CN103735499A - Ulifloxacin hydrochloride eye drop and preparation method thereof - Google Patents
Ulifloxacin hydrochloride eye drop and preparation method thereof Download PDFInfo
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Abstract
The invention provides a ulifloxacin hydrochloride eye drop and a preparation method thereof. The ulifloxacin hydrochloride eye drop is directly prepared by raw material ulifloxacin hydrochloride, every milliliter of the eye drop comprises 1-5 milligrams of ulifloxacin hydrochloride, and other components comprise suitable auxiliary materials for eye-drop preparation or water for injection. The ulifloxacin hydrochloride eye drop can effectively prevent and treat eye sensitive bacteria infection, especially Gram-negative bacterium including pseudomonas aeruginosa with growing drug resistance, has high bioavailability, can stay in eyes for long time, has prominent post-antibiotic effect, is beneficial to reducing single dose of medicine, has good curative effect and low cost, has simple and convenient production technology and short production cycle, meets the requirement of large scale production, and has practical significance for treating eye infectious diseases with growing drug resistance.
Description
Technical field
The present invention relates to a kind of hydrochloric acid NM394 eye drop and preparation method thereof, belong to pharmaceutical technology field.Hydrochloric acid NM394 eye drop of the present invention can effectively prevent and treat eye sensitive organism and infect.
Background technology
Infectious eye disease refers to the class diseases associated with inflammation by the caused eye of the pathogen such as antibacterial, fungus, virus, mycoplasma, rickettsia, spirillum and parasite and appendages, it is eye commonly encountered diseases, often cause part tissue of eye to damage in various degree, can have a strong impact on vision, even blinding.In recent years, due to a variety of causes such as environmental pollutions, infectious eye disease is in rising trend, and conditioned pathogen increase, and cause of disease kind is more, wider, and along with the application of extensive pedigree antibiotic, the drug resistance of antibacterial constantly increases.
The anatomical structure of eye and appendages thereof is special, once occur infecting, be easy to spread to deep tissues and offside, adding environmental factors, sanitary condition, the change of body autoimmunity, the application of extensive pedigree antibiotic and the factors such as transition of bacterium living beings characteristic, there is certain difficulty in the diagnosis of infectious eye disease and treatment.
According in Mays, 2012 such as the Zhang Bin of Tianjin ophthalmologic hospital clinical laboratory, antibacterial is the main pathogenic fungi of infectious eye disease, accounts for 87.73% of infectious sample.During antibacterial infects, gram positive coccus accounts for 76.03%, and staphylococcus epidermidis proportion is up to 46.15%; Gram negative bacilli accounts for 19.69%, in the majority with non-zymocyte, and wherein Pseudomonas aeruginosa accounts for 28.98% (40/138); Grain-positive bacillus accounts for 4.28%.Corneal ulcer incubation period of being caused by Pseudomonas aeruginosa is short, morbidity is anxious, progress is fast, very easily blinding.Pseudomonas aeruginosa in conjunctival sac secretions can be pathogenic bacterium, causes conjunctivitis; Also can be conditioned pathogen, be present in conjunctival sac, when immunity of organisms is low, cause ocular disease.Aqueous humor infects Pseudomonas aeruginosa can cause endophthalmitis, and severe patient must be extractd eyeball.Pseudomonas aeruginosa reproductive capacity is strong, when serious, can cause breaking out with popular in hospital.The drug resistance result of analyzing infectious eye disease pathogen shows: the drug resistance of gram positive coccus is higher, and staphylococcus epidermidis is to the resistant rate of penicillin, erythromycin, oxazacillin and norfloxacin higher (>70.00%); Gram negative bacilli be take Pseudomonas aeruginosa as main, and it has very high drug resistance to ampicillin/sulbactam, Fu side's Sulfamethoxazole, cefotaxime, and resistant rate reaches 100%.(Zhang Bin etc., the pathogenic distribution of infectious eye disease and drug resistance analysis, the sick magazine of Chinese clinical infection, 2012,5(4): 205-209).
Antimicrobial Resistance of Pseudomonas Aeruginosa is stronger, often be many drug resistances, this bacterium resistance mechanism is complicated, the expression, the outer membrane protein change that mainly contain the multiple beta-lactamase of generation, epicyte active efflux system cause the change of permeability decline, penicillin-binding protein and form biomembrane etc., and most of beta-Lactam antibiotics, chloromycetin, sulfonamides, rifampicin etc. are existed to drug resistance.Research shows that Pseudomonas aeruginosa has same resistance mechanism to fluoroquinolones, and quinolones, as levofloxacin, ciprofloxacin, lomefloxacin, declines year by year to some extent to the sensitivity of Pseudomonas aeruginosa.
Ophthalmology antibacterials kind is less, and using dosage, drug level, frequency of utilization etc. are different with intravenous drip medication.The drug resistance of antibacterial constantly increases, and the drug resistance of same antibacterial constantly changes with treatment, and experience diagnosis and treatment are difficult to prove effective, and more and more rely on the examining report of laboratory.The current conventional antibiotic of ophthalmology can be divided into chloromycetin (representing that medicine is chloromycetin), aminoglycosides (representing that medicine is gentamycin) and quinolones and (represent that medicine only has ofloxacin, ciprofloxacin, levofloxacin, norfloxacin etc. are several) etc. three major types.It is worth mentioning that current antibiotic eye drops is after long-term clinical observation, find to have side effect and drug resistance phenomenon in various degree.As Chloramphenicol Eye Drop, applicating history is very long, and drug-resistant bacteria is many and antibacterial effect is obviously reduced; But also likely can cause that whole body hematopoietic function destroys, and when serious, may also can cause death, all there had been such adverse effect record home and abroad.Disposable levofloxacin hydrochloride eye drops also has drug-resistant bacteria fall and make antibacterial effect obviously low through long-term utilization, and because fluoroquinolones is extensive at clinical departments, extensive application, Main Pathogenic Bacteria increases its resistant rate.(antibacterials are in the reasonable application of clinical ophthalmology for Huashan Hospital Affiliated To Fudan Univ ophthalmology, Xiao Yiqin etc., and Shanghai is medical, and 2010,31(7)).
