CN101342370A - Instant jelly glue of carbomer for eyes - Google Patents
Instant jelly glue of carbomer for eyes Download PDFInfo
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- CN101342370A CN101342370A CNA2007101226880A CN200710122688A CN101342370A CN 101342370 A CN101342370 A CN 101342370A CN A2007101226880 A CNA2007101226880 A CN A2007101226880A CN 200710122688 A CN200710122688 A CN 200710122688A CN 101342370 A CN101342370 A CN 101342370A
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Abstract
The present invention discloses a Carbomer in-situ-forming ophthalmic gel and a preparation method thereof. 1000g of the Carbomer in-situ-forming ophthalmic gel of the present invention contains 10g to 40g of Carbomer, 0.05g to 1g of preservative, 1.0g to 7.5g of osmo-regulator and 30g to 150g of gel matrix, and the rest substances are acid buffer, alkali buffer and water for injection. By optimizing the auxiliary materials and improving the technique, the present invention enriches the pharmaceutical dosage forms of Carbomer, greatly prolongs the residence time of the drug in the eyes and improves the curative effect, and moreover, the Carbomer in-situ-forming ophthalmic gel does not generate any untoward irritation reaction.
Description
[technical field]
The invention belongs to medical technical field, be specifically related to a kind of instant jelly glue of carbomer for eyes.
[background technology]
Instant gel for eye is also named eye with gel on the throne or ocular in-situ gel, its preparation is liquid when room temperature is placed, after splashing into ophthalmic, because the variation of temperature, pH value and ionic strength is converted into gel, can be trapped in ophthalmic in a long time, thereby reach the extended treatment time, strengthen the effect that therapeutic effect reduces drug loss.
Instant gel for eye also is not a kind of very sophisticated pharmaceutical preparation at present, temperature dependent, the instant gel for eye of principle such as pH value and ionic strength immaturity still also in commercialization, this is except the meticulous technology of needs because of this dosage form, suitable adjuvant, the appropriate coupling that also needs instant gel for eye Chinese medicine and technology and adjuvant, otherwise just can not reach room temperature and be placed as liquid state, be converted into gel after splashing into ophthalmic, this field work still needs a large amount of basic research, have only U.S. food Drug Administration to ratify a kind of Timoptic-XE (Timo1o1 Malaeate Ophthalmic Gel forming Solution) listing at present, belong to ionic strength responsive type instant gel for eye, and other ophthalmic remedies still in the anophthalmia gel on the throne emerge.
Patent documentation CN1377706A discloses a kind of ocular in-situ gel preparation with suitable phase transition temperature, it merges the combination that utilizes the different model poloxamer, prepared the ocular in-situ gel preparation that contains medicine and water soluble polymer adjuvant, contain poloxamer 407 and poloxamer 188 in the preparation, also can add concentration less than 3% water soluble polymer adjuvant, this situ-gel has suitable phase transition temperature, can form gel with the liquid condition administration and on the live cornea surface at ambient temperature.It is very expensive pharmaceutic adjuvants that but this patent is used poloxamer 407 and 188, and this working of an invention process is more complicated also, thereby also needs the process of the new instant gel for eye of further research and development.
The chemistry of carbomer is called the cross linked polyacrylate resin.Carbomer (carbomer) and acrylic acid crosslinked resin and these polyacrylic acid series product use the most extensive at present, are applied in external emulsion, cream frost, the gel.Carbomer under the neutral environment (carbomer) system is fabulous gel-type vehicle, apparent sparkling and crystal-clear, feel is lubricated, be fit to very much be used for preparing frost or gel, because technology is simple, good stability uses aftersensation comfortable simultaneously, therefore in topical, particularly in skin and gel for eye, has extensive use.These polymer are used to optimize the rheological property of water solution system.Carbomer commonly used has:
1. carbomer (Carbomer) 941, viscosity: 4000～11000mPa.s, residual solvent: 0.2%, characteristics: can produce the colloid transparency height that low viscous permanent Emulsion and suspended substance produced, anti-ionic nature is relatively good in containing the ion system.The scope of application: local medicine-applying system, high Emulsion Stabilization has rare gel of good clarity
2. carbomer (Carbomer) 934, viscosity: 30000～40000mPa.s, residual solvent: 0.2%, characteristics: thickening effect is good, has permanent stability when high viscosity, has short fluidity in aqueous solution.The scope of application: local medicine-applying system, stable when high viscosity, be used for dense gel, Emulsion, suspensoid.
