CN102579600B - Method for preparing decumbent corydalis tuber eye drop and product - Google Patents
Method for preparing decumbent corydalis tuber eye drop and product Download PDFInfo
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- CN102579600B CN102579600B CN 201210082380 CN201210082380A CN102579600B CN 102579600 B CN102579600 B CN 102579600B CN 201210082380 CN201210082380 CN 201210082380 CN 201210082380 A CN201210082380 A CN 201210082380A CN 102579600 B CN102579600 B CN 102579600B
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Abstract
The invention relates to a method for preparing a decumbent corydalis tuber eye drop and a product. The method comprises the following steps of: dissolving a decumbent corydalis tuber extract, heating, and keeping temperature; heating auxiliary materials for dissolving; and regulating the pH value, regulating permeation pressure, stirring and mixing uniformly, filtering and packaging into separate bags. The method is characterized in that: the pH value of the decumbent corydalis tuber eye drop is regulated to be between 4.6 and 6.5, and the permeation pressure is regulated to be between 0.24 and 0.360 smol/kg; the decumbent corydalis tuber extract is dissolved by using a diluted phosphoric acid solution, wherein the concentration of the diluted phosphoric acid solution is less than or equal to 0.5 mol/L, and a mass ratio of protopine in the decumbent corydalis tuber extract to the mole of phosphoric acid is (0.32-0.43 gram):(0.0036-0.0048 mol); and glycerol is used as a permeation pressure regulator, and the pH value is regulated by using disodium hydrogen phosphate. The decumbent corydalis tuber eye drop has a mild effect, and the compliance of patients is improved greatly, so the decumbent corydalis tuber eye drop is an eye drop which is small in irritation and high in stability.
Description
Technical field
The invention belongs to the ophthalmic remedy technical field of pharmaceutical preparation, be specifically related to preparation method and the product of the minimum and decumbent corydalis tuber eye drop that has good stability of a kind of zest.
Background technology
The dry tuber of the Papaveraceae of doing nothing summer Corydalis Subgen. Capnites plant Hotseason grow Corydalis decumhens (Thunb.) Pers., the main component of its extract is alkaloids, comprises protopine (protopine), allocryptopine, cryptocavine, hidden product palmatine, tetrahydropalmatine, corypalmine, dihydro palmatine, palmatine, jateorhizine etc.Decumbent corydalis tuber eye drop is the eye drop of the preparation take Rhizoma Corydalis Decumbentis extract as primary raw material, and its main effective ingredient protopine (protopine) is relaxing smooth muscle directly, also can the antagonism acetylcholine and barium chloride to the spastic contraction of eye muscle.Decumbent corydalis tuber eye drop has blood circulation-activating eyesight-improving, Shujin function, be used for juvenile hyperopia power due to the retardance of blood stasis muscle arteries and veins descend, can not watching for a long time; Teenage pseudomyopia disease is seen above-mentioned patient.
Decumbent corydalis tuber eye drop is the new drug of the seventies exploitation in last century, owing to be subjected to the restriction of prevailing circumstances and condition, and adjuvant and not bery perfect in the original prescription, and have comparatively significantly zest; By constantly groping, the formulation and technology of decumbent corydalis tuber eye drop just gradual perfection gets up in very long thereafter historical process; The decumbent corydalis tuber eye drop of circulation is produced according to standard under version Chinese Pharmacopoeia this product item in 2010 and is made in the market, and its zest is obviously improved than initial product is existing, but still be difficult to eliminate one when using sexual stimulus.
When splashing into ophthalmic moment, most of patient's reflection had one to cross sexual stimulus (twinge), especially the responsive especially children and adolescents of pain is difficult to accept especially, even subjectivity is discontinued medication when decumbent corydalis tuber eye drop used; Splashing into rear strong impulse initiation lacrimal secretion increases, and has seriously reduced especially the bioavailability of medicine, affects the treatment.Above deficiency has limited applying of this product, makes it to bring into play well due Social benefit and economic benefit; Therefore, the zest that further reduces decumbent corydalis tuber eye drop is to improve the key of patient compliance and curative effect.
Owing to containing multiple alkaloid in the decumbent corydalis tuber eye drop, need in original prescription and preparation method thereof use that strong acid---hydrochloric acid solution dissolves, thereby cause eye drop pH lower, produce a comparatively strong mistake sexual stimulus; Yet in case reduce the consumption of acid or improve system pH, one crosses sexual stimulus has no doubt reduced, but system stability reduces greatly, very easily produces vaporific precipitation in the put procedure.In order to obtain stable product, decumbent corydalis tuber eye drop (original prescription) has adopted lower pH scope (3-4.5), just usually need be controlled at below 3.5 more stablely, exceeded people's emmetropia tolerance range (5-8), thereby zest is larger.
Summary of the invention
The preparation method and the product that the purpose of this invention is to provide the minimum and decumbent corydalis tuber eye drop that has good stability of a kind of zest.