In choice for use ophthalmology antibiotic medicine, not only to consider the effectiveness of medicine, also to consider drug resistance and the safety of medicine simultaneously.Doctor be take targetedly a kind of antibacterial drug therapy as main in rule when treatment infectious eye disease, and the Drug therapy that eye antibacterial infects mainly adopts local application.In the pathogen infecting on eye antibacterial, gram positive bacteria be take staphylococcus as main, is secondly streptococcus, streptococcus pneumoniae etc.; Gram negative bacilli is common with Pseudomonas aeruginosa, is secondly Bacillus proteus and escherichia coli etc.
Kind and other site infection of body that eye antibacterial infects have a great difference, and the existence of blood-ocular barrier and corneal epithelium makes antibacterials application within the eye have certain particularity.The antimicrobial spectrum of every kind of antibacterials is not identical with indication, and eye clinical diagnosis, bacteriology checking and drug sensitive test thereof can be used as the important references of selecting medicine.While selecting antibacterials, must understand antimicrobial spectrum, the antibacterial action feature of medicine used, to select corresponding active drug.To the not clear infection of pathogen, should adopt extensive pedigree antibiotic or antibacterials use in conjunction.For serious ocular infection, antibacterial culturing often obtains again negative findings, often treats therapy by rule of thumb and carries out.Now, for pathogenic bacterium, select medicine to have 2 palpuses to note: one, from character and the position of infecting, analyze possible pathogenic bacterium; Its two, be the curative effect of patient's medication.Medications as enough in a kind of antibacterials after 3～5 days clinical symptoms be still not improved, should consider to use instead other effectively antibacterial drug therapy, in order to avoid affect the state of an illness adversely.So more effective, the safe eye medicinal of developing new product variety infects and has important clinical therapeutic value for treatment eye antibacterial.
The international Ulifloxacin by name of NM394, chemistry 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3) sulfur nitrogen heterocycle by name also (3,2-a) quinoline-3-carboxylic acid, thiophene fourth pyridine-quinoline carboxylic acid derivative.
NM394 structural formula:
Hydrochloric acid NM394 is the hydrochlorate of NM394, and in body, effective ingredient is NM394:
NM394 has broad-spectrum antibacterial action to gram positive bacteria and gram negative bacteria, and anaerobe, legionella and chlamydia etc. are all had to activity, and anti-gram-negative bacteria external activity is outstanding in fluoroquinolone.Compare with ciprofloxacin, Gatifloxacin and levofloxacin, in NM394 Jin Portugal bacterium, escherichia coli and Pseudomonas aeruginosa cell, be easier to accumulate, short-term bactericidal action is stronger; Particularly for ophthalmology, endanger large Pseudomonas aeruginosa, be better than ciprofloxacin, levofloxacin and Moxifloxacin.In addition, this kind also has longer post antibiotic effect, more more lasting than ciprofloxacin.Experiment in vivo and vitro all shows, NM394 is has a broad antifungal spectrum not only, and activity in vivo is strong, have good bactericidal action and post antibiotic effect, cytotoxicity low, to central nervous system, move the advantage such as few of dividing a word with a hyphen at the end of a line.
Though NM394 has good antibacterial activity, but injection application also has crystalluria and injury of kidney. according to the research of Ishida S etc., rat is scheduled to last to the quiet note of surrounding, 3mg/kg dosage group is not found obvious problem, 10,30mg/kg dosage group rat water consumption and urine discharge capacity obviously increase, and find crystal material and small epithelial cells in urinary sediment thing.So, to the NOAEL of rat (not observing the levels of drugs of untoward reaction) dosage, should be 3mg/kg.After NM394 chemical modification, be transformed into the prulifloxacin (Prulifloxacin) of oral administration, prulifloxacin is developed by Japanese new drug company and the joint research of Mingzhi company, and its Tabules was got permission to go on the market in Japan in 2002.Prulifloxacin be the 4th generation fluoroquinolone antibacterial agent, it is NM394 prodrug, in vivo through serum enzymatic hydrolysis, removes modification group on C7 position, obtains active component NM394.The maximum feature of NM394 is to comprising that the gram negative bacteria of the ever-increasing Pseudomonas aeruginosa of drug resistance has good antibacterial activity.The oral rear metabolism of prulifloxacin is rapid, in body circulation, generally can't detect original shape medicine, can only be measured to its active metabolite NM394, and plasma half-life is 7.7～8.9 hours.
CN200610097346.3 discloses Prulifloxacin active body injection, and wherein this invention is directly used in intravenous NM394 injection, makes active medicine NM394 directly enter blood, brings into play rapidly therapeutical effect.
The application of the NM394 hydrochloric acid that CN201010128827.2 discloses a kind of novel stabilising in preparing anti-infectives, this invention is with the form direct injection of thiophene fourth pyridine quinoline carboxylic acid, improve dissolubility, improved the bioavailability of this medicine, improved therapeutic effect simultaneously.
The application of the NM394 mesylate that CN201010133378.0 discloses a kind of novel stabilising in preparing anti-infectives, wherein this invention is with the form direct injection of thiophene fourth pyridine quinoline methanesulfonic acid hydrochlorate.CN101003540 discloses the fluoro-1-methyl-4-of 6-oxo-7-(1-piperazinyl)-4H-[1,3] thiazine [3,2-a] quinoline-3-carboxylic acid mesylate and preparation method and its usage, in patent specification, this salt pH value is 2.90 left and right.
