CN105012404B - It is a kind of to be used to treat eye drops of scheroma and preparation method thereof - Google Patents
It is a kind of to be used to treat eye drops of scheroma and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of eye drops and preparation method for being used to treat scheroma.The eye drops supplementary material includes 10 parts of 40 parts of 6 10 parts of 12 parts of 1.5 3.3 parts of 130 170 parts of extract, borneol, bacteriostatic agent, solubilizer, borax, the boric acid containing bear gall powder.The physicochemical property of chemical composition contained by medicinal material of the present invention in formula, remove the use of volatile oil, the dosage of borneol and bear gall powder is have adjusted, and borneol and bear gall powder are added from different modes, reduces muddy opalescence etc. caused by conventional bear gall powder Adding Way, it ensure that effective component, meanwhile this preparation directly acts on agents area, dosage is greatly reduced, the onset time of medicine is accelerated, improves curative effect.
Description
Technical field
The invention belongs to field of traditional Chinese, and in particular to a kind of eye drops and preparation method for being used to treat scheroma.
Background technology
Basis-reinforcing eyesight-improving particle is oral formulations, by safflower, myrobalan, Corydalis impatiens (Pall.) Fisch, cloves, borneol, the taste medicinal material of bear gall powder 6 and
Sucrose is made, and there is regulation to burst gas, function of improving eyesight, for fuzzy viewing caused by gas of bursting, hot eyes is dry and astringent to wait disease, and clinical efficacy is true
Cut, its applied code is WS-10485 (ZD-0485) -2002, and safflower and Corydalis impatiens (Pall.) Fisch promoting blood circulation to remove blood stasis, heat-clearing solution are strongly fragrant, logical in side
Through sharp gas；Cloves regulating QI and lowering the adverseness invigorating the spleen；Borneol is sensible, Xie Yu, goes screen, improving eyesight；Bear gall clears liver and improve vision；Myrobalan balances the property of medicine, drop
Fire profit liver, the wherein main function of cloves is regulating QI and lowering the adverseness invigorating the spleen.
Patent document《A kind of basis-reinforcing eyesight-improving dropping pill for treating illness in eye and preparation method thereof》(CN1709419, hereinafter referred to as
" basis-reinforcing eyesight-improving dropping pill application ") basis-reinforcing eyesight-improving dropping pill is disclosed, borneol, bear gall powder are dissolved with ethanol；Cloves, safflower extraction are waved
Hair oil；Drying and crushing after myrobalan, north to the Great Wall purple water extract-alcohol precipitation, spray into containing borneol, bear gall powder ethanol, extraction volatile oil after obtain
Extract；Basis-reinforcing eyesight-improving dropping pill is made after adding the matrix of dripping pill, while defines the usage ratio of main ingredient and auxiliary material.
Basis-reinforcing eyesight-improving formula is mainly used in eye disease, and basis-reinforcing eyesight-improving particle or basis-reinforcing eyesight-improving dropping pill are oral system
Agent, get to eye focus by steps such as gastrointestinal absorptions and play a role, first pass effect causes medicine to destroy serious and medicine
Whole body is distributed after thing absorbs, and eye focus blood concentration is relatively low, therefore basis-reinforcing eyesight-improving formula is made into eye drops local application, more
Be advantageous to medicine and play curative effect.In addition, first safflower steam extraction is waved in basis-reinforcing eyesight-improving particle and basis-reinforcing eyesight-improving dropping pill application
Hair oil, then flavonoids is extracted, by prolonged high temperature, the active ingredient flavonoids loss in safflower is very big.
Composition in basis-reinforcing eyesight-improving particle or basis-reinforcing eyesight-improving dropping pill application is made into eye drops, not only needs adjustment to permeate
Pressure, pH value to appropriate numerical value, it is also desirable to which solving the addition of bear gall powder and extract stimulates sex chromosome mosaicism.Medicine containing bear gall powder is done
Into eye drops, customary preparation methods are that bear gall powder is dissolved in the solution for being then added to and preparing after ethanol, but obtained drop
Ocular fluid easily appears cloudy precipitate；Also, for the raw material of basis-reinforcing eyesight-improving particle or dripping pill without processing, excitant is too strong, does not apply to
In eyes local application.
In addition, the dosage of eye drops is far smaller than the dosage of oral formulations, it is also desirable to is suitably adjusted for raw material.
Basis-reinforcing eyesight-improving preparation is made into eye drops, not yet finds precedent or document report at present.
The content of the invention
For overcome the deficiencies in the prior art, the present invention provides a kind of eye drops for being used to treat scheroma；The present invention also carries
The preparation method of the eye drops is supplied.
To achieve the above object, the present invention uses following technical proposals：
A kind of eye drops for being used to treat scheroma, the parts by weight composition of supplementary material are as follows：
Extract 130-170 parts containing bear gall powder
Borneol 1.5-3.3 parts
Bacteriostatic agent 1-2 parts
Solubilizer 6-10 parts
40 parts of borax
10 parts of boric acid
Volumetric concentration 80-95% ethanol 6-10 parts
Appropriate water for injection
5000 times of amount volumes are made altogether
Wherein the extract containing bear gall powder is prepared by the following method：
Safflower 340-400 parts, myrobalan 340-400 parts, Corydalis impatiens (Pall.) Fisch 110-130 parts are taken by weight, add volume ratio 65-
95% ethanol extracts 2-4 times in 45-80 DEG C, and each 6-10 times of dosing material weight measures volume, each extraction time 1-4 hours, filter
Cross, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add the 3-5 times of water for measuring volume, obtain alcohol
Aqueous suspension；Bear gall powder 8-12 parts by weight are taken, are added to after being dissolved in water in foregoing alcohol aqueous suspension, are stirred 10-30 minutes, it is quiet
Put 12-48 hours, filter, filtrate decompression concentration, spray drying, obtain the extract containing bear gall powder.