3. carbomer (Carbomer) 934P, viscosity: 30000～40000mPa.s, residual solvent: 60ppm, characteristics: when high viscosity, have permanent stability, because residual solvent trace, be more suitable in the oral medicinal preparation scope of application: oral, local and new drug-supplying system, controlled release matrix tablet.
4. carbomer (Carbomer) 940, viscosity: 40000～60000mPa.s, residual solvent: 0.2%, characteristics: the high viscosity tackify is effective.The scope of application: be used for external preparation more, be suitable for preparing gel, ointment, couplant.
5. carbomer (Carbomer) 1342, viscosity: 20000～40000mPa.s, residual solvent: 0.2%, characteristics: have efficient thickening effect, can produce as clear as crystal water or pure hydrocolloid, have stronger anti-ion-type., the scope of application: local medicine-applying system reaches good rheology improver, polymerization emulsification in the presence of electrolyte.
6. carbomer (Carbomer) 980, viscosity: 40000～80000mPa.s, residual solvent: 0.2%, characteristics: high viscosity and be fit to do the gel product, the scope of application: local medicine-applying system, crystallization clear and bright gel, water or spirit solvent
The carbomer eye drop is a kind of ophthalmic preparation comparatively commonly used, but exists the collyrium loss that splashes into ophthalmic big clinically, and the holdup time is short, and these problems have all limited the curative effect of carbomer eye drop and more widely-used.
[summary of the invention]
The object of the present invention is to provide a kind of instant jelly glue of carbomer for eyes.
Another object of the present invention is to provide the preparation method of instant jelly glue of carbomer for eyes.
Specifically, 1000 milliliters of instant jelly glue of carbomer for eyes of the present invention contain: carbomer 10-40g, and antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-7.5 gram, gel-type vehicle 30-150 gram, surplus is acid-base buffer agent and water for injection.
Contain in above-mentioned 1000 milliliters of gels: carbomer 10-30g, antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-5.5 gram, gel-type vehicle 30-100 gram, surplus is acid-base buffer agent and water for injection.
Above-mentioned acid-base buffer agent is controlled at the pH value of described instant jelly glue of carbomer for eyes between the 4.15-8.73.
Foregoing preservatives is selected from one or more in phenethanol, benzyl alcohol, sodium benzoate, methyl hydroxybenzoate and the ethyl hydroxybenzoate; Described osmotic pressure regulator is a sodium chloride; Described acid-base buffer agent is selected from hydrochloric acid, sulphuric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium citrate, citric acid, triethanolamine, diethanolamine, the ethanolamine 2 kinds or multiple; Described gel-type vehicle is selected from one or more in Polyethylene Glycol, methylcellulose, ethyl cellulose, polyacrylic acid and the sodium polyacrylate.
Above-mentioned acid-base buffer agent is selected from hydrochloric acid and triethanolamine, and the mol ratio of the two is 1: 0.5-2.
Above-mentioned acid-base buffer agent is selected from hydrochloric acid and sodium citrate, and the mol ratio of the two is 1: 0.2-2.
Above-mentioned gel-type vehicle is selected from Polyethylene Glycol and methylcellulose, and the weight ratio of the two is 1: 50-5000.
Above-mentioned Polyethylene Glycol is selected from one or more among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000, PEG-6000, PEG-10000 and the PEG-20000.
Above-mentioned Polyethylene Glycol is selected from one or more among PEG-1500, PEG-4000 and the PEG-6000.
The preparation method of instant jelly glue of carbomer for eyes of the present invention is: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer, antiseptic is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and stir after adding acid-base buffer agent, cross microporous filter membrane and filter, filtrate reheat to 40 ℃, add osmotic pressure regulator and gel-type vehicle while hot, be stirred to room temperature, add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Instant gel for eye is divided into three kinds: responsive to temperature type, pH value responsive type and ionic strength responsive type, wherein the responsive to temperature type instant gel for eye is easy to industrialization relatively, the present invention also realizes by the responsive to temperature type instant gel for eye, but grope to find the stability of responsive to temperature type gel and can under the local temperature of people's eyeball, be converted into the pH value of gel and instant gel at once whether stable relation is close through inventor's experiment.The inventor adopts the acid-base buffer agent of larger capacity to guarantee pH value stable of instant gel for eye, thereby has guaranteed that gel has responsive and suitable phase transition temperature.
The present invention has enriched the pharmaceutical dosage form of carbomer by the optimization of adjuvant and the improvement of technology, has prolonged medicine greatly in the eye holdup time, has improved curative effect, and does not have the pessimal stimulation reaction.
