Patent Publication Number: US-2021169779-A1

Title: Ophthalmic drug preparation and uses thereof

Description:
TECHNICAL FIELD 
     The present disclosure belongs to a pharmaceutical technology, and particularly relates to a pharmaceutical preparation for preventing and treating eye fatigue, eye dryness and distending pain and eye angiosclerosis as well as application thereof. 
     BACKGROUND ART 
     With the progress of society, the smooth communication of the Internet as well as the popularization and wide application of paperless office and screen products such as smartphones and televisions, the work, study and lifestyles of people have changed, and staring at a screen has become a basic habit. If staring at a flickering screen at short distance for a long time, eye ciliary muscle contracts for a long time without relaxing, which easily causes diseases such as eye dryness, distending pain, asthenopia and eye angiosclerosis, damaging the eyes and vision. 
     Panax notoginseng is sweet and slightly bitter in taste, and warm in nature, and has the effects of activating blood circulation to dissipate blood stasis, eliminating swelling, relieving pain, and stopping bleeding and healing. Modern science has proven that the panax notoginseng contains ginsenoside and notoginsenoside components, and thus can obviously shorten bleeding and blood coagulation time and have a good effect of stopping bleeding; can promote division growth and number increasing of various blood cells, promote proliferation and release processes of bone marrow cells, increase the number and activity of bone marrow erythrocytes, and thus achieve a function of promoting hematopoiesis; can significantly inhibit formation of aortic intimal plaques of experimental atherosclerosis rabbits; can excite nervous centralis, improve mental and physical power, and thus shows fatigue resistance; can significantly improve the phagocytic ratio and phagocytic index of macrophages of mice, increase the sum of leukocytes in peripheral blood, and reduce the movement index of the leukocytes; can obviously inhibit all of increasing of capillary permeability, inflammatory exudation, tissue edema, leukocyte migration as well as late granulation tissue hyperplasia caused by acute inflammations; and can reduce lipid peroxides in an organism, and thus has an anti-aging effect. Various pharmacological activities of the panax notoginseng are used for treatment of various cardiovascular and cerebrovascular diseases. An extract of the panax notoginseng is made into drugs such as “Xuesaitong”, “Guanxinning” and “Xueshuantong” on the market. The effect of activating blood circulation to dissipate blood stasis of the panax notoginseng is also widely applied to traumatic injury drugs, so that strain muscle tissues are recovered. However, there has been no panax notoginseng product for eye ciliary muscle fatigue, asthenopia and other eye problems on the market. 
     Many Chinese patents for asthenopia are disclosed, many of which use the panax notoginseng for component preparation. For example, the patent CN103099977B discloses the invention of “Externally Used Ophthalmic Drug Composition and Use of Externally Used Ophthalmic Drug Composition in Application of Treatment of Uveitis”, and the composition is prepared into an eye drop from a pimecrolimus eye drop, a panax notoginseng ginsenoside Rb1, a fructus forsythiae extract aqueous solution and a herba imperatae extract aqueous solution, which is used for ophthalmic treatment of uveitis. The patent CN103520548B discloses the invention of “Asthenopia Improving Pharmaceutical Composition and Preparation Method thereof”, and the composition is prepared into an oral preparation prepared from fructus lycii, semen cassiae, radix morindae officinalis, radix glycyrrhizae, radix notoginseng, radix puerariae, herba lophatheri, fructus citri sarcodactylis and the like, which is used as a drug for relieving asthenopia. The patent application CN102960713A discloses the invention of “Health Care Product for Controlling Screen Contamination”, and the composition is prepared into an oral preparation from phaseolus calcaratus, dictyophora phalloidea, pseudo-ginseng, American ginseng, pork liver, Chinese anisopappus flowers, cortex moutan, radix rehmanniae, fructus lycii, poria cocos, fructus crataegi, selenium-rich green tea, radix astragali, and fructus mori is used for eliminating contamination to a human body by various electronic products, and preventing and treating damages to eyes, hematopoiesis, and nervous and immune systems of the human body caused by electronic screens, etc. Currently, there are no pharmaceutical preparations for preventing and treating eye fatigue, eye dryness and distending pain and eye angiosclerosis by using notoginsenosides as well as new dosage forms thereof. 