It is currently preferred, a kind of eye drops for being used to treat scheroma, wherein the extract containing bear gall powder is by such as lower section
Method is prepared：
364 parts of safflower, 364 parts of myrobalan, 121 parts of Corydalis impatiens (Pall.) Fisch are taken by weight, add the ethanol of volume ratio 90% in 60 DEG C
Extraction 2 times, for the first time plus 8 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes, extraction 2 hours, filtration, filtrate recovery
50 DEG C of survey relative density 1.20-1.25 are concentrated under reduced pressure into after ethanol again, the water of 4 times of amount volumes is added, obtains alcohol aqueous suspension；Take bear
The parts by weight of courage powder 10.5, it is added in foregoing alcohol aqueous suspension, stirs 25 minutes after being dissolved in water, stand 24 hours, filters, filter
Liquid is concentrated under reduced pressure, and spray drying, obtains the extract containing bear gall powder.
Currently preferred, a kind of to be used to treat the eye drops of scheroma, the parts by weight composition of supplementary material is as follows：
146 parts of extract containing bear gall powder
2.5 parts of borneol
1.5 parts of bacteriostatic agent
7.5 parts of solubilizer
40 parts of borax
10 parts of boric acid.
7.5 parts of volumetric concentration 80-95% ethanol
Appropriate water for injection
5000 times of amount volumes are made altogether
A kind of eye drops for being used to treat scheroma of the present invention, wherein bacteriostatic agent is selected from benzene Zha Lvte, benzene pricks bromine
One or both of spy, preferably benzene Zha Lvte；The one kind or two of solubilizer in polyethylene glycol 400, Macrogol 600
Kind, preferably Macrogol 600；Ethanol volumetric concentration is preferably 95%.
Supplementary material of the present invention without special instruction be market purchase.
A kind of preparation method for being used to treat the eye drops of scheroma, step are as follows：
1) extract containing bear gall powder is prepared：Safflower 340-400 parts, myrobalan 340-400 parts, Corydalis impatiens (Pall.) Fisch are taken by weight
110-130 parts, adding volume ratio 65-95% ethanol and extracted 2-4 times in 45-80 DEG C, each 6-10 times of dosing material weight measures volume,
Each hour extraction time 1-4, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add
Enter 3-5 times and measure volume of water, obtain alcohol aqueous suspension；Bear gall powder 8-12 parts by weight are taken, foregoing alcohol water is added to after being dissolved in water and is suspended
In liquid, 10-30 minutes are stirred, stand 12-48 hours, filtration, filtrate decompression concentration, spray drying, are produced；
2) eye drops is prepared：1.5-3.3 part borneols are taken by weight, and adding 6-10 part volumetric concentration 80-95% ethanol makes
Dissolving, adds 6-10 part solubilizer, filters to obtain borneol solution for standby；By the extract containing bear gall powder of 130-170 parts by weight
It is added in the 200-4500 times of water for injection for measuring volume, stirring and dissolving, filters to obtain water hypostasis solution；Above-mentioned borneol solution is taken to add
Enter into water hypostasis solution, it is stirring while adding, add the 100-4400 times of water for injection for measuring volume, add 40 parts of boraxs,
10 parts of boric acid and 1-2 part bacteriostatic agents, are stirred to dissolve, and inject water to 5000 times of amount volumes, mix, filtration, produce.
Currently preferred, a kind of preparation method for being used to treat the eye drops of scheroma, step is as follows：
1) extract containing bear gall powder is prepared：364 parts of safflower, 364 parts of myrobalan, 121 parts of Corydalis impatiens (Pall.) Fisch are taken by weight, are added
Enter the ethanol of volume ratio 90% to extract 2 times in 60 DEG C, for the first time plus 8 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes,
Extraction 2 hours, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add 4 times of amount bodies
Long-pending water, obtain alcohol aqueous suspension；The parts by weight of bear gall powder 10.5 are taken, are added to after being dissolved in water in foregoing alcohol aqueous suspension, are stirred
25 minutes, 24 hours are stood, filtration, filtrate decompression concentration, spray drying, is produced；
2) eye drops is prepared：2.5 parts of borneols are taken by weight, and adding 7.5 parts of ethanol of volume ratio 95% makes dissolving, adds
7.5 parts of solubilizer, filter to obtain borneol solution for standby；The extract containing bear gall powder of 146 parts by weight is added to 2500 times of amount bodies
In long-pending water for injection, stirring and dissolving, water hypostasis solution is filtered to obtain；Above-mentioned borneol solution is taken to be added in water hypostasis solution, side
Edged stirs, and adds the water for injection of 2000 times of amount volumes, then 40 parts of boraxs of addition, 10 parts of boric acid and 1.5 parts into solution
Bacteriostatic agent, it is stirred to dissolve, injects water to 5000 times of amount volumes, mix, filtration, produce.
The present invention times amount volume refers to the corresponding relation of weight and volume, and unit is ml/g or L/kg.
Compared with prior art, advantage is as follows by the present invention：
1. it is a discovery of the invention that volatile oil composition directly acts on eyes local time in basis-reinforcing eyesight-improving oral formulations, stimulate
Property it is too big, curative effect is had no effect on after removal, thus, invention removes the cloves in prescription, has been abandoned to cloves, safflower volatilization
The extraction and use of oil, while decrease the destruction to safflower flavonoids.
