CN106236706A - A kind of levofloxacin hydrochloride slow release eye drop - Google Patents
A kind of levofloxacin hydrochloride slow release eye drop Download PDFInfo
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- CN106236706A CN106236706A CN201610774150.7A CN201610774150A CN106236706A CN 106236706 A CN106236706 A CN 106236706A CN 201610774150 A CN201610774150 A CN 201610774150A CN 106236706 A CN106236706 A CN 106236706A
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
A kind of levofloxacin hydrochloride slow release eye drop, it is with levofloxacin hydrochloride as pharmacodynamic raw materials, it is equipped with hyaluronic acid sodium and plays thickening agent effect, it is equipped with complexing of metal ion agent, osmotic pressure regulator and pH adjusting agent described on the acceptable pharmaceutics of eye local again, the ophthalmic preparation of prepared one-tenth, in every 100 weight portion finished product preparation, the content of levofloxacin hydrochloride is 0.30～1.00 weight portions；In every 100 weight portion finished product preparation, the content of hyaluronic acid sodium is 0.1～1.00 weight portions.Medicinal liquid viscosity of the present invention is high, extends the medicine holdup time within the eye, adds the absorption of medicine, improves the bioavailability of eye drop.The present invention is added without any preservative, improves the biological safety of eye drop.
Description
Technical field
The present invention relates to medicinal preparation, especially the medicine of ophthalmology external bacterial-infection resisting.
Background technology
Various bacteria all can attack human body eye surface, causes eye antibacterial to infect, is most commonly that bacterial conjunctivitis
And bacterial keratitis.If this type of patient not treat in time and effectively or Therapeutic Method is improper by acceptance, may result in a conjunctiva
Major injury, cornea ulcer with perforation, make visual deterioration the most blind.Clinical research find, quinolones be treatment this two
Plant the more effective medicine of ocular disease.Levofloxacin hydrochloride is third generation quinolone antibiotic, and it can permeates cell membranes
In entrance bacterial body, destroy the activity of DNA of bacteria gyrase so that it is the duplication of transcribing of DNA cannot be carried out, and then causes antibacterial
Cellular entities apoptosis.Additionally, the antimicrobial spectrum of levofloxacin hydrochloride is relatively wide, cover most gram positive bacteria, Ge Lanyin
Property bacterium and propionibacterium etc. easily induce the anaerobism Pseudomonas of ocular infection disease.Therefore, the most clinical conventional hydrochloric acid levofloxacin
Bacterial conjunctivitis that star eye drops in treatment sensitive bacterial causes, bacterial keratitis.
But, the levofloxacin eye drops without thickening agent of current Clinical practice can not stop the most for a long time
Stay, need repeatedly eye drip to maintain and effectively treat concentration；Tradition Levofloxacin Eye drop/levofloxacin hydrochloride eye drip
The eye drops such as liquid/levofloxacin lactate eye drops all use benzalkonium chloride (BAC) can suppress eye drip as preservative, preservative
Liquid stores and the germ contamination of the process of use, but for needing the patient of life-time service eye drop, the preservative in eye drop
Corneal epithelium lipid layer can be destroyed, change the permeability of cell, cause more reactive compound to pass through.Preservative also can cause
As conjunctival congestion, shed tears, photophobia, the anaphylaxis such as calcination or sensation of pricking, preservative not only damages ocular cell slimy,
Cause lacrimal gland function to be degenerated, even can damage eyes and cause blindly.
Therefore, exploitation one can stop the most for a long time, prevents from storing, transporting and use by self bacteriostasis
Bacterial conjunctivitis, the medicine of bacterial keratitis that the treatment sensitive bacterial of the germ contamination of process causes become urgently to be resolved hurrily
Thing.
Summary of the invention
It is an object of the invention to provide that a kind of local action is effective, bioavailability is high, stable in properties, toxic and side effects relatively
Bacterial conjunctivitis that little, drug main to cause at locally acting treatment sensitive bacterial, the medicine system of bacterial keratitis
Agent.
The present invention is achieved in that
A kind of levofloxacin hydrochloride slow release eye drop, is with levofloxacin hydrochloride as pharmacodynamic raw materials, is equipped with hyaluronic acid sodium and rises
Thickening agent effect, then be equipped with complexing of metal ion agent described on the acceptable pharmaceutics of eye local, osmotic pressure regulator and
PH adjusting agent, the ophthalmic preparation of prepared one-tenth, in every 100 weight portion finished product preparation the content of levofloxacin hydrochloride be 0.30～
1.00 weight portion；In every 100 weight portion finished product preparation, the content of hyaluronic acid sodium is 0.1～1.00 weight portions；Hyaluronic acid sodium is
Good consumption is, in every 100 weight portion finished product preparation, the content of hyaluronic acid sodium is 0.488% weight portion.