     SUMMARY OF THE INVENTION 
     The present disclosure is directed to provide an ophthalmic pharmaceutical preparation for preventing and treating asthenopia, eye dryness and distending pain, and eye angiosclerosis as well as a preparation method and application thereof. 
     In order to realize the above objectives of the present disclosure, the present disclosure provides the following technical solutions. 
     Provided is an ophthalmic pharmaceutical preparation, an effective component of the ophthalmic pharmaceutical preparation is a notoginsenoside extract. The notoginsenoside extract is prepared and extracted from panax notoginseng. 
     The notoginsenoside extract contains the following components with a total content of 45 to 95%: a notoginsenoside R1, a notoginsenoside R2, a ginsenoside Rg1, a ginsenoside Rg2, a ginsenoside Re, a ginsenoside Rb1, a ginsenoside Rb2, a ginsenoside Rd, a ginsenoside Rf, a ginsenoside Rc, a ginsenoside Rh1 and a gypenoside IX. 
     Further preferably, the notoginsenoside extract contains the following components with a total content of 75 to 90%: the notoginsenoside R1, the ginsenoside Rg1, the ginsenoside Re, the ginsenoside Rb1 and the ginsenoside Rd. 
     Further, in the notoginsenoside extract, a content of the notoginsenoside R1 (C 47 H 80 O 18 ) is equal to or greater than 3.0%. A content of the ginsenoside Rg1 (C 42 H 72 O 14 ) is equal to or greater than 15.0%. A content of the ginsenoside Re (C 48 H 82 O 18 ) is equal to or greater than 1.0%. A content of the ginsenoside Rb1 (C 54 H 92 O 23 ) is equal to or greater than 20.0%. A content of the ginsenoside Rd (C 48 H 82 O 19 ) is equal to or greater than 2.5%. 
     Furthermore, in the notoginsenoside extract, the content of the notoginsenoside R1 (C 47 H 80 O 18 ) is equal to or greater than 5.0%. The content of the ginsenoside Rg1 (C 42 H 72 O 14 ) is equal to or greater than 25.0%. The content of the ginsenoside Re (C 48 H 82 O 18 ) is equal to or greater than 2.5%. The content of the ginsenoside Rb1 (C 54 H 92 O 23 ) is equal to or greater than 30.0%. The content of the ginsenoside Rd (C 48 H 82 O 19 ) is equal to or greater than 5%. 
     As a preferred solution, a weight percentage content of the notoginsenoside extract in the pharmaceutical preparation is 0.1 to 30%. 
     Further, the weight percentage content of the notoginsenoside extract in the pharmaceutical preparation is 0.2 to 10%. 
     Dosage forms of the preparation are collyria, eye drops, eye ointments or eye pads. The pads may be prepared by immersing or loading the prepared eye drops and eye ointments onto thin film materials. 
     As another preferred solution, the notoginsenoside extract in the pharmaceutical preparation is the only effective component, and the pharmaceutical preparation is prepared from 0.1 to 30% by weight of the notoginsenoside extract and 70 to 99.9% by weight of a pharmaceutically acceptable carrier and/or excipient. Further, the pharmaceutical preparation is prepared from 0.2 to 10% by weight of the notoginsenoside extract and 90 to 99.8% by weight of the pharmaceutically acceptable carrier and/or excipient. 
     The pharmaceutically acceptable carrier is selected from one or more of water, normal saline, vaseline, liquid paraffin, lanolin and glycerine. 
     As yet another preferred solution, for the pharmaceutical preparation, the effective component, the notoginsenoside extract, is added into artificial tears or various eye drop drugs with a therapeutical effect. The artificial tears are known to those of skill in the art, and may be composed of one or more of anhydroglucose-70, polyethylene glycol 400, a sodium carboxymethylcellulose eye drop, vitamin A, carbomer sorbic acid, sodium hyaluronate, polyvinyl alcohol, etc. 
     The various eye drop drugs with the therapeutical effect are purchased from the market. 
     Application of the above pharmaceutical preparation to preparation of drugs for preventing and treating asthenopia, eye dryness and distending pain, and eye angiosclerosis is also within the protection scope of the present disclosure. 