2. the usage amount of borneol is oral formulations in basis-reinforcing eyesight-improving original side, eye drops is not suitable for, the present invention have adjusted ice
The dosage of piece.In addition, the present invention is also improved the feed postition of wherein bear gall powder, add the dosage of bear gall powder with to
Disappear refining losses, and eliminates the problem that easily appeared cloudy precipitate caused by eye drops uses bear gall powder.
3. to have selected borax-boric acid system by many experiments be auxiliary material to the present invention, both as osmotic pressure regulator, and it is simultaneous
Make pH adjusting agent, the present invention, which also selects, examines bacteriostatic agent and solubilizer.After testing, eye drops of the invention meets pharmacopeia to drop
Every regulation of ocular fluid.
4. eye drop preparation prepared by the present invention compared with oral formulations, not only greatly reduces drug dose, and due to
Medicine directly acts on lesions position, accelerates onset time, improves curative effect.
Embodiment
Following embodiments and experimental example are used to further illustrate but be not limited to the present invention.
Experimental example 1, extraction process experiment
This experiment is by the way of single factor test and orthogonal test are combined, with hydroxyl radical carthamin yellow carthamus A (referred to as：HSYA)、
The weighted average coefficients of total alkaloid are inspection target, to species (water, ethanol), solvent concentration (65-95%), the dosage of solvent
The factor such as (6-10 times), extraction time (1-4h), number (2-4 times), temperature control (45-90 DEG C) is in optimized selection, and finds
Extracting temperature, solvent dosage and extraction time have a great influence to extraction result, are determined that optimum extraction process is so as to screen：Medicine
Material adds 90% ethanol and extracted 2 times, and for the first time plus 8 times are measured, and are extracted 3 hours, second plus 8 times of amounts, extraction 2 hours, extraction temperature
Degree control is at 60 DEG C, and the extract obtained yield of technique is 14.3% according to this.
Experimental example 2：Water sinks technological experiment
Safflower 91g, myrobalan 91g, Corydalis impatiens (Pall.) Fisch 30.25g are weighed, adds 90% ethanol to extract 2 times, for the first time plus 8 times are measured bodies
Product, extract 3 hours, second plus 8 times of amount volumes, extract 2 hours, filtration, filtrate recycling ethanol, being further concentrated to relative density is
When 1.25 (50 DEG C of surveys), it is divided into 3 parts, first part plus 3 times and measures water, second part plus 4 times amount water, the 3rd part plus 5 times amount water, divide
It is not added in above-mentioned alcohol aqueous suspension, stirs, stand 48 hours, filtration, be concentrated under reduced pressure, determine content, calculates gallic acid
The rate of transform.
The heavy industrial analysis table of the water of table 1
As a result show, add 3 times of amount volume of water, content is slightly lower, and relatively difficult during filtering, 4 times and 5 times amount volume of water, contains
It is little to measure difference, when consideration adds 5 times of amount volume of water, concentration time will extend, therefore select the water for adding 4 times of amount volumes to enter water-filling
It is heavy.
Experimental example 3, the experiment of bear gall powder processing mode
Bear gall powder is water soluble ingredient, and conventional method and documents and materials method be after adding a certain amount of water dissolving,
Directly carry out next step operation.
The present invention is had found using the above method, is carried out next step preparation after the dissolving of bear gall powder water, is unavoidably become turbid
Phenomenon, it can not also be avoided using high speed centrifugation mode.
The present invention is found through experiments that, is added to after the dissolving of bear gall powder water in ethanol extract and adds water precipitation, after filtering
Be further concentrated to dry, dissolved with water, add corresponding auxiliary material, eye drop preparation is made, can solved the above problems, specific experiment and
As a result it is as follows：
Mother liquor：Alcohol extracting-water precipitating thing prepared by experimental example 2 adds suitable quantity of water dissolving after drying.
Technique one：Bear gall amidin (1ml, which contains, takes bear gall powder 0.05g) 4ml is taken to be added in 80ml mother liquors, mix, shake
It is even, add water to supply 100ml, place 48h, observe solution character and detect the amount retained of wherein bear gall powder.
Technique two：Bear gall amidin (1ml, which contains, takes bear gall powder 0.05g) 4ml is taken, adds 2ml Macrogol 600s
(PEG600) 4ml, it is well mixed, is added in 80ml mother liquors, mix, shake up, add water to supply 100ml, place 48h, observation is molten
Fluidity shape and the amount retained for detecting wherein bear gall powder.
Technique three：Bear gall amidin (1ml, which contains, takes bear gall powder 0.05g) 4ml is taken, adds 2ml Tween 80 2ml, mixing is equal
It is even, it is added in 80ml mother liquors, mixes, shake up, add water to supply 100ml, place 48h, observes solution character and detect wherein bear
The amount retained of courage powder.
Technique four：Bear gall powder 0.5g is taken first to add the dissolving of 2ml water, adding 80ml alcohol aqueous suspension, (i.e. experimental example 2 is made
) in, stirring, 48h is placed, observe solution character and detect the amount retained of wherein bear gall powder.
The bear gall powder processing mode of table 2 is screened
Contained bear gall amount/theoretical bear gall content * 100% in decoction after 2d amount retaineds (%)=2 day
Conclusion：Experimental result is shown, bear gall powder is dissolved in water and is then added in different extraction solution, technique one and technique
Three there is turbid phenomenon at once, and technique two turbid phenomenon occurs after placing 48h；And after bear gall powder is merged with ethanol extract
Enter the heavy processing of water-filling again, resulting solution is placed does not occur deposited phenomenon more than 48h, and does not add any auxiliary material and (polyethylene glycol, tell
80) temperature, facility is provided for later stage preparation process.In 48h amount retaineds, the result of technique four reaches more than 90%.Meanwhile in view of
Bear gall powder is lost (about 10%) in the process, so present invention amount of bear gall powder on formula brings up to what original side was measured
110%.