For reducing zest, after deliberation, one, avoid using the dissolving with hydrochloric acid Rhizoma Corydalis Decumbentis extract, but use the dilute phosphoric acid solution dissolving instead, reduce Ocular irritation on the one hand, also help to improve on the other hand product stability, this is that the present invention is peculiar; This be because: phosphoric acid is moderate strength acid, and hydrochloric acid then be strong acid, the former than latter acidity a little less than, phosphoric acid have zest little, non-volatile, be difficult for decomposing, almost do not have oxidisability, stable in properties plurality of advantages, and hydrochloric acid is volatile, stimulates greatly, corrosivity is strong; Phosphoric acid is ternary acid, three step ionization modes, and system pH is constant, has good common-ion effect and the preparation effect mitigation of its preparation, zest are also just reduced greatly; Use the favourable labor protection of phosphoric acid solution, safe, favorable environment protection and China's green development strategy requirement;
Two, the AMSP in the decumbent corydalis tuber eye drop (original prescription), disodium hydrogen phosphate,anhydrous consumption are reduced, reduced largely the ionic strength of system, thereby reduce zest, its effect mitigation, zest are reduced;
Three, part sodium dihydrogen phosphate, disodium hydrogen phosphate,anhydrous and sodium chloride in the glycerol replacement minimizing original prescription that the employing biocompatibility is good are as osmotic pressure regulator, product is had than high degree of comfort, and glycerol has moisture-keeping functions, more can increase the wettability of eye drop;
Four, particularly importantly, on the basis that above prescription is adjusted, the pH of decumbent corydalis tuber eye drop is carried out series of optimum, find a crucial pH scope, make it can either overcome original eye drop pH and cross the low zest that produces, have again good stability.
Five, by repeatedly groping, obtain the best compound method of the present invention, specifically: 1, polyoxyethylene sorbitan monoleate is directly joined in the Rhizoma Corydalis Decumbentis extract phosphoric acid solution, improve its solubilization-aid effect, so not only improved preparation stability, but also made medicinal liquid more clear and bright and eliminated vaporific precipitation; 2, " being heated to 100 ℃ of insulations 30 minutes " with former preparation method changes " being heated to 90 ℃ of insulations 30 minutes " into, makes medicinal liquid avoid high temperature, and more stable.
Six, this product contains Chinese medicine extract and thickening agent, impurity is more and viscosity is larger, adopt general aseptic filtration method, easily stop up filter element, cause the part thickening agent to be trapped the medicinal liquid reduced viscosity, the present invention gropes the multiple micropore filter aseptic filtration method of uniqueness, has guaranteed the gentle viscosity of product sterilized water.
One of technical scheme of the present invention: a kind of preparation method of decumbent corydalis tuber eye drop, it comprises dissolving and the heat tracing of Rhizoma Corydalis Decumbentis extract, adjusting, stirring and evenly mixing, filtration and the packing of the heating for dissolving of adjuvant, the adjusting of pH value, osmotic pressure, it is characterized in that regulating decumbent corydalis tuber eye drop pH value to 4.6-6.5, osmotic pressure is between 0.24-0.36 Osmol/kg, and described Rhizoma Corydalis Decumbentis extract adopts the appended Rhizoma Corydalis Decumbentis extract quality standard of decumbent corydalis tuber eye drop of Chinese Pharmacopoeia.
Adopt dilute phosphoric acid solution dissolving Rhizoma Corydalis Decumbentis extract in the preparation method, the concentration of described dilute phosphoric acid solution is equal to or less than 0.5mol/L, and the quality of the protopine in the Rhizoma Corydalis Decumbentis extract and the mol ratio of phosphoric acid are 0.32-0.43g:0.0036-0.0048 mol.
Preferably:
Use glycerol as osmotic pressure regulator, regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.24-0.36 Osmol/kg.
Regulate the pH value to 4.6-6.5 of decumbent corydalis tuber eye drop with sodium hydrogen phosphate.
Solubilizing agent is directly joined in the dilute phosphoric acid solution of Rhizoma Corydalis Decumbentis extract.
The heat tracing process is: heat 85-95 ℃, be incubated 25-35 minutes.
Adopt multiple micropore filter aseptic filtration, filtrate is aseptic subpackaged under hundred grades of laminar flow hood.
The pH that regulates described decumbent corydalis tuber eye drop is 5.2-6.0, and osmotic pressure is between 0.27-0.33 Osmol/kg.
Further preferred:
Every 1000ml decumbent corydalis tuber eye drop is made by following steps:
A, take by weighing Rhizoma Corydalis Decumbentis extract by the consumption 0.32-0.43g of protopine, add in 0.0036-0.0048 mol dilute phosphoric acid solution, the concentration of dilute phosphoric acid solution is equal to or less than 0.5mol/L, in 85-95 ℃ stir 10-15 minutes after, to wherein adding described solubilizing agent 3-8g, stir, make its dissolving, and 85-95 ℃ of insulations 25-35 minutes, for subsequent use;
B, with sodium dihydrogen phosphate 0.1-3.0g, disodium edetate 0.2-0.8g, antibacterial 0.1-0.8g and glycerol, add 300ml and be heated in 85-95 ℃ the water for injection, stir and make dissolving, be cooled to 45-55 ℃; Wherein the consumption of glycerol is to regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.24-0.36 Osmol/kg;
C, with two kinds of solution mixings of above-mentioned steps A and step B; Or adding again the thickening agent mixing, the consumption of thickening agent is equal to or less than 2.0g, adds thickening agent and described thickening agent is dissolved in the 200ml water stirring and dissolving before;
Be cooled to again room temperature, with disodium phosphate soln regulation system pH to 4.6-6.5, get the thing that makes of step C;
D, add water to full dose, mixing gets the thing that makes of step D;
Or the medicinal alcohol solution of adding freshener, the medicinal alcohol solution usage of freshener is equal to or less than 4g, the mass ratio 1:1-15 of freshener and medicinal alcohol in the medicinal alcohol solution of described freshener, and in advance freshener is dissolved in the medicinal alcohol, under agitation slowly add the making in the thing of step C, stirring and dissolving adds water to full dose again, mixing gets the thing that makes of step D;
E, the thing sampling of making of step D is detected, the multiple micropore filter aseptic filtration of qualified rear employing, filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
Described solubilizing agent contains a kind of in the poly-hydrocarbon oxygen ester of polyoxyethylene sorbitan monoleate, Oleum Ricini and the poloxamer at least.
