromide.
3. eye drop according to claim 2, it is characterised in that: this eye drop is the crude drug by following percentage composition and adjuvant is prepared from:
Dexamethasone 0.1%w/v, tobramycin 0.3%w/v, sodium chloride 0.4%w/v, hypromellose 0.4%w/v, disodium edetate 0.005%w/v, concentration are 5% benzalkonium bromide solution 0.2%v/v, Tween 80 0.05%v/v, sodium sulfate 1.0%w/v, dilute hydrochloric acid 1.5%v/v.
4. the eye drop described in claims 1 to 3 any one, it is characterised in that: the pH value of described eye drop is 6.0～6.5.
5. the method preparing eye drop described in claim 3 or 4, it comprises the steps:
A, weigh other components except dexamethasone, dilute hydrochloric acid according to formula ratio, dissolved with water for injection, through 0.22 μm of filtering with microporous membrane, obtain settled solution A；
B, weighing dexamethasone according to formula ratio, the water for injection to prepare total amount 15% suspends, and adds dilute hydrochloric acid and regulates pH value to 3.0～4.0, high cut disperse emulsification technology is adopted to carry out emulsification pretreatment, prepare dexamethasone suspension, degerming through 0.22 μm of filtering with microporous membrane, obtain suspension B；
C, suspension B is proceeded in solution A, stirring, mix homogeneously, regulate pH value to 6.0～6.5, to obtain final product.
6. preparation method according to claim 5, it is characterised in that: the emulsification pretreatment condition described in b step is: 1000r/min, 15min.
7. preparation method according to claim 5, it is characterised in that: in the suspension B described in b step, the mean diameter of dexamethasone microgranule is less than 120nm, and the dexamethasone diameter of particle of 80% is at below 100nm.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105997866A (en) * | 2016-07-13 | 2016-10-12 | 成都明慈医药科技有限公司 | Suspension containing dexamethasone and preparation method of suspension |
| CN113559059A (en) * | 2021-07-21 | 2021-10-29 | 上海应用技术大学 | Cationic nano suspension and preparation method and application thereof |
| CN115006412A (en) * | 2022-05-20 | 2022-09-06 | 北京诺康达医药科技股份有限公司 | Compound tobramycin eye drops and preparation method thereof |
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| CN103565816A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Tobramycin-dexamethasone eye drops |
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| CN103565816A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Tobramycin-dexamethasone eye drops |
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| 余庆臻: "复方妥布霉素混悬滴眼剂的研制", 《上海医药》 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105997866A (en) * | 2016-07-13 | 2016-10-12 | 成都明慈医药科技有限公司 | Suspension containing dexamethasone and preparation method of suspension |
| CN105997866B (en) * | 2016-07-13 | 2019-08-20 | 成都明慈医药科技有限公司 | A kind of suspension and preparation method thereof containing dexamethasone |
| CN113559059A (en) * | 2021-07-21 | 2021-10-29 | 上海应用技术大学 | Cationic nano suspension and preparation method and application thereof |
| CN113559059B (en) * | 2021-07-21 | 2023-04-28 | 上海应用技术大学 | Cationic nano suspension and preparation method and application thereof |
| CN115006412A (en) * | 2022-05-20 | 2022-09-06 | 北京诺康达医药科技股份有限公司 | Compound tobramycin eye drops and preparation method thereof |
| CN115006412B (en) * | 2022-05-20 | 2023-11-10 | 北京诺康达医药科技股份有限公司 | Compound tobramycin eye drops and preparation method thereof |
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| CN105708844B (en) | 2019-02-19 |
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