Experimental example 4, eye drop preparation technological experiment
(1) addition of borneol
According to the physicochemical property of borneol, ethanol is selected as carrier solvent, and investigate the volumetric concentration that have selected ethanol.
As a result find, the ethanol of 80-95% concentration is good for the solute effect of borneol, especially 95% ethanol, ice
Piece dissolving is rapid, no precipitation, therefore the feed postition of borneol is preferably：Dissolved using 95% ethanol and added after forming solution.
(2) selection of carrier solvent
According to the physicochemical property of said extracted raw material, water is selected as carrier solvent, and adjust the usage amount of borneol.Enter
Tests below is gone：
1g borneols are weighed, adding 3g95% ethanol makes dissolving, adds 3g Macrogol 600s, and filtration is standby.
The extract 3.2g containing bear gall powder is weighed, 50ml waters for injection is added, stirring and dissolving, takes 0.35g borneol solution to add
Enter into alcohol aqueous suspension, it is stirring while adding, add water for injection to make into 100ml, obtaining brown color supernatant liquid, (surveying decoction pH value is
3.43) it is good, to let cool rear clarity, it is good that 4 DEG C of low temperature stand overnight rear clarity.It is determined that the solvent of this product is used as using water.(3)
The selection of pH adjusting agent
The pH value of normal eye tolerance is 5.0~9.0, during pH value 6.0~8.0 eyes without sense of discomfort, eye to alkalescence relatively
Sensitivity, stronger acids can more make eye injury.By prescription preparating liquid is determined, it is 3.4 or so to measure pH value, does not set ocular fluid at us
In pH value range (6.0~8.0), so primarily determining that with borax and boric acid regulating liquid medicine pH value to 6.5 or so.
3 three months observation pH value tables of comparisons of table
As seen from the experiment, when adjusting pH value with boric acid-borax buffer salt system, the pH value of system is kept not substantially
Become, and the pH value is applied to eye drops.
(4) selection of bacteriostatic agent
The conventional bacteriostatic agent of eye drops is benzalkonium chloride and benzalkonium bromide, and the two property, effect are similar.The present invention is pricked with benzene
The concentration selection of bacteriostatic agent is investigated exemplified by oronain.The preparation of sample is carried out using different amounts of benzalkonium chloride, it is steady by three months
Qualitative investigation, its fungistatic effect quality is observed, determines bacteriostatic agent dosage.
The selection of the bacteriostatic agent dosage of table 4
Experimental result shows, using benzalkonium chloride of the concentration more than 0.02% as bacteriostatic agent, do not occurred within 3 months
Mildew phenomena, consider the security of stability of drug products and patient medication, it is determined that from 0.03% benzalkonium chloride as bacteriostatic agent
Optimal dosage.
(5) selection of solubilizer
The influence of Tween 80 and PEG400, PEG600 to borneol solubilizing effect has been investigated in experimentation, has as a result added and tells
During temperature 80, solution neutrality carves existing turbid phenomenon, and solution is clarified when making solubilizer with PEG400 or PEG600, so from
The solution configured is added PEG400 or PEG600, observation increases by PEG400 or PEG600 as solubilizer according to following table dosage
Molten effect.
Table 5PEG400 and PEG600 solubilizing effect contrast table
As a result show, when PEG400 or PEG600 dosages account for more than the 0.1% of total amount of liquid, solution clarification, no precipitation
Thing, therefore be solubilizer from PEG400 or PEG600, optimal dosage is 0.15%.
(6) selection of osmotic pressure regulator
Sodium chloride solution of the adaptable osmolarity ranges of eyeball equivalent to 0.6%-1.5%, just have more than 2% obvious
It is uncomfortable.Hypotonic solution should be adjusted to isotonic solution with suitable material.The present invention is with borax-boric acid (volume ratio 4:1) buffer
Salt system maintains pH value, and to reduce supplementary product consumption, the present invention continues to select borax-boric acid (4:1) buffer salt system is oozed to adjust
Pressure thoroughly.
The osmotic pressure of table 6 adjusts table
Conclusion：It can be obtained by test data, when borax-boric acid (4:1) when dosage is 1.0%, the osmotic pressure of gained finished product
The relatively osmotic pressure of human eye tear, so selection borax-boric acid (4:1) dosage is 1.0%.
(7) stability experiment
Take the sample of the formulation and technology preparation by determination appropriate, put high temperature (60 DEG C), low temperature (4 DEG C) and strong light respectively
10 days under the conditions of (4500Lx), detected respectively at sampling in 0,5,10 day, investigate the stability of sample,
The influence factor result of the test of table 7
Conclusion：After this product is placed 10 days under the conditions of high temperature (60 DEG C), low temperature (4 DEG C) and illumination (4500lx) respectively, respectively
Item quality index illustrates the sample quality stabilization prepared by this formulation and technology, therefore determine this formulation and technology for most without significant change
Whole formulation and technology.
Experimental example 5, lagophthalmos irritation test
First, test material：
1st, medicine：10% Sodium fluorescein, brownish red clear liquid, specification 5ml：500mg, lot number 210486,
Cardinal health manufacturing services BV are produced.
2nd, prepared by tested material：
Without medicine auxiliary material：Take benzalkonium chloride 1.5g, PEG6007.5g, 95% ethanol 7.5g, borax 40g, boric acid 10g, injection
With appropriate amount of water, 5000ml is made, produces.
Eye drops containing volatile oil：Prepare volatile oil by basis-reinforcing eyesight-improving dropping pill application, obtain 5.5ml, in conventional manner with β-
CD is included, and separately takes the extract 146g containing bear gall powder, borneol 2.5g, benzalkonium chloride 1.5g, PEG6007.5g, 95% ethanol
7.5g, borax 40g, boric acid 10g, appropriate water for injection, are made 5000ml, produce.
