CN115804752A - Preparation method of eye drops containing digitoxin - Google Patents
Preparation method of eye drops containing digitoxin Download PDFInfo
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- CN115804752A CN115804752A CN202310071088.5A CN202310071088A CN115804752A CN 115804752 A CN115804752 A CN 115804752A CN 202310071088 A CN202310071088 A CN 202310071088A CN 115804752 A CN115804752 A CN 115804752A
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Abstract
The invention relates to a preparation method of eye drops containing digitoxin, which comprises the following steps: step one, putting 20g of boric acid and 0.1g of esculetin into 500ml of water for injection, stirring for 5 minutes at room temperature to dissolve, then adding a liquid digitalis leaf extract, stirring for 5 minutes at room temperature to dissolve, adjusting the pH value of the solution to 5.5-6.5 by using sodium hydroxide, stirring for 5 minutes, and adding purified water to 1000ml; step two, sterile filtration and filling; the eye drop containing digitonin has the packaging specification of 0.4ml, namely 0.006mg of digitonin and 0.040mg of esculetin.
Description
Technical Field
The invention relates to preparation of a medicinal preparation, in particular to a preparation method of a novel eye drop containing digitoxin.
Background
Eye drops containing digitoxin are marketed drugs, and have the following general names: the esculin and digitalisglycosides eye drops comprise the following components: every 10ml contains digitoxin 0.15mg, esculetin 1.0mg, and adjuvants including boric acid and purified water, and has indications of fundus macular degeneration and asthenopia, specification of 0.4ml comprises digitoxin 0.006mg, esculetin 0.040mg.
Wherein the Digitalis glycosides (English name: digitalis glycosides) is extract of Digitalis leaves, contains more than 20 kinds of cardiac glycosides, is mainly prepared by condensing 3 kinds of different cardiac aglycone-Digitalis aglycone, hydroxyl Digitalis aglycone, and Digitalis logarithm aglycone with different sugar, and can be dissolved in water as extract of Digitalis leaves for ophthalmic use.
The digitalis leaf extract sold in the market at present comprises an aqueous extract and an alcohol extract, and the content is 20-60 percent (weight percentage) calculated by digitalis glycoside.
Esculetin is a coumarin compound extracted from dry branch bark or dry bark of Fraxinus rhynchophylla Hance of Oleaceae, is white crystalline powder at room temperature, and can be prepared by synthesis method with chemical name: 6- (. Beta. -D-glucopyranosyloxy) -7-hydroxy-2H-1-benzofuran-2-one, chemical name in English: 6- (beta-D-glucopyranosyloxy) -7-hydroxy-2H-1-benzopyran-2-one. Other names for esculetin include: castanoside, esculin, aesculin, esculin, bicolorin, crataegin, enallachrome, escorsyl, escletin 6-beta-D-glucoside, and Escloline.
Solubility of esculetin: can be dissolved in hot water, hot ethanol, acetic acid, methanol, pyridine and chloroform, and is slightly soluble in cold water and ethanol. Very slightly dissolved in ether.
The prior art reports about the preparation method of eye drops prepared from digitalis extract and esculetin, such as: chinese patent CN200510030723.7 example 3 and Chinese patent CN200610147972.9 example 19, both of which were dosed with a dried extract of Digitalis purpurea, wherein the extract was derived from an organic layer such as chloroform, ethyl acetate, etc.
Chinese patent CN200910242110.8 example 2 discloses the preparation and use of a digitalis extract, wherein the extract is derived from an aqueous layer, and CN200910090337.5 the digitalis extract prepared in comparative example 2 is derived from an aqueous layer.
In the prior art, all the components of the extract contain digitonin, but the content and the components are different due to different extraction methods, and the digitalis leaf extract contains components with low water solubility, so that the dried digitalis extract is difficult to dissolve in water, the operation difficulty in the eye drop preparation process is increased, the stability of the obtained eye drop aqueous solution preparation is poor, the storage time is short, and the precipitation or color change of the solution occurs during long-time or low-temperature storage, so that the production of the medicine is difficult.