Described antibacterial contains a kind of in ethyl hydroxybenzoate, methyl hydroxybenzoate, propyl hydroxybenzoate, benzalkonium bromide, benzalkonium chloride and the chlorobutanol at least.
Described thickening agent contains a kind of in hyaluronic acid sodium, polyvidone, carbomer, poloxamer, sodium carboxymethyl cellulose, hypromellose, polyvinyl alcohol and the chitosan at least.
Described freshener contains a kind of in natural Broneolum Syntheticum, synthetic borneol and the Mentholum at least.
Further preferred:
Every 1000ml decumbent corydalis tuber eye drop is made by following steps:
(1) consumption by protopine 0.375g takes by weighing Rhizoma Corydalis Decumbentis extract, add in the 400ml 0.01mol/L dilute phosphoric acid solution, in 90 ℃ stir 10 minutes after, to wherein adding polyoxyethylene sorbitan monoleate 5g, stir, make its dissolving, and be heated to 90 ℃ of insulations 30 minutes, for subsequent use;
(2) with sodium dihydrogen phosphate 1g, disodium edetate 0.5g, ethyl hydroxybenzoate 0.5g and glycerol, add 300ml and be heated in 90 ℃ the water for injection, stir and make dissolving, be cooled to 50 ℃; Wherein the consumption of glycerol is to regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.27-0.33 Osmol/kg;
(3) hyaluronic acid sodium 1.0g is dissolved in the 200ml water, stirring and dissolving, for subsequent use;
(4) with three kinds of solution mixings of above-mentioned steps (1), step (2) and step (3), be cooled to again room temperature, with disodium phosphate soln regulation system pH to 5.2-6.0, get the thing that makes of step (4);
(5) natural Broneolum Syntheticum 0.25g is dissolved among the medicinal alcohol 2ml, under agitation slowly adds the making in the thing of step (4), stirring and dissolving adds water to full dose, mixing; Get the thing that makes of step (5);
(6) the thing sampling that makes of step (5) detected, the multiple micropore filter aseptic filtration of qualified rear employing, filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
Two of technical scheme of the present invention: the decumbent corydalis tuber eye drop of the preparation method preparation of described decumbent corydalis tuber eye drop, it contains Rhizoma Corydalis Decumbentis extract and adjuvant, every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and dilute phosphoric acid solution 0.0036-0.0048 mol that protopine is 0.32-0.43g, and adjuvant; Described adjuvant comprises following component: medicinal alcohol solution 0-4g, sodium hydrogen phosphate and the glycerol of sodium dihydrogen phosphate 0.1-3.0g, solubilizing agent 3-8g, disodium edetate 0.2-0.8g, antibacterial 0.1-0.8g, thickening agent 0-2.0g, freshener, and all the other are water for injection; The concentration of wherein said dilute phosphoric acid solution is equal to or less than 0.5mol/L, the mass ratio 1:1-15 of freshener and medicinal alcohol in the medicinal alcohol solution of freshener; The amount of sodium hydrogen phosphate is for regulating pH value to 4.6-6.5; The amount of glycerol is for regulating osmotic pressure between 0.24-0.36 Osmol/kg.
Preferably:
Every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and phosphoric acid solution 0.004 mol that protopine is 0.375g, sodium dihydrogen phosphate 0.8-1.5g, polyoxyethylene sorbitan monoleate 4-6g, disodium edetate 0.4-0.6g, ethyl hydroxybenzoate 0.4-0.6g, hyaluronic acid sodium 0.8-1.2g, natural Broneolum Syntheticum 0.20-0.30g, medicinal alcohol 2-3ml, sodium hydrogen phosphate and glycerol, all the other are water for injection; The concentration of wherein said dilute phosphoric acid solution is equal to or less than 0.5mol/L, and the amount of sodium hydrogen phosphate is for regulating pH value to 5.0-6.2, and the amount of glycerol is for regulating osmotic pressure between 0.24-0.36 Osmol/kg.
Further preferred:
Every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and 400ml0.01mol/L dilute phosphoric acid solution that protopine is 0.375g, sodium dihydrogen phosphate 1g, polyoxyethylene sorbitan monoleate 5g, disodium edetate 0.5g, ethyl hydroxybenzoate 0.5g, hyaluronic acid sodium 1.0g, natural Broneolum Syntheticum 0.25g, medicinal alcohol 2ml, sodium hydrogen phosphate and glycerol, all the other are water for injection; The amount of wherein said sodium hydrogen phosphate is for regulating pH value to 5.2-6.0, and the amount of glycerol is for regulating osmotic pressure between 0.27-0.33 Osmol/kg.
