CN114246826A - Preservative-free low-irritation single-dose packaged diquafosol sodium eye drops and preparation method thereof - Google Patents
Preservative-free low-irritation single-dose packaged diquafosol sodium eye drops and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to preservative-free low-irritation single-dose packaged diquafosol sodium eye drops and a preparation method thereof. The invention provides diquafosol sodium single-dose eye drops, which are composed of the following substances in 100 mL: the composition comprises diquafosol tetrasodium serving as an active ingredient, an isotonic regulator, a buffering agent, a pH regulator diluted hydrochloric acid or sodium hydroxide for regulating the pH value of the composition to 7.2-7.8, and the balance of water for injection.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to preservative-free low-irritation single-dose packaged diquafosol sodium eye drops and a preparation method thereof.
Background
The global incidence of dry eye is 5.5% to 33.7%. Dry eye is a chronic, progressive disease, a multifactorial ocular surface disease characterized primarily by an imbalance in tear film homeostasis with accompanying symptoms of ocular discomfort. Therapeutic approaches to dry eye include patient education, physical therapy, drug therapy, and surgical intervention where necessary.
The therapeutic agent for dry eye mainly comprises artificial tears and skinA steroid hormone, a non-steroidal anti-inflammatory drug, and an immunosuppressive agent. In recent years, P2Y2Receptor agonists are gaining increasing attention. Diquafosol tetrasodium (DQS) at 3% concentration is a P2Y2Receptor agonists by activating P2Y in conjunctival epithelial cells2The receptor makes the maintenance of the tear film independent of the lacrimal gland, but the conjunctiva spontaneously secretes tears and mucin, and improves the stability of the tear film and the hydration of the ocular surface.
The 3% DQS eye drops have good treatment effect in the treatment of mild and moderate dry eyes, and serious adverse reactions of eyes and the whole body caused by DQS are not found. Adverse reactions of dry eye patients using 3% DQS eye drops are mostly mild. Adverse reactions of 3% DQS eye drops include localized foreign body sensation, lacrimation, increased secretion, conjunctival congestion, edema, ocular pain, blepharitis, etc. The adverse reactions of half of patients disappear after 1 week of continuous use of the DQS eye drops, and the adverse reactions of most patients disappear after 1 month. So far, no systemic adverse reaction caused by 3% DQS eye drops is found. No obvious changes are found in eye examination such as slit lamp examination, intraocular pressure, fundus examination, optimal corrected vision and the like.
The literature: lee JH, 2017, 21(2):189-195 reports that in combination with the previous research results on benzalkonium chloride cytotoxicity, the 3% DQS eye drops can cause cytopathy of corneal epithelial cells through an ex vivo experiment, and the DQS eye drops are considered to be possibly related to benzalkonium chloride serving as a preservative in the preparation.
Benzalkonium chloride is the most widely used bacteriostatic agent at present, and is reported in the Clin Ophthalmol, 2016, 10: 331-336, and more than 70% of ophthalmic preparations take benzalkonium chloride as the bacteriostatic agent. Bacteriostatic agents such as benzalkonium chloride damage the tear film and ocular epithelial cells, and this damaging effect is increased with the increase of the administration time, and in patients with glaucoma and dry eye, who need to be administered for a long time, there is a possibility that "secondary" damage may be caused to their ocular tissues by using bacteriostatic agent-containing eye drops (document: Expert Rev opthalmol, 2009, 4 (1): 59-64).
Japanese market Diquas is 5ml multi-dose package, the specification states that the additives of the eye drops are sodium hydrogen phosphate hydrate (buffer), EDTA-2Na (stabilizer), sodium chloride and potassium chloride (isotonic agent) and chlorhexidine gluconate (preservative). The diquafosol sodium eye drops imported from China (trade name: Lieisi) are packaged in 5ml of multi-dose packages, and the additives described in the specification are sodium hydrogen phosphate hydrate (buffer), sodium chloride, potassium chloride (isotonic agent) and benzalkonium chloride (preservative).