     Beneficial Effects: the present disclosure applies functions of activating blood circulation to dissipate blood stasis, eliminating swelling and relieving pain of the panax notoginseng, and is made into the dosage forms special for eye disease medication, and pharmacological experiments prove that the drug is safe and effective without stimulation, and has a curative effect on damages to eyes and vision caused by eye dryness, distending pain, asthenopia, eye angiosclerosis and the like, thereby having a better clinical application prospect. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present application is illustrated in detail below in combination with specific embodiments. 
     Embodiment 1 
     Preparation of Notoginsenoside Extract 1 
     20 kilograms of panax notoginseng are weighed, crushed into coarse powder through a wet method, and subjected to reflux extraction 3 times with 60% ethanol at weight ratios of 1:10, 1:8 and 1:8 respectively, 3 hours each time. An extracting solution is collected and filtered. A filtrate is taken to recycle the ethanol till no alcohol taste exists. Water is added to prepare a solution containing 0.5 to 1.0 g of a crude drug per 1 ml. The solution is loaded onto a macroporous adsorption resin column, and eluted with water and 70% to 90% ethanol liquid respectively. An 80% ethanol eluant is collected, concentrated and dried to obtain the notoginsenoside extract. 
     As determined with a total panax notoginseng saponins content determination method in Chinese Pharmacopoeia (I), the contents of all components are as follows: a content of a notoginsenoside R1 (C 47 H 80 O 18 ) is 6.2%, a content of a ginsenoside Rg1 (C 42 H 72 O 14 ) is 28.4%, a content of a ginsenoside Re (C 48 H 82 O 18 ) is 3.1%, a content of a ginsenoside Rb1 (C 54 H 92 O 23 ) is 32.7%, and a content of a ginsenoside Rd (C 48 H 82 O 19 ) is 5.8%. 
     Embodiment 2 
     Preparation of Notoginsenoside Extract 2 
     20 kilograms of radix notoginseng are weighed, crushed into coarse powder through a wet method, and subjected to reflux extraction 3 times with 70% ethanol at weight ratios of 1:10, 1:8 and 1:8 respectively, 3 hours each time. An extracting solution is collected and filtered. A filtrate is taken to recycle the ethanol till no alcohol taste exists. Water is added to prepare a solution containing 0.5 to 1.0 g of a crude drug per 1 ml. The solution is loaded onto a macroporous adsorption resin column, and eluted with water and 70% to 90% ethanol liquid respectively. An 80% ethanol eluant is collected, concentrated and dried to obtain the notoginsenoside extract. 
     As determined with a total panax notoginseng saponins content determination method in Chinese Pharmacopoeia (I), the contents of all components are as follows: a content of a notoginsenoside R1 (C 47 H 80 O 18 ) is 8.3%, a content of a ginsenoside Rg1 (C 42 H 72 O 14 ) is 31.4%, a content of a ginsenoside Re (C 48 H 82 O 18 ) is 7.1%, a content of a ginsenoside Rb1 (C 54 H 92 O 23 ) is 34.7%, and a content of a ginsenoside Rd (C 48 H 82 O 19 ) is 6.8%. 
     Embodiment 3 
     Preparation of Notoginsenoside Extract 3 
     20 kilograms of panax notoginseng are weighed, crushed into coarse powder through a wet method, and subjected to reflux extraction 3 times with 80% ethanol at weight ratios of 1:10, 1:8 and 1:8 respectively, 3 hours each time. An extracting solution is collected and filtered. A filtrate is taken to recycle the ethanol till no alcohol taste exists. Water is added to prepare a solution containing 0.5 to 1.0 g of a crude drug per 1 ml. The solution is loaded onto a macroporous adsorption resin column, and eluted with water and 70% to 90% ethanol liquid respectively. An 80% ethanol eluant is collected, concentrated and dried to obtain the notoginsenoside extract. 
     As determined with a total panax notoginseng saponins content determination in Chinese Pharmacopoeia (I), the contents of all components are as follows: a content of a notoginsenoside R1 (C 47 H 80 O 18 ) is 5.5%, a content of a ginsenoside Rg1 (C 42 H 72 O 14 ) is 31.9%, a content of a ginsenoside Re (C 48 H 82 O 18 ) is 4.2%, a content of a ginsenoside Rb1 (C 54 H 92 O 23 ) is 34.9%, and a content of a ginsenoside Rd (C 48 H 82 O 19 ) is 6.2%. 
     Embodiment 4 
     Notoginsenoside Eye Drop 
