CN102512362A - Formula and preparation method of compound ciprofloxacin eye drops - Google Patents
Formula and preparation method of compound ciprofloxacin eye drops Download PDFInfo
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- CN102512362A CN102512362A CN201110431897XA CN201110431897A CN102512362A CN 102512362 A CN102512362 A CN 102512362A CN 201110431897X A CN201110431897X A CN 201110431897XA CN 201110431897 A CN201110431897 A CN 201110431897A CN 102512362 A CN102512362 A CN 102512362A
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Abstract
The present invention discloses a formula and a preparation method of compound ciprofloxacin eye drops, the formula takes ciprofloxacin and borneol as basic components, a solubilizer, a thickening agent, a preservative, an isotonic regulator, a PH regulator and sterile water for injection are supplemented to prepare the ophthalmic preparation. The borneol is added for the eye drops in the invention on the basis of the ciprofloxacin ophthalmic preparation, the eye drops possess multiple functions of resisting bacterial and diminishing inflammation, relieving swelling and pain, and cooling and relieving itching.
Description
Technical field
The present invention relates to the prescription and the method for preparing of kind of a kind of compound ciprofloxacin eye drop.
Background technology
Disposable levofloxacin hydrochloride eye drops tool broad-spectrum antibacterial action, at present disposable levofloxacin hydrochloride eye drops is used for responsive microbial outer eye infection (like conjunctivitis etc.).
Disposable levofloxacin hydrochloride eye drops has the middle part to stimulate through long-term clinical application reaction to eye, and it is excessive that concentration is accumulated by frequent eye dripping eye topical remedy, and the damage of corneal is maximum.With the prolongation of administration time and the reinforcement of toxic degree, the degree of pathological changes and scope are strengthened, medicament for the eyes can cause in the part dose dependent cytotoxic effect [list of references: Yang Xiaohui. the clinical analysis of medicine property keratopathy. international ophthalmology magazine 2007; 7 (3): 861,862].
The present invention has increased Borneolum Syntheticum in disposable levofloxacin hydrochloride eye drops.Borneolum Syntheticum has nebula and makes eye bright, the effect of reducing swelling and alleviating pain.Borneolum Syntheticum has the antiviral pharmacotoxicological effect of antiinflammatory on the one hand, and Borneolum Syntheticum can increase the corneal permeability of other medicines on the other hand, is a kind of very promising penetration enhancer.Borneolum Syntheticum can promote the ocular absorption of No. one, TCM Ophthalmology medicine for external use virus.Borneolum Syntheticum can make the phospholipid bilayer motion of corneal epithelial cells of rabbit film more orderly; Thereby increase the permeability [list of references: Wu CJ of corneal epithelial cell; Huang QW; Qi HY, et al.Promoting effect of borneol on the permeability of puerarin eye drops and timolol maleate eye drops through the cornea in vitro.Pharmazie2006; 61 (9): 783,788 and Fan Lanlan, Tang is by it, Lu Jingfen, etc. Borneolum Syntheticum is to the short chemosmotic experimentation of corneal epithelial cells of rabbit film. Chinese TCM Ophthalmology magazine 1998; 8 (2): 67,69].
Through experiment confirm, the Borneolum Syntheticum eye drop of eye prolonged application 0.25～1g/L concentration increases with the increase eye table zest scoring of concentration to some extent, and eye is shown equal nonirritant.Cornea to being easy to generate drug accumulation can not produce pathologic lesion yet, and other each tissue of ophthalmic is not all had dealed with medicine went like iris, retina, optic nerve.
Summary of the invention
[0005] the object of the present invention is to provide and a kind ofly be used for responsive microbial outer eye and infect (like conjunctivitis etc.) and can effectively alleviate the stimulation of eye drip eye, and the pharmaceutical formulation and the method for preparing of the corneal permeability symptom of increase other medicines.
For achieving the goal, the present invention adopts following technical scheme to be achieved:
A kind of compound ciprofloxacin eye drop of the present invention, it comprises following component:
All the other are solvent.
Wherein, said isotonic agent is that in sodium chloride, potassium chloride, boric acid, sodium sulfate, Chile saltpeter, potassium nitrate, sodium acetate, mannitol, glycerol, propylene glycol, the glucose one or more are composite.