Described complexing of metal ion agent is disodium edetate, sodium gluconate, sodium tartrate, sodium citrate, amino three second
Any one of acid or the combination in any of described kind.The consumption of complexing of metal ion agent is with the weight with levofloxacin hydrochloride
Ratio is expressed as, levofloxacin hydrochloride: complexing of metal ion agent=1: 0.01～0.50.
Described osmotic pressure regulator is any in sodium chloride, potassium chloride, glucose, boric acid, Borax, glycerol, mannitol
A kind of or the combination in any of described kind, the osmotic pressure molar density of regulation eye drop is 280～330mOsmol/kg.
Described pH adjusting agent is any one of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid, Borax or institute
Stating the combination in any of kind, the pH value of regulation finished product medicament is 5.0～7.0.
The levofloxacin hydrochloride slow release eye drop without preservative prepared by the inventive method, utilizes hydrochloric acid left oxygen fluorine
The antibiotic and sterilizing ability widely of husky star self, except treating bacterial conjunctivitis, the bacterial corneal that sensitive bacterial causes
Outside inflammation, moreover it is possible to prevent from storing, transport and use during the pollution of microorganism, reduce life-time service eye drop pair Han preservative
The risk of damage of ocular, improves biological safety.
In formula, thickening agent hyaluronic acid sodium is a kind of natural materials being present in eye and the some other position of health.Glass
The characteristic of acid sodium is can to form a kind of rule, stable, long-acting moisture film in ocular surface, is difficult to be washed away, and will not
Cause blurred vision and eyes can be protected for a long time not have dry and astringent and excitement.Hyaluronic acid sodium can make the active drug for the treatment of level
Thing, at ocular extended residence time, improves ophthalmic bioavailability, substantially reduces administration number of times, contributes to increasing complying with of patient
Property and treatment success rate, and the medicine stimulation to eye can be alleviated, promote the healing of eye wounds, alleviate ophthalmic uncomfortable symptom.
Accompanying drawing explanation
Fig. 1 is experimental example 2 illustration, the average drug-time curve (n after the eye drop entitled of the present invention of figure and reference preparation administration
=5)
Detailed description of the invention
The invention will be further described by the following examples.
The preparation of embodiment 1-6 does not contains levofloxacin hydrochloride slow release eye drop raw material components and the consumption of preservative
By technical solution of the present invention, the preparation levofloxacin hydrochloride slow release eye drop available adjuvant kind without preservative
It is not limited to kind listed by upper table, it is also possible to have following multiple choices:
Complexing of metal ion agent: complexing of metal ion agent conventional on pharmaceutics can be used, such as disodium edetate, gluconic acid
Any one of sodium, sodium tartrate, sodium citrate, aminotriacetic acid or the combination in any of described kind；Complexing of metal ion agent
Consumption be expressed as with the weight ratio with levofloxacin, levofloxacin hydrochloride: complexing of metal ion agent=1: 0.01～
0.50。
The osmotic pressure molar density using osmotic pressure regulator regulation finished product eye drop is 280～330mOsmol/kg；Institute
Stating osmotic pressure regulator is any one of sodium chloride, potassium chloride, glucose, boric acid, Borax, glycerol, mannitol or described
The combination in any of kind.
The pH value using pH adjusting agent regulation finished product eye drop is 5.0～7.0；Described pH adjusting agent is sodium hydroxide, salt
Any one of acid, sodium citrate, citric acid, boric acid, Borax or the combination in any of described kind, the pH of regulation finished product medicament
Value is 5.0～7.0.
Preparation method is for make it disperse to let cool thickening agent hyaluronic acid sodium water for injection, as solution 1；Use water for injection
Dissolved metal ions chelating agent, as solution 2；Merge two liquid, stir, the left oxygen of hydrochloric acid that addition water for injection has dissolved
Flucloxacillin, adds to the full amount of water for injection, and stirs evenly.The osmotic pressure molar density using osmotic pressure regulator to regulate finished product eye drop is
260～340mOsmol/kg；The pH value using pH adjusting agent regulation finished product eye drop is 5.0～7.0, filters, subpackage, to obtain final product.
Used by prepare utensil and packing container must sterilizing.
The beneficial effect of the present invention levofloxacin hydrochloride slow release eye drop without preservative is obtained by following experimental example
To prove.