In reports of prior art documents, patent document CN108403625 of Dongguan medical stone discloses diquafosol sodium eye drops containing a chelating agent, and the technology to be solved is the precipitation problem in the diquafosol sodium eye drops; patent document CN1228053 by shentian pharmaceutical corporation discloses eye drops containing uridine phosphate, and the solution is to use benzalkonium chloride as an antiseptic at an effective concentration; patent document CN103282039 of shentian pharmaceutical company discloses eye drops containing diquafosol and a method for producing the same, and aims to suppress the generation of insoluble precipitates in eye drops by using an analog such as EDTA-2Na as a chelating agent. Patent document CN108853016A of Guangzhou Daguan optical pharmacy discloses diquafosol sodium eye drops and a preparation method thereof, and solves the problem of irritation caused by benzalkonium chloride or chlorhexidine gluconate serving as a preservative by using a chitosan macromolecular compound as a partial thickening agent and also serving as a bacteriostatic agent and using boric acid as a pH regulator and also serving as a bactericide and borax to form a buffer pair and isotonic system.
Disclosure of Invention
The invention aims to solve the problems that the multidose diquafosol sodium eye drops containing the preservative have certain potential safety hazards and the like, and provides a novel single-dose diquafosol sodium eye drop containing no preservative and a preparation method thereof, which can avoid the secondary pollution of microorganisms and the toxic and side effects of the preservative on eyes during the use process of the multidose eye drops.
The invention provides diquafosol sodium single-dose eye drops, which are composed of the following substances in 100 mL: the composition comprises diquafosol tetrasodium serving as an active ingredient, an isotonic regulator, a buffering agent, a pH regulator diluted hydrochloric acid or sodium hydroxide for regulating the pH value of the composition to 7.2-7.8, and the balance of water for injection.
Specifically, the eye drops comprise the following components:
wherein the isotonicity adjusting agent is selected from: sodium chloride and/or potassium chloride, and/or sodium chloride,
wherein the buffer is selected from: one or more of anhydrous disodium hydrogen phosphate, dihydrate disodium hydrogen phosphate, heptahydrate disodium hydrogen phosphate, and dodecahydrate disodium hydrogen phosphate.
The active ingredient of the single-dose eye drops can be diquafosol tetrasodium anhydride or a hydrate of the diquafosol tetrasodium, such as diquafosol tetrasodium tetrahydrate and/or octahydrate. The dosage of the compound is 30mg/ml based on diquafosol tetrasodium anhydride.
The isoosmotic adjusting agent 1 is selected from sodium chloride. The dosage is preferably 2.0-9.0 mg/ml, more preferably 4.0-4.5 mg/ml, and most preferably 4.1mg/ml, based on anhydrous sodium chloride.
The isoosmotic adjusting agent 2 is selected from potassium chloride. The dosage is preferably 1.0 to 3.0mg/ml, more preferably 1.0 to 2.0mg/ml, and most preferably 1.5mg/ml, based on potassium chloride anhydride.
The buffer is selected from disodium hydrogen phosphate anhydride, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate heptahydrate, and disodium hydrogen phosphate dodecahydrate is most preferable. The dosage of the disodium hydrogen phosphate dodecahydrate is preferably 1.0-5.0 mg/ml, more preferably 1.5-2.5 mg/ml, and most preferably 2.0 mg/ml. The pH regulator is selected from dilute hydrochloric acid or sodium hydroxide.
The concentration of the hydrochloric acid is 0.1 mol/L.
The concentration of the sodium hydroxide is 0.1 mol/L.
The eye drops are independently packaged in a single dose, the volume range of the independently packaged container is 0.3-1.0 mL/piece, the preferable single dose packaging specification is 0.4 mL/piece, 0.5 mL/piece and 0.9 mL/piece, and the more preferable single dose packaging specification is 0.4 mL/piece.
Preferably, the eye drops comprise the following components:
more preferably, the eye drops of the present invention comprise the following components:
the invention also provides a preparation method of the diquafosol sodium single-dose eye drops.