The pH of described decumbent corydalis tuber eye drop is 5.2-6.0, and osmotic pressure is between 0.27-0.33 Osmol/kg.
Described Rhizoma Corydalis Decumbentis extract adopts the appended Rhizoma Corydalis Decumbentis extract quality standard of decumbent corydalis tuber eye drop of Chinese Pharmacopoeia:
Character; For brown color to tan powder and granule; Bitter in the mouth.
Differentiate: add bismuth potassium iodide test solution, reddish brown precipitation; Silico-tungstic acid, faint yellow precipitation; Potassium mercuric iodide, faint yellow precipitation.
Check: moisture content; Must not cross 5.0%
Residue on ignition: must not cross 0.8%
Heavy metal: must not cross 20/1000000ths
Arsenic salt: must not cross 2/1000000ths
Assay: contain protopine and must not be less than 25.0%, by dry product
Storage: sealing, put dry place.
The invention solves the decumbent corydalis tuber eye drop zest, the acid solution of its key point searching effect milder dissolving Rhizoma Corydalis Decumbentis extract and suitable pH scope, satisfy simultaneously product zest and stable aspect requirement.By improving its original prescription and production technology, and optimize on this basis the pH scope of eye drop, thereby fundamentally solved the zest problem of this product, make its action temperature and, greatly improved patient's compliance (compliance), simultaneously, eye drop 2 year effect duration inner liquid medicine clear and bright all the time, produce without vaporific precipitation, also avoided the too fast signs of degradation of main component to occur, product stability is good, is the decumbent corydalis tuber eye drop that a kind of zest is minimum and have good stability.
The present invention has also solved product that original prescription and technique produces and has dripped with rear the patient and impel lacrimal secretion because of its zest, and tear constantly washes away a table organization, causes fluid loss and reduces medicine in the concentration of eye, thereby the problem such as lessen the curative effect.Simultaneously, it is not good that preparation method of the present invention has solved the clarity of long-term this product of puzzlement, the time phenomenons such as vaporific precipitation are arranged, and improved the problems such as principal agent ingredient stability.
Description of drawings
Fig. 1 is that the cornea method of hatching is estimated the former decumbent corydalis tuber eye drop of original prescription and the embodiment of the invention 1 new decumbent corydalis tuber eye drop Ocular irritation comparison diagram.
Fig. 2 is cornea tissue sections observation comparison diagram behind the former decumbent corydalis tuber eye drop of original prescription and the embodiment of the invention 1 new decumbent corydalis tuber eye drop multiple dosing.
The specific embodiment
The present invention is by the following examples can the invention will be further described, yet scope of the present invention is not limited to following embodiment.
Embodiment 1
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.375g
Natural Broneolum Syntheticum 0.25g
Sodium dihydrogen phosphate 1.0g
Disodium hydrogen phosphate,anhydrous adjust pH to 5.8
Glycerol is transferred osmotic pressure to 0.29 Osmol/kg
Polyoxyethylene sorbitan monoleate 5.0g
Disodium edetate 0.5g
Ethyl hydroxybenzoate 0.5g
Hyaluronic acid sodium 1.0g
Medicinal alcohol 2ml
Inject water and make 1000ml
Preparation method:
(1) consumption by described protopine 0.375g takes by weighing Rhizoma Corydalis Decumbentis extract, add in the 400ml 0.01mol/L dilute phosphoric acid solution, in 90 ℃ stir 10 minutes after, to wherein adding described polyoxyethylene sorbitan monoleate 5g, stir, make its dissolving, and 90 ℃ of insulations 30 minutes, for subsequent use;
(2) sodium dihydrogen phosphate 1g, disodium edetate 0.5g and ethyl hydroxybenzoate 0.5g and glycerol are added 300ml and be heated in 90 ℃ the water for injection, stir and make dissolving, be cooled to 50 ℃; Wherein the consumption of glycerol is to regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.29 Osmol/kg;
(3) described hyaluronic acid sodium 1.0g is dissolved in the 200ml water, stirring and dissolving, for subsequent use;
(4) with three kinds of solution mixings of above-mentioned steps (1), step (2) and step (3), be cooled to again room temperature, with disodium phosphate soln regulation system pH to 5.8, get the thing that makes of step (4);
(5) natural Broneolum Syntheticum 0.25g is dissolved among the medicinal alcohol 2ml, under agitation slowly adds the making in the thing of step (4), stirring and dissolving adds water to full dose, mixing; Get the thing that makes of step (5);
(6) the thing sampling that makes of step (5) detected, the multiple micropore filter aseptic filtration of qualified rear employing, filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
Embodiment 2
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.355g
Sodium dihydrogen phosphate 3.0g
Disodium hydrogen phosphate,anhydrous adjust pH to 4.6
Glycerol is transferred osmotic pressure to 0.28 Osmol/kg
Polyoxyethylene sorbitan monoleate 3.0g
Disodium edetate 0.3g
Ethyl hydroxybenzoate 0.1g
Inject water and make 1000ml
Preparation method:
(1) consumption by described protopine 0.355g takes by weighing in the Rhizoma Corydalis Decumbentis extract adding 400ml 0.01mol/L phosphoric acid solution, in 90 ℃ of stirrings 10 minutes, to the polyoxyethylene sorbitan monoleate 3.0g that wherein adds recipe quantity, stir and make dissolving, and 90 ℃ of insulations 30 minutes, for subsequent use;
(2) sodium dihydrogen phosphate 3.0 g, disodium edetate 0.3g and ethyl hydroxybenzoate 0.1g and glycerol are added 300ml and be heated in 90 ℃ the water for injection, stir and make dissolving, let cool to approximately 50 ℃; With above-mentioned two kinds of solution mixings, and be cooled to room temperature.With disodium phosphate soln regulation system pH to 4.6; The glycerol consumption is for transferring osmotic pressure to 0.28 Osmol/kg;
(3) add water to full dose, mixing; Sampling detects, the multiple micropore filter aseptic filtration of qualified rear employing, and filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
Embodiment 3
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.395g
Natural Broneolum Syntheticum 0.5g
Sodium dihydrogen phosphate 2.0g
Disodium hydrogen phosphate,anhydrous adjust pH to 5.0
Glycerol is transferred osmotic pressure to 0.31 Osmol/kg
Polyoxyethylene sorbitan monoleate 5.0g
Disodium edetate 0.8g
Ethyl hydroxybenzoate 0.8g
Hyaluronic acid sodium 2.0g
Medicinal alcohol 3ml
Inject water and make 1000ml
Preparation method is similar with embodiment 1.