Experimental example 1 pharmacodynamics test
As the preparation prepared by the method that the embodiment of the present invention 2 is recorded as trial target, 0.3% levofloxacin hydrochloride is used to drip
Ocular fluid (reference preparation I, Beijing Lixiang Pharmaceutical Co., Ltd, trade name: Lang Yue, specification 24mg:8ml), 0.3% hydrochloric acid left oxygen fluorine
Husky star eye drop (reference preparation II, Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd., trade name: Helen, specification 5ml:15mg),
Normal saline is as reference substance, by pharmacodynamics test, illustrates that levofloxacin eye drops of the present invention has slow release effect,
Therapeutic effect can be improved.
1. the foundation of damage type bacterial conjunctivitis model
The preparation of 1.1 infectious bacteria suspensions: the staphylococcus aureus liquid cultivating 2d is diluted to 5 with 0.9% sodium chloride injection
×109cfu·ml-1(using standard opacity tube to determine).
1.2 conjunctival damage and conjunctiva infect: with aseptic No. 6 syringe needles in rabbit upper tarsal conjunctiva draw 4mm × 4mm "+", just to draw
Being broked into preferably, pulling eye eyelid becomes little cup-shaped gently, instills 2 infectious bacteria suspensions to conjunctiva scar carefully, restores eyelid gently, all
The images of left and right eyes of rabbit all carries out conjunctiva infection according to same method.
2. the treatment of damage type bacterial conjunctivitis
2.1 experiments set 3 groups:
A. self-control levofloxacin hydrochloride slow release eye drop+Helen's eye drop；
B. self-control levofloxacin hydrochloride slow release eye drop+bright happy eye drop；
C. self-control levofloxacin hydrochloride slow release eye drop+physiological saline solution.
Often 6 animals of group, every animal left eye and right eye are respectively dropped into trial target and reference substance.To infecting conjunctivitis animal
Continuous use 7d, each 1 time of every day at upper and lower noon, each 0.1ml, observes eye and sheds tears and secretions situation, conjunctival congestion and edema
Situation.
2.2 observation index and standards of grading: sign (conjunctiva, edema, secretions) according to severity extent be divided into without, slight,
It is 0 point, 1 point, 2 points, 3 points that moderate, severe are scored respectively.Conjunctival congestion is divided into: be 0 point without hyperemia；Palpebral conjunctiva is congested, and color is scarlet
It it is 1 point；Palpebral conjunctiva and fornical conjunctiva are congested, color between scarlet and purplish red be 2 points；Palpebral conjunctiva and bulbar conjunctiva are congested, and color is purplish red is 3
Point.Chemosis is divided into: be 0 point without edema；Visible chemosis is 1 point；Edema between 1～3/be 2 points；Conjunctiva water
Swelling and protruding from eyeball is 3 points.Secretions is done nothing 0 point, and less is 1 point, mostly relatively is 2 points, i.e. promising 3 points of a lot of wiping.
3. the therapeutic effect of bacterial conjunctivitis
After infection of staphylococcus aureus 24h, lagophthalmos is aubergine, with obvious edema and to make eye be semi-closed shape, great Liang Fen
Secretion soaks eyelid, eyelashes and eye peripheral region.The concrete therapeutic effect of bacterial conjunctivitis is shown in Table 1.
Each group of ocular injury score-sheet tested by table 1
Result shows, sample sets disappears in d3 edema and secretions, and conjunctiva has slight hyperemia, and d5 conjunctival congestion disappears；Helen's group
Still having slight conjunctival congestion and edema at d3, secretions disappears, and d4 edema disappears, and d5 conjunctival congestion disappears；Lang Yue group is at d6 still
Having slight conjunctival congestion, d7 is wholly absent；Normal saline still has slight conjunctival congestion and edema at d7.Therefore, self-control hydrochloric acid is left
Ofloxacin slow-release eye drops in treatment effect is better than matched group, is particularly substantially better than Lang Yue and saline control, and Helen
Comparison drug effect is suitable.
The experimental example 2 pharmacokinetic studies in rabbit aqueous humor
As the preparation prepared by the method that the embodiment of the present invention 2 is recorded as trial target, 0.3% levofloxacin hydrochloride is used to drip
Ocular fluid (reference preparation I, Beijing Lixiang Pharmaceutical Co., Ltd, trade name: Lang Yue, specification 24mg:8ml), 0.3% hydrochloric acid left oxygen fluorine
Husky star eye drop (reference preparation II, Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd., trade name: Helen, specification 5ml:15mg),
Normal saline is as reference substance, by the pharmacokinetic studies in rabbit aqueous humor, illustrates that levofloxacin hydrochloride of the present invention drips
Ocular fluid has slow release effect, can improve the bioavailability of medicine.
