Pearl eye-drops and preparation method thereof

Abstract

The present application relates to a kind of pearl eyesight-dropping liquid and its preparation method, by pearl liquid, borneol, glycerol sodium phosphate, poloxamer 188, ethanol, water for injection, can also contain sodium chloride and hydroxyphenyl ethyl ester, poloxamer 188, glycerol sodium phosphate, ethanol are used as the auxiliary material of pearl eyesight-dropping liquid, poloxamer 188, glycerol sodium phosphate 2 auxiliary material use, can greatly reduce the amount of ethanol in the case of completely dissolving borneol in pearl eyesight-dropping liquid, in addition, the stability of the obtained pearl eyesight-dropping liquid is also significantly improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to pearl eye-drops and a preparation method thereof. BACKGROUND

[0002] The pearl eye-drops are a clear liquid prepared from pearl liquid and borneol. The main component in the pearl hydrolysate is pearl, which has the functions of calming the heart and soothing the nerves, nourishing yin and extinguishing fire, clearing heat and phlegm, removing nebula and improving eyesight, and detoxifying and promoting tissue regeneration. The borneol has the functions of opening all orifices, dispersing stagnated fire, removing nebula and improving eyesight, and reducing swelling and relieving pain; the borneol is easily absorbed through the mucous membrane and subcutaneous tissue. The pearl eye-drops are mainly used for visual fatigue and chronic conjunctivitis, and can improve the symptoms such as eye swelling, eye itching, eye pain, eye dryness, and eye astringency that cannot last for a long time. The borneol component is a colorless transparent or white translucent flaky crisp crystal, which is easily soluble in ethanol, trichloromethane or diethyl ether, and almost insoluble in water. In the preparation process of the eye drops, ethanol or other alcohols are needed to dissolve the borneol, for example, 3-5 ml of ethanol is added to 1000 ml in the formula of Chinese application 200410067013.7, 5 ml of propylene glycol is added to 1000 ml in the formula of Chinese application 201210037634.5, and 3-6 ml of butanediol is added to 1000 ml in the formula of Chinese application 201310404998.7. However, ethanol, propylene glycol and butanediol have inhibitory effect on the central nervous system and strong stimulation effect. In addition, in the preparation process of a large amount of pearl eye-drops, the use of high-concentration ethanol, propylene glycol and butanediol requires the production workshop to have explosion-proof function, and the production cost and safety risk of the enterprise are very large. Even if ethanol is used to dissolve the borneol, the preparation process is easy to precipitate, the content of borneol in the pearl eye-drops is still low, and the content of borneol in the quality standard WS3-B-3281-98-2017 standard of the pearl eye-drops is not less than 0.2 mg per 1 ml, and the actual feeding amount is 1 mg / ml. SUMMARY

[0003] In view of the above technical problems, it is of positive significance to research a pearl eye-drops with reduced alcohol auxiliary material amount, improved dissolution amount of borneol in the preparation and high stability. The inventor has obtained a pearl eye-drops in a large number of researches on the pearl eye-drops for a long time. The eye-drops can greatly reduce the alcohol amount, have high borneol content and high quality stability, increase the safety of drug use, and are convenient to produce, which are obviously superior to the prior art.

[0004] The technical scheme provided by the application is as follows.

[0005] The pearl eye-drops are composed of pearl liquid, borneol, poloxamer 188, glycerol sodium phosphate, ethanol and water for injection.

[0006] The content of pearl liquid is 2%, borneol is 0.1%, ethanol is 0.15%, poloxamer 188 is 0.002-0.004%, and sodium glycerophosphate is 0.06-0.08%.

[0007] The inventors unexpectedly discovered through numerous experiments that by adding poloxamer 188 and sodium glycerophosphate, they could dissolve borneol in Pearl Brightening Eye Drops while significantly reducing the amount of ethanol used. During the preparation process, the borneol did not precipitate out and maintained extremely high stability.

[0008] Preferably, the content of poloxamer 188 is 0.003% and the content of sodium glycerophosphate is 0.07%.

[0009] Preferably, Pearl Brightening Eye Drops may also contain 0.05% ethylparaben and 0.8% sodium chloride.

[0010] Preferably, the specifications of Pearl Brightening Eye Drops are 8ml / vial, 10ml / vial and 15ml / vial.

[0011] This invention also provides a method for preparing pearl eye drops, comprising the following steps:

[0012] 1. Add poloxamer 188 to ethanol, stir to disperse and dissolve, to obtain the first solution;

[0013] 2. Add borneol to the first solution and stir to dissolve, thus obtaining the second solution;

[0014] 3. Dissolve sodium glycerophosphate in water for injection to obtain the third solution;

[0015] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquids, add the pearl liquid while stirring, and finally add water for injection to the total volume and stir well.