Non-volatile oil droplet ocular fluid：Prepared by embodiment 1.
3rd, animal：New zealand rabbit 25, male and female dual-purpose, female person is without pregnant, body weight 2.5-3.0kg, Shandong Shandong Pharmaceutical Group
There is provided, quality certification number：Shandong kinoplaszm word D20120922.
Instrument：Slit-lamp microscope, model YT-02, instrument platform：Suzhou Medical Instruments Factory produces.
2nd, experimental method
1st, animal preselects：Visually observe：Cornea is without muddiness.Conjunctiva is without congested, oedema and secretion, and pupil is circular, both sides
Deng big, light is reflected good.Slit lamp examination：Corneal transparency, no cloudiness, spot screen；Iris texture is clear, no congestion and edema.It is glimmering
Light uniformly dyeing color：L0% Sodium fluoresceins, face the used time with 5 times of normal saline dilution.Physiological saline is used after being dripped per lagophthalmos
Rinse well.It is that cornea is normal to observe the uncolored person of cornea.Pre- anophthalmia disease is selected through above-mentioned and healthy rabbits 25 are served only for this examination
Test.
2nd, eye irritation is tested
2.1 short-term multiple dosings are to Eye irritation：From adult healthy new zealand rabbit 10, male and female dual-purpose, body weight 2.5~
3.0kg, 2 groups of volatile oil group and experimental group are randomly divided into, every group of animal eyelash is cut off.Eye on the left of every animal of volatile oil group
Tested material (0.1ml/ eyes) is dripped in conjunctival sac.Eye conjunctiva intracapsular drop in right side is control without medicine auxiliary material；Every animal left side of experimental group
Tested material (0.1ml/ eyes) is dripped in branch hole conjunctival sac.Eye conjunctiva intracapsular drop in right side is control without medicine auxiliary material；Pressed every time during administration
Compel nasolacrimal duct, and eye is passively closed 5~l0s.The every 15min eye droppings of each group is once.Successive administration 2h.Record administration after 6h,
24h, 48h, 72h to 7d eyes local excitation response situation.
2.2 long term administration eye irritant tests：From adult healthy new zealand rabbit 10, male and female dual-purpose, body weight 2.5~
3.0kg, 2 groups of volatile oil group and experimental group are randomly divided into, every group of animal eyelash is cut off.Eye on the left of every animal of volatile oil group
Tested material (0.1ml/ eyes) is dripped in conjunctival sac.Eye conjunctiva intracapsular drop in right side is control without medicine auxiliary material；Every animal left side of experimental group
Tested material (0.1ml/ eyes) is dripped in branch hole conjunctival sac.Eye conjunctiva intracapsular drop in right side is control without medicine auxiliary material.Pressed every time during administration
Compel nasolacrimal duct, and eye is passively closed 5~l0s.5 times a day, successive administration observe weekly and record after on-test within 4 weeks to
Off-test.
3rd, number of winks determines：Take pre-selection healthy animal 5.Male and female dual-purpose.Every group of animal eyelash is cut off.Every dynamic
Eye conjunctiva is intracapsular on the left of thing drips tested material (0.1ml/ eyes).Eye conjunctiva intracapsular drop in right side is control without medicine auxiliary material.Administration every time
When oppress and nasolacrimal duct and eye is passively closed 5~10s, immediately record number of winks in l0min.5 animals are calculated respectively
The average number of winks of images of left and right eyes.Evaluate excitant of the medicine to eye (number of winks at most excitant is big).
3rd, result
1st, eye irritation is tested：It is one that every horn film, iris and the score value of conjunctiva stimulate the reaction, which are added,
The total mark of animal subject Eye irritation reaction.It is exactly this total mark divided by number of animals of the stimulate the reaction of each animal subject
Last score value of the tested material to eye irritation.Integration 0~3 is nonirritant, and integration 4-8 is slight stimulation, and integration 9-12 is
Moderate excitant, integration are strong and stimulating more than 13.It the results are shown in Table 8.
The irritation test result of table 8
| Without medicine auxiliary material n=5 | Volatile oil group n=5 | Experimental group n=5 | |
| Cornea | 0 | 2.2±0.84 | 0 |
| Iris | 0 | 2.8±0.84 | 0 |
| Conjunctiva | 0 | 5.8±1.92 | 0.8±0.84 |
| Total mark | 0 | 10.8±2.59 | 0.8±0.84 |
| P values | —— | ＜ 0.01 | ＞ 0.05 |
Note：Experimental group is compared with without medicine auxiliary material, P>0.05, statistics indifference；Volatile oil group with compared with without medicine auxiliary material,
P ＜ 0.01, pole significant difference.
By the finding of table 8, the irritant test of eye drops containing volatile oil is shown as moderate excitant, especially to conjunctiva excitant compared with
By force；And experimental group and without medicine auxiliary material group then to lagophthalmos vacuum response.
2nd, animal number of winks determines：Number of winks after record each group animal is put drops in one's eyes in l0min, is statistically analyzed
T is examined.It the results are shown in Table 9.
Table 9 is to rabbit number of winks measurement result
| Number of winks/10min, n=5 | P values | |
| Without medicine auxiliary material group | 7.6±1.14 | —— |
| Experimental group | 7.8±1.10 | ＞ 0.05 |
Note：Experimental group is compared with without medicine auxiliary material, P>0.05, statistics indifference.
As a result show：Experimental group there was no significant difference compared with without medicine auxiliary material (P>0.05) eye drops pair of the present invention, is illustrated
Lagophthalmos is nonirritant.