[specific embodiment]
Following embodiment and experimental example further describe the present invention, but described embodiment and experimental example only are used to illustrate the present invention rather than restriction the present invention.In the invention in the methylcellulose methoxyl content be 27-32%.
Embodiment 1
Prescription: 400 milliliters of sodium citrates of Acritamer 940 10 gram hydrochloric acid (0.05mol/L), 9.6 grams
5 milliliters of methylcellulose 5.0 gram phenethanol 0.5 gram ethanol
Sodium chloride 1.0 gram PEG-1000 20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add Acritamer 940, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 2
Prescription: Acritamer 940 10 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 8.8 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.0 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add Acritamer 940, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 3
Prescription: Acritamer 940 10 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram sodium benzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add Acritamer 940, and adding sodium citrate, sodium hydroxide and sodium benzoate, stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 4
Prescription: Carbopol 941 10 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride 7.5.0 grams of ethanol PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add Carbopol 941, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 5
Prescription: Carbopol 941 10 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 14.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add Carbopol 941, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply 1000 milliliters of weight, stir and make its formation even gel, promptly aseptic subpackaged.
Embodiment 6
Prescription: Carbopol 941 20 gram hydrochloric acid (0.05mol/L) 250 milliliters
Triethanolamine 10 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 1.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add Carbopol 941, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 7
Prescription: carbomer 934 20 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 12 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 6.0 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 934, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 8
Prescription: carbomer 934 20 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 12 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 934, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 9
Prescription: carbomer 934 40 gram hydrochloric acid (0.05mol/L) 400 milliliters
The basic cellulose 5.0 gram phenethanol of sodium citrate 8.8 grams 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 934, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 10
Prescription: carbomer 934 40 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 8.8 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 934, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 11
Prescription: carbomer 934 P 40 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 934 P, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, be added dropwise to while stirring in the above solution, and add sodium citrate, sodium hydroxide and sodium benzoate stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 12
Prescription: carbomer 934 P 30 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 934 P, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat add PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 13
Prescription: carbomer 934 P 30 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 14.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.2 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 934 P, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 14
Prescription: carbomer 934 P 30 gram hydrochloric acid (0.05mol/L) 250 milliliters
Triethanolamine 30 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 934 P, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 15
Prescription: carbomer 934 P 30 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 12 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.8 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 934 P, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 16
Prescription: carbomer 980 25 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 13 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 980, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 17
Prescription: carbomer 980 40 gram hydrochloric acid (0.05mol/L) 400 milliliters
Sodium citrate 8.8 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 980, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 18
Prescription: carbomer 980 40 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 8.8 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 980, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply 000 milliliter of weight to 1, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 19
Prescription: carbomer 980 20 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram sodium benzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 980, and adding sodium citrate, sodium hydroxide and sodium benzoate, stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 20
Prescription: carbomer 980 20 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 980, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 21
Prescription: carbomer 1,342 20 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 14.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.5 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 1342, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat add PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 22
Prescription: carbomer 1,342 25 gram hydrochloric acid (0.05mol/L) 250 milliliters
Triethanolamine 15 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 1.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, cool off 80 ℃, add carbomer 1342, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 23
Prescription: carbomer 1,342 25 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 16 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.0 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 1342, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 24
Prescription: carbomer 1,342 30 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 15 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.0 gram PEG-10000,10 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add carbomer 1342, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, 40 ℃ of filtrate reheat, add PEG-400, PEG-10000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
The pH value of experimental example 1-gel of the present invention is measured
1 method summary
This method is made indicating electrode with glass electrode, makes reference electrode with saturated calomel electrode, with pH4,7 or 9 standard buffer solutions location, measures the pH value of gel.
2 instruments
2.1 acidometer: measuring range 0～14pH; Accuracy of reading≤0.02pH.
2.2pH glass electrode, isopotential point is about pH7.
2.3 saturated calomel electrode.
2.4 thermometer: 0～100 ℃ of measuring range.
2.5 plastic cup: 50 milliliters.
2.6 the scientific calculator of band wire regression equation.
3 reagent
3.1 pH4 standard buffer solution
Accurately take by weighing 10.21 gram Potassium Hydrogen Phthalates (KHC8H2O4), be dissolved in reagent water and be settled to 1L.Because this solution dilution effect is little, needn't be dry before the weighing.It is mouldy that this solution is placed several Zhou Houhui, adds a little microsolubility phenol or its chemical compound (as thymol) and make antifungus agent and can prevent that here phenomenon takes place.