Embodiment 4
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.376g
Synthetic borneol 0.2g
Sodium dihydrogen phosphate 0.1g
Disodium hydrogen phosphate,anhydrous adjust pH to 6.5
Glycerol is transferred osmotic pressure to 0.30 Osmol/kg
Polyoxyethylene sorbitan monoleate 8.0g
Disodium edetate 0.2g
Ethyl hydroxybenzoate 0.5g
Medicinal alcohol 2ml
Inject water and make 1000ml
Preparation method:
(1) consumption by described protopine 0.376g takes by weighing in the Rhizoma Corydalis Decumbentis extract adding 400ml 0.01mol/L phosphoric acid solution, and in 90 ℃ of stirrings 10 minutes, to wherein adding polyoxyethylene sorbitan monoleate 8.0g, stir and make dissolving, and 90 ℃ of insulations 30 minutes, for subsequent use;
(2) sodium dihydrogen phosphate 0.1g, disodium edetate 0.2g and ethyl hydroxybenzoate 0.5g and glycerol are added 300ml and be heated in 90 ℃ the water for injection, stir and make dissolving, let cool to approximately 50 ℃; Wherein the glycerol consumption is for transferring osmotic pressure to 0.30 Osmol/kg;
(3) with above-mentioned two kinds of solution mixings, and be cooled to room temperature.With disodium phosphate soln regulation system pH to 6.5;
(4) synthetic borneol 0.2g is dissolved among the medicinal alcohol 2ml, under agitation slowly adds the making in the thing of step (4), stirring and dissolving adds water to full dose, mixing;
(5) sampling detects, the multiple micropore filter aseptic filtration of qualified rear employing, and filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
Embodiment 5
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.385g
Natural Broneolum Syntheticum 0.25g
Sodium dihydrogen phosphate 0.5g
Disodium hydrogen phosphate,anhydrous adjust pH to 6.0
Glycerol is transferred osmotic pressure to 0.32 Osmol/kg
Oleum Ricini gathers hydrocarbon oxygen ester 5.0g
Disodium edetate 0.5g
Benzalkonium bromide 0.1g
Carbomer 0.2g
Medicinal alcohol 2.5ml
Inject water and make 1000ml
The poly-hydrocarbon oxygen ester of Oleum Ricini is adopted in solubilizing agent, and antibacterial adopts benzalkonium bromide, and thickening agent adopts carbomer, and preparation method is similar with embodiment 1.
Embodiment 6
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.380g
Mentholum 0.3g
Sodium dihydrogen phosphate 1.5g
Disodium hydrogen phosphate,anhydrous adjust pH to 5.2
Glycerol is transferred osmotic pressure to 0.29 Osmol/kg
Poloxamer 8.0g
Disodium edetate 0.5g
Ethyl hydroxybenzoate 0.5g
Sodium carboxymethyl cellulose 0.5g
Medicinal alcohol 3ml
Inject water and make 1000ml
Preparation method is similar with embodiment 1.
Embodiment 7
[prescription]
Rhizoma Corydalis Decumbentis extract contains protopine 0.390g
Sodium dihydrogen phosphate 1.5g
Disodium hydrogen phosphate,anhydrous adjust pH to 5.5
Glycerol is transferred osmotic pressure to 0.27 Osmol/kg
Polyoxyethylene sorbitan monoleate 5.0g
Disodium edetate 0.5g
Ethyl hydroxybenzoate 0.5g
Hypromellose 2.0g
Inject water and make 1000ml
Preparation method is similar with embodiment 1.