The preparation method comprises the following steps:
A. putting injection water with the amount of about 40-80% of the prescription amount into a concentration tank, opening a freezing water jacket of the concentration tank, cooling the injection water to 30 +/-5 ℃, sequentially adding the isotonic regulator sodium chloride and potassium chloride with the amount of the prescription amount and the buffering agent disodium hydrogen phosphate dodecahydrate into the concentration tank, and stirring for dissolving; then adding the active ingredient diquafosol tetrasodium in the prescription amount, and stirring for dissolving; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
B. filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
C. cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
D. filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
E. filling the liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing to obtain the finished product.
The invention has the beneficial effects that: the diquafosol sodium single-dose eye drops provided by the invention do not contain preservatives, so that potential risks and toxic and side effects on eyes caused by the preservatives are avoided, the aseptic operation filling process is adopted, the aseptic requirements of products are guaranteed, and safer and more reliable diquafosol sodium eye drops are provided for patients.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples are intended to illustrate certain preferred embodiments of the invention and are not intended to limit the scope of the invention.
The starting materials used in the reference examples and in examples 1 to 3 were all produced in the same batch by the prior art process.
Example 1
Prescription
Preparation process
A. 140Kg of injection water with the prescription amount of about 70 percent is put into a concentration tank, a freezing water jacket of the concentration tank is opened, the injection water is cooled to 30 +/-5 ℃, 820g of isotonic regulator sodium chloride and 300g of potassium chloride with the prescription amount and 400g of disodium hydrogen phosphate dodecahydrate as a buffering agent with the prescription amount are sequentially added into the concentration tank, and the mixture is stirred and dissolved; then 6000g of diquafosol tetrasodium serving as an active ingredient in a prescription amount is added, and the mixture is stirred and dissolved; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
B. filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
C. cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
D. filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
E. filling liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing;
F. carrying out leak detection on the semi-finished product according to requirements;
G. and (5) performing lamp inspection on the sample subjected to leak detection, and detecting visible foreign matters. And packaging, inspecting and warehousing the samples qualified by lamp inspection.
Example 2
Prescription
Preparation process
A. Adding 175Kg of injection water with the prescription amount of about 70 percent into a concentration tank, opening a freezing water jacket of the concentration tank, cooling the injection water to 30 +/-5 ℃, sequentially adding 1025g of isotonic regulator sodium chloride and 375g of potassium chloride with the prescription amount and 500g of disodium hydrogen phosphate dodecahydrate as a buffering agent with the prescription amount into the concentration tank, and stirring for dissolving; then 7500g of diquafosol tetrasodium of the active ingredient with the prescription amount is added, stirred and dissolved; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
B. filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
C. cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
D. filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
E. filling liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing;
F. carrying out leak detection on the semi-finished product according to requirements;
G. and (5) performing lamp inspection on the sample subjected to leak detection, and detecting visible foreign matters. And packaging, inspecting and warehousing the samples qualified by lamp inspection.
Example 3
Prescription
Preparation process
A. 315Kg of injection water with the prescription amount of about 70 percent is put into a concentration tank, a freezing water jacket of the concentration tank is opened, the injection water is cooled to 30 +/-5 ℃, the isotonicity regulator of the prescription amount of sodium chloride 1845g and potassium chloride 675g and the buffering agent of disodium hydrogen phosphate dodecahydrate of the prescription amount of 900g are sequentially added into the concentration tank, and the mixture is stirred and dissolved; then 13500g of diquafosol tetrasodium serving as an active ingredient in a prescription amount is added, and the mixture is stirred and dissolved; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
B. filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
C. cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
D. filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
E. filling liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing;
F. carrying out leak detection on the semi-finished product according to requirements;
G. and (5) performing lamp inspection on the sample subjected to leak detection, and detecting visible foreign matters. And packaging, inspecting and warehousing the samples qualified by lamp inspection.
Example 4 irritation test
Referring to relevant regulations in the technical guidance principle of research on irritation, allergy and hemolysis of chemical drugs, the rabbit eye irritation test is carried out by adopting a one-time administration method and a multi-time administration method in the experiment.
Examination before administration
Both eyes of each animal were examined for 1% sodium fluorescein 24h before the test, and animals with eye irritation symptoms, corneal defects, and conjunctival lesions were not used for the test.