4th, conclusion
Experiment finds that the volatile oil component in basis-reinforcing eyesight-improving is stronger to lagophthalmos excitant, is moderate excitant, removes volatilization
The short-term multiple and long term administration irritant test of eye drops after oil component has no significant effect (P ＞ 0.05) to lagophthalmos, and rabbit is blinked
Eye number no significant difference (P compared with without medicine auxiliary material>0.05).After eye drops of the experimental animal using the present invention, cornea of both eyes
Transparent, no muddiness, iris texture is clear, and conjunctiva is without hyperemia, no oedema, without secretion.
Experimental example 6, the clinical observation to treating xerophthalmia
1st, clinical data
Thanks for your advice awards the diagnostic analysis standard of suggestion with reference to sweat for diagnostic criteria, including foreign body sensation, sensation of dryness, gargalesthesia, photophobia,
It is envious, intolerant to flue dust etc..(bibliography：Open sweat to hold, Zhou Zulian, Zhao Chengrong, wait scheroma to score and be classified and artificial tear curative effect
Research [J] the ophthalmology research of evaluation, 1994,12 (1):25-27)
Selected patient 108, wherein man 53, female 55；25~75 years old age, average (50.4 ± 7.8) year.Using with
Patient is divided into three groups by the method for machine packet, 1 group for the treatment of group and control, compares 2 groups each 36.Sex between three groups of cases, the age,
The data such as the course of disease and the state of an illness is statistically analyzed, not statistically significant, has comparativity.
TCM syndrome standards of grading：Using symptom integral method
The scheroma clinical symptoms of table 10 are classified score standard
(bibliography：The clinical research of Xie Like, Zhu Zhirong, Zhang Mingming Xiaoyao Sans joint Shengmai San treatment scheroma
[J] China TCM Ophthalmology magazine, 2009,1 (2)：71-73)
2nd, experimental method
2.1 treatment method：Treatment group subject gives basis-reinforcing eyesight-improving eye drops made from embodiment 1,6 times a day, control 1
Subject's orally former technique basis-reinforcing eyesight-improving particle is organized, 3 times a day, each 5g, 2 groups of subjects of control are orally dripped according to basis-reinforcing eyesight-improving
Dripping pill prepared by ball application, 3 times a day, each 5g, is used in conjunction 4 weeks.Forbid during experiment plus similar in being acted on trial drug
Pharmaceuticals, if any the complication relevant with disease, can anti symptom treatment, but it is noted that test group with control group in drug combination
Harmony in terms of species and dosage.
2.2 efficacy determination：Syndrome integral before therapeutic index=(syndrome integral after syndrome integral-treatment before treatment)/treatment
× 100%.Effectively：Clinical symptom relief, syndrome integral reduce >=30%；It is invalid：Clinical symptoms are not improved, even plus
Weight, syndrome integral are reduced<30%.
3rd, result
During medication, 2 groups for the treatment of group and control respectively have 1 case to lose, and 1 group of control has 2 cases to lose.
Clinical efficacy comparison：Treatment group's total effective rate 92%, control group total effective rate 82%, comparing between two groups has conspicuousness
Difference (P<0.05).
The Clinical efficacy comparison of table 11
Wherein, compared with 1 group of control, * * P ＜ 0.01；Compared with 2 groups of control, #P ＜ 0.05
As a result show, basis-reinforcing eyesight-improving eye drops made from extractive composition of the present invention has good for treatment scheroma
Curative effect, effect pole are significantly better than former technique basis-reinforcing eyesight-improving particle (P ＜ 0.01), are significantly better than the basis-reinforcing eyesight-improving dropping pill of dripping pill application
(P ＜ 0.05).
Table uses dose comparison on 12nd
The daily medicinal material doses of eye drop preparation is far smaller than granule group it can be seen from above-mentioned daily dose comparison data
And dripping pill group, particle, the usage amount of dripping pill are equivalent to 52 times of eye drops of the present invention.
Research found, eliminating the eye drops of volatile oil, not only excitant is substantially reduced, and curative effect is slightly lifted, while greatly
Reduce usage amount greatly.
Following embodiments can realize the effect of above-mentioned experimental example.
Embodiment 1, a kind of eye drops for being used to treat scheroma, supplementary material composition are as follows：
5000ml is made
Its preparation method is：
1) extract containing bear gall powder is prepared：Safflower 364g, myrobalan 364g, Corydalis impatiens (Pall.) Fisch 121g are taken, adds volume ratio
90% ethanol is extracted 2 times in 60 DEG C, and for the first time plus 8 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes, it is small to extract 2
When, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add the water of 4 times of amount volumes,
Obtain alcohol aqueous suspension；Bear gall powder 10.5g is taken, is added to after being dissolved in water in foregoing alcohol aqueous suspension, is stirred 25 minutes, stands 24
Hour, filtration, filtrate decompression concentration, spray drying, produce；
2) eye drops is prepared：2.5g borneols are weighed, adding 95% ethanol 7.5g makes dissolving, adds 7.5g PEG600,
Filter standby；Extract containing bear gall powder is added in 2500ml waters for injection, stirring and dissolving, filters, take above-mentioned borneol molten
Liquid is added in water hypostasis solution, stirring while adding, adds 2000ml waters for injection；Added again into solution 40g boraxs,
10g boric acid and 1.5g benzene Zha Lvte, are stirred to dissolve, inject water to 5000ml, mix, and filtration, produce.