The contrast experiment of the embodiment of the invention 1
One, original prescription (Chinese Pharmacopoeia prescription)
Rhizoma Corydalis Decumbentis extract contains protopine 375mg
Natural Broneolum Syntheticum 0.25g
Sodium chloride 3.9g
AMSP 8.0g
Disodium hydrogen phosphate,anhydrous adjust pH to 3.3
Hyaluronic acid sodium 1.0g
Polyoxyethylene sorbitan monoleate 5.0g
Disodium edetate 0.5g
Ethyl hydroxybenzoate 0.5g
Ethanol 2ml
Water for injection adds to 1000ml
Former preparation method (Chinese Pharmacopoeia preparation method):
Above ten flavors, Rhizoma Corydalis Decumbentis extract adds an amount of hydrochloric acid solution, and heating is stirred, and dissolving is filtered, and is for subsequent use.Get hyaluronic acid sodium and add in the suitable quantity of water, stirring and dissolving, for subsequent use.AMSP, sodium chloride, disodium edetate, ethyl hydroxybenzoate add in the suitable quantity of water, heating, stirring makes dissolving, add while hot above-mentioned Rhizoma Corydalis Decumbentis extracting solution, stir evenly, be heated to 100 ℃ and be incubated 30 minutes, cooling, add polyoxyethylene sorbitan monoleate and above-mentioned hyaluronic acid sodium solution, adjust pH value of solution with an amount of disodium hydrogen phosphate,anhydrous.Natural Broneolum Syntheticum adds an amount of ethanol makes dissolving, under agitation slowly adds in the mentioned solution, stirs evenly, and adds water to 1000ml, and mixing filters, and get final product.
Two, primary stability test and index of correlation contrast
Carry out indices comparative study and adopt the plan listing to pack under (polyester eye drop bottle) condition according to the decumbent corydalis tuber eye drop of embodiment 1 described prescription and preparation method thereof preparation with according to the decumbent corydalis tuber eye drop that original prescription and preparation method thereof prepares, under 40 ℃ ± 2 ℃, relative humidity 25 ± 5% conditions, accelerated six months and under 25 ℃ ± 2 ℃, relative humidity 25 ± 5% conditions two-year Journal of Sex Research steady in a long-term, the indexs such as its visible foreign matters passed examination rate, sterility assurance level, total recovery, medicament contg see Table one:
Table one, the present invention and original prescription technique
The eye drop of preparationComparison sheet as a result
| Formulation and technology number | Visible foreign matters passed examination rate | Sterility assurance level | Total recovery | Protopine content (0 o'clock) | Protopine content (accelerating in 6 months) | Protopine content (keeping sample for a long time in 2 years) | Remarks |
| Embodiment 1(technique of the present invention) | 99.27% | Reach aseptic fully | 98.76% | 99.42% | 98.36% | 98.97% | Three batches of meansigma methodss |
| Reference example (original prescription technique) | 87.98% | Meet the microbial limit requirement | 87.37% | 98.94% | 93.75% | 94.81% | Three batches of meansigma methodss |
Illustrate:
1, be capacity production in batches, 1,000,000 milliliters every batch, every bottled 10 milliliters;
2, upper table data are continuous three batches meansigma methods.
Table one shows, decumbent corydalis tuber eye drop indices of the present invention all is better than former side.
Three, researching and analysing eye irritation
For the eye irritation to decumbent corydalis tuber eye drop of the present invention is estimated, we have carried out isolated cornea to the eye drop before and after improving and have hatched evaluation, the research of multiple dosing rabbit eye zest, rabbit eye one excessively sexual stimulus research and human clinical trial.
We hatched the evaluation irritation test in 2011 at Shanghai isolated cornea that medicine has carried out.Respectively at after hatching in decumbent corydalis tuber eye drop (original prescription), the decumbent corydalis tuber eye drop of the present invention, clean with normal saline flushing, formalin solution is fixed with the isolated rabbit cornea, makes H﹠amp; The E section, in test under microscope cornea structure degree of impairment, the result as shown in Figure 1.
The result shows that decumbent corydalis tuber eye drop (original prescription) causes conjunctival epithelial cell partly to come off, and decumbent corydalis tuber eye drop (the present invention) is not to the isolated cornea injury; This shows: decumbent corydalis tuber eye drop (the present invention) physicochemical property is more gentle, and zest is than the obvious reduction of decumbent corydalis tuber eye drop (original prescription), and the product biocompatibility after the improvement is good.
Carried out the research of multiple dosing rabbit eye zest in 2011 at the Shanghai medicine, one week of successive administration, every day 6 times, before administration every day and last administration after 1,2,4,24,48,72 h carry out examination of eyes with slit lamp.According to the Draize grade form rabbit eye situation is given a mark simultaneously, and the corneal tissue is made H﹠amp after off-test; The E section is in test under microscope cornea structure degree of impairment; The result is shown in accompanying drawing 2.
The result shows: it is 0.385 that the multiple dosing of decumbent corydalis tuber eye drop (original prescription) stimulates average integral, and it is 0.128 that one of decumbent corydalis tuber eye drop (the present invention) is crossed the sexual stimulus average integral; Decumbent corydalis tuber eye drop (original prescription) causes conjunctival epithelial cell partly to come off, and decumbent corydalis tuber eye drop (the present invention) is not to the isolated cornea injury.This shows that decumbent corydalis tuber eye drop (the present invention) zest is significantly less than decumbent corydalis tuber eye drop (original prescription) group.