At present, not yet have to adopt that to take hydrochloric acid NM394 be the directly relevant report of the hydrochloric acid NM394 eye drop of preparation of raw material, also do not have thiophene fourth pyridine class eye drop to declare clinical research and listing is used.Eye drop belongs to external preparation, all different from injection route of administration, site of action, and application process is also different; Hydrochloric acid NM394 eye drop is researched and developed for the disease of this labyrinth organ of eyes, from common hydrochloric acid NM394 injection at viscosity, promote the aspect material application such as absorptions, antibacterial and requirement to have obviously different.
Summary of the invention
The object of the invention is for current antibiotic eye drops after clinical practice for many years, finding has side effect and drug resistance phenomenon in various degree, develops the hydrochloric acid NM394 eye drop that meets large-scale production and clinical needs.NM394 dissolubility in water is little, in preparation eye drop and use procedure, can wash out because local concentration is high, directly affect the accuracy of patient's use and dosage, NM394 antibacterial ability is subject to the impact of pH larger in addition, so be prepared into hydrochloric acid NM394, strengthen dissolubility, then be adjusted to best antimicrobial pH and just can better solve preparation technique problem.
The present invention also provides take hydrochloric acid NM394 as the direct preparation method of the hydrochloric acid NM394 eye drop of preparation of raw material.
Hydrochloric acid NM394 eye drop described in the present invention, every milliliter of hydrochloric NM394 1-5 milligram, other is ophthalmic preparation proper auxiliary materials or water for injection.Ophthalmic preparation proper auxiliary materials referring to 2010 editions two appendix IG ophthalmic preparations of Chinese Pharmacopoeia and eye drop require, appendix II pharmaceutic adjuvant.In eye drop, can add the adjuvant that regulates osmotic pressure, pH, viscosity and increase drug solubility and preparation stability, and can add antibacterial and the antioxidant of suitable concentration, adjuvant used should not reduce drug effect or produce local excitation, and unless otherwise specified, eye drop should ooze with tear etc.Ophthalmic preparation adjuvant is common as follows:
(1) pH adjusting agent
Conventional have abbreviation phosphate buffer (phosphate buffer, Sharpe phosphate buffer), borate buffer (borate buffer, borate buffer solution, Palitzsch's buffer solution), lucky Fei Shi buffer, acetate buffer (acetic acid-sodium-acetate buffer, acetate buffer), hydrochloric acid, acetic acid, a sodium hydroxide solution etc.
(2) osmotic pressure regulator
Conventional have sodium chloride, glucose, boric acid, a Borax etc.Glycerol has adjusting and oozes the multiple actions such as adjust blood pressure, stabilizing agent, cosolvent, moisturizing.
(3) antibacterial
The antibacterial using in ophthalmic preparation should meet following requirement in principle: 1. effectiveness: antibacterial should have broad-spectrum antiseptic ability, and antibacterial (particularly green pus bacterium) and the breeding of fungus are had to restraint or lethality, and effect rapidly.2. safety: in the frequency of usage and concentration of clinical regulation, Bu Huidui ocular tissue (particularly cornea) causes to stimulate and injury.3. stability: the compositions such as antibacterial and principal agent and other adjuvants do not produce chemical reaction after mixing, and the pH of preparation, osmotic pressure are not caused to negative effect; Antibacterial self should be more stable, heat-resisting, can preserve for a long time.The antibacterial using in ophthalmic preparation at present, is nearly all difficult to meet completely these desirable requirements above.Therefore, need to be from antibacterial and the compatibility of principal agent and other compositions, the impact of sterilizing and stability equal angles be selected the above antibacterial requiring of As soon as possible Promising Policy.In addition,, due to the differences such as kind, pH value, the antibacterial that may pollute or fungal species of contained principal agent and adjuvant in ophthalmic preparation, also can there is corresponding change in the valid density of needed antibacterial.
General eye drop is multi-dose formulation, after once using, cannot keep aseptic, therefore need to add antibacterial.Selected antibacterial answers bacteriostasis rapid, and fungistatic effect reliable (staphylococcus aureus and bacillus pyocyaneus can be killed in 1h), has suitable pH, and non-stimulated to eyes, stable in properties, with principal agent and additives generation incompatibility.Common antibacterial in ophthalmic preparation can be divided into following a few class according to its chemical constitution and character: 1. parabens (parabens), as methyl hydroxybenzoate, ethyl hydroxybenzoate etc.; 2. cationic surfactant, as benzalkonium chloride, benzalkonium bromide etc.; 3. alcohols, as chlorobutanol; 4. organic mercury class, as thimerosal, Mercury pernitrate.; 5. acids, as sorbic acid; 6. new bacteriostatic agent, polyquaternium (import ophthalmic preparation tear so prescription in existing use).Conventional as benzalkonium chloride, benzalkonium bromide, Benzene Chloride first azanol (0.01%～0.02%), thimerosal (0.005%～0.01%), phenethanol (0.5%), chlorobutanol (0.35%～0.5%), methyl parahydroxybenzoate and propyl p-hydroxybenzoate mixture (methyl parahydroxybenzoate 0.03%～0.1%, propyl p-hydroxybenzoate 0.01%) etc.
Single antibacterial, often the pH value because of prescription is not suitable for, or has incompatibility can not reach the object of rapid sterilization with other compositions.Adopt compound antibacterial can bring into play synergism.Practice confirms that good compatibility is as follows: benzalkonium chloride and edetate sodium.Edetate sodium itself is there is no bacteriostasis, but a small amount of edetate sodium can make other antibacterial strengthen the effect of bacillus pyocyaneus; Benzalkonium chloride and chlorobutanol add edetate sodium or oxybenzene esters again; Phenoxyethanol and oxybenzene esters.