Disclosure of Invention
Compared with the prior art, the invention utilizes the characteristic that the digitalis leaf extract is slightly soluble in water, adopts liquid digitalis leaf extract for feeding, greatly improves the dissolving speed, improves the preparation efficiency, and also has the unexpected discovery that the stability of the eye drops is greatly improved and the medicine quality is improved.
The preparation method comprises the following steps:
step one, putting 20g of boric acid and 0.1g of esculetin into 500ml of water for injection, stirring for 5 minutes at room temperature to dissolve, then adding a liquid digitalis leaf extract, stirring for 5 minutes at room temperature to dissolve, adjusting the pH value of the solution to 5.5-6.5 by using sodium hydroxide, stirring for 5 minutes, and adding purified water to 1000ml;
filtering the liquid medicine into a sterile storage tank, then filling into a unit dose container made of polyethylene particles under the protection of nitrogen, and sealing and packaging to obtain the polyethylene composition; wherein the eye drop containing digitonin has a packaging specification of 0.4ml, containing digitonin 0.006mg, and containing esculetin 0.04mg.
Wherein the unit dose container made of polyethylene particles is a disposable container with a capacity of 0.4 ml.
The invention discovers that boric acid and esculetin which can be dissolved only by heating are firstly put into water to be stirred, esculetin can be quickly dissolved without heating (boric acid has a dissolving assisting effect), and the liquid digitalis leaf extract prepared by the method can be added after the boric acid and the esculetin are dissolved, so that the two medicines can be quickly dissolved without heating, the operation is accelerated, the efficiency is improved, and the product is more stable.
The invention further discovers that the nitrogen is introduced in the filling process, so that the oxidation reaction can be prevented, the formula composition of the invention is simpler and safer, and no other additives are needed.
The key point of the invention is that the liquid digitalis leaf extract is prepared by the following method,
1) Adding 90% (V/V) ethanol solution 300ml into 100g folium Digitalis Purpureae coarse powder, reflux extracting at 80 deg.C for 60 min for three times, mixing extractive solutions, recovering ethanol from extractive solution, concentrating, centrifuging, and filtering to obtain solid containing digitonin;
2) Dispersing the solid with 150ml water, extracting with equal volume of chloroform for three times, mixing chloroform layers, washing chloroform solution with 1L 2% (W/W) NaOH solution, separating chloroform layer, washing chloroform layer with water until water layer is neutral, separating chloroform layer, collecting all water layers and NaOH solution layer, mixing, and concentrating to obtain 100ml concentrate containing digitonin;
3) The concentrate containing digitoxin is dissolved in 100ml50% acetone aqueous solution, extracted twice with equal volume of ethyl acetate, and separated to obtain water layer containing digitoxin at concentration of 1.36mg/10ml by HPLC.
The liquid digitalis leaf extract is prepared by utilizing the characteristics that part of digitalis glycoside is dissolved in water and part of digitalis glycoside is slightly soluble in water, and the liquid digitalis leaf extract is added, so that the dissolving speed is greatly improved, the preparation efficiency is improved, and in addition, the unexpected discovery is also realized, the stability of the obtained eye drops is also greatly improved, and the medicine quality is improved.
The invention discovers that the solubility of glycosides depends on the molecular structure, the polarity is generally large, the more glycosyl groups, the greater the water solubility; if the aglycone is macromolecular or low polar and the glycosyl is less, the water solubility is poor. The invention utilizes the characteristic to obtain the digitalis leaf extract which is soluble in water and is suitable for preparing eye drops through the improvement of an extraction method.