1. medication: use the design of own control, cross-over experiment, clean phase 7d.Healthy new zealand rabbit 25, divides at random
It is 5 groups, often group 5 10, experimentation be can't help drinking-water.Often group successively gives to make levofloxacin hydrochloride slow release by oneself the most at random and drips
Ocular fluid 50 μ l, 0.17,0.5,0.75,1,1.5,2,3,4,6 and 8h extraction aqueous humor 100 μ l after being administered, measure through HPLC and be administered
The content of levofloxacin in rear rabbit aqueous humor.7d cleans after date, gives reference preparation I, same treatment.After date is cleaned again through 7d
Give reference preparation II, same treatment.
2. data analysis: carry out data process and mapping with 3p97, Microsoft Excel 2003 and Origin6.0,
Calculate half-life t1/2With mean residence time MRT, curve-parabola-fitting method is utilized to calculate tmaxAnd Cmax。AUC0-tWith trapezoidal faces area method
Try to achieve, AUC0-∞=AUC0-t+Cn/ λ, and calculate relative bioavailability Fr.With paired t inspection to self-control eye drop and reference system
Agent I, II carries out relative bioavailability statistical analysis, the results are shown in Table 2.With AUC0-tCalculate, show that self-control eye drop is to reference system
The relative bioavailability of agent I, II is 213.5% and 110.4%, and average Drug-time curve is shown in Fig. 1 eye drop of the present invention and reference
Average drug-time curve (n=5) figure after preparation administration.
The main pharmacokinetic parameters (x ± s, n=5) of eye drop and reference preparation made by oneself by table 2
Result shows, after lagophthalmos single-dose, Pharmacokinetic Results display levofloxacin hydrochloride all meets one-level in 3 kinds of preparations
Kinetic character, the AUC of this preparation is 2 times of reference preparation I, and bioavailability significantly improves；After being administered 4h, the room of this preparation
Water drug level is significantly higher than reference preparation I, and action time significantly extends；Bioavailability is without significantly compared with reference preparation II
Difference.Therefore, in ordinary eye drops, add thickening agent, aqueous humor concentration can be increased and extend action time, improving the left oxygen of hydrochloric acid
Flucloxacillin, in the curative effect of eye, reduces eye drip number of times.
Experimental example 3 vitro cytotoxicity, acute toxicity, irritation test
As the preparation prepared by the method that the embodiment of the present invention 2 is recorded as trial target.With reference to GB/T16886.5-2003 " medical treatment
Apparatus biological assessment the 5th part: vitro cytotoxicity is tested " in test method evaluate the vitro cytotoxicity of this eye drop；
With reference to " pharmacological experimental methodology ", evaluate its acute toxicity and skin wound repair.
1. vitro cytotoxicity test
The preparation of 1.1 samples:
A. test specimen: 0.1ml is made by oneself levofloxacin hydrochloride slow release eye drop and drops in 8 layers of filter paper dick of diameter 10mm
On；
B. negative control: the high density polyethylene (HDPE) disk of a diameter of 10mm；
C. positive control: scribble the polrvinyl chloride disk of a diameter of 10mm of dioctyl phthalate；
D. saline control: 0.1ml normal saline is dropped on 8 layers of filter paper dick of diameter 10mm.
1.2 operating procedures: use agar diffusion method detection cytotoxicity.Take the l cell (letter normally passed on
Claim L-929 cell) 10ml, it is inoculated in the culture dish of a diameter of 90mm, every ware inoculating cell 3 × 106Individual, at 37 DEG C, 5%CO2
After incubator cultivates 24h, discard original fluid, add 10ml agar culture medium (3% agar and the RPMI 1640 cell training of 2 times
Nutrient solution is by 1: 1 mixing), after it solidifies, put in each plate positive and negative and each 1 of saline control, test specimen 2,
Operation repetitive 5 ware, in 37 DEG C, 5%CO2Incubator is further cultured for 24h, discards all samples (test specimen, positive and negative and physiology
Saline control), after 0.01% neutral red staining 20min, carry out result evaluation.
1.3 deliberated indexs: use under inverted microscope viewing test sample and positive and negative and saline control disk and week
Enclose region of fading, and fade index and the dissolving index of each sample of metrics evaluation as shown in table 3, then determine each group thin by table 4
The classification of cellular toxicity reaction.