(4) viscosity-controlling agent
Cry again thickening agent, prolongation of effect agent.Suitably increase the viscosity of eye drop, can make medicine time of staying prolongation within the eye, also can make zest weaken.Conventional methylcellulose (mc), polyvinyl alcohol (pva), polyvidone (pvp), hypromellose, hyaluronic acid sodium etc.Some thickening agent may also have solubilising or sorbefacient effect, as hypromellose, hyaluronic acid sodium etc.
(5) other (stabilizing agent, solubilizing agent and cosolvent)
For labile drug, need add antioxidant and metal-chelator; The medicine that dissolubility is little need add solubilizing agent or cosolvent; Macromolecular drug absorption can not add absorption enhancer when good.
Prepare hydrochloric acid NM394 eye drop and must consider the various factorss such as physicochemical property, in conjunction with specific experiment effect, decide scheme.Hydrochloric acid NM394 is off-white color or faint yellow solid, molecular formula C
16h
19cLFN
3o
3s, molecular weight 389.7, when in water, dissolubility is 25 ℃, 59.7mg/ml is solvable, and NM394 is 2.7mg/ml genus slightly soluble.Hydrochloric acid NM394 has certain stability to 60 ℃ of high temperature, high humiditys, possesses the preparation primary condition that can prepare every milliliter of hydrochloric NM394 1-5 milligram, but wants comprehensive Design prescription, technique, by specific experiment effect, decides scheme.
The pH value of eye drop directly affects the curative effect to the stimulation of eye and medicine.The pH value of normal eye tolerance be 5.0～9.0, pH6.0～8.0 o'clock eyes without sense of discomfort, and the pH value of human body tear is 7.4, is less than 5.0 and be greater than 11.4 and have obvious irritation.The selection of pH value should take into account drug solubility, stability and the many factors such as zest to eye.Hydrochloric acid NM394 is when pH5.5, to colon bacillus and Pseudomonas aeruginosa effect, strong 4-16 is doubly during than pH7, in order to bring into play the effect to infection such as the Pseudomonas aeruginosas of clinical refractory, increase hydrochloric acid NM394 solubility property simultaneously, hydrochloric acid NM394 eye drop slant acidity pH5-7 of the present invention, preferred pH5.5 ± 0.5, pH adjusting agent is selected from phosphate buffer (phosphate buffer, Sharpe phosphate buffer), boric acid series buffer (borate buffer, borate buffer solution, Palitzsch's buffer solution), lucky Fei Shi buffer, acetate series buffer (acetic acid-sodium-acetate buffer, acetate buffer), hydrochloric acid, acetic acid, sodium hydroxide solution.
In specific experiment, find that hydrochloric acid NM394 is soluble in water, its aqueous solution also there will be inadequate stabilization, and hydrochloric acid NM394 aqueous solution is not very stable to illumination and heating especially, can pass and produce some catabolites in time, degraded can affect the treatment and produce toxic and side effects.The compound structure of xacin-series is met hydrochloric acid, may separate out or zest side effect generation, if 2% hydrochloric acid lomefloxacin injection is at northern China low temperature crystallize, and if ciprofloxacin can orally make that injection or the irritant side effect of other preparations occur and unsuccessful.5mg/ml hydrochloric acid NM394 aqueous solution pH5.0 in the time of 25 ℃, needs research to be adjusted in compared with large-temperature range, and pH is in proper states.
In order to solve series of technical, by repeatedly studying, comprehensive assessment, filters out following hydrochloric acid NM394 eye drop technical scheme: hydrochloric acid NM394 eye drop, every milliliter contains hydrochloric acid NM394 1-5 milligram, and other is suitable eye adjuvant and water for injection.Hydrochloric acid NM394 eye drop, preferably every milliliter of every finished product contains hydrochloric acid NM394 1-5 milligram, and suitable eye is osmotic pressure regulator 1-20 milligram with adjuvant, and antibacterial is (0.0001-5 milligram) in right amount, viscosity-controlling agent 0.2-0.5 milligram and water for injection.Osmotic pressure regulator is selected from sodium chloride, glucose, boric acid, potassium chloride, glycerol; Viscosity-controlling agent is selected from methylcellulose, polyvinyl alcohol, polyvidone, hypromellose, hyaluronic acid sodium; Antibacterial is selected from benzalkonium chloride, benzalkonium bromide, thimerosal, phenethanol, chlorobutanol, parabens.Described hydrochloric acid NM394 eye drop pH value is 5.0-7.0, preferably pH value is 5.5 ± 0.5, and described pH adjusting agent is selected from phosphate buffer (phosphate buffer, Sharpe phosphate buffer), boric acid series buffer (borate buffer, borate buffer solution, Palitzsch's buffer solution), lucky Fei Shi buffer, acetate series buffer (acetic acid-sodium-acetate buffer, acetate buffer), sodium acetate-borate buffer, hydrochloric acid, acetic acid, sodium hydroxide solution.