One-time administration method
Taking 20 healthy and normal New Zealand rabbits with two eyes, half each of the males and the females, and 2.0-2.5 kg of body weight, randomly dividing the rabbits into 2 groups, and 10 rabbits each group. 0.2mL of Lieishi preparation obtained in example 1 and China was added to the left eyelid and 0.2mL of physiological saline was added to the right eye at the same time as a control. The cornea, conjunctiva, iris and secretion were observed for 1h, 24h, 48h and 72h, respectively, and as a result, no irritation reaction such as congestion, lacrimation, photophobia, edema and secretion increase was observed in the group of example 1. The change of the cornea and the iris is checked by adopting a handheld slit lamp, and no abnormity is found. The Lieishi group had 4 rabbit eyes with partial hyperemia and lacrimation.
Multiple administration method
Taking 20 healthy and normal New Zealand rabbits with two eyes, half each of the males and the females, and 2.0-2.5 kg of body weight, randomly dividing the rabbits into 2 groups, and 10 rabbits each group. The eyes were examined by dropping 0.2mL of the solution to the left eye and physiological saline to the right eye each time, qid, continuously dropping for 14 days, 1h, 24h, 48h and 72h before and after the last administration of the preparation Lieisi in example 1 and the preparation marketed in China, and the local reaction condition every day was recorded, so that no abnormality was found in the left and right eyes of the example group. The Leeishi group had 5 rabbit eyes with partial hyperemia, lacrimation and increased secretions.
The result shows that the eye drops of the invention have no special stimulation response to rabbit eyes. Is obviously superior to the Lieishi group.
Example 540 ℃ (RH < 25%) expedites the review
The samples obtained in example 1, example 2 and example 3, DIQUAS, a product sold in Japan, and Lieishi, a product sold in China, were allowed to stand for 3 months under 40 ℃ (RH < 25%), and samples were taken at 0 day and 3 months to measure the properties, color and clarity of the solution, osmotic pressure, pH, related substances and contents thereof.
TABLE 1 test results of samples for 0 day
TABLE 2 sample 40 deg.C (RH < 25%) 3 month test results
The results show that the stability of the diquafosol sodium eye drops provided by the invention is not inferior to that of the Japanese preparation DIQUAS and the Chinese preparation Lieisi.
The invention has been described herein with reference to certain embodiments. However, the present invention should not be considered as limited thereto, as variations thereof will become apparent to those skilled in the art in light of the disclosure set forth herein. All patents, patent applications, and references cited are incorporated herein by reference in their entirety.
Claims (9)
1. An eye drop containing diquafosol sodium is characterized by comprising the following components:
the rest is the water for injection,
wherein the isotonicity adjusting agent is selected from: sodium chloride and/or potassium chloride, and/or sodium chloride,
wherein the buffer is selected from: one or more of anhydrous disodium hydrogen phosphate, dihydrate disodium hydrogen phosphate, heptahydrate disodium hydrogen phosphate, and dodecahydrate disodium hydrogen phosphate.
2. An ophthalmic solution according to claim 1 wherein the isotonicity adjusting agent is selected from the group consisting of: sodium chloride and potassium chloride, and the like,
wherein the dosage is preferably 2.0-9.0 mg/ml, more preferably 4.0-4.5 mg/ml, most preferably 4.1mg/ml based on anhydrous sodium chloride,
the dosage is preferably 1.0-3.0 mg/ml, more preferably 1.0-2.0 mg/ml, and most preferably 1.5mg/ml based on potassium chloride anhydride.
3. An ophthalmic solution according to claim 1 wherein the buffering agent is present in an amount of 1.5 to 2.5mg/ml, most preferably 2.0mg/ml, based on disodium hydrogen phosphate dodecahydrate.
4. An ophthalmic solution as claimed in claim 1 wherein the pH adjusting agent is selected from dilute hydrochloric acid or sodium hydroxide.
5. An ophthalmic solution according to claim 1, wherein the diquafosol tetrasodium is diquafosol tetrasodium anhydride or a hydrate of diquafosol tetrasodium.