The digitalis leaf extract obtained by the method is a compound digitalis glycoside extract, contains a plurality of components, the main component is water-soluble, but part of the digitalis leaf extract is amphiphilic, namely the extract is soluble in water and can be dissolved in an organic solvent, so that the extract is a component which can be dissolved in water. In the process of the invention, step 1) is a 90% ethanol extraction followed by removal of the ethanol to give a product dissolved in water and drying to give a solid which contains water soluble and amphiphilic components but is predominantly water soluble. And 2) extracting by using chloroform, wherein the purpose of removing fat-soluble components in the solid in the previous step is to wash a chloroform layer by using an alkaline aqueous solution so as to retain effective components to the maximum extent and avoid taking away a small amount of amphiphilic components from the chloroform to remove the amphiphilic components completely, and finally, all water layers in the step are collected together and concentrated, wherein the main components are water-soluble, but some are amphiphilic components. Step 3) dissolving the concentrate of the previous step with an aqueous solution of acetone is not problematic because the components therein are both water-soluble and amphiphilic, extraction with ethyl acetate is carried out in order to remove the amphiphilic fraction thereof which is more prone to lipid solubility, making the product more readily soluble in water, and the resulting aqueous layer is the product of the present invention, in which the digitonin content is 1.36mg/10ml.
The invention is treated by the above, especially the concentrate of step 3) is dissolved by 100ml of 50% acetone aqueous solution, extracted twice by equal volume of ethyl acetate, the ethyl acetate layer is separated to obtain the aqueous layer containing the extract of digitalis leaf, in order to remove the amphipathic component which is more inclined to fat solubility in the aqueous layer, the product is more easily dissolved in water, the aqueous layer can be directly used as raw material to feed after detecting and adjusting the concentration, for liquid preparation, the feeding method can solve all problems caused by insolubility of digitalis glycoside which is insoluble material in the preparation process, overcome the defects of the prior art, and obtain unexpected technical effects. The method of the invention is superior to the prior art in the aspects of material dissolution speed and product stability.
Drawings
FIG. 1 is a HPLC chromatogram of a liquid extract of Digitalis purpurea according to the present invention.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
The eye drop formula containing digitoxin comprises the following components:
esculetin 0.1g
Adding liquid extract of folium Digitalis Purpureae (added amount is calculated according to digitonin) 15mg
Boric acid 20g
Proper amount of sodium hydroxide
Purified water was added to 1000ml.
The preparation method comprises the following steps:
step one, putting 20g of boric acid and 0.1g of esculetin into 500ml of water for injection, stirring for 5 minutes at room temperature to dissolve, then adding a liquid digitalis leaf extract (the addition amount is 0.015g according to the digitalis glycoside), stirring for 5 minutes at room temperature to dissolve, adjusting the pH value of the solution to 5.5-6.5 by using sodium hydroxide, stirring for 5 minutes, and adding purified water to 1000ml;
filtering the liquid medicine into a sterile storage tank, then filling into a unit dose container made of polyethylene particles under the protection of nitrogen, and sealing and packaging to obtain the polyethylene composition;
wherein the eye drop containing digitonin has a package size of 0.4ml, contains digitonin 0.006mg, and esculetin 0.04mg.
Wherein the unit dose container made of the polyethylene particles is a disposable container with a capacity of 0.5 ml.
The preparation method of the liquid digitalis leaf extract comprises the following steps:
1) Adding 90% (V/V) ethanol solution 300ml into 100g folium Digitalis Purpureae coarse powder, reflux extracting at 80 deg.C for 60 min for three times, mixing extractive solutions, recovering ethanol from extractive solution, concentrating, centrifuging, and filtering to obtain solid containing digitonin;
2) Dispersing the solid with 150ml water, extracting with equal volume of chloroform for three times, mixing chloroform layers, washing chloroform solution with 1L 2% (W/W) NaOH solution, separating chloroform layer, washing chloroform layer with water until water layer is neutral, separating chloroform layer, collecting all water layers and NaOH solution layer, mixing, and concentrating to obtain 100ml concentrate containing digitonin;
3) The concentrate containing digitoxin is dissolved in 100ml of 50% acetone aqueous solution, extracted twice with equal volume of ethyl acetate, separated to obtain an aqueous layer containing digitoxin, and the aqueous layer is detected by HPLC, wherein the concentration of digitoxin is 1.36mg/10ml.