     100 g of the notoginsenoside extract prepared in Embodiment 1 is taken to be dissolved in 300 ml of normal saline. 0.3 g of activated carbon is added. A mixed solution is stirred, filtered after still standing for 8 hours, and finely filtered with a 0.22 μm film. A mixed solution is diluted to reach a constant volume of 1000 ml, sealed, sterilized at a high temperature and subpackaged into eye drop bottles, 1 ml per bottle, to obtain 1000 bottles of eye drops. 
     Embodiment 5 
     Notoginsenoside Eye Pad 
     The eye drop prepared in Embodiment 4 is taken to infiltrate 100 square centimeters of a non-woven fabric to obtain the notoginsenoside eye pad. 
     Embodiment 6 
     Notoginsenoside Eye Ointment 
     Medical yellow vaseline, glycerine and lanolin are taken and evenly mixed at a proportion of 8:2:1 to prepare an eye ointment matrix. 30 g of the notoginsenoside extract prepared in Embodiment 1 is added into 3000 g of the matrix, and evenly mixed to obtain the notoginsenoside eye ointment. The notoginsenoside eye ointment is subpackaged in a sterile state, 3 g per bottle, to obtain 1000 bottles. 
     Embodiment 7 
     Notoginsenoside Hydrogel 
     30 g of 2% carbomer gel, 5 g of glycerine, 0.5 g of hyaluronic acid and 45 g of purified water are taken and evenly mixed. Then 20 g of the notoginsenoside extract prepared in Embodiment 1 and 0.1 g of ethylparaben are added and evenly stirred by a homogenizer. Vacuum debubbling and bottling are conducted to obtain the notoginsenoside hydrogel. 
     Embodiment 8 
     Notoginsenoside Artificial Tears 
     20 g of a sterile solution containing 50 mg of a notoginsenoside per ml is added into 80 g of a sterile solution containing 15 mg of polyvinyl alcohol per ml and evenly mixed and filtered to obtain the notoginsenoside artificial tears. 
     Embodiment 9 
     20.0 g of the notoginsenoside extract prepared in Embodiment 1 is weighed precisely. 980.0 g of purified water is added to prepare a solution with a concentration of 2% to obtain an eye drop. Then non-woven fabrics are infiltrated with the solution and then pasted to eye rims, which may relieve eye fatigue and sour and distending feelings of eyes. 
     Embodiment 10 
     The eye drop prepared in Embodiment 9 is taken and mixed with artificial tears at 1:1, and is then dripped into eyes, which can eliminate discomfort caused by eye dryness and distending pain and eye angiosclerosis. The artificial tears are composed of one or more of anhydroglucose-70, polyethylene glycol 400, a sodium carboxymethyl cellulose eye drop, vitamin A, carbomer sorbic acid, sodium hyaluronate, polyvinyl alcohol, etc. 
     Embodiment 11 
     The eye drop prepared in Embodiment 9 is taken and mixed with a commercially available eye drop at 1:1, and is then dripped into eyes, which can also eliminate discomfort caused by eye dryness and distending pain and eye angiosclerosis when treating various phlegm syndrome diseases of the eyes. 
     Embodiment 12 
     Asthenopia Relieving Drug Stimulation Experiment 1 
     The notoginsenoside extract prepared in Embodiment 1 is pipetted precisely. Purified water is added to prepare different concentration gradients of solutions to obtain experimental eye drops. 
     1. Grouping: the right eye of each rabbit is dosed with the experimental eye drops (according to the concentration gradients), and the left eye of each rabbit is dosed with equivalent normal saline. 
     Dosage Way: lower eyelids are pulled gently, and dosed with 30 μl of the experimental eye drops by a pipette, and then eyes are closed for five seconds. 
     Stimulation Dosage Frequency: nine times a day, and dosage once every 1 hour. 
     Dosage is conducted for one day totally. 1 hour after last dosage, observation is conducted. Observation results are recorded. 
     Grouping Standards: A total of 8 rabbits are grouped into a group A and a group B at random with 4 rabbits in each group, and four different concentrations are set in each group for experiments. Stimulation experiments and pharmacological experiments are conducted synchronously, and both are: right eyes are dosed with the experimental eye drops, and left eyes are dosed with the equivalent normal saline as control. Observed data are based on left eye control. For scoring standards, reference is made to a Draize scoring table. Observation results are shown in Table (1). 
     