6. An ophthalmic solution according to claim 1, consisting of:
7. an ophthalmic solution according to claim 1, consisting of:
8. a method for producing an ophthalmic solution according to claim 1, which comprises the steps of:
putting injection water with the amount of about 40-80% of the prescription amount into a concentration tank, opening a freezing water jacket of the concentration tank, cooling the injection water to 30 +/-5 ℃, sequentially adding the isotonic regulator sodium chloride and potassium chloride with the amount of the prescription amount and the buffering agent disodium hydrogen phosphate dodecahydrate into the concentration tank, and stirring for dissolving; then adding the active ingredient diquafosol tetrasodium in the prescription amount, and stirring for dissolving; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
filling the liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing to obtain the finished product.
9. A process for the preparation of an ophthalmic solution as claimed in claim 1, which comprises the steps of:
preparation process
A. 140Kg of injection water with the prescription amount of about 70 percent is put into a concentration tank, a freezing water jacket of the concentration tank is opened, the injection water is cooled to 30 +/-5 ℃, 820g of isotonic regulator sodium chloride and 300g of potassium chloride with the prescription amount and 400g of disodium hydrogen phosphate dodecahydrate as a buffering agent with the prescription amount are sequentially added into the concentration tank, and the mixture is stirred and dissolved; then 6000g of diquafosol tetrasodium serving as an active ingredient in a prescription amount is added, and the mixture is stirred and dissolved; adding 0.1mol/L hydrochloric acid or sodium hydroxide as a pH regulator to regulate the pH of the liquid medicine to 7.2-7.8, and continuously stirring for about 15 min;
B. filtering the liquid medicine in the concentration tank to a dilution tank by a 0.45um polyethersulfone or 0.45um polyvinylidene fluoride filter element, wherein the filtering pressure is less than 0.16 Mpa;
C. cooling the liquid medicine in the diluting preparation tank to 30 +/-5 ℃ of injection water to fix the volume to the prescription amount, and then stirring for about 20 min; sampling to detect the properties, visible foreign matters, pH and content of the intermediate;
D. filtering the liquid medicine in the diluting preparation tank to a buffer tank before filling through a redundant 0.22um polyether sulfone or 0.22um polyvinylidene fluoride filter element;
E. filling liquid medicine into a single-dose packaging container on a blowing, filling and sealing three-in-one filling machine under the A/B level environment, and sealing;
F. carrying out leak detection on the semi-finished product according to requirements;
G. and (4) performing lamp inspection on the sample subjected to leak detection, inspecting visible foreign matters, packaging, inspecting and warehousing the sample qualified by the lamp inspection.
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| CN202011004289.6A CN114246826A (en) | 2020-09-23 | 2020-09-23 | Preservative-free low-irritation single-dose packaged diquafosol sodium eye drops and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117838628A (en) * | 2024-03-01 | 2024-04-09 | 广州市桐晖药业有限公司 | Diquafosol sodium eye drops and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105232452A (en) * | 2015-10-28 | 2016-01-13 | 广东三蓝药业股份有限公司 | Bacteriostat-free ofloxacin eye drops and preparation process thereof |
| CN108853016A (en) * | 2018-09-26 | 2018-11-23 | 广州大光制药有限公司 | A kind of ophthalmic solution sodium eye drops and preparation method thereof |
-
2020
- 2020-09-23 CN CN202011004289.6A patent/CN114246826A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105232452A (en) * | 2015-10-28 | 2016-01-13 | 广东三蓝药业股份有限公司 | Bacteriostat-free ofloxacin eye drops and preparation process thereof |
| CN108853016A (en) * | 2018-09-26 | 2018-11-23 | 广州大光制药有限公司 | A kind of ophthalmic solution sodium eye drops and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| IKHYUN JUN ET AL: "Effects of Preservative-free 3% Diquafosol in Patients with Preexisting Dry Eye Disease after Cataract Surgery: A Randomized Clinical Trial" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117838628A (en) * | 2024-03-01 | 2024-04-09 | 广州市桐晖药业有限公司 | Diquafosol sodium eye drops and preparation method thereof |
| CN117838628B (en) * | 2024-03-01 | 2024-05-28 | 广州市桐晖药业有限公司 | Diquafosol sodium eye drops and preparation method thereof |
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