Sodium cromoglycate eye drops without antioxidant

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a cromolyn sodium eye drop without antioxidant. The cromolyn sodium eye drop comprises cromolyn sodium liposome and pharmaceutically acceptable additives; a formula is preferred in the preparation process of the cromolyn sodium liposome, so that the cromolyn sodium liposome has a high drug loading and encapsulation efficiency, and lays a foundation for further preparation into a preparation. In addition, the cromolyn sodium liposome eye drop of the application does not add antioxidant, and also has high stability, and is qualified in a sterile test and has high light stability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a cromolyn sodium eye drop without antioxidant. BACKGROUND

[0002] Cromolyn sodium, also known as disodium cromoglicate, has a good preventive and therapeutic effect on immediate allergic reactions. Its mechanism of action is that it can stabilize the cell membrane of mast cells, prevent mast cell degranulation, thereby inhibiting the release of histamine, 5-hydroxytryptamine, slow-reacting substance and other allergic reaction mediators, and further inhibiting the adverse effects of allergic reaction mediators on tissues. Its effect of inhibiting the release of allergic reaction mediators is achieved by inhibiting intracellular cyclic phosphoric acid diesterase, thereby increasing the concentration of intracellular cyclic phosphoric acid diester (cAMP), preventing the transport of calcium ions into mast cells, thereby stabilizing the mast cell membrane and preventing the release of allergic reaction mediators.

[0003] Clinical studies have found that cromolyn sodium is effective not only for allergic asthma in which allergic factors play a major role, but also for chronic asthma in which allergic effects are not obvious. It is used for allergic rhinitis and seasonal pollenosis, and can rapidly control symptoms. It is also effective for chronic allergic eczema and certain skin pruritus when used as a soft ointment. 2% to 4% eye drops are suitable for pollenosis, conjunctivitis, spring keratoconjunctivitis and other allergic conjunctivitis.

[0004] Due to the poor stability and high hygroscopicity of cromolyn sodium, it is easy to discolor when exposed to light. In many research reports, it is mentioned that white flocculent substances are easily generated after cromolyn sodium eye drops are placed, and discoloration is easily generated after the product is opened. In order to avoid discoloration, decomposition and precipitation of eye drops during use or storage, sodium pyrosulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, vitamin C, thiourea and other antioxidants are added in the prior art, but the corresponding drug safety hazards are also increased.

[0005] European Patent EP83200047.5 discloses a medical composition containing cromolyn sodium liposomes, and the liposomes comprise one or more of lecithin 2-(tetradecyl) phosphatidylcholine, 2-(hexadecyl) phosphatidylcholine or 2-(octadecyl) phosphatidylcholine. The liposomes directly participate in the site of allergic conditions (such as the lung), which can increase the retention level of cromolyn sodium in the site, thereby obtaining an increased duration of action. SUMMARY

[0006] To overcome the deficiencies of the prior art, the present application provides an eye drop containing cromolyn sodium liposomes, which solves the problems of poor stability and discoloration of cromolyn sodium when exposed to light, and does not add antioxidants, thereby improving drug safety.

[0007] Specifically, the technical scheme of the present application is as follows:

[0008] The present application provides a sodium cromoglicate eye drop, which comprises: sodium cromoglicate liposome, pharmaceutically acceptable additives;

[0009] The preparation method of the sodium cromoglicate liposome is as follows:

[0010] Phospholipid and lactic acid are dissolved in a solvent, and rotary evaporation is performed under reduced pressure with water bath heating to obtain a blank liposome film. Sodium cromoglicate is added to the blank liposome film, a buffer solution is added to adjust the pH, and rotary evaporation is continued under reduced pressure with water bath heating. Filtration, washing, and drying are performed to obtain sodium cromoglicate liposome.

[0011] In an embodiment, the phospholipid is selected from at least one of dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, and dimyristoyl phosphatidylethanolamine.

[0012] In an embodiment, the lactic acid is selected as L-lactic acid; the pH is adjusted to 6.0-8.0 during the preparation of the sodium cromoglicate liposome; the water bath heating temperature during the preparation of the sodium cromoglicate is 42-58°C. As the solvent evaporates and distills out, the L-lactic acid is partially converted into lactic anhydride, which plays a role in adjusting the fluidity of the liposome membrane; the solvent is selected from at least one of ethanol, isopropanol, water, and chloroform; the molar ratio of sodium cromoglicate, phospholipid, and lactic acid is 1:1-3:0.1-0.5.

[0013] In a more preferred embodiment:

[0014] The phospholipid is selected as dimyristoyl phosphatidylethanolamine.

[0015] The pH is adjusted to 6.5-7.5 during the preparation of the sodium cromoglicate.

[0016] The water bath heating temperature during the preparation of the sodium cromoglicate is 52-55°C.

[0017] The solvent is ethanol and water.

[0018] The molar ratio of sodium cromoglicate, phospholipid, and lactic acid is 1:1.5:0.2.

[0019] Further, the additives are pH adjusters, isotonicity adjusters, and preservatives.

[0020] The pH regulator is selected from at least one of borate