Described PH regulator is that in phosphoric acid dichloro sodium, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, Borax, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid, the phosphoric acid one or more are composite;
Described stabilizing agent be sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium nitrite, sodium thiosulfate, ascorbic acid (vitamin C), thiourea, ascorbyl stearate, dibutyl hydroxy toluene, cysteine, disodiumedetate (EDTA-2Na, disodium edetate), calcio-disodium edetate, dimercaptopropanol, BAL, glycerol, mannitol, in one or more are composite;
Said thickening agent is that in hyaluronate sodium, chondroitin sulfate, methylcellulose, hypromellose, hydroxypropyl methylcellulose, cellulose, polyvidone, polyvinylpyrrolidone, polyvinyl alcohol, the carbomer one or more are composite;
Said solubilizing agent is a kind of in ethanol, tween, glycerol, propylene glycol, the Polyethylene Glycol.
Described antiseptic is a benzalkonium bromide solution.
Solvent is a water for injection.
Preferred compound ciprofloxacin eye drop of the present invention, each component is following:
All the other are solvent.
Most preferred compound ciprofloxacin eye drop of the present invention, each component is following:
Ciprofloxacin (in ciprofloxacin) 30.0g
All the other are solvent.
The present invention also provides the method for preparing of compound ciprofloxacin eye drop, and its preparation process is following:
With the water for injection of 200～400ml of about amount of preparation, put into Agitation Tank.
Ciprofloxacin is placed stainless steel cask, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Stabilizing agent, isotonic agent are placed enamel pan, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Water for injection with 150～300ml places the enamel ingredients pot, slowly adds thickening agent, stirs, boil swelling after, be cooled to below 60 ℃, put into the mixer weighing, suck Agitation Tank.
With antiseptic, add an amount of water for injection, suck Agitation Tank.
Solubilizing agent is placed the enamel ingredients pot, add Borneolum Syntheticum, add an amount of water for injection, pour Agitation Tank into, add an amount of water for injection near 1000ml.
Regulate PH with PH regulator 1, cooling.Medicinal liquid behind 0.22～0.45um filtering with microporous membrane 1～5 time, fill.
It is that screening process is following through what screen that prescription of the present invention is formed:
1, the adjustment of viscosity
The suitable viscosity of eye drop is between 4.0～5.0mPas, and using this hydrophilic high molecular material of hypromellose increases solution viscosity, can reduce loss, prolong drug and cornea time of contact, helps drug osmotic.
2, the adjustment of PH
PH value has very significant effects to eye drop, and the inappropriate meeting of pH value causes stimulation to eye, increases lacrimal secretion, causes medicine to run off rapidly, even the damage eye mask.The pH value that normal eyes can tolerate is 5.0～9.0, numbness when pH value is 6.0～8.0, and less than 5.0 with all tangible sensation can be arranged greater than 11.0 o'clock, in order to alleviate sense of discomfort as far as possible, ophthalmic solution should have the pH value identical with tear.The present invention is with hydrogen sodium sodium adjustment PH7.0～8.0.
3, the adjusting of osmotic pressure
The osmotic pressure of ophthalmic solution should be tried one's best and wave equates that the osmotic pressure of tear is 7.4 atmospheric pressure.Hyperosmotic solution makes cornea dry out within the eye, makes dry and produces uncomfortable sensation; Hypisotonic solution can make the cornea tissue cell swell and produce stimulation.The too high or too low eye that also can stimulate of solution osmotic pressure increases tear, causes medicinal liquid dilution or loss rapidly, and therefore general ophthalmic solution all should be regulated its osmotic pressure.Eyes are higher than blood to the toleration of osmotic pressure, can tolerate the osmotic pressure scope that is equivalent to 0.5%～2.0% sodium chloride solution.Most of people are acceptables in the scope of 0.7%～1.5% sodium chloride, so the osmotic pressure scalable of ophthalmic solution is in this scope.
4, the maintenance of sterility
As the antibacterial of eye drop, not only require effectively, also to have lower toxicity, water soluble.With benzalkonium bromide in the antibacterial that meets these requirements, nontoxic, non-stimulated, stable in properties, fast light, heat-resisting, non-volatility, but long-term storage.
5, stabilizing agent confirms
Disodium edetate is widely used in eye drop, and low toxicity is water-soluble, and has coordination property widely, almost can form stable chelate with all metal ions, makes product more stable.
6, solubilizing agent confirms
The effect of solubilizing agent is to increase the dissolubility of Borneolum Syntheticum in water, and Borneolum Syntheticum tool volatility is prone to distillation, and is almost insoluble in water.Tween 80 is high to the dissolubility of Borneolum Syntheticum, and in water, also is prone to dissolve, and tween content under these conditions is harmless to human body.