Embodiment 2, a kind of eye drops for being used to treat scheroma, supplementary material composition are as follows：
5000ml is made
Its preparation method is：
1) extract containing bear gall powder is prepared：Take safflower 340g, myrobalan 340g, Corydalis impatiens (Pall.) Fisch 110g, 65% ethanol of addition
Extracted 2 times at 45 DEG C, for the first time plus 6 times are measured ethanol, are extracted 1 hour, second plus 6 times of amount ethanol, extraction 1 hour, are filtered, filter
Liquid reclaims ethanol, then is concentrated under reduced pressure into relative density as 1.20-1.25 (50 DEG C of surveys), adds the water of 3 times of concentrate weight, takes bear
Courage powder 8g, adds suitable quantity of water to dissolve, and bear gall amidin is added in alcohol aqueous suspension, stirs 10min, cold heavy 12 hours, filter
Cross, filtrate is concentrated under reduced pressure again, spray drying, produces；
2) eye drops is prepared：1.5g borneols are weighed, adding 6g80% ethanol makes dissolving, adds 6gPEG400, and filtration is standby
With；Extract containing bear gall powder is added in 200ml waters for injection, stirring and dissolving, filters, take above-mentioned borneol solution to be added to
It is stirring while adding in water hypostasis solution, add 4400ml waters for injection；Added again into solution 40g boraxs, 10g boric acid and
1g benzene Zha Lvte, are stirred to dissolve, and inject water to 5000ml, mix, and filtration, produce.
Embodiment 3, a kind of eye drops for being used to treat scheroma, supplementary material composition are as follows：
5000ml is made
Its preparation method is：
1) extract containing bear gall powder is prepared：Take safflower 400g, myrobalan 400g, Corydalis impatiens (Pall.) Fisch 130g, 95% ethanol of addition
Extracted 4 times at 80 DEG C, every time plus 10 times are measured ethanol, are extracted 4 hours, filtration, filtrate recycling ethanol, then be concentrated under reduced pressure into relatively close
Spend for 1.20-1.25 (50 DEG C survey), add the water of 5 times of concentrate weight, take bear gall powder 12g, add suitable quantity of water to dissolve, bear gall powder
The aqueous solution is added in alcohol aqueous suspension, stirs 30min, cold heavy 48 hours, filtration, filtrate is concentrated under reduced pressure again, is spray-dried, i.e.,
；
2) eye drops is prepared：3.3g borneols are weighed, adding 10g90% ethanol makes dissolving, adds 10gPEG600, filters
It is standby；Extract containing bear gall powder is added in 4500ml waters for injection, stirring and dissolving, filters, take above-mentioned borneol solution to add
Enter into water hypostasis solution, it is stirring while adding, add 100ml waters for injection；40g boraxs, 10g boric acid are added into solution again
With 2g benzene Zha Xiute, it is stirred to dissolve, injects water to 5000ml, mix, filtration, produces.
Embodiment 4, a kind of eye drops for being used to treat scheroma, supplementary material composition are as follows：
5000ml is made
Its preparation method is：
1) extract containing bear gall powder is prepared：Safflower 364g, myrobalan 364g, Corydalis impatiens (Pall.) Fisch 121g are taken, adds volume ratio
90% ethanol is extracted 2 times in 60 DEG C, and for the first time plus 10 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes, it is small to extract 2
When, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add 4 times of amount water, obtain alcohol water
Suspension；Bear gall powder 10.5g is taken, is added to after being dissolved in water in foregoing alcohol aqueous suspension, is stirred 25 minutes, stands 24 hours,
Filtration, filtrate decompression concentration, spray drying, is produced；
2) eye drops is prepared：3.3g borneols are weighed, adding 10g95% ethanol makes dissolving, adds 10gPEG600, filters
It is standby；Extract containing bear gall powder is added in 2500ml waters for injection, stirring and dissolving, filters, take above-mentioned borneol solution to add
Enter into water hypostasis solution, it is stirring while adding, add 2000ml waters for injection；40g boraxs, 10g boron are added into solution again
Acid and 2g benzene Zha Lvte, are stirred to dissolve, inject water to 5000ml, mix, and filtration, produce.
Claims (8)
1. a kind of eye drops for being used to treat scheroma, is characterised by, the parts by weight composition of its supplementary material is as follows：
Extract 130-170 parts containing bear gall powder
Borneol 1.5-3.3 parts
Bacteriostatic agent 1-2 parts
Solubilizer 6-10 parts
40 parts of borax
10 parts of boric acid
Volumetric concentration 80-95% ethanol 6-10 parts
Appropriate water for injection
5000 times of amount volumes are made altogether；
Wherein the extract containing bear gall powder is prepared by the following method：
Safflower 340-400 parts, myrobalan 340-400 parts, Corydalis impatiens (Pall.) Fisch 110-130 parts are taken by weight, add volume ratio 65-95%
Ethanol extracts 2-4 times in 45-80 DEG C, and each 6-10 times of dosing material weight measures volume, each extraction time 1-4 hours, filters, filter
50 DEG C of survey relative density 1.20-1.25 are concentrated under reduced pressure into after liquid recovery ethanol again, the 3-5 times of water for measuring volume is added, obtains alcohol water and mix
Suspension；Bear gall powder 8-12 parts by weight are taken, are added to after being dissolved in water in foregoing alcohol aqueous suspension, stir 10-30 minutes, are stood
12-48 hours, filtration, filtrate decompression concentration, spray drying, obtain the extract containing bear gall powder；
Described times amount volume refers to the corresponding relation of weight and volume, and unit is ml/g or L/kg.