One of optimal technical scheme is: every milliliter of every finished product contains 2 milligrams of hydrochloric acid NM394s, 9 milligrams of osmotic pressure regulators, 0.7 milligram of antibacterial, 0.35 milligram of viscosity-controlling agent.Wherein osmotic pressure regulator is 9 milligrams, sodium chloride, 12 milligrams of glucoses or 4 milligrams, sodium chloride and 7 milligrams of mixture of glucose; Antibacterial is 0.15 milligram of 0.5 milligram of methyl parahydroxybenzoate and propyl p-hydroxybenzoate; Viscosity-controlling agent is 0.35 milligram of methylcellulose.Described hydrochloric acid NM394 eye drop pH value is 5.0-7.0, and preferably pH value is 5.5 ± 0.5.PH adjusting agent is selected from phosphate buffer, borate buffer, borate buffer solution, acetate buffer solution, acetate buffer, sodium acetate-borate buffer, lucky Fei Shi buffer, hydrochloric acid, acetic acid, sodium hydroxide solution etc.
Preparation method of the present invention is to take hydrochloric acid NM394 as raw material preparation, every milliliter of hydrochloric NM394 1-5 milligram, and other is adjuvant and water for injection for eye.According to hydrochloric acid NM394, be dissolved in the character of acid medium, adopt the main materials and auxiliary materials method of preparation separately: hydrochloric acid NM394 adds appropriate water for injection, and adjust pH 5～7 is entirely molten; Mix with osmotic pressure regulator, viscosity-controlling agent, antibacterial solution etc. again, inject water to enough, after semi-finished product inspection content, pH value are qualified, through 100 ℃ of 30min circulation steam sterilizations, aseptic subpackaged, pack and get final product.
Hydrochloric acid NM394 eye drop of the present invention can effectively prevent and treat eye sensitive organism and infect, and has following characteristics:
1, has a broad antifungal spectrum.Hydrochloric acid NM394 eye drop has broad-spectrum antibacterial action to gram positive bacteria and gram negative bacteria, than third generation fluoroquinolone, legionella and chlamydia etc. is all had to activity as ciprofloxacin, levofloxacin magnitude, anti-gram-negative bacteria external activity is outstanding in fluoroquinolone.Compare with ciprofloxacin, Gatifloxacin and levofloxacin, in hydrochloric acid NM394 Jin Portugal bacterium, escherichia coli and Pseudomonas aeruginosa cell, be easier to accumulate, short-term bactericidal action is stronger; Particularly for ophthalmology, endanger large Pseudomonas aeruginosa, be better than ciprofloxacin, levofloxacin and Moxifloxacin.
2, there is long-acting feature, longer post antibiotic effect.Hydrochloric acid NM394 eye drop is has a broad antifungal spectrum not only, and activity in vivo is strong, has good bactericidal action, and the internal metabolism time long also there is post antibiotic effect, there is long-acting feature.
3, toxic and side effects is low.Hydrochloric acid NM394 eye drop cytotoxicity is low, to central nervous system, move the advantage such as few of dividing a word with a hyphen at the end of a line, and zest is little, is adapted at eye and uses.
4, this hydrochloric acid NM394 eye drop be take hydrochloric acid NM394 and is directly prepared as raw material, and production technology is convenient and simple, the cycle is short, and steady quality meets large-scale production needs.
In a word; this hydrochloric acid NM394 eye drop to the ever-increasing Pseudomonas aeruginosa of drug resistance particularly at interior gram positive bacterial infection; bioavailability is high; the ophthalmic time of staying is long, and post antibiotic effect is outstanding, is conducive to reduce the abuse of medicine; well cost is low simultaneously for therapeutic effect; production technology is convenient and simple, the cycle is short, meets large-scale production needs, for treating the ocular infection disease of drug resistance day by day, is of practical significance.
Hydrochloric acid NM394 eye drop of the present invention, take hydrochloric acid NM394 as raw material preparation, every milliliter of hydrochloric NM394 1-5 milligram, and other is suitable eye adjuvant and water for injection.Hydrochloric acid NM394 eye drop passes through Formulation, experiment screening, and assay, stability experiment, toxicity test result etc. meet following condition:
(1) assay
The 90-110% that this product hydrochloric acid NM394 content is labelled amount.
(2) stability experiment
This product, through simulation listing packing, keeps sample 24 months for a long time in room temperature, and indices and comparison in 0 day are without significant change.It is 2 years that effect duration fixes tentatively.
(3) pH
Hydrochloric acid NM394 eye drop pH value is 5.0-7.0.Consider hydrochloric acid NM394 eye drop dissolubility, stability and antibacterial characteristics, pH value preferably 5.5 ± 0.5.
(4) toxicity test
1, hypersensitive test: 20 of the Cavia porcelluss that participation is tested, intramuscular injection hydrochloric acid NM394 eye drop 0.5ml next day of per, totally three times, then be divided into two groups, first group of lumbar injection 1ml eye drop on the 14th after injection first, second group drips and takes liquid at latter the 21st day jugular vein injection 1ml of injection first, immediately observing response.All there is not scratching with pawl the anaphylaxiss such as nose, sneeze, perpendicular hair, tic, dyspnea, gatism, shock and death in result.
2, irritation test: A, give 20 of adult healthy Japan large ear rabbits, use respectively hydrochloric acid NM394 eye drop and each 2 eye drips of normal saline for every group 10 two, after certain hour, bolt is looked into lacrimal secretion and conjunctival reaction situation.Result and normal saline are for comparing, and lacrimal secretion and conjunctival reaction are all normal.Administration 1,2,4,24,48,72h and 7 days, check that adult healthy Japan large ear rabbit eyes result shows, conjunctiva, cornea, iris irritant reaction, and hydrochloric acid NM394 eye drop is to eye nonirritant.B, 15 volunteers, drip 3 every day, and each 2, for three days on end, after result administration, experimenter's eye is local without uncomfortable, no abnormality seen sign.
3, subacute toxicity test: to 10 of mices, drip day and take twice, after continuous 15 days, check that body weight and liver are showed no toxic reaction.
