CN101342165A - Instant gel rubber of thyroxine liothyronine for eyes - Google Patents
Instant gel rubber of thyroxine liothyronine for eyes Download PDFInfo
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- CN101342165A CN101342165A CNA2007101226876A CN200710122687A CN101342165A CN 101342165 A CN101342165 A CN 101342165A CN A2007101226876 A CNA2007101226876 A CN A2007101226876A CN 200710122687 A CN200710122687 A CN 200710122687A CN 101342165 A CN101342165 A CN 101342165A
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Abstract
The invention discloses an immediate type ophthalmic gelatin of thyroxine liothyronine and a preparation method thereof. 100 milliliters of the immediate type ophthalmic gelatin of thyroxine liothyronine contains 0.1 to 3 grams of thyroxine powder extract, 0.05 to 1 gram of preservative, 1.0 to 7.5 grams of permeation pressure conditioning agent and 30 to 150 grams of gelatin substrate. Remaining components are acid-base buffer regent and water for rejection. The invention enriches the dosage forms of the thyroxine powder extract by optimizing auxiliary materials and improving technology so that lag time in eyes is greatly prolonged and curative effect is improved without adverse stimulus reaction.
Description
[technical field]
The invention belongs to technical field of medicine, be specifically related to a kind of thyroxine liothyronine instant gel for eye.
[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 (Timolol 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.
Patent documentation CN86104027A and CN1011118B have provided the raw material production and the concrete preparation of thyroxine liothyronine eyedrops, technology.This eye drop is produced by Wuhan Wujing Medicine Co., Ltd, and commodity are called " cataract is clear " eye drop; It is a kind of novel cataractous medicine of treatment of professor Ying Shihao of General Hospital of Tianjin Medical Univ. invention, can alleviate the muddiness of senile cataract, increases the crystal transparency, improves vision.
[summary of the invention]
The object of the present invention is to provide a kind of thyroxine liothyronine instant gel for eye.
Another object of the present invention is to provide the preparation method of thyroxine liothyronine instant gel for eye.
Specifically, 1000 milliliters of thyroxine liothyronine instant gel for eye of the present invention contain: thyroid powder extract 0.1-3 gram, 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: thyroid powder extract 0.1-1 gram, 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 thyroxine liothyronine instant gel for eye between the 4.21-8.88.
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 thyroxine liothyronine instant gel for eye of the present invention is: with the water for injection heated and boiled, be cooled to 80 ℃, add the thyroid powder extract, antiseptic is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and stir behind the adding acid-base buffer agent, crossing microporous filter membrane filters, 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.
By the optimization of adjuvant and the improvement of technology, enriched the pharmaceutical dosage form of thyroxine liothyronine, prolonged medicine greatly in the eye holdup time, improve curative effect, and do not had 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: thyroid powder extract 0.1 gram hydrochloric acid (0.05mol/L) 400 milliliters
Sodium citrate 9.1 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 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 the thyroid powder extract, 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: thyroid powder extract 1 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 9.1 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 the thyroid powder extract, 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: thyroid powder extract 1.5 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, 1.0 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 the thyroid powder extract, 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: thyroid powder extract 0.1 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, 7.5 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 the thyroid powder extract, 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: thyroid powder extract 1.0 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 the thyroid powder extract, 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 6
Prescription: thyroid powder extract 1.5 gram hydrochloric acid (0.05mol/L) 250 milliliters
Triethanolamine 10 gram methylcellulose 5.5 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, be cooled to 80 ℃, add the thyroid powder extract, 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: thyroid powder extract 1.0 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 13 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, be cooled to 80 ℃, add the thyroid powder extract, 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, 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 8
Prescription: thyroid powder extract 0.2 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 14 gram methylcellulose 5.5 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 the thyroid powder extract, 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: thyroid powder extract 3.0 gram hydrochloric acid (0.05mol/L) 400 milliliters
Sodium citrate 9.1 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 7.5 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 the thyroid powder extract, 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 10
Prescription: thyroid powder extract 3.0 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 9.1 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, be cooled to 80 ℃, add the thyroid powder extract, 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 11
Prescription: thyroid powder extract 0.5 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, 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 the thyroid powder extract, sodium benzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, 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 12
Prescription: thyroid powder extract 5 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 the thyroid powder extract, 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 13
Prescription: thyroid powder extract 1.5 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, be cooled to 80 ℃, add the thyroid powder extract, 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: thyroid powder extract 1.5 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, 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, be cooled to 80 ℃, add the thyroid powder extract, 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 15
Prescription: thyroid powder extract 0.5 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 the thyroid powder extract, 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, 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 16
Prescription: thyroid powder extract 1.5 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, be cooled to 80 ℃, add the thyroid powder extract, 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 17
Prescription: thyroid powder extract 0.2 gram hydrochloric acid (0.05mol/L) 400 milliliters
Sodium citrate 9.1 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, be cooled to 80 ℃, add the thyroid powder extract, 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 18
Prescription: thyroid powder extract 1.5 gram sulphuric acid (0.05mol/L) 200 milliliters
Sodium citrate 9.1 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, be cooled to 80 ℃, add the thyroid powder extract, 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 19
Prescription: thyroid powder extract 1.0 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 the thyroid powder extract, 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 20
Prescription: thyroid powder extract 1.0 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 the thyroid powder extract, 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: thyroid powder extract 5.0 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, be cooled to 80 ℃, add the thyroid powder extract, 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 22
Prescription: thyroid powder extract 5.0 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, be cooled to 80 ℃, add the thyroid powder extract, 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 23
Prescription: thyroid powder extract 1.5 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 15 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 the thyroid powder extract, 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, 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 24
Prescription: thyroid powder extract 1.6 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 41 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 the thyroid powder extract, 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-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 4.21-8.88.