The present invention also provides assay, stability test, toxicity test and the irritation test result of said preparation, and is specific as follows:
1, assay
The hydrochloric ciprofloxacin of these article should be 90%～110% of labelled amount
2, stability test
These article are through simulation listing packing, and at 40 ℃, relative humidity 75% condition held 6 months with keep sample for a long time and investigate 18 months, each item is investigated index and relatively do not had significant change in 0 day.
Conclusion: these article are through influence factor's experiment, and accelerated test and room temperature are investigated 18 months, and the result shows: each item index does not have obvious variation.These article should place below 25 ℃ and preserve, and it is 2 years that effect duration can fix tentatively.These article preparation technology is convenient feasible, quality controllable.
3, toxicity test:
Material: compound hydrochloric acid ciprofloxacin eye drop, 0.9% normal saline.Healthy white rabbit, 20, male and female are regardless of, quality 2.5～2.8kg.24h before the experiment beginning is with 20g/L fluorescein sodium corneal dyeing.
Test method: 8 white rabbit are divided into 2 groups at random, 4 every group.The 1st group all drips reagent.The 2nd group drips normal saline and does own control.Medication will be splashed in the conjunctival sac by reagent 50 μ L for drawing back the palpebra inferior of rabbit eyes gently, make the passive closed 3s of upper and lower eyelid, to prevent lost by the reagent thing.After the administration 1,2,4,24,48, the IR of 72h and 7d slit lamp observation eye drop corneal, iris and conjunctiva.Standards of grading by the eye IR in each inspection write down integration.The IR score value addition of cornea, iris and conjunctiva of each animal gets total mark observing time with each, and one group integration summation divided by number of animals, is promptly got last score value.0～3 fen nonirritant, 4～8 fens slight zests, 9～12 fens moderate zests, 13～16 fens intensity zests.
Experiment confirm, the scoring of two groups of IRs all＜3 minutes, eye is shown equal nonirritant.Cornea to being easy to generate drug accumulation can not produce pathologic lesion yet, and other each tissue of ophthalmic is not all had dealed with medicine went like iris, retina, optic nerve.
Long term toxicity test: 12 white rabbit are divided into 3 groups at random, 4 every group.1 group of blank group, 2 groups of normal saline matched groups, 3 groups of same irritant experiments of compound hydrochloric acid ciprofloxacin eye drop group medication.4 times/d, continuous 4wk.During 28d behind the last eye dripping auricular vein get blood 6mL, it is biochemical to make routine blood test and blood respectively.
Long term toxicity test can disclose dosage poisonous effect relation, toxicity target organ, nontoxic amounts of reactants and the safety range of medicine.The biochemical each item index of routine blood test and blood changes in the blood parameters analysis all has its certain sense: anemia, hemorrhage and haemolysis can cause that RBC descends; Anemia can cause that HGB descends; Bone marrow depression can cause PLT to reduce; Bacterial infection and bone marrow stimulate can cause the WBC rising.ALT is the liver function sensitive indicator, is most commonly used to evaluating liver infringement or hepatic disease; AST mainly is present in skeletal muscle and the cardiac muscle, and normal relevant with the infringement of these tissues; TP and ALB can reduce when malnutrition or hepatic and renal function long-term damage; BUN and Cr are the indexs of assessment kidney blood filtration ability, and Cr has more specificity than BUN.In a word, blood routine and biochemical indicator can reflect potential target organ damage.Dirty body has also been explained the influence degree of dealed with medicine went to a certain extent than the result of coefficient except that the blood parameter.
In this experiment, more than three groups blood routine compare with matched group with biochemical indicator and do not have significant difference, the dirty body of each experimental group does not have significance than difference of coefficients.Above-mentioned experimental result can think that eye prolonged application compound hydrochloric acid ciprofloxacin eye drop does not have influence to the function of organization of internal organs such as blood system and Liver and kidney.
4, synergism contrast experiment: material: compound hydrochloric acid ciprofloxacin eye drop, disposable levofloxacin hydrochloride eye drops (component is removed Borneolum Syntheticum, Tween 80), Borneolum Syntheticum eye drop (component demineralizing acid ciprofloxacin).Healthy white rabbit, 18, male and female are regardless of, quality 2.5～2.8kg.24h before the experiment beginning is with 20g/L fluorescein sodium corneal dyeing.