The specific embodiment
By the specific embodiment, further illustrate the present invention below, but not as restriction of the present invention.Following hydrochloric acid NM394 eye drop preparation is with adjuvant for meeting the adjuvant requirement of eye drop eye, and reagent is analytical pure.
Embodiment 1
Hydrochloric acid NM394 (preparation of aseptic powder raw material):
In retort, add 5L water and 1.5L acetone, add 1 kilogram of NM394 powder in 10-15 ℃, stir the lower 2mol/L of dropping hydrochloric acid 1.5L, stirring reaction 1.5 hours, adds 0.05 kilogram of active carbon, stirs filtration decarburization 20 minutes; Filtrate is arrived sterilizing room crystallizer through the filter pressing of 0.22um microporous filter membrane.Under stirring, drip acetone 35L to separating out solid, within 4 hours, add.Be incubated 0-5 ℃ and stir 5 hours, filter, with acetone 6L, divide secondary to wash, 35 ℃ of vacuum dryings, obtain 0.84 kilogram of hydrochloric acid NM394 aseptic powder raw material.
Embodiment 2
Hydrochloric acid NM394 eye drop, every milliliter contains hydrochloric acid NM394 3mg, PVP mg, ethyl hydroxybenzoate 0.3mg.
Prescription:
Hydrochloric acid NM394 30g
Polyvinylpyrrolidone (being polyvidone PVP) 400g
Ethyl hydroxybenzoate 3g
Glycerol is appropriate
Acetic acid-sodium-acetate buffer (acetate buffer, pH5.5) appropriate
Water for injection adds to 10L.
Preparation technology:
Getting hydrochloric acid NM394 30g is dissolved in 2L water for injection; Separately get PVP 0g, ethyl hydroxybenzoate 3g, glycerol 300ml is dissolved in 5L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add acetic acid-sodium-acetate buffer, inject water to 10L, semi-finished product inspection content is qualified, regulates pH value to 5.5, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
The synthetic macromolecule of PVP is both water-soluble, is dissolved in again majority of organic solvent, toxicity very low, has excellent solubility property and physiological compatibility.The hydrochloric acid NM394 eye drop that the PVP of take is carrier has certain viscosity, mobility is little, splash into ophthalmic and can form the thin medicine film of one deck at eyeball surface, have certain delayed release effect, the stability of prolong drug action time within the eye and raising medicine, can reduce zest, Shorten the Treatment Process, remove rapidly hyperemia and the edema of focus, medication is convenient, reduces medication number of times.
Embodiment 3
Hydrochloric acid NM394 eye drop, every milliliter of finished product contains hydrochloric acid NM394 1mg, PVP mg, ethyl hydroxybenzoate 0.4mg.
Prescription:
Hydrochloric acid NM394 5g
Polyvinylpyrrolidone 200g
Ethyl hydroxybenzoate 2g
Glycerol is appropriate
Acetate buffer is appropriate
5% sodium hydroxide solution is appropriate
Water for injection adds to 5L.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in 1L water for injection; Separately get polyvinylpyrrolidone 200g, ethyl hydroxybenzoate 1.5g, glycerol 150ml is dissolved in 3L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add acetate buffer, inject water to about 5L, 5% sodium hydroxide solution regulates pH value to 6.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, be cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 4
Hydrochloric acid NM394 eye drop, every milliliter of finished product contains hydrochloric acid NM394 1mg, PVP mg, ethyl hydroxybenzoate 0.3mg.
Prescription:
Hydrochloric acid NM394 10g
PVP 0g
Ethyl hydroxybenzoate 3g
Glycerol is appropriate
Acetate buffer is appropriate
Water for injection adds to 10L.
Preparation technology:
Get in the molten 2L water for injection of hydrochloric acid NM394 10g; Separately get PVP 0g, ethyl hydroxybenzoate 3g, glycerol 300ml is dissolved in 5L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add acetate buffer, inject water to amount of preparation 10L, regulate pH value to 5.0, through 100 ℃ of 30min circulation steam sterilizations, be cooled to room temperature, semi-finished product inspection content is qualified, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 5
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 2mg, PVP mg, ethyl hydroxybenzoate 0.3mg, glycerol 0.03ml.
Prescription:
Hydrochloric acid NM394 50g
PVP 0g
Ethyl hydroxybenzoate 3g
Glycerol is appropriate
Acetate buffer is appropriate
Water for injection adds to 10L.
Preparation technology:
Getting hydrochloric acid NM394 50g is dissolved in 2L water for injection; Separately get PVP 0g, ethyl hydroxybenzoate 3g, glycerol 300ml is dissolved in 5L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add acetate buffer, inject water to amount of preparation 10L, regulate pH value to 5.5 ± 0.5, through 100 ℃ of 30min circulation steam sterilizations, be cooled to room temperature, semi-finished product inspection content is qualified, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 6
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, methyl parahydroxybenzoate 0.42mg, propyl p-hydroxybenzoate 0.065mg, sodium chloride 3.8mg, glycerol 0.01ml.
Prescription:
Hydrochloric acid NM394 10g
Methyl parahydroxybenzoate 4.2g
Propyl p-hydroxybenzoate 0.65g
Sodium chloride 38g
Glycerol 100ml
Borate buffer is appropriate
Water for injection adds to 10L.
Preparation technology:
Getting hydrochloric acid NM394 10g is dissolved in 4L water for injection; Separately get methyl parahydroxybenzoate 4.2g, propyl p-hydroxybenzoate 0.65g, sodium chloride 38g, glycerol 100ml, add 5L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add borate buffer, inject water to 10L, semi-finished product inspection content is qualified, regulates pH value to 5-7, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 7
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 3mg, lysine 5mg, chlorobutanol 4.4mg, sodium chloride 6.4mg, 1,2 propylene glycol 0.22g, methylcellulose 0.3mg, lecithin 0.5mg.