3.2 pH7 standard buffer solution
Accurately take by weighing 3.5 grams respectively through 120 ± 10 ℃ of dry 2h and be cooled to the pure disodium hydrogen phosphate,anhydrous of top grade (Na2HPO4) of room temperature, and 3.40 gram top grade pure phosphoric acid potassium dihydrogens (KH2PO4), be dissolved in reagent water together and be settled to 1L.The solution for preparing should be avoided being stain by Atmospheric Carbon Dioxide.6 Zhou Houying prepare again.
3.3 pH9 standard buffer solution
Accurately take by weighing the 3.81 gram pure Boraxs of top grade (Na2B4O710H2O), be dissolved in the reagent water of no carbon dioxide and be settled to 1L.The solution for preparing should be avoided contacting with Atmospheric Carbon Dioxide as far as possible.Should prepare again all around.
The pH value of above-mentioned standard buffer solution under condition of different temperatures is as shown in table 1.
The pH value of table 1 standard buffer solution under different temperatures
4 analytical procedures
4.1 the preparation of electrode
4.1.1 new glass electrode or put no glass electrode for a long time should place the pH4 standard buffer solution to soak diel in advance.Finish using, also should be placed in the above-mentioned buffer and soak, be not placed on the medium-term and long-term immersion of reagent water.If find that grunge pollution is arranged, preferably be placed on 0.1mol/L hydrochloric acid in the use, the 0.1mol/L sodium hydroxide, circulation immersion is each 5 minutes in the 0.1mol/L hydrochloric acid.After cleaning with reagent water, in the pH4 buffer, soak again.
4.1.2 preferably be immersed in before saturated potassium chloride electrode uses in the weak solution of 10 times of saturated potassium chloride solution dilutions.During storage the inlet jam-pack of upper end, breakdown then during use.Should often note injecting saturated potassium chloride solution to certain liquid level from inlet.
4.2 instrumental correction
After instrument is opened half an hour, press the regulation of instrument description, return to zero, operating procedures such as temperature-compensating and full scale correction.
4.3 pH location
As the case may be, select following a kind of method location.
4.3.1 single-point location
Select a kind of pH value and the approaching standard buffer solution of tested gel phase for use.Before the location earlier with reagent water flushing electrode and plastic cup more than 2 times.Electrode bottom water droplet is blotted lightly (not going wiping) with clean filter paper then in order to avoid electrode bottom static electrification causes the reading instability with filter paper.To locate buffer and pour in the plastic cup, immerse electrode, shake the plastic cup several seconds slightly.Measure gelling temp (requiring consistent), find the pH value of location buffer under this temperature, instrument is positioned to this pH value with location buffer temperature.Repeat zeroing, proofread and correct and locate 1～2 time, till stable.
4.3.2 twice location
Get the pH7 standard buffer solution earlier according to last method location.Behind the electrode wash clean, another localization criteria buffer (if tested gel is acid, is selected the pH4 buffer; If alkalescence is selected the pH9 buffer) pour in the plastic cup, after electrode bottom water droplet blots gently with filter paper, electrode is immersed in the cup, shake the several seconds slightly, press read switch.Adjust the pH value that the slope knob makes the reading indication or shows the second location buffer under this probe temperature.Repeat 1～2 time two point location be operated to stable till.
4.3.3 3 return the location
Three plastic cups of wash clean are inserted pH4,7,9 standard buffer solutions respectively.Get one of them earlier by behind the 4.3.1 location, measure the pH value of two standard buffer solutions in addition again.The standard value of three standard buffer solutions under probe temperature and corresponding pH value reading value are stored at the enterprising line retrace of computer.If the regressand value of being obtained by three reading values differs with standard value and all is not more than 0.02pH unit, can think that instrument and electrode are normal, can carry out the pH mensuration of gel.
4.4 the mensuration of gel
After plastic cup and electrode cleaned with reagent water, the tested gel flushing of reuse 2 times or more than.Then, immerse electrode and carry out pH value and measure.Take reading.
5. the pH value data of gel of the present invention see Table 1
The pH value of table 1 gel of the present invention
Description of test thus, gel pH value of the present invention is between the 4.15-8.73.
The phase transition temperature of experimental example 2-gel of the present invention is measured
The assay method of phase transition temperature is with reference to the method for testing of patent documentation CN1377706A Instructions Page 3 experiment one, and the gained data are temperature range, see the following form 2
The phase transition temperature of table 2 gel of the present invention
Description of test thus, the phase transition temperature of gel of the present invention be between 28-36 ℃, can satisfy at instant gel room temperature of the present invention to be in liquid state, is converted into the solid, shaped gel after splashing into ophthalmic, reaches the effect of prolong drug delay effect.