Test method: 18 white rabbit are divided into 3 groups at random, 6 every group.The 1st group drips compound hydrochloric acid ciprofloxacin eye drop.The 2nd group drips disposable levofloxacin hydrochloride eye drops.The 3rd group drips the Borneolum Syntheticum eye drop.Medication will be splashed in the conjunctival sac by reagent 50 μ L for drawing back the palpebra inferior of rabbit eyes gently, make the passive closed 3s of upper and lower eyelid, to prevent lost by the reagent thing.After the administration 1,2,4,24,48, the IR of 72h and 7d slit lamp observation eye drop corneal, iris and conjunctiva.Standards of grading by the eye IR in each inspection write down integration.The IR score value addition of cornea, iris and conjunctiva of each animal gets total mark observing time with each, and one group integration summation divided by number of animals, is promptly got last score value.0～3 fen nonirritant, 4～8 fens slight zests, 9～12 fens moderate zests, 13～16 fens intensity zests.
Experiment confirm, the scoring of first group of IR all＜3 minutes, to eye table nonirritant; Second group of IR scoring had slight zest to the eye table between 3～5 minutes; The scoring of the 3rd group of irritative response all＜3 minutes, to eye table nonirritant.Three groups of tests show that the synergism of compound hydrochloric acid ciprofloxacin eye drop strengthens, and reduces the zest of medicine.
The specific embodiment:
Embodiment 1
With the water for injection of about 200ml, put into Agitation Tank.
Ciprofloxacin 30.0 is placed stainless steel cask, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Disodium edetate 1g, sodium chloride 70g are placed enamel pan, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Water for injection with 150～300ml places the enamel ingredients pot, slowly adds hypromellose 30g, stirs, boil swelling after, be cooled to below 60 ℃, put into the mixer weighing, suck Agitation Tank.
Benzalkonium bromide 20ml with 5% adds an amount of water for injection, sucks Agitation Tank.
With Tween 80,3g places enamel pan, adds Borneolum Syntheticum 1g again, adds an amount of water for injection, pours Agitation Tank into, adds an amount of water for injection near 1000ml.
Sodium hydroxide 40ml～50ml with 1mol/L regulates PH, cooling.Medicinal liquid behind 0.22～0.45um filtering with microporous membrane 1～5 time, fill.
Embodiment 2
With the water for injection of about 200ml, put into Agitation Tank.
Ciprofloxacin 30.0 is placed stainless steel cask, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Disodium edetate 1g, sodium chloride 80g are placed enamel pan, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
Water for injection with 150～300ml places the enamel ingredients pot, slowly adds hypromellose 28g, stirs, boil swelling after, be cooled to below 60 ℃, put into the mixer weighing, suck Agitation Tank.
Benzalkonium bromide 18ml with 5% adds an amount of water for injection, sucks Agitation Tank.
With Tween 80,4g places enamel pan, adds Borneolum Syntheticum 1g again, adds an amount of water for injection, pours Agitation Tank into, adds an amount of water for injection near 1000ml.
Sodium hydroxide 40ml～50ml with 1mol/L regulates PH, cooling.Medicinal liquid behind 0.22～0.45um filtering with microporous membrane 1～5 time, fill.
Claims (8)
1. a compound ciprofloxacin eye drop is characterized in that, comprises ciprofloxacin and Borneolum Syntheticum.
2. according to the eye drop of claim 1, it is characterized in that, also comprise, isotonic agent, PH regulator, stabilizing agent, thickening agent, solubilizing agent, antiseptic, solvent.
3. according to the eye drop of claim 1, it is characterized in that prescription is formed as follows:
All the other are solvent.
4. according to the eye drop of claim 3, it is characterized in that, wherein
Said isotonic agent is selected from one or more in sodium chloride, potassium chloride, boric acid, sodium sulfate, Chile saltpeter, potassium nitrate, sodium acetate, mannitol, glycerol, propylene glycol, the glucose;
Described PH regulator is selected from one or more in phosphoric acid dichloro sodium, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, Borax, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid, the phosphoric acid;
Described stabilizing agent be selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium nitrite, sodium thiosulfate, ascorbic acid (vitamin C), thiourea, ascorbyl stearate, dibutyl hydroxy toluene, cysteine, disodiumedetate (EDTA-2Na, disodium edetate), calcio-disodium edetate, dimercaptopropanol, BAL, glycerol, mannitol, in one or more;
Said thickening agent is selected from one or more in hyaluronate sodium, chondroitin sulfate, methylcellulose, hypromellose, hydroxypropyl methylcellulose, cellulose, polyvidone, polyvinylpyrrolidone, polyvinyl alcohol, the carbomer;
Said solubilizing agent is selected from one or more in ethanol, tween, glycerol, propylene glycol, the Polyethylene Glycol;
Described antiseptic is selected from benzalkonium bromide solution;
Solvent is a water for injection.