Prescription:
Hydrochloric acid NM394 15g
Lysine 25g
Chlorobutanol 22g
Sodium chloride 32g
1,2 propylene glycol 1.1g
Methylcellulose 1.5g
Lecithin 2.5g
Phosphate buffer is appropriate
Water for injection adds to 5L.
Preparation technology:
Getting hydrochloric acid NM394 15g is dissolved in the water for injection containing lysine 25g, lecithin 2.5g; Separately get recipe quantity chlorobutanol, sodium chloride, 1,2 propylene glycol, methylcellulose 1.5g and be dissolved in appropriate water for injection, stirring and dissolving; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 8
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 2mg, lecithin 0.5mg, lysine 3mg, sodium chloride 9mg, methyl parahydroxybenzoate 0.5mg and propyl p-hydroxybenzoate 0.16mg, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 10g is dissolved in the water for injection containing lysine 15g, lecithin 2.5g; Separately get sodium chloride 45g, methyl parahydroxybenzoate 2.5g and propyl p-hydroxybenzoate 0.8g, methylcellulose 1.75g is dissolved in appropriate water for injection, stirring and dissolving; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 9
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, lecithin 0.5mg, lysine 3mg, 12 milligrams of glucoses, methyl parahydroxybenzoate 0.5mg and propyl p-hydroxybenzoate 0.16mg, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in the water for injection containing lysine 15g, lecithin 2.5g; Separately get 60 grams of glucoses, methyl parahydroxybenzoate 2.5g and propyl p-hydroxybenzoate 0.8g, methylcellulose 1.75g is dissolved in appropriate water for injection, stirring and dissolving; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 10
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 5mg, lecithin 0.5mg, lysine 3mg, 12 milligrams of glucoses, methyl parahydroxybenzoate 0.5mg and propyl p-hydroxybenzoate 0.16mg, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 25g is dissolved in the water for injection containing lysine 15g, lecithin 2.5g; Separately get 60 grams of glucoses, methyl parahydroxybenzoate 2.5g and propyl p-hydroxybenzoate 0.8g, methylcellulose 1.75g is dissolved in appropriate water for injection, stirring and dissolving; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 11
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 3mg, lecithin 0.5mg, lysine 3mg, 7 milligrams of glucoses, 4 milligrams, sodium chloride, methyl parahydroxybenzoate 0.5mg and propyl p-hydroxybenzoate 0.16mg, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 15g is dissolved in the water for injection containing lysine 15g, lecithin 2.5g; Separately get 35 grams of glucoses, 20 grams, sodium chloride, methyl parahydroxybenzoate 2.5g and propyl p-hydroxybenzoate 0.8g, methylcellulose 1.75g and be dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 12
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 3mg, 12 milligrams of glucoses, methyl parahydroxybenzoate 0.5mg and propyl p-hydroxybenzoate 0.16mg, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 15g is dissolved in the water for injection 2L containing lysine 15g, lecithin 2.5g; Separately get 35 grams of glucoses, 20 grams, sodium chloride, methyl parahydroxybenzoate 2.5g and propyl p-hydroxybenzoate 0.8g, methylcellulose 1.75g and be dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 13
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 12 milligrams of glucoses, 5% benzalkonium bromide 0.004ml, methylcellulose 0.35mg.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in water for injection 2L; Separately get 60 grams of glucoses, 5% benzalkonium bromide 20ml, methylcellulose 1.75g are dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 14
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 7 milligrams, sodium chloride, 5% benzalkonium bromide 0.004ml, hydroxypropyl methylcellulose 3mg.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in water for injection 2L; Separately get 35 grams, sodium chloride, 5% benzalkonium bromide 20ml, hydroxypropyl methylcellulose 15g are dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate phosphate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 15
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 1 milligram of hyaluronic acid sodium, benzalkonium chloride 0.5mg, sodium chloride 5mg.
Preparation technology:
Getting hydrochloric acid NM394 1g is dissolved in 50 ℃ of water for injection 700ml; Separately get 5 grams, sodium chloride, benzalkonium chloride 0.5g, hyaluronic acid sodium 1g are dissolved in 200ml water for injection, 50 ℃ of heated and stirred are dissolved; Two liquid are merged, filter, cooling, add appropriate phosphate buffer, the cooling amount of preparation 1L that injects water to, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, be cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 16
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 1 milligram of hyaluronic acid sodium, thimerosal 0.01mg, sodium chloride 5mg.
Preparation technology:
Getting hydrochloric acid NM394 1g is dissolved in 50 ℃ of water for injection 700ml; Separately get 5 grams, sodium chloride, thimerosal 0.01g, hyaluronic acid sodium 1g are dissolved in 200ml water for injection, 50 ℃ of heated and stirred are dissolved; Two liquid are merged, filter, cooling, add appropriate phosphate buffer, the cooling amount of preparation 1L that injects water to, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, be cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 17
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 7 milligrams, sodium chloride, 5% benzalkonium bromide 0.004ml, hydroxypropyl methylcellulose 3mg.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in water for injection 2L; Separately get 35 grams, sodium chloride, 5% benzalkonium bromide 20ml, hydroxypropyl methylcellulose 15g are dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate lucky Fei Shi buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
Embodiment 18
Hydrochloric acid NM394 eye drop, every milliliter of every finished product contains hydrochloric acid NM394 1mg, 7 milligrams, sodium chloride, 5% benzalkonium bromide 0.004ml, hydroxypropyl methylcellulose 3mg.