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 27-36 ℃, 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 1,4,7,9,12,16,18,19,22 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.
The application of experimental example 4-instant gel for eye of the present invention
1. physical data:
1.1 experimental group: 12 of 8 examples, male 5 examples, women 3 examples, 59 years old～68 years old age.Vision: manual at the moment 9 examples, index 3 examples at the moment.Intraocular foreign body, detachment of retina and vitreous opacity are got rid of in eye X sheet and ophthalmology ultrasound diagnosis.
1.2 matched group: 12 of 8 examples, male 5 examples, women 3 examples, 53 years old～65 years old age.Vision: manual at the moment 8 examples, index 3 examples at the moment.Intraocular foreign body, detachment of retina and vitreous opacity are got rid of in eye X sheet and ophthalmology ultrasound diagnosis.
2. therapeutic modality:
2.1. experimental group: instant gel for eye of the present invention (embodiment 20), 1-2 drip/time, every day 3-4 time; Treatment is 3 months continuously.
2.2 matched group: thyroxine liothyronine eyedrops: each 1～2,3～4 times on the 1st; Treatment is 3 months continuously.
3. therapeutic outcome
3.1 experimental group: treatment back naked vision: 4 examples more than 4.5,4.0-4.5 person's 3 examples, 4.0 following person's 1 examples
3.2 matched group: treatment back naked vision: 1 example more than 4.5,4.0-4.5 person's 5 examples, 4.0 following person's 2 examples.
4. conclusion: instant gel for eye of the present invention has than thyroxine liothyronine eyedrops cataract and has better therapeutic.
Claims (9)
1. thyroxine liothyronine instant gel for eye, it is characterized in that containing in 1000 milliliters of described gels: thyroid powder extract 0.1-3 gram, 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 thyroxine liothyronine of claim 1 instant gel for eye, it is characterized in that containing in 1000 milliliters of described gels: thyroid powder extract 0.1-1 gram, 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 thyroxine liothyronine of claim 2 instant gel for eye, it is characterized in that described acid-base buffer agent is controlled at the pH value of described thyroxine liothyronine instant gel for eye between the 4.21-8.88.
4. according to the arbitrary described thyroxine liothyronine instant gel for eye 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 thyroxine liothyronine of claim 4 instant gel for eye, 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 thyroxine liothyronine of claim 4 instant gel for eye, 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 thyroxine liothyronine of claim 4 instant gel for eye, 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 thyroxine liothyronine of claim 7 instant gel for eye, 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 thyroxine liothyronine instant gel for eye is characterized in that described Polyethylene Glycol is selected from one or more among PEG-1500, PEG-4000 and the PEG-6000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101226876A CN101342165A (en) | 2007-07-13 | 2007-07-13 | Instant gel rubber of thyroxine liothyronine for eyes |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101226876A CN101342165A (en) | 2007-07-13 | 2007-07-13 | Instant gel rubber of thyroxine liothyronine for eyes |
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| CN101342165A true CN101342165A (en) | 2009-01-14 |
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| CNA2007101226876A Pending CN101342165A (en) | 2007-07-13 | 2007-07-13 | Instant gel rubber of thyroxine liothyronine for eyes |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705497A (en) * | 2013-12-11 | 2014-04-09 | 武汉威立得生物医药有限公司 | Application of liothyronine in preparation of medicine for treatment or prevention of influenza virus infection |
| CN105168170A (en) * | 2015-10-19 | 2015-12-23 | 上海长城药业有限公司 | Thyroid tablets and preparation method thereof |
| CN115645361A (en) * | 2022-09-30 | 2023-01-31 | 天津市眼科医院 | Ophthalmic preparation for strengthening cornea biomechanical property and application of T3 |
-
2007
- 2007-07-13 CN CNA2007101226876A patent/CN101342165A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705497A (en) * | 2013-12-11 | 2014-04-09 | 武汉威立得生物医药有限公司 | Application of liothyronine in preparation of medicine for treatment or prevention of influenza virus infection |
| CN103705497B (en) * | 2013-12-11 | 2015-04-01 | 武汉威立得生物医药有限公司 | Application of liothyronine in preparation of medicine for treatment or prevention of influenza virus infection |
| CN105168170A (en) * | 2015-10-19 | 2015-12-23 | 上海长城药业有限公司 | Thyroid tablets and preparation method thereof |
| CN115645361A (en) * | 2022-09-30 | 2023-01-31 | 天津市眼科医院 | Ophthalmic preparation for strengthening cornea biomechanical property and application of T3 |
| CN115645361B (en) * | 2022-09-30 | 2023-11-21 | 天津市眼科医院 | Ophthalmic preparation for enhancing biomechanical property of cornea and application of T3 |
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Open date: 20090114 |