[0016] 5. After filtration and sterilization using a 0.22μm filter cartridge, the solution is filled into eye drop bottles according to specifications to obtain Pearl Brightening Eye Drops.

[0017] This invention uses poloxamer 188, sodium glycerophosphate, and ethanol as excipients for Pearl Brightening Eye Drops. The use of poloxamer 188 and sodium glycerophosphate can greatly reduce the amount of ethanol used while completely dissolving the borneol in Pearl Brightening Eye Drops, and it does not use other alcohols such as propylene glycol. The combined use of the two has unexpected effects. In particular, the combination of poloxamer 188 (0.003%) and sodium glycerophosphate (0.07%) is the most effective, significantly improving the stability of Pearl Brightening Eye Drops while dissolving the borneol in them.

[0018] The preparation method of the pearl eye drops of the present invention involves first dissolving ethanol and poloxamer 188, then adding borneol and stirring to dissolve, and finally adding the borneol solution to a sodium glycerophosphate solution and mixing. This process step plays a key role in the preparation of the pearl eye drops. Changing the operation steps will cause the borneol in the pearl eye drops to not dissolve smoothly and precipitate out during the preparation process. Detailed Implementation

[0019] To make the present invention easier to understand, specific embodiments of the present invention will be further described below. The specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention.

[0020] Example 1: Preparation of Pearl Eye Drops

[0021] Specific preparation method:

[0022] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0023] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0024] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0025] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0026] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0027] Example 2: Preparation of Pearl Eye Drops

[0028] Specific preparation method:

[0029] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0030] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0031] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0032] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0033] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 10ml increments to obtain Pearl Brightening Eye Drops.

[0034] Example 3: Preparation of Pearl Eye Drops

[0035] Specific preparation method:

[0036] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0037] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0038] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0039] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0040] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 15ml increments to obtain Pearl Brightening Eye Drops.

[0041] Example 4: Preparation of Pearl Eye Drops

[0042] Specific preparation method:

[0043] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0044] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0045] 3. Add 7g of sodium glycerophosphate and 5g of ethylparaben to 100ml of water for injection, boil and stir to dissolve, and obtain the third solution;

[0046] 4. While stirring, slowly add the second liquid to the third liquid. After the third liquid is added, add 200ml of pearl liquid and 80g of sodium chloride while stirring and stirring to dissolve. Finally, add water for injection to a total volume of 10000ml and stir well.

[0047] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0048] Example 5: Preparation of Pearl Eye Drops

[0049] Specific preparation method:

[0050] 1. Add 0.2g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0051] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0052] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0053] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0054] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0055] Example 6: Preparation of Pearl Eye Drops

[0056] Specific preparation method:

[0057] 1. Add 0.4g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0058] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0059] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0060] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0061] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0062] Example 7: Preparation of Pearl Eye Drops

[0063] Specific preparation method:

[0064] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0065] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0066] 3. Add 6g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0067] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0068] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0069] Example 8: Preparation of Pearl Eye Drops

[0070] Specific preparation method:

[0071] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0072] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0073] 3. Add 8g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0074] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0075] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0076] Example 9: Preparation of Pearl Eye Drops

[0077] Specific preparation method:

[0078] 1. Add 0.2g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0079] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0080] 3. Add 6g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0081] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0082] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0083] Example 10 Preparation of Pearl Eye Drops

[0084] Specific preparation method:

[0085] 1. Add 0.4g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0086] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0087] 3. Add 8g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0088] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0089] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0090] Comparative Example 1: Preparation of Pearl Brightening Eye Drops

[0091] Specific preparation method:

[0092] 1. Add 0.1g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0093] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0094] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0095] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0096] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0097] According to the specific preparation test results, referring to the preparation method of this application, when carrying out the second step of dissolving borneol, the amount of poloxamer 188 exceeded the range of this application, and the borneol could not be completely dissolved.

[0098] Comparative Example 2: Preparation of Pearl Brightening Eye Drops

[0099] Specific preparation method:

[0100] 1. Add 0.5g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0101] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0102] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0103] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0104] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0105] According to the specific preparation test results, referring to the preparation method of this application, when carrying out the second step of dissolving borneol, the amount of poloxamer 188 exceeded the range of this application, and the borneol could not be completely dissolved.

[0106] Comparative Example 3: Preparation of Pearl Brightening Eye Drops

[0107] Specific preparation method:

[0108] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0109] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0110] 3. Add 5g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0111] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0112] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0113] According to the specific preparation test results, referring to the preparation method of this application, when mixing the solution in step 4, the amount of sodium glycerophosphate exceeded the range of this application, and borneol was analyzed.