Preparation technology:
Getting hydrochloric acid NM394 5g is dissolved in water for injection 2L; Separately get 35 grams, sodium chloride, 5% benzalkonium bromide 20ml, hydroxypropyl methylcellulose 15g are dissolved in appropriate water for injection, heated and stirred is dissolved; Two liquid are merged, filter, add appropriate sodium acetate-borate buffer, inject water to amount of preparation 5L, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, is cooled to room temperature, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a hydrochloric acid NM394 eye drop, is characterized in that, take hydrochloric acid NM394 as raw material preparation, every milliliter of hydrochloric NM394 1-5 milligram, and other is suitable eye adjuvant and water for injection.
2. hydrochloric acid NM394 eye drop as claimed in claim 1, it is characterized in that, described eye is with adjuvant containing osmotic pressure regulator, viscosity-controlling agent, antibacterial, pH adjusting agent, and described osmotic pressure regulator is selected from sodium chloride, glucose, boric acid, potassium chloride, glycerol; Viscosity-controlling agent is selected from methylcellulose, polyvinyl alcohol, polyvidone, hypromellose, hyaluronic acid sodium; Antibacterial is selected from benzalkonium chloride, benzalkonium bromide, thimerosal, phenethanol, chlorobutanol, parabens; PH adjusting agent is selected from phosphate buffer, boric acid series buffer, lucky Fei Shi buffer, acetate series buffer, sodium acetate-borate buffer, hydrochloric acid, acetic acid, sodium hydroxide solution.
3. hydrochloric acid NM394 eye drop as claimed in claim 1, is characterized in that, described viscosity-controlling agent is selected from methylcellulose, polyvinyl alcohol, polyvidone, hypromellose, hyaluronic acid sodium.
4. hydrochloric acid NM394 eye drop as claimed in claim 1, is characterized in that, described osmotic pressure regulator is selected from sodium chloride, glucose, boric acid, potassium chloride, glycerol.
5. hydrochloric acid NM394 eye drop as claimed in claim 1, it is characterized in that, described pH adjusting agent is selected from phosphate buffer, boric acid series buffer, lucky Fei Shi buffer, acetate series buffer, sodium acetate-borate buffer, hydrochloric acid, acetic acid, sodium hydroxide solution.
6. hydrochloric acid NM394 eye drop as claimed in claim 1, it is characterized in that, every milliliter contains hydrochloric acid NM394 1-5 milligram, suitable eye with adjuvant be osmotic pressure regulator 1-20 milligram, antibacterial in right amount, viscosity-controlling agent 0.2-0.5 milligram and water for injection.
7. hydrochloric acid NM394 eye drop as claimed in claim 1, is characterized in that pH value 5-7.
8. hydrochloric acid NM394 eye drop as claimed in claim 1, is characterized in that pH value 5.5 ± 0.5.
9. its preparation method of hydrochloric acid NM394 eye drop as claimed in claim 1, is characterized in that, comprises the following steps: hydrochloric acid NM394 adds appropriate water for injection, makes entirely molten; Again with the solution mixed dissolution such as osmotic pressure regulator, viscosity-controlling agent, antibacterial, inject water to enough, after semi-finished product inspection content, pH value are qualified, through circulation steam sterilization, aseptic subpackaged, pack and get final product.
10. the preparation method of hydrochloric acid NM394 eye drop as claimed in claim 9, is characterized in that, comprises the following steps: get hydrochloric acid NM394 (corresponding amount of preparation 5-25g) and be dissolved in 1L water for injection; Separately get polyvinylpyrrolidone 200g, ethyl hydroxybenzoate 1.5g, glycerol 150ml is dissolved in 3L water for injection, heating for dissolving; Two liquid are merged, filter, from filter, add acetate buffer solution, the cooling amount of preparation 5L that injects water to, regulate pH value to 5.5 ± 0.5, semi-finished product inspection content is qualified, through 100 ℃ of 30min circulation steam sterilizations, use 0.22um filtering with microporous membrane, aseptic subpackaged, pack and get final product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383069A (en) * | 2017-08-25 | 2017-11-24 | 兆科药业（合肥）有限公司 | Hydrochloric acid NM394 crystal and its production and use |
| CN107501298A (en) * | 2017-08-25 | 2017-12-22 | 兆科药业（合肥）有限公司 | Hydrochloric acid NM394 crystal and its production and use |
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| CN101003540A (en) * | 2006-01-18 | 2007-07-25 | 广州白云山制药股份有限公司广州白云山制药总厂 | Anti infectious compound and usage |
| CN101172108A (en) * | 2006-10-31 | 2008-05-07 | 江苏正大天晴药业股份有限公司 | Prulifloxacin active body injection |
| CN102198134A (en) * | 2010-03-22 | 2011-09-28 | 北京联木医药技术发展有限公司 | Use of new stable Ulifloxacin hydrochloride in preparation of anti-infection medicine |
| 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 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101003540A (en) * | 2006-01-18 | 2007-07-25 | 广州白云山制药股份有限公司广州白云山制药总厂 | Anti infectious compound and usage |
| CN101172108A (en) * | 2006-10-31 | 2008-05-07 | 江苏正大天晴药业股份有限公司 | Prulifloxacin active body injection |
| CN102198134A (en) * | 2010-03-22 | 2011-09-28 | 北京联木医药技术发展有限公司 | Use of new stable Ulifloxacin hydrochloride in preparation of anti-infection medicine |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107383069A (en) * | 2017-08-25 | 2017-11-24 | 兆科药业（合肥）有限公司 | Hydrochloric acid NM394 crystal and its production and use |
| CN107501298A (en) * | 2017-08-25 | 2017-12-22 | 兆科药业（合肥）有限公司 | Hydrochloric acid NM394 crystal and its production and use |
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| CN103735499B (en) | 2016-01-20 |
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