Instant gel for eye is divided into three kinds: responsive to temperature type, pH value responsive type and ionic strength responsive type, wherein the responsive to temperature type instant gel for eye is easy to industrialization relatively, the present invention also realizes by the responsive to temperature type instant gel for eye, but grope to find the stability of responsive to temperature type gel and can under the local temperature of people's eyeball, be converted into the pH value of gel and instant gel at once whether stable relation is close through inventor's experiment.The inventor adopts the acid-base buffer agent of larger capacity to guarantee pH value stable of instant gel for eye, thereby has guaranteed that gel has responsive and suitable phase transition temperature.
The test that the eye of experimental example 3-instant gel for eye of the present invention stimulates
40 New Zealand white rabbit are divided into 10 groups, in each group rabbit conjunctival capsule, splash into instant gel for eye of the present invention (embodiment 1,4,7,9,12,16,18,20,22 and 23) respectively, stimulation test is with interior high frequency points left eye, per 45 minutes once, each 1, and be contrast with normal saline point right eye simultaneously, continuous 4 times.Each treated animal conjunctiva of regular check, iris and cornea tissue there is no reactions such as hyperemia, edema, secretions adhesion behind eye dripping.This shows that instant gel for eye of the present invention is safe, and is non-stimulated to ocular tissue.
Claims (9)
1. instant jelly glue of carbomer for eyes is characterized in that containing in 1000 milliliters of described gels: carbomer 10-40g, and antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-7.5 gram, gel-type vehicle 30-150 gram, surplus is acid-base buffer agent and water for injection.
2. according to the described instant jelly glue of carbomer for eyes of claim 1, it is characterized in that containing in 1000 milliliters of described gels: carbomer 10-30g, antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-5.5 gram, gel-type vehicle 30-100 gram, surplus is acid-base buffer agent and water for injection.
3. according to the described instant jelly glue of carbomer for eyes of claim 2, it is characterized in that described acid-base buffer agent is controlled at the pH value of described instant jelly glue of carbomer for eyes between the 4.15-8.73.
4. according to the arbitrary described instant jelly glue of carbomer for eyes of claim 1-3, it is characterized in that described antiseptic is selected from one or more in phenethanol, benzyl alcohol, sodium benzoate, methyl hydroxybenzoate and the ethyl hydroxybenzoate; Described osmotic pressure regulator is a sodium chloride; Described acid-base buffer agent is selected from hydrochloric acid, sulphuric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium citrate, citric acid, triethanolamine, diethanolamine, the ethanolamine 2 kinds or multiple; Described gel-type vehicle is selected from one or more in Polyethylene Glycol, methylcellulose, ethyl cellulose, polyacrylic acid and the sodium polyacrylate.
5. according to the described instant jelly glue of carbomer for eyes of claim 4, it is characterized in that described acid-base buffer agent is selected from hydrochloric acid and triethanolamine, the mol ratio of the two is 1: 0.5-2.
6. according to the described instant jelly glue of carbomer for eyes of claim 4, it is characterized in that described acid-base buffer agent is selected from hydrochloric acid and sodium citrate, the mol ratio of the two is 1: 0.2-2.
7. according to the described instant jelly glue of carbomer for eyes of claim 4, it is characterized in that described gel-type vehicle is selected from Polyethylene Glycol and methylcellulose, the weight ratio of the two is 1: 50-5000.
8. according to the described instant jelly glue of carbomer for eyes of claim 7, it is characterized in that described Polyethylene Glycol is selected from one or more among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000, PEG-6000, PEG-10000 and the PEG-20000.
9. described according to Claim 8 instant jelly glue of carbomer for eyes is characterized in that described Polyethylene Glycol is selected from one or more among PEG-1500, PEG-4000 and the PEG-6000.
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| CNA2007101226880A CN101342370A (en) | 2007-07-13 | 2007-07-13 | Instant jelly glue of carbomer for eyes |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101226880A CN101342370A (en) | 2007-07-13 | 2007-07-13 | Instant jelly glue of carbomer for eyes |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512357A (en) * | 2012-01-11 | 2012-06-27 | 厦门大学 | Nerve growth factor ophthalmic gel and preparation method thereof |
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2007
- 2007-07-13 CN CNA2007101226880A patent/CN101342370A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512357A (en) * | 2012-01-11 | 2012-06-27 | 厦门大学 | Nerve growth factor ophthalmic gel and preparation method thereof |
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