       
         
           
               
            
               
                   
               
               
                 Rabbit Stimulation Experiment Scoring Table (1) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 A1 right 
                 A2 right 
                 A3 right 
                 A4 right 
                 B1 right 
                 B2 right 
                 B3 right 
                 B4 right 
               
               
                   
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
               
               
                   
               
               
                 Concen- 
                 10% 
                 5% 
                 2.5% 
                 1.25% 
                 10% 
                 5% 
                 2.5% 
                 1.25% 
               
               
                 trations 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Situa- 
                 Upper 
                 Upper 
                 Slight 
                 No eye 
                 Slight 
                 Eyelid 
                 Slight 
                 No eye 
               
               
                 tions 
                 eyelid 
                 eyelid 
                 eyelid 
                 edema; 
                 upper 
                 edema; 
                 eyelid 
                 edema; 
               
               
                   
                 edema; 
                 edema; a 
                 edema; 
                 faint 
                 eyelid 
                 and a 
                 edema; a 
                 few faint 
               
               
                   
                 faint 
                 small 
                 colloidal 
                 yellow 
                 edema; 
                 small 
                 small 
                 yellow 
               
               
                   
                 yellow 
                 number of 
                 secretions; 
                 secretions; 
                 and faint 
                 number of 
                 number of 
                 waxy 
               
               
                   
                 colloidal 
                 faint 
                 and 
                 and a 
                 yellow 
                 faint 
                 white 
                 secretions; 
               
               
                   
                 secretions; 
                 yellow 
                 blood 
                 small 
                 colloidal 
                 yellow 
                 secretions; 
                 and a 
               
               
                   
                 and 
                 colloidal 
                 streaks at 
                 number of  
                 secretions. 
                 colloidal 
                 and a 
                 small 
               
               
                   
                 cornea 
                 secretions; 
                 the 
                 blood 
                   
                 secretions. 
                 small 
                 number of 
               
               
                   
                 bottom 
                 and 
                 corneas 
                 streaks at 
                   
                   
                 number of 
                 blood 
               
               
                   
                 color 
                 blood 
                 and 
                 the 
                   
                   
                 blood 
                 streaks at 
               
               
                   
                 deepening. 
                 streaks at 
                 eyelids. 
                 corneas. 
                   
                   
                 streaks at 
                 the 
               
               
                   
                   
                 the 
                   
                   
                   
                   
                 the 
                 corneas. 
               
               
                   
                   
                 corneas. 
                   
                   
                   
                   
                 corneas. 
                   
               
               
                 Scores 
                 4 
                 3 
                 3 
                 2 
                 3 
                 2 
                 3 
                 2 
               
               
                   
               
               
                 Note: 
               
               
                 all records in the table are the left eye situations in comparison with right eye blank controls, and the scores of 3 or below are considered as no stimulation. 
               
            
           
         
       
     
     2. After the rabbits are recovered completely, the concentration gradients are changed. The stimulation experiments are repeated once according to the above processes. Observation results are shown in Table (2). 
     
       
         
           
               
            
               
                   
               
               
                 Rabbit Stimulation Experiment Scoring Table (2) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 A1 right 
                 A2 right 
                 A3 right 
                 A4 right 
                 B1 right 
                 B2 right 
                 B3 right 
                 B4 right 
               
               
                   
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
               
               
                   
               
               
                 Concen- 
                 2% 
                 1.5% 
                 0.8% 
                 1.25% 
                 2% 
                 1.5% 
                 0.8% 
                 1.25% 
               
               
                 trations 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Situa- 
                 Being 
                 No eye 
                 No eye 
                 No eye 
                 No eye 
                 Being 
                 No eye 
                 Being 
               
               
                 tions 
                 consistent 
                 edema; 
                 edema; 
                 edema; a 
                 edema; 
                 consistent 
                 edema; 
                 consistent 
               
               
                   
                 with the 
                 and a 
                 colloidal 
                 small 
                 colloidal 
                 with the 
                 and a 
                 with the 
               
               
                   
                 left eye. 
                 small 
                 secretions; 
                 number of 
                 secretions; 
                 left eye. 
                 small 
                 left eye. 
               
               
                   
                   
                 number of 
                 and a 
                 faint 
                 and a 
                   
                 number of 
                   
               
               
                   
                   
                 blood 
                 small 
                 yellow 
                 small 
                   
                 blood 
                   
               
               
                   
                   
                 streaks at 
                 number of 
                 secretions; 
                 number of 
                   
                 streaks at 
                   
               
               
                   
                   
                 the 
                 blood 
                 and a 
                 blood 
                   
                 the 
                   
               
               
                   
                   
                 corneas. 
                 streaks at 
                 small 
                 streaks at 
                   
                 corneas. 
                   
               
               
                   
                   
                   
                 the 
                 number of 
                 the 
                   
                   
                   
               
               
                   
                   
                   
                 corneas. 
                 blood 
                 corneas. 
                   
                   
                   
               
               
                   
                   
                   
                   
                 streaks at 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 the 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 corneas. 
                   
                   
                   
                   
               
               
                 Scores 
                 0 
                 1 
                 2 
                 2 
                 2 
                 0 
                 1 
                 0 
               
               
                   
               
            
           
         
       
     
     Asthenopia Relieving Drug Stimulation Experiment 2 
     Dosage Concentration: 1.25%. 
     Grouping: the right eye of each rabbit is dosed with the experimental eye drops, and the left eye of each rabbit is dosed with equivalent normal saline. 
     Dosage Way: lower eyelids are pulled gently, and dosed with 30 μl of the experimental eye drops by a pipette, and then eyes are closed for five seconds. 
     Stimulation Dosage Frequency: nine times a day, and dosage once every 1 hour. 
     Dosage is conducted for five days totally. 1 hour after last dosage every day, observation is conducted. Observation results are shown in Table (3). 
     