2. eye drops according to claim 1, is characterised by, the extract containing bear gall powder is prepared by the following method：
364 parts of safflower, 364 parts of myrobalan, 121 parts of Corydalis impatiens (Pall.) Fisch are taken by weight, are added the ethanol of volume ratio 90% and are extracted 2 in 60 DEG C
Secondary, for the first time plus 8 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes, extraction 2 hours, filtration, filtrate recycling ethanol
It is concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 again afterwards, adds the water of 4 times of amount volumes, obtain alcohol aqueous suspension；Take bear gall powder
10.5 parts by weight, it is added in foregoing alcohol aqueous suspension, stirs 25 minutes after being dissolved in water, stand 24 hours, filtration, filtrate subtracts
Pressure concentration, spray drying, obtains the extract containing bear gall powder.
3. eye drops according to claim 1, is characterised by, the parts by weight composition of its supplementary material is as follows：
146 parts of extract containing bear gall powder
2.5 parts of borneol
1.5 parts of bacteriostatic agent
7.5 parts of solubilizer
40 parts of borax
10 parts of boric acid
7.5 parts of volumetric concentration 80-95% ethanol
Appropriate water for injection
5000 times of amount volumes are made altogether.
4. according to any described eye drops of claim 1-3, it is characterised by, the bacteriostatic agent is selected from benzene Zha Lvte, benzene pricks bromine
One or both of spy；The solubilizer is selected from one or both of polyethylene glycol 400, Macrogol 600.
5. eye drops according to claim 4, is characterised by, the bacteriostatic agent is benzene Zha Lvte, and the solubilizer is poly-
Ethylene glycol 600.
6. according to any described eye drops of claim 1-3, it is characterised by, the volumetric concentration of the ethanol is 95%.
7. the preparation method of eye drops according to claim 1, is characterised by, step is as follows：
1) extract containing bear gall powder is prepared：Safflower 340-400 parts, myrobalan 340-400 parts, Corydalis impatiens (Pall.) Fisch 110- are taken by weight
130 parts, add volume ratio 65-95% ethanol and extracted 2-4 times in 45-80 DEG C, each 6-10 times of dosing material weight measures volume, every time
Hour extraction time 1-4, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add 3-
5 times of amount volume of water, obtain alcohol aqueous suspension；Bear gall powder 8-12 parts by weight are taken, are added to after being dissolved in water in foregoing alcohol aqueous suspension,
10-30 minutes are stirred, stand 12-48 hours, filtration, filtrate decompression concentration, spray drying, are produced；
2) eye drops is prepared：1.5-3.3 part borneols are taken by weight, adding 6-10 part volumetric concentration 80-95% ethanol makes dissolving,
6-10 part solubilizer is added, filters to obtain borneol solution for standby；The extract containing bear gall powder of 130-170 parts by weight is added to
In the 200-4500 times of water for injection for measuring volume, stirring and dissolving, water hypostasis solution is filtered to obtain；Above-mentioned borneol solution is taken to be added to water
It is stirring while adding in hypostasis solution, the 100-4400 times of water for injection for measuring volume is added, adds 40 parts of boraxs, 10 parts of boron
Acid and 1-2 part bacteriostatic agents, are stirred to dissolve, and inject water to 5000 times of amount volumes, mix, filtration, produce.
8. the preparation method of eye drops according to claim 7, is characterised by, step is as follows：
1) extract containing bear gall powder is prepared：364 parts of safflower, 364 parts of myrobalan, 121 parts of Corydalis impatiens (Pall.) Fisch are taken by weight, add body
Long-pending to be extracted 2 times in 60 DEG C than 90% ethanol, for the first time plus 8 times are measured volumes, are extracted 3 hours, second plus 8 times of amount volumes, extract 2
Hour, filter, be concentrated under reduced pressure into 50 DEG C of survey relative density 1.20-1.25 after filtrate recycling ethanol again, add 4 times and measure volumes
Water, obtain alcohol aqueous suspension；The parts by weight of bear gall powder 10.5 are taken, are added to after being dissolved in water in foregoing alcohol aqueous suspension, stir 25 points
Clock, 24 hours are stood, filtration, filtrate decompression concentration, spray drying, produced；
2) eye drops is prepared：2.5 parts of borneols are taken by weight, and adding 7.5 parts of ethanol of volume ratio 95% makes dissolving, adds 7.5
Part solubilizer, filters to obtain borneol solution for standby；The extract containing bear gall powder of 146 parts by weight is added to 2500 times and measures volume
In water for injection, stirring and dissolving, water hypostasis solution is filtered to obtain；Above-mentioned borneol solution is taken to be added in water hypostasis solution, side edged
Stirring, the water for injection of 2000 times of amount volumes is added, then 40 parts of boraxs of addition, 10 parts of boric acid and 1.5 parts are antibacterial into solution
Agent, it is stirred to dissolve, injects water to 5000 times of amount volumes, mix, filtration, produce；
Described times amount volume refers to the corresponding relation of weight and volume, and unit is ml/g or L/kg.
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| CN1709419A (en) * | 2005-06-13 | 2005-12-21 | 北京正大绿洲医药科技有限公司 | Basis-reinforcing eyesight-improving dropping pill for treating eye disease and its preparing method |
| CN103185768A (en) * | 2011-12-31 | 2013-07-03 | 山东阿如拉药物研究开发有限公司 | Quality detection method for traditional Chinese medicine preparation for strengthening foundation and improving eyesight |
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| CN1709419A (en) * | 2005-06-13 | 2005-12-21 | 北京正大绿洲医药科技有限公司 | Basis-reinforcing eyesight-improving dropping pill for treating eye disease and its preparing method |
| CN103185768A (en) * | 2011-12-31 | 2013-07-03 | 山东阿如拉药物研究开发有限公司 | Quality detection method for traditional Chinese medicine preparation for strengthening foundation and improving eyesight |
Non-Patent Citations (1)
| Title |
|---|
| SS熊胆眼药水刺激性研究;刘天强等;《亚太传统医药》;20090630;第5卷(第6期);第22-25页 * |
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