Table 3 fades index and dissolves index assessment standard
Table 4 cell-cytotoxic reaction grading evaluation criteria
| Classification | Fade index | Dissolve index | Explanation |
| 0 | 0 | 0 | No cytotoxicity |
| 1 | 1 | 1 | Mild hepatocellular toxicity |
| 2 | 2～3 | 2～3 | Moderate cytotoxicity |
| 3 | 4～5 | 4～5 | Severe cytotoxicity |
1.4 result of the tests:
The each group of index that fades refers to table 5 with dissolving index results.
Table 5 is respectively organized cell and is faded index and dissolve index results
Being analyzed from table 5, negative control, positive control, saline control, the cell-cytotoxic reaction of test specimen are respectively
0,2,1,1 grade.
2. acute toxicity test
2.1 select mice 20, are equally divided into test sample group and blank group, often group 10, all use intravenous injection mode to give
Medicine, test sample group presses 15mg kg with levofloxacin hydrochloride slow release eye drop-1It is administered once, is equivalent to clinical consumption per day of being grown up
(adult every day levofloxacin hydrochloride be 4.5mg, proportionately body mass 60kg calculate, dosage is 0.075mg kg-1)200
Times；Blank group is to the normal saline of same volume.After injection, observe general state and the death toll of 14d mice, and
Record changes of body mass.
2.2 result of the tests: after injection mice the observation period in order, movable, appetite normal, breathes steadily, without fainting from fear,
The toxic reactions such as paralysis and death, Mice Body quality day by day increases.Utilize SPSS statistical software by blank group and test sample
Organize t check analysis between the weight group of every day, the results are shown in Table 6.
Table 6 respectively organizes Mice Body mass ratio relatively (g, x ± s, n=10)
| Time/d | Test sample group | Blank group |
| 1 | 17.5±0.6 | 17.7±0.5 |
| 2 | 18.3±1.0 | 18.5±0.8 |
| 3 | 19.7±1.1 | 20.2±0.8 |
| 5 | 21.3±1.3 | 21.9±0.8 |
| 7 | 22.8±1.3 | 23.6±0.8 |
| 10 | 25.6±1.5 | 26.6±0.7 |
| 14 | 30.4±1.5 | 31.6±0.6 |
As shown in Table 6, test sample group and blank group mice changes of body mass in 14d do not have notable difference, show this
Experiment mice weight is had not significant impact by ocular fluid.
3. skin wound repair experiment
3.1 experimental procedures: selecting large ear rabbit 12, before experiment, 24h cuts and shaves its spinal column both sides, back by hair preserved skin, unhairing scope
For 3cm × 3cm, it is randomly divided into intact group of skin and skin injury group, often group 6, separately in the spinal column both sides of skin injury group rabbit
It is divided into " # " with aseptic syringe needle, is as the criterion with oozing of blood.Use consubstantiality left and right sides own control, by levofloxacin hydrochloride slow release eye drip
Drop, on the gauze piece of 2.5cm × 2.5cm, is applied ointment or plaster at back, left side, negative control normal saline is dripped to 2.5cm ×
On the gauze piece of 2.5cm, applying ointment or plaster at back, right side, fix 6h with semiclosed property binder, each consumption is 1.5mg d-1,
Every day 1 time, continuous use 7d.After last medication 24h, remove left drug with warm water, respectively at 1,24,48,72h Continuous Observation
And record coating position with or without the situation such as erythema and edema.3.2 deliberated indexs: erythema and edema are marked by following standard:
Without erythema 0 point, erythema is visible as 1 point reluctantly, clearly visible 2 points of erythema, Severe erythema 3 points, and aubergine erythema also has eschar shape
Become 4 points；Without edema 0 point, the most visible 1 point of edema, edge exceeds the edema 2 points of surrounding skin, cutaneous protuberance about 1mm, profile
Clearly edema is 3 points, the edema 4 points that cutaneous protuberance 1mm range above expands.Mean scores=(erythematous response total score+edema
Reaction total score)/every treated animal number, carry out stimulus intensity evaluation by mean scores, skin irritation intensity evaluation standard is shown in Table 7.
Table 7 skin irritation intensity evaluation standard
| Score value | Response type |
| 0.0～0.49 | Nonirritant |
| 0.5～2.99 | Slight zest |
| 3.0～5.99 | Moderate zest |
| 6.0～8.0 | Strong and stimulating |
3.3 result of the tests: remove after applicator 1,24,48,72h, observe each area skin tissue reaction situation, intact group of skin
Rabbit medication side, control sides skin all do not find erythema and edema, skin irritation intensity evaluation to be nonirritant, and (mean scores is
0).When damaged skin group 1,24h only 1 erythema and edema occur, after 48h react mean scores be 0, after 5d, wound is all healed
Closing, substantially recover normal condition, skin irritation evaluation is nonirritant (mean scores is respectively less than 0.50), and concrete outcome is shown in Table
8。
Mouse skin stimulation test result respectively organized by table 8
Homemade vitro cytotoxicity, acute toxicity and skin irritation without preservative levofloxacin hydrochloride slow release eye drop
Reaction all meets concerned countries specification and requirement.This experimentation demonstrates the safety of this eye drop medication, reduces eye drop
Damaging action and stimulation to eye.