       
         
           
               
            
               
                   
               
               
                 Rabbit Stimulation Experiment Scoring Table (3) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 A1 right 
                 A2 right 
                 A3 right 
                 A4 right 
                 B1 right 
                 B2 right 
                 B3 right 
                 B4 right 
               
               
                   
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
                 eye 
               
               
                   
               
               
                 First day 
                 No eye 
                 Being 
                 No eye 
                 No eye 
                 No eye 
                 A small 
                 No eye 
                 Being 
               
               
                   
                 edema; 
                 consistent 
                 edema; 
                 edema; 
                 edema; 
                 number 
                 edema; 
                 consistent 
               
               
                   
                 and a 
                 with the 
                 and a 
                 and a 
                 and 
                 of 
                 and a 
                 with the 
               
               
                   
                 small 
                 left eye. 
                 small 
                 small 
                 colloidal 
                 colloidal 
                 small 
                 left eye. 
               
               
                   
                 number 
                   
                 number 
                 number 
                 secretions. 
                 secretions. 
                 number 
                   
               
               
                   
                 of blood 
                   
                 of blood 
                 of faint 
                   
                   
                 of blood 
                   
               
               
                   
                 streaks at 
                   
                 streaks at 
                 yellow 
                   
                   
                 streaks at 
                   
               
               
                   
                 the 
                   
                 the 
                 secretions. 
                   
                   
                 the 
                   
               
               
                   
                 corneas. 
                   
                 corneas. 
                   
                   
                   
                 corneas. 
                   
               
               
                 Scores 
                 1 
                 0 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
               
               
                 Second 
                 No eye 
                 Being 
                 No eye 
                 No eye 
                 No eye 
                 A small 
                 No eye 
                 Being 
               
               
                 day 
                 edema; 
                 consistent 
                 edema; 
                 edema; 
                 edema; 
                 number 
                 edema; 
                 consistent 
               
               
                   
                 and a 
                 with the 
                 and a 
                 and a 
                 and 
                 of 
                 and a 
                 with the 
               
               
                   
                 small 
                 left eye. 
                 small 
                 small 
                 colloidal 
                 colloidal 
                 small 
                 left eye. 
               
               
                   
                 number 
                   
                 number 
                 number 
                 secretions. 
                 secretions. 
                 number 
                   
               
               
                   
                 of blood 
                   
                 of blood 
                 of faint 
                   
                   
                 of blood 
                   
               
               
                   
                 streaks at 
                   
                 streaks at 
                 yellow 
                   
                   
                 streaks at 
                   
               
               
                   
                 the 
                   
                 the 
                 secretions. 
                   
                   
                 the 
                   
               
               
                   
                 corneas. 
                   
                 corneas. 
                   
                   
                   
                 corneas. 
                   
               
               
                 Scores 
                 1 
                 0 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
               
               
                 Third 
                 No eye 
                 Being 
                 No eye 
                 No eye 
                 No eye 
                 Being 
                 No eye 
                 Being 
               
               
                 day 
                 edema; 
                 consistent 
                 edema; 
                 edema; 
                 edema; 
                 consistent 
                 edema; 
                 consistent 
               
               
                   
                 and a 
                 with the 
                 and a 
                 and a 
                 and faint 
                 with the 
                 and a 
                 with the 
               
               
                   
                 small 
                 left eye. 
                 small 
                 small 
                 yellow 
                 left eye. 
                 small 
                 left eye. 
               
               
                   
                 number 
                   
                 number 
                 number 
                 colloidal 
                   
                 number 
                   
               
               
                   
                 of blood 
                   
                 of blood 
                 of faint 
                 secretions. 
                   
                 of blood 
                   
               
               
                   
                 streaks at 
                   
                 streaks at 
                 yellow 
                   
                   
                 streaks at 
                   
               
               
                   
                 the 
                   
                 the 
                 secretions. 
                   
                   
                 the 
                   
               
               
                   
                 corneas. 
                   
                 corneas. 
                   
                   
                   
                 corneas. 
                   
               
               
                 Scores 
                 1 
                 0 
                 1 
                 1 
                 1 
                 0 
                 1 
                 0 
               
               
                 Fourth 
                 No eye 
                 Slight 
                 No eye 
                 No eye 
                 No eye 
                 Being 
                 No eye 
                 Being 
               
               
                 day 
                 edema; 
                 eyelid 
                 edema; 
                 edema; 
                 edema; 
                 consistent 
                 edema; 
                 consistent 
               
               
                   
                 and a 
                 edema. 
                 and a 
                 and a 
                 and faint 
                 with the 
                 faint 
                 with the 
               
               
                   
                 small 
                   
                 small 
                 small 
                 yellow 
                 left eye. 
                 yellow 
                 left eye. 
               
               
                   
                 number 
                   
                 number 
                 number 
                 colloidal 
                   
                 secretions; 
                   
               
               
                   
                 of blood 
                   
                 of blood 
                 of faint 
                 secretions. 
                   
                 and a 
                   
               
               
                   
                 streaks at 
                   
                 streaks at 
                 yellow 
                   
                   
                 small 
                   
               
               
                   
                 the 
                   
                 the 
                 secretions. 
                   
                   
                 number 
                   
               
               
                   
                 corneas. 
                   
                 corneas. 
                   
                   
                   
                 of blood 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 streaks at 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 the 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 corneas. 
                   
               
               
                 Scores 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
                 2 
                 0 
               
               
                 Fifth day 
                 No eye 
                 Being 
                 No eye 
                 No eye 
                 No eye 
                 Being 
                 No eye 
                 Being 
               
               
                   
                 edema; 
                 consistent 
                 edema; 
                 edema; a 
                 edema; 
                 consistent 
                 edema; 
                 consistent 
               
               
                   
                 and a 
                 with the 
                 and a 
                 small 
                 and a 
                 with the 
                 faint 
                 with the 
               
               
                   
                 small 
                 left eye. 
                 small 
                 number 
                 small 
                 left eye. 
                 yellow 
                 left eye. 
               
               
                   
                 number 
                   
                 number 
                 of faint 
                 number 
                   
                 secretions; 
                   
               
               
                   
                 of blood 
                   
                 of blood 
                 yellow 
                 of blood 
                   
                 and a 
                   
               
               
                   
                 streaks at 
                   
                 streaks at 
                 secretions; 
                 streaks at 
                   
                 small 
                   
               
               
                   
                 the 
                   
                 the 
                 and a 
                 the 
                   
                 number 
                   
               
               
                   
                 corneas. 
                   
                 corneas. 
                 small 
                 corneas. 
                   
                 of blood 
                   
               
               
                   
                   
                   
                   
                 number 
                   
                   
                 streaks at 
                   
               
               
                   
                   
                   
                   
                 of blood 
                   
                   
                 the 
                   
               
               
                   
                   
                   
                   
                 streaks at 
                   
                   
                 corneas. 
                   
               
               
                   
                   
                   
                   
                 the 
                   
                   
                   
                   
               
               
                   
                   
                   
                   
                 corneas. 
                   
                   
                   
                   
               
               
                 Scores 
                 1 
                 0 
                 1 
                 2 
                 1 
                 0 
                 2 
                 0 
               
               
                   
               
            
           
         
       
     
     Results of the above stimulation experiments show that the notoginsenoside eye drop drug is safe for rabbit eyes, and has no toxic and stimulation effects. 
     Embodiment 13 
     Asthenopia Relieving Pathological Experiment 1 
     I. Materials and Methods: 
     (1) Experimental Animals and Grouping: 7 New Zealand rabbits are divided into 3 groups, 2 of the rabbits (numbers A and B) are in a normal group with five eyeballs in total, for the remaining 5 rabbits (numbers C, D, E, F and G), the left eyes are dosed with normal saline and used as a model group, and right eyes are dosed with a total panax notoginseng saponin eye drop and used as a dosage group. 
     (2) Experimental Materials: Rose Bengal, the total panax notoginseng saponin extract, and the normal saline. 
     (3) Submission Organs: rabbit eyeball HE slices (if submission samples are the left eyes, L is added behind their numbers, and if submission samples are the right eyes, R is added behind their numbers, for example, AL refers to the left eye of the rabbit A). 
     (4) Checking Method: the rabbits in the model group and the dosage group are injected with 5 ml of the 5% Rose Bengal at ear veins, a tropicamide eye drop is taken as a mydriatic eye drop, a procaine eye drop is taken as a local anesthetic, a green laser (532 nm) irradiates the eyes for modeling, and the normal group is not treated. The dosage group uses the 1.25% total panax notoginseng saponin eye drop (dissolved with the normal saline) for eye dropping for 1 week, once a day, 35 ul each time, and the model group is dosed with the normal saline in parallel. After the experiments are completed, the eyeballs are anatomised. After fixation, parts that we need are got. The parts are dehydrated, embedded with paraffin, and sliced up (4 μm thick). Slices are subjected to HE staining. Each part of retinas is observed under an optical microscope to check whether there are lesions or not and check types and degrees of the lesions. According to the degrees of the lesions, the lesions are sequentially semi-quantified to be slight (0.5 score), mild (1 score), moderate (2 scores), and serious (3 scores), and no negative lesion tissue (0 score). 
     Asthenopia Relieving Pathological Experiment 2 
     Experimental Animals and Grouping the Same as Experiment 1 
     (1) 4 normal eyeballs are clear in structures of all layers and have no obvious lesion. A retina under an optical microscope is composed of 10 layers of structures: sequentially from inside to outside, (1) an internal limiting membrane, which is extremely thin and has no cell; (2) a nerve fiber layer, which consists of non-medullated axons of ganglion cells and is narrow and lamellar; (3) a ganglion cell layer, which consists of cell bodies of the ganglion cells, wherein the cells are mutually connected and are single-layer cells; (4) an inner plexiform layer, which is composed of axons of bipolar cells and axons of the ganglion cells and has no obvious cell; (5) inner nuclear layers, which are composed of the bipolar cells connecting cone cells and rod cells and are about 4 layers; (6) an outer plexiform layer, which is formed by matching foot processes of retinal cells with dendrites of the bipolar cells mutually, and has no obvious cell; (7) outer nuclear layers, where cell nucleuses of visual cells are located, and which have about 8 to 10 layers of cells; and (8) to (10): sequentially an external limiting membrane, a visual cell layer and a retinal pigment epithelium (no pigment for rabbits). 
     (2) Model Group (5 Rabbits): 
     Retinas are clear in structures of all layers. As for nerve fiber layers, nerve fiber layers of retinas of 3 rabbits have mild edema, with symptoms that tissues are loose, and vacuoles are formed in obvious parts. As for ganglion cell layers, the number of cells of a ganglion cell layer of one rabbits is reduced, in which there are a very few karyopyknosis cells. There are a very few karyopyknosis cells in ganglion cell layers of another 2 rabbits. As for inner nuclear layers, the number of cells of inner nuclear layers of retinas of 3 rabbits is reduced slightly, and 2 rabbits have mild edema. 
     (3) Dosage Group (5 Rabbits) 
     Retinas are clear in structures of all layers, and have no obvious lesion in ganglion cell layers. As for nerve fiber layers, a nerve fiber layer of the retina of one rabbits has mild edema. As for ganglion cell layers, there are a few karyopyknosis cells in the ganglion cell layers of 3 rabbits. There is no obvious lesion in inner nuclear layers, outer nuclear layers and other layers. 
     Asthenopia Relieving Pathological Experiment 3 
     Experimental Animals and Grouping the Same as Experiment 1 
     1. In the experiment, 5% Rose Bengal is utilized to be injected into ear veins, and a laser irradiates eyes for modeling. Lesions of retinas of rabbits in a model group are mainly manifested as nerve fiber layers or inner nuclear layers edema, karyopyknosis cells, and reduced number of cells of the inner nuclear layers. 
     2. After drug application, the number of cases of the above lesions is significantly reduced, and the degrees are significantly reduced. It shows that the drug is safe and effective. 
                            Retinal Lesion Pathological Check Table                             Groups   Normal group   Model group   Dosage group                                                                         Parts   AL   AR   BL   BR   CL   DL   EL   FL   GL   CR   DR   ER   FR   GR               Internal limiting                                                               membrane                                                               Nerve fiber layer                   1   1           1               1           edema                                                               Ganglion cell                                   1                           reducing                                                               Karyopyknosis                           1   1   1       1     1   Several           cell                                                               Inner plexiform                                                               layer                                                               Inner nuclear                       1       1                               layer edema                                                               Cell reducing                   1   1           1                           Outer plexiform                                                               layer                                                               Outer nuclear                                                               layer cell                                                               reducing                                                               External limiting                                                               membrane                                                               Visual cell layer                                                                                                                     Total scores   0   2   3   1   2   4   0   1   0.5   1   0                                         Mean values                   2.4   0.5       SD                   1.1402   0                       Response rate   100%       Cure rate    79%                                     Significance                   P &lt; 0.01                    
The above experiments show that the total panax notoginseng saponin eye drop is safe for the rabbit eyes, and has a curative effect on damages to the eyes and vision caused by eye dryness, distending pain, asthenopia, eye angiosclerosis and the like.