[0114] Comparative Example 4: Preparation of Pearl Brightening Eye Drops

[0115] Specific preparation method:

[0116] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0117] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0118] 3. Add 9g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0119] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0120] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0121] According to the specific preparation test results, referring to the preparation method of this application, when mixing the solution in step 4, the amount of sodium glycerophosphate exceeded the range of this application, and borneol was analyzed.

[0122] Comparative Example 5: Preparation of Pearl Brightening Eye Drops

[0123] Specific preparation method:

[0124] 1. Add 0.3g of poloxamer 188 to 14ml of ethanol, stir to dissolve, and obtain the first solution;

[0125] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0126] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0127] 4. While stirring, slowly add the second liquid to the third liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0128] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0129] According to the specific preparation test results, referring to the preparation method of this application, when dissolving borneol in step 2, the amount of ethanol used exceeded the range of this application, and the borneol could not be completely dissolved.

[0130] Comparative Example 6: Preparation of Pearl Brightening Eye Drops

[0131] Specific preparation method:

[0132] 1. Add 0.3g of poloxamer 188 to 15ml of ethanol, stir to dissolve, and obtain the first solution;

[0133] 2. Add 10g of borneol to the first solution, stir to dissolve, and obtain the second solution;

[0134] 3. Add 7g of sodium glycerophosphate to 100ml of water for injection, stir to dissolve, and obtain the third solution;

[0135] 4. While stirring, slowly add the third liquid to the second liquid. After adding all the liquid, add 200ml of pearl liquid while stirring. Finally, add water for injection to a total volume of 10,000ml and stir well.

[0136] 5. Sterilize by filtration with a 0.22μm filter cartridge, and fill into an eye drop bottle in 8ml increments to obtain Pearl Brightening Eye Drops.

[0137] For specific preparation test results, referring to the preparation method of this application, when the solution mixing in step 4 was carried out, the solution addition method was changed, and borneol was analyzed.

[0138] Based on the experimental results of the examples and comparative examples (the comparative examples have many conditions that exceed the technical solution of this application, and due to space limitations, they are not listed one by one in this application, but the experimental results are consistent with the listed comparative examples), it can be seen that the specific dosage of poloxamer 188 and sodium glycerophosphate in the Pearl Brightening Eye Drops of this application, as well as the preparation method, can successfully prepare Pearl Brightening Eye Drops by reducing the amount of ethanol. However, the Pearl Brightening Eye Drops cannot be prepared beyond the technical solution of this application.

[0139] This invention provides the following experimental and comparative results:

[0140] Samples 1-10: Pearl Eye Drops Prepared in Examples 1-10 of this Invention

[0141] Sample 11: Commercially available pearl eye drops

[0142] Accelerated stability studies were conducted on samples 1–7 (40℃±2℃, RH 75%±5%). Samples were taken at 0, 3, and 6 months. The quality indicators were examined according to the Pearl Brightening Eye Drops quality standard WS3-B-3281-98-2017. The specific results are shown in Table 1.

[0143] Table 1. Results of the accelerated test of Pearl Brightening Eye Drops

[0144]

[0145] As can be seen from the results in Table 1, the pearl eye drops prepared by the present invention have significantly improved borneol content and stability compared with the prior art, and the stability of Examples 1-4 is the best.

[0146] The above description is merely a preferred embodiment of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. Pearl Brightening Eye Drops, characterized in that... It is composed of pearl liquid, borneol, sodium glycerophosphate, ethanol, poloxamer 188, and water for injection. The pearl liquid contains 2%, borneol contains 0.1%, ethanol contains 0.15%, poloxamer 188 contains 0.002-0.004%, and sodium glycerophosphate contains 0.06-0.08%, and is prepared according to the following steps: (1) Add poloxamer 188 to ethanol, stir to disperse and dissolve, and obtain the first solution; (2) Add borneol to the first solution and stir to dissolve, thus obtaining the second solution; (3) Dissolve sodium glycerophosphate in water for injection by stirring to obtain the third solution; (4) While stirring, slowly add the second liquid to the third liquid. After the third liquid is added, add the pearl liquid while stirring. Finally, add water for injection to the total volume and stir evenly. (5) Filter and sterilize with a 0.22μm filter cartridge, and fill into an eye drop bottle according to specifications to obtain Pearl Brightening Eye Drops.

2. The pearl-infused eye drops as described in claim 1, characterized in that, The content of poloxamer 188 is 0.003%.

3. The pearl-infused eye drops as described in claim 1, characterized in that, The content of sodium glycerophosphate is 0.07%.

4. The pearl-infused eye drops as described in claim 1, characterized in that, The aforementioned Pearl Brightening Eye Drops also contain 0.05% ethylparaben and 0.8% sodium chloride.

5. The pearl-infused eye drops as described in any one of claims 1-4, characterized in that, The specifications of the Pearl Brightening Eye Drops are: 8ml / vial, 10ml / vial and 15ml / vial.

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