Experimental example 4 inhibitory effect development test
As the preparation prepared by the method that the embodiment of the present invention 3 is recorded as trial target, 0.3% levofloxacin eye drops
(Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd., trade name: Helen, specification 5ml:15mg) as reference substance, by antibacterial effect
Power development test, illustrates that the levofloxacin eye drops without preservative can utilize self bacteriostasis, suppression to store, transport
Defeated, use during the microorganism that is likely to result in pollute, improve its biological safety.Development test is with reference to " Chinese Pharmacopoeia " 2015
Year four general rule 1121 inhibitory effect inspection techniques of version.
1. prepared by bacterium solution
Learn from else's experience 35 DEG C cultivate the Pseudomonas aeruginosa of 24h, staphylococcus aureus, escherichia coli TSA slant culture fit
Amount, the Sabouraud glucose agar slant culture of 25 DEG C of Candida albicans cultivating 48h of separately learning from else's experience is appropriate, is separately added into
Appropriate aseptic 0.9% sodium chloride solution, makes the number containing bacterium and is about 108cfu·ml-1Bacteria suspension (this bacteria suspension is for antibacterial
Potency test).Take above-mentioned bacteria suspension to make the number containing bacterium be about 50～100cfu with aseptic 0.9% sodium chloride solution times amount dilution
ml-1Bacteria suspension (this bacteria suspension be used for microbial enumeration method confirmatory experiment)；Learn from else's experience 25 DEG C and cultivate the aspergillus niger Sharpe Portugal of 7d
Grape sugar agar slant culture, adds the 5ml 0.9% aseptic sodium chloride solution containing 0.05% (ml/ml) polyoxyethylene sorbitan monoleate and washes lower spore
Son, makes the number containing bacterium and is about 107～108cfu·ml-1Spore suspension (this spore suspension for inhibitory effect test).With containing
0.05% (ml/ml) polyoxyethylene sorbitan monoleate 0.9% aseptic sodium chloride solution times amount dilution make containing spore count be about 50～
100cfu·ml-1Spore suspension (this spore suspension be used for microbial enumeration method confirmatory experiment).
2. the confirmatory experiment of microbial enumeration method
Antibacterial and levofloxacin have stronger antibacterial activity, therefore, during bacterial count test, membrane-filter procedure should be used to cut
Except bacteriostatic activity.Meanwhile, flouroquinolone drugs and metal ion (Ca2+、Mg2+、Al3+) complexation can occur and cause its antibacterial work
Property decline, therefore select in pH7.0 sterile NaCl-peptone buffer agent add 0.05mol L-1Manganese sulfate.Fungal count
Direct inoculation is used during test.
2.1 count of bacteria verification methods: take trial target and reference substance 1ml and 50～100cfu test organisms respectively, use pH7.0
Sterile NaCl-peptone buffer agent (sulfur acid manganese 0.05mol L-1) it being diluted to 100ml, full dose passes through membrane filter
After, then with pH7.0 sterile NaCl-peptone buffer agent (sulfur acid manganese 0.05mol L-1) rinse filter membrane 4 times (every time
400ml), filter membrane is labelled to trypticase soy agar culture medium flat plate, measures bacterium number.
2.2 fungal count verification methods: take trial target and reference substance 1ml and 50～100cfu test organisms respectively, note respectively
Enter in same plate, pour into trypticase soy agar culture medium and Sabouraud glucose agar immediately.By direct inoculation
Measure its clump count.The results are shown in Table 9.
Table 9 method of counting the result
3. inhibitory effect assay method
Prepared by 3.1 samples: take trial target and reference substance (loading amount 5ml) 4 respectively, and transferring content thing is to tool plug sterile glass test tube
In, mixing, standby.5 parts are prepared altogether with method.
3.2 sample inoculation: take the Pseudomonas aeruginosa, staphylococcus aureus, escherichia coli, white made under " 1 " item
(bacteria suspension number Han bacterium is about 10 to color candidiasis bacteria suspension8cfu·ml-1) and Aspergillus niger spores suspension (spore suspension contain spore count
It is about 108cfu·ml-1), direct inoculation test organisms 0.1ml is in above-mentioned 5 parts of samples respectively, the a kind of test of inoculation of each container
Bacterium, is sufficiently mixed, and makes the test organisms in sample be uniformly distributed.Then the sample of inoculation is put during testing 25 DEG C of incubators
In, stored protected from light.