The content determination of digitonin in the liquid digitonin leaf extract belongs to the prior art, and can be detected by adopting a method in Chinese patent CN 200610147972.9.
Example 2
The liquid digitalis leaf extract HPLC chromatogram adopts a chromatographic column (200 mm multiplied by 4.6mm,5 mu m) with octadecylsilane chemically bonded silica as a filler; water-acetonitrile is used as a mobile phase (the volume ratio of water to acetonitrile is 1: 1); the flow rate is 1ml/min; the detection wavelength is 220nm. 20 mu l of the liquid digitalis leaf extract is taken and detected under the chromatographic conditions, and the obtained chromatogram is shown in figure 1.
Comparative example:
preparation of dried digitalis leaf extract:
1) Adding 90% ethanol solution 300ml into 100g of folium Digitalis Purpureae coarse powder, reflux extracting at 80 deg.C for 60 min for three times, mixing extractive solutions, recovering ethanol from the obtained extractive solution, and centrifuging and filtering the concentrated solution to obtain solid.
2) Dispersing the solid with 150ml water, extracting with equal volume of chloroform for three times, mixing chloroform layers, washing the chloroform solution with 1L 2% (W/W) NaOH solution, separating chloroform layer, washing chloroform layer with water until water layer is neutral, separating chloroform layer, mixing water layer and NaOH solution layer, and concentrating to obtain 100ml concentrate;
3) Drying the concentrate to obtain dried folium Digitalis Purpureae extract 51.2mg, and content determination shows that the dried folium Digitalis Purpureae extract contains digitonin 20.4mg.
The preparation method for preparing the eye drops containing the digitoxin by adopting the dried digitoxin leaf extract comprises the following steps:
1) Step one, putting 20g of boric acid and 0.1g of esculetin into 500ml of water for injection, then adding 15mg of dried digitalis leaf extract, heating to 40 ℃, stirring for 30 minutes to dissolve, adjusting the pH value of the solution to 5.5-6.5 by using sodium hydroxide, stirring, and adding purified water to 1000ml.
2) Filtering the liquid medicine into a sterile storage tank, then filling into a unit dose container made of polyethylene particles under the protection of nitrogen, and sealing and packaging to obtain the polyethylene composition;
wherein the eye drop containing digitonin has a package size of 0.4ml, contains digitonin 0.006mg, and esculetin 0.04mg.
Examples of the experiments
The beneficial effects of the present invention are further illustrated by experimental data below.
1. Solubility test
The experiment adopts the following method for feeding, 20g of boric acid and 0.1g of esculetin are added into 500ml of water for injection, and then 0.015g of digitalis leaf extract is added;
the feeding method adopts the same method, and the digitonin is prepared by the following different methods:
1) A Digitalis purpurea leaf extract batch was prepared by the method of the present invention, example 1
2) Chinese patent CN2005100307237 example preparation example 1 method for preparing digitalis leaf extract feed
3) Chinese patent CN200610147972.9 example 15 method for preparing digitalis leaf extract feed
4) Comparative example method of the invention preparation of a Digitalis purpurea leaf extract feed
After observing the material prepared by different methods, the material dissolution time under the condition of stirring at room temperature is shown in the following table:
TABLE 1 dissolution time Table
2. Stability survey
According to the packaging specification of 0.4ml, the eye drops containing digitoxin is prepared from 0.006mg of digitoxin and 0.04mg of esculetin by the following four methods:
1) The extract of Digitalis purpurea leaf was prepared and eye drops were prepared by the method of the present invention example 1
2) Chinese patent CN2005100307237 the method of preparation example 1 is used to prepare digitalis leaf extract, and the method of preparation example 3 is used to prepare eye drops
3) Chinese patent CN200610147972.9 extract of Digitalis purpurea prepared by the method of example 15, and eye drop prepared by the method of example 19
4) Comparative example method of the present invention preparation of Digitalis purpurea leaf extract and eye drops
The method of the invention in example 2 was used for the determination of the content.