Carry out multiple dosing rabbit eye one in 2011 at the Shanghai medicine and spent sexual stimulus research, one week of successive administration, every day 6 times; It is 10.25 that one of decumbent corydalis tuber eye drop (original prescription) is crossed the sexual stimulus average integral, it is 3.09 that one of decumbent corydalis tuber eye drop (the present invention) is crossed the sexual stimulus average integral, namely one of decumbent corydalis tuber eye drop (the present invention) group crosses sexual stimulus and is significantly less than decumbent corydalis tuber eye drop (original prescription) group.
Carried out relevant clinical verification test in 2011, through 120 routine successive administrations 10 day every day 2 randomized, double-blind, the right and left eyes own control clinical trial (actual finish 116 examples) of decumbent corydalis tuber eye drop (the present invention) with decumbent corydalis tuber eye drop (original prescription) eye irritation, the result shows: decumbent corydalis tuber eye drop (the present invention) test total mark is 564, and decumbent corydalis tuber eye drop (original prescription) test total mark is 2080; Data are carried out t check, the result: everyone zest integration of decumbent corydalis tuber eye drop (the present invention) is 4.8621 ± 6.09475, and everyone zest integration of decumbent corydalis tuber eye drop (original prescription) is 17.9310 ± 11.08836, T=14.388, P＜0.01; Namely eye irritation has the difference of remarkable statistical significance between two samples; This shows: the zest of decumbent corydalis tuber eye drop (the present invention) is significantly less than decumbent corydalis tuber eye drop (original prescription) group.
Comprehensive above-mentioned serial zest development test proves that decumbent corydalis tuber eye drop (the present invention) is more gentle, the non-irritating eye drop of a kind of physicochemical property, has effectively solved decumbent corydalis tuber eye drop (original prescription) zest large, the problem that patient compliance is poor.
Claims (11)
1. the preparation method of a decumbent corydalis tuber eye drop, it comprises dissolving and the heat tracing of Rhizoma Corydalis Decumbentis extract, adjusting, stirring and evenly mixing, filtration and the packing of the heating for dissolving of adjuvant, the adjusting of pH value, osmotic pressure, it is characterized in that adopting dilute phosphoric acid solution dissolving Rhizoma Corydalis Decumbentis extract, the concentration of described dilute phosphoric acid solution is equal to or less than 0.5mol/L, and the quality of the protopine in the Rhizoma Corydalis Decumbentis extract and the mol ratio of phosphoric acid are 0.32-0.43g:0.0036-0.0048 mol; Use glycerol as osmotic pressure regulator, regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.24-0.36 Osmol/kg; Regulate the pH value to 4.6-6.5 of decumbent corydalis tuber eye drop with sodium hydrogen phosphate; Solubilizing agent is directly joined in the dilute phosphoric acid solution of Rhizoma Corydalis Decumbentis extract; The heat tracing process is: heat 85-95 ℃, be incubated 25-35 minutes; Described Rhizoma Corydalis Decumbentis extract adopts the appended Rhizoma Corydalis Decumbentis extract quality standard of decumbent corydalis tuber eye drop of Chinese Pharmacopoeia.
2. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 1 is characterized in that every 1000ml decumbent corydalis tuber eye drop made by following steps:
A, take by weighing Rhizoma Corydalis Decumbentis extract by the consumption 0.32-0.43g of protopine, add in 0.0036-0.0048 mol dilute phosphoric acid solution, the concentration of dilute phosphoric acid solution is equal to or less than 0.5mol/L, in 85-95 ℃ stir 10-15 minutes after, to wherein adding solubilizing agent 3-8g, stir, make its dissolving, and 85-95 ℃ of insulations 25-35 minutes, for subsequent use;
B, with sodium dihydrogen phosphate 0.1-3.0g, disodium edetate 0.2-0.8g, antibacterial 0.1-0.8g and glycerol, add 300ml and be heated in 85-95 ℃ the water for injection, stir and make dissolving, be cooled to 45-55 ℃; Wherein the consumption of glycerol is to regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.24-0.36 Osmol/kg;
C, with two kinds of solution mixings of above-mentioned steps A and step B; Or adding again the thickening agent mixing, the consumption of thickening agent is equal to or less than 2.0g, adds thickening agent and described thickening agent is dissolved in the 200ml water stirring and dissolving before;
Be cooled to again room temperature, with disodium phosphate soln regulation system pH to 4.6-6.5, get the thing that makes of step C;
D, add water to full dose, mixing gets the thing that makes of step D;
Or the medicinal alcohol solution of adding freshener, the medicinal alcohol solution usage of freshener is equal to or less than 4g, the mass ratio 1:1-15 of freshener and medicinal alcohol in the medicinal alcohol solution of described freshener, and in advance freshener is dissolved in the medicinal alcohol, under agitation slowly add the making in the thing of step C, stirring and dissolving adds water to full dose again, mixing gets the thing that makes of step D;
E, the thing sampling of making of step D is detected, the multiple micropore filter aseptic filtration of qualified rear employing, filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
3. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 2 is characterized in that described solubilizing agent contains a kind of in polyoxyethylene sorbitan monoleate, the poly-hydrocarbon oxygen ester of Oleum Ricini and the poloxamer at least.
4. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 2 is characterized in that described antibacterial contains a kind of in ethyl hydroxybenzoate, methyl hydroxybenzoate, propyl hydroxybenzoate, benzalkonium bromide, benzalkonium chloride and the chlorobutanol at least.
5. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 2 is characterized in that described thickening agent contains a kind of in hyaluronic acid sodium, polyvidone, carbomer, poloxamer, sodium carboxymethyl cellulose, hypromellose, polyvinyl alcohol and the chitosan at least.
6. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 2 is characterized in that described freshener contains a kind of in natural Broneolum Syntheticum, synthetic borneol and the Mentholum at least.
7. the preparation method of a kind of decumbent corydalis tuber eye drop according to claim 2 is characterized in that every 1000ml decumbent corydalis tuber eye drop made by following steps:
(1) consumption by protopine 0.375g takes by weighing Rhizoma Corydalis Decumbentis extract, add in the 400ml 0.01mol/L dilute phosphoric acid solution, in 90 ℃ stir 10 minutes after, to wherein adding polyoxyethylene sorbitan monoleate 5g, stir, make its dissolving, and be heated to 90 ℃ of insulations 30 minutes, for subsequent use;
(2) with sodium dihydrogen phosphate 1g, disodium edetate 0.5g, ethyl hydroxybenzoate 0.5g and glycerol, add 300ml and be heated in 90 ℃ the water for injection, stir and make dissolving, be cooled to 50 ℃; Wherein the consumption of glycerol is to regulate the osmotic pressure of decumbent corydalis tuber eye drop between 0.27-0.33 Osmol/kg;
(3) hyaluronic acid sodium 1.0g is dissolved in the 200ml water, stirring and dissolving, for subsequent use;
(4) with three kinds of solution mixings of above-mentioned steps (1), step (2) and step (3), be cooled to again room temperature, with disodium phosphate soln regulation system pH to 5.2-6.0, get the thing that makes of step (4);
(5) natural Broneolum Syntheticum 0.25g is dissolved among the medicinal alcohol 2ml, under agitation slowly adds the making in the thing of step (4), stirring and dissolving adds water to full dose, mixing; Get the thing that makes of step (5);
(6) the thing sampling that makes of step (5) detected, the multiple micropore filter aseptic filtration of qualified rear employing, filtrate is aseptic subpackaged under hundred grades of laminar flow hood, and get final product.
8. the decumbent corydalis tuber eye drop of the preparation method of the described a kind of decumbent corydalis tuber eye drop of arbitrary claim preparation according to claim 1-6, it contains Rhizoma Corydalis Decumbentis extract and adjuvant, every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and dilute phosphoric acid solution 0.0036-0.0048 mol that protopine is 0.32-0.43g, and adjuvant; Described adjuvant comprises following component: medicinal alcohol solution 0-4g, sodium hydrogen phosphate and the glycerol of sodium dihydrogen phosphate 0.1-3.0g, solubilizing agent 3-8g, disodium edetate 0.2-0.8g, antibacterial 0.1-0.8g, thickening agent 0-2.0g, freshener, and all the other are water for injection; The concentration of wherein said dilute phosphoric acid solution is equal to or less than 0.5mol/L, the mass ratio 1:1-15 of freshener and medicinal alcohol in the medicinal alcohol solution of freshener; The amount of sodium hydrogen phosphate is for regulating pH value to 4.6-6.5; The amount of glycerol is for regulating osmotic pressure between 0.24-0.36 Osmol/kg.
9. a kind of decumbent corydalis tuber eye drop according to claim 8, it is characterized in that every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and phosphoric acid solution 0.004 mol that protopine is 0.375g, sodium dihydrogen phosphate 0.8-1.5g, polyoxyethylene sorbitan monoleate 4-6g, disodium edetate 0.4-0.6g, ethyl hydroxybenzoate 0.4-0.6g, hyaluronic acid sodium 0.8-1.2g, natural Broneolum Syntheticum 0.20-0.30g, medicinal alcohol 2-3ml, sodium hydrogen phosphate and glycerol, all the other are water for injection; The concentration of wherein said dilute phosphoric acid solution is equal to or less than 0.5mol/L, and the amount of sodium hydrogen phosphate is for regulating pH value to 5.0-6.2, and the amount of glycerol is for regulating osmotic pressure between 0.24-0.36 Osmol/kg.
10. a kind of decumbent corydalis tuber eye drop according to claim 9, it is characterized in that every 1000ml is prepared from by following material: contain Rhizoma Corydalis Decumbentis extract and 400ml0.01mol/L dilute phosphoric acid solution that protopine is 0.375g, sodium dihydrogen phosphate 1g, polyoxyethylene sorbitan monoleate 5g, disodium edetate 0.5g, ethyl hydroxybenzoate 0.5g, hyaluronic acid sodium 1.0g, natural Broneolum Syntheticum 0.25g, medicinal alcohol 2ml, sodium hydrogen phosphate and glycerol, all the other are water for injection; The amount of wherein said sodium hydrogen phosphate is for regulating pH value to 5.2-6.0, and the amount of glycerol is for regulating osmotic pressure between 0.27-0.33 Osmol/kg.
11. the described a kind of decumbent corydalis tuber eye drop of the arbitrary claim of claim 8-9, the pH that it is characterized in that described decumbent corydalis tuber eye drop is 5.2-6.0, and osmotic pressure is between 0.27-0.33 Osmol/kg.
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