3.3 survival Counting alive microbial have just inoculated 0h, 6h, 24h, 7d, 14d, 28d at test sample, respectively from above-mentioned each sample
Container takes sample 1ml, is diluted to 1: 10,1: 10 with pH7.0 sterile NaCl-peptone buffer agent2、1∶103Deng dilution level.
Counting alive microbial method is carried out by the confirmatory experiment of microbial enumeration method under " 2 " item.Wherein measure antibacterial and use membrane-filter procedure
And trypticase soy agar culture medium；Measure fungus and use direct inoculation and Sabouraud glucose agar.Measure every part
Bacterium number contained in test sample.
3.4 inhibitory effect result of the tests are shown in Table 10.
Table 10 inhibitory effect bacterium amount count results
Result shows, experimental group and matched group all can reach the inhibitory effect standard of " Chinese Pharmacopoeia " version in 2015.Therefore, can profit
With the abundant antibacterial efficacy of levofloxacin hydrochloride self, prevent the eye drop of multiple-unit container in normal storage or use process
Harm user caused due to pollution and the breeding of microorganism.
Claims (5)
1. a levofloxacin hydrochloride slow release eye drop, it is characterised in that it is with levofloxacin hydrochloride as pharmacodynamic raw materials,
Be equipped with hyaluronic acid sodium and play thickening agent effect, then be equipped with complexing of metal ion agent described on the acceptable pharmaceutics of eye local,
Osmotic pressure regulator and pH adjusting agent, the ophthalmic preparation of prepared one-tenth, levofloxacin hydrochloride in every 100 weight portion finished product preparation
Content be 0.30～1.00 weight portions；In every 100 weight portion finished product preparation, the content of hyaluronic acid sodium is 0.1～1.00 weight
Part.
Levofloxacin hydrochloride slow release eye drop the most according to claim 1, it is characterised in that the consumption of hyaluronic acid sodium
For, in every 100 weight portion finished product preparation, the content of hyaluronic acid sodium is 0.488% weight portion.
Levofloxacin hydrochloride slow release eye drop the most according to claim 1, it is characterised in that described complexing of metal ion
Agent is any one of disodium edetate, sodium gluconate, sodium tartrate, sodium citrate, aminotriacetic acid or described kind
Combination in any；The consumption of complexing of metal ion agent is expressed as with the weight ratio with levofloxacin, levofloxacin: metal ion
Chelating agent=1: 0.01～0.50.
Levofloxacin hydrochloride slow release eye drop the most according to claim 1, it is characterised in that described osmotic pressure regulator
For any one of sodium chloride, potassium chloride, glucose, boric acid, Borax, glycerol, mannitol or the combination in any of described kind,
The osmotic pressure molar density of regulation finished product medicament is 280～330mOsmol/kg.
Levofloxacin hydrochloride slow release eye drop the most according to claim 1, it is characterised in that described pH adjusting agent is hydrogen
Any one of sodium oxide, hydrochloric acid, sodium citrate, citric acid, boric acid, Borax or the combination in any of described kind, be adjusted to
The pH value of product medicament is 5.0～7.0.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108066282A (en) * | 2018-01-17 | 2018-05-25 | 中山万汉制药有限公司 | A kind of Levofloxacin Eye drop and preparation method thereof |
| CN108309930A (en) * | 2018-03-19 | 2018-07-24 | 武汉百纳礼康生物制药有限公司 | A kind of Ofloxacin gel with liquid crystal structure nano eyedrop and preparation method thereof |
| CN110876714A (en) * | 2019-11-22 | 2020-03-13 | 南京知和医药科技有限公司 | Levofloxacin sustained-release eye drops and preparation process thereof |
| CN112587480A (en) * | 2020-12-24 | 2021-04-02 | 苏州工业园区天龙制药有限公司 | Preparation method of levofloxacin eye drops |
| CN112618485A (en) * | 2021-03-01 | 2021-04-09 | 南京恒道医药科技有限公司 | Sustained-release levofloxacin eye drops and preparation method and application thereof |