Experiment 1, accelerated stability experiment at 45 ℃ for 90 days, the results are shown in the following table:
TABLE 2 high temperature accelerated stability table
Experiment 2, 90 days irradiation accelerated stability experiment under 4500LX conditions, the results are given in the following table:
TABLE 3 table of light accelerated stability
3. Animal experiments:
the effect of eye drops containing digitoxin prepared in the embodiment 1 of the invention on experimental macular degeneration of rats
The experimental method comprises establishing macular degeneration rat model by sodium iodate tail vein injection, randomly dividing the modeled rats into 2 groups, each group containing 10 rats, which are physiological saline group and eye drop group containing digitoxin. The normal group 10 animals were normally bred, and on day 1 after molding, the normal saline and the eye drops containing digitoxin were respectively dropped into the eyes for 3 times/day, the administration time was respectively 9, 00, 12, and 15, the total administration time was 10 days, and the animals were treated 10 days later, and the pathological tissues of the retina were observed and examined.
The fixing, dehydrating, embedding and sectioning methods of pathological tissues comprise the following steps:
(1) Material taking: quickly picking up eyeballs after rats are anesthetized, and carefully removing redundant muscle and conjunctival tissues;
(2) Fixing:
1) Pre-fixing in 4% PFA solution for 20min after performing anterior chamber puncture;
2) The cornea was cut along the limbus, the anterior segment and part of the vitreous body were removed, and the remaining tissue was again placed in 4% PFA solution and fixed at 4 ℃ for 24h;
(3) And (3) dehydrating: removing the PFA solution, placing the tissue in an EP tube filled with 30% sucrose solution for dehydration, and finishing the dehydration when the tissue is immersed into the bottom of the tube;
(4) Embedding: discarding the sucrose solution, placing the tissue in an embedding box filled with an O.C.T embedding medium, placing the long axis direction of the optic nerve in parallel with the long edge of the embedding box, and slowly freezing the tissue by using liquid nitrogen after placing the position; after the tissue is completely frozen, the tissue is stored in a refrigerator at-80 ℃.
(5) Slicing: taking out the tissue block from-80 deg.C refrigerator, and balancing in-20 deg.C refrigerator for 30min. Cutting into 8 μm sections along the long axis direction of optic nerve of eyeball by using a freezing microtome, collecting 2-3 samples from each section by using a clean anti-dropping glass slide when the optic nerve of the tissue is observed, airing at room temperature, adding O.C.T, placing the sections into a glass staining jar filled with acetone after the O.C.T is dried, and fixing for 15min; drying and storing at-20 deg.C.
Staining the slices by a TUNEL method, air-drying, and storing in a refrigerator at-20 ℃ in a dark place; observing by using a fluorescence inverted microscope on the next day, respectively exciting by using ultraviolet light and green light, randomly selecting 3 slices in each group, randomly selecting 5 fields for shooting by each slice, respectively counting the number of apoptosis positive cells and the total number of cells in each field, and calculating the apoptosis rate (%) = the number of apoptosis positive cells/the total number of cells in the same field multiplied by 100%.
TUNEL assay for retinal apoptosis results:
at 10 days, a large number of uniformly condensed or crescent apoptotic cells were observed in the retinal pigment epithelium and outer nuclear layer of the model control group, and the difference was statistically significant (P < 0.05) compared with the normal group. Compared with the model control group, the eye drop group containing digitoxin has reduced apoptosis of retinal pigment epithelium layer and outer nuclear layer (P is less than 0.05).
TABLE 4 comparison of% apoptosis rate of retinal cells in groups of rats 10 days after administration
Note, including: the difference was statistically significant (P) compared to the normal group<0.05)。 & : the differences were statistically significant (P) compared to the model groups<0.05)。
The conclusion is that the eye drops containing digitoxin has protective effect on retina of experimental dry AMD rat, can improve retina cell function and pathological tissue damage, and can inhibit apoptosis of macular degeneration retina cell of experimental rat.