5. according to the eye drop of claim 3, it is characterized in that each set of dispense is such as following:
All the other are solvent.
6. according to the eye drop of claim 3, it is characterized in that each set of dispense is such as following:
All the other are solvent.
7. the prescription of the described eye drop of claim 1 and method for preparing is characterized in that it may further comprise the steps:
A, water for injection that will about 200ml are put into Agitation Tank.
B, ciprofloxacin 26～35g is placed stainless steel cask, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
C, stabilizing agent 0.01g～5g, isotonic agent 0.1～80g are placed enamel pan, after the water for injection dissolving with about 100～200ml of configuration amount, suck Agitation Tank.
D, place the enamel ingredients pot, slowly add thickening agent 1g～50g, stir with the water for injection of 150～300ml, boil swelling after, be cooled to below 60 ℃, put into the mixer weighing, suck Agitation Tank.
E, with antiseptic 1ml～30ml, add an amount of water for injection, suck Agitation Tank.
F, solubilizing agent 1g～10g is placed enamel pan, add Borneolum Syntheticum 0.9～1.1g, add an amount of water for injection, pour Agitation Tank into, add an amount of water for injection near 1000ml.
G, use the PH regulator to regulate PH, cooling as 1ml～50ml.Medicinal liquid behind 0.22～0.45um filtering with microporous membrane 1～5 time, fill.
8. the assay method of the eye drop of claim 1, step is following:
(1) observation of character, these article are colourless or yellowish clear liquid.
(2) pH value is measured: measure PH in accordance with the law and should meet the requirement when preparing.
(3) related substance: precision is measured these article 15ml, quantitatively dilutes with mobile phase A and processes the solution that contains ciprofloxacin 0.45mg among every 1ml approximately, as need testing solution; Precision is measured in right amount, quantitatively dilutes with mobile phase A and processes the solution that contains 0.9 μ g among every 1ml approximately, as contrast solution.Measure according to the method under the ciprofloxacin item.In the need testing solution chromatogram if any impurity peaks [except that RRT less than 0.2 the peak and ethyl hydroxybenzoate peak (RRT about 2.75)], impurity A (262nm detection) by external standard method with calculated by peak area, must not cross 0.3%.Impurity C (278nm detection) must not be greater than 2.5 times of contrast solution main peak area by the calculated by peak area (multiply by correction factor 0.6) after proofreading and correct; Impurity B, D and E peak (278nm detection) all must not be greater than contrast solution main peak areas by the calculated by peak area (multiply by correction factor 0.7,1.4 and 6.7 respectively) after proofreading and correct; Other single impurity (278nm detection) peak area must not be greater than contrast solution main peak area.Each impurity (278nm detection) proofread and correct the back peak area with must not be greater than 3.5 times of contrast solution main peak area.
(4) osmotic pressure molar density: measure the osmotic pressure molar density ratio in accordance with the law and answer the coincidence method provisioning request.
(5) assay:
1. precision is measured these article 3ml (being equivalent to ciprofloxacin 9mg approximately), puts in the 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, and precision is measured 20 μ l and injected chromatograph of liquid, the record chromatogram; Other gets the ciprofloxacin reference substance, measures with method, by the content of external standard method with C17H18FN3O3 in the calculated by peak area test sample.
2. get an amount of naphthalene, use dissolve with ethanol, and be diluted to the solution that contains 2mg among every 1ml, shake up, as inner mark solution.Precision is measured these article 2ml, accurate inner mark solution 1ml, the mixing of adding; Get 1 μ l inject gas chromatograph, measure, calculate, promptly get.
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| CN104027302A (en) * | 2013-03-07 | 2014-09-10 | 中国医药工业研究总院 | 17 alpha-ethynylandrost-5-alkenyl-3 beta, 7 beta, 17 beta-triol preparation for eyes |
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Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Co-patentee after: JINGXI JIMIN KEXIN GROUP Co.,Ltd. Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co., Ltd Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Co-patentee before: JINGXI JIMIN KEXIN GROUP Co.,Ltd. Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. |