| CN114569551A (en) * | 2022-03-21 | 2022-06-03 | 杭州赫尔斯科技有限公司 | Atropine eye drops and preparation method thereof |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101278905A (en) * | 2008-05-13 | 2008-10-08 | 山东博士伦福瑞达制药有限公司 | Ophthalmic composition containing natamycin, use and preparation method thereof |
| CN101278908A (en) * | 2008-05-18 | 2008-10-08 | 程浩文 | Eye drop capable of significantly increasing medicament effect |
| CN101455633A (en) * | 2009-01-06 | 2009-06-17 | 河北科技大学 | Disposable levofloxacin lactate eye drops without bacteria inhibitor and preparation method thereof |
| CN101461777A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable levofloxacin hydrochloride eye drops without bacteriostatic agent and preparation method thereof |
| CN101461779A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable ofloxacin eye drops without bacteriostatic agent and preparation method thereof |
| CN102283805A (en) * | 2011-06-29 | 2011-12-21 | 扬子江药业集团有限公司 | Method for preparing eye drops containing non-ionic cellulose derivatives |
| CN102670494A (en) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | Eye drop and preparation method and application thereof |
| CN103432069A (en) * | 2013-09-12 | 2013-12-11 | 安徽环球药业股份有限公司 | Ofloxacin eye drop without bacteriostatic agent and preparation method of ofloxacin eye drop |
| CN104414968A (en) * | 2013-09-09 | 2015-03-18 | 南京长澳医药科技有限公司 | Levofloxacin single-dose eye drops and preparation method thereof |
| CN105232452A (en) * | 2015-10-28 | 2016-01-13 | 广东三蓝药业股份有限公司 | Bacteriostat-free ofloxacin eye drops and preparation process thereof |
-
2016
- 2016-08-31 CN CN201610774150.7A patent/CN106236706A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101278905A (en) * | 2008-05-13 | 2008-10-08 | 山东博士伦福瑞达制药有限公司 | Ophthalmic composition containing natamycin, use and preparation method thereof |
| CN101278908A (en) * | 2008-05-18 | 2008-10-08 | 程浩文 | Eye drop capable of significantly increasing medicament effect |
| CN101455633A (en) * | 2009-01-06 | 2009-06-17 | 河北科技大学 | Disposable levofloxacin lactate eye drops without bacteria inhibitor and preparation method thereof |
| CN101461777A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable levofloxacin hydrochloride eye drops without bacteriostatic agent and preparation method thereof |
| CN101461779A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable ofloxacin eye drops without bacteriostatic agent and preparation method thereof |
| CN102283805A (en) * | 2011-06-29 | 2011-12-21 | 扬子江药业集团有限公司 | Method for preparing eye drops containing non-ionic cellulose derivatives |
| CN102670494A (en) * | 2012-05-22 | 2012-09-19 | 宁夏康亚药业有限公司 | Eye drop and preparation method and application thereof |
| CN104414968A (en) * | 2013-09-09 | 2015-03-18 | 南京长澳医药科技有限公司 | Levofloxacin single-dose eye drops and preparation method thereof |
| CN103432069A (en) * | 2013-09-12 | 2013-12-11 | 安徽环球药业股份有限公司 | Ofloxacin eye drop without bacteriostatic agent and preparation method of ofloxacin eye drop |
| CN105232452A (en) * | 2015-10-28 | 2016-01-13 | 广东三蓝药业股份有限公司 | Bacteriostat-free ofloxacin eye drops and preparation process thereof |
Non-Patent Citations (1)
| Title |
|---|
| 顾其胜主编: "《玻璃酸钠生产与临床应用》", 31 May 2012, 上海科学技术出版社 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108066282A (en) * | 2018-01-17 | 2018-05-25 | 中山万汉制药有限公司 | A kind of Levofloxacin Eye drop and preparation method thereof |
| CN108066282B (en) * | 2018-01-17 | 2018-11-23 | 中山万汉制药有限公司 | A kind of Levofloxacin Eye drop and preparation method thereof |
| CN108309930A (en) * | 2018-03-19 | 2018-07-24 | 武汉百纳礼康生物制药有限公司 | A kind of Ofloxacin gel with liquid crystal structure nano eyedrop and preparation method thereof |
| CN110876714A (en) * | 2019-11-22 | 2020-03-13 | 南京知和医药科技有限公司 | Levofloxacin sustained-release eye drops and preparation process thereof |
| CN112587480A (en) * | 2020-12-24 | 2021-04-02 | 苏州工业园区天龙制药有限公司 | Preparation method of levofloxacin eye drops |
| CN112618485A (en) * | 2021-03-01 | 2021-04-09 | 南京恒道医药科技有限公司 | Sustained-release levofloxacin eye drops and preparation method and application thereof |
| CN114569551A (en) * | 2022-03-21 | 2022-06-03 | 杭州赫尔斯科技有限公司 | Atropine eye drops and preparation method thereof |
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