Claims (2)
1. A preparation method of eye drops containing digitoxin is characterized by comprising the following steps:
step one, putting 20g of boric acid and 0.1g of esculetin into 500ml of water for injection, stirring for 5 minutes at room temperature to dissolve, then adding a liquid digitalis leaf extract, stirring for 5 minutes at room temperature to dissolve, adjusting the pH value of the solution to 5.5-6.5 by using sodium hydroxide, stirring for 5 minutes, and adding purified water to 1000ml;
filtering the liquid medicine into a sterile storage tank, then filling into a unit dose container made of polyethylene particles under the protection of nitrogen, and sealing and packaging to obtain the polyethylene composition; the preparation method of the liquid digitalis leaf extract comprises the following steps:
1) Taking 100g of digitalis leaf coarse powder, adding 300ml of 90% ethanol solution, carrying out reflux extraction for 60 minutes at 80 ℃, extracting for three times in total, mixing extracting solutions, recovering ethanol from the extracting solutions, concentrating, and carrying out centrifugal filtration to obtain a solid containing digitalis glycoside;
2) Dispersing the solid with 150ml water, extracting with equal volume of chloroform for three times, mixing chloroform layers, washing chloroform solution with 1L 2% NaOH solution, separating chloroform layer, washing chloroform layer with water until water layer is neutral, separating chloroform layer, collecting all water layers and NaOH solution layer, mixing, and concentrating to obtain 100ml concentrate containing digitoxin;
3) The concentrate containing digitoxin is dissolved in 100ml50% acetone aqueous solution, extracted twice with equal volume of ethyl acetate, and separated to obtain water layer containing digitoxin at concentration of 1.36mg/10ml by HPLC.
2. The process according to claim 1, wherein the ophthalmic solution containing digitoxin has a package size of 0.4ml, 0.006mg of digitoxin and 0.04mg of esculetin.
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|---|---|---|---|---|
| CN1954855A (en) * | 2005-10-26 | 2007-05-02 | 信谊药厂 | Eye preparation containing sodium hyaluronate for treating fundus macular degeneration and its preparation method |
| CN101209312A (en) * | 2006-12-26 | 2008-07-02 | 信谊药厂 | Digitalis extract and preparation thereof |
| CN101623377A (en) * | 2009-08-05 | 2010-01-13 | 锦州奥鸿药业有限责任公司 | Digitalis extract as well as preparation method and application thereof |
| CN101874848A (en) * | 2009-12-08 | 2010-11-03 | 于洪儒 | Digitalis extract, preparation method and application thereof |
| WO2022268048A1 (en) * | 2021-06-22 | 2022-12-29 | Nanjing Nutrabuilding Bio-Tech Co., Ltd | Use of l-ergothioneine for alleviating and preventing age-related visual degeneration |
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2023
- 2023-02-07 CN CN202310071088.5A patent/CN115804752B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1954855A (en) * | 2005-10-26 | 2007-05-02 | 信谊药厂 | Eye preparation containing sodium hyaluronate for treating fundus macular degeneration and its preparation method |
| CN101209312A (en) * | 2006-12-26 | 2008-07-02 | 信谊药厂 | Digitalis extract and preparation thereof |
| CN101623377A (en) * | 2009-08-05 | 2010-01-13 | 锦州奥鸿药业有限责任公司 | Digitalis extract as well as preparation method and application thereof |
| CN101874848A (en) * | 2009-12-08 | 2010-11-03 | 于洪儒 | Digitalis extract, preparation method and application thereof |
| WO2022268048A1 (en) * | 2021-06-22 | 2022-12-29 | Nanjing Nutrabuilding Bio-Tech Co., Ltd | Use of l-ergothioneine for alleviating and preventing age-related visual degeneration |
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| 高敏: "七叶洋地黄双苷滴眼液治疗LASIK术后早期视疲劳的临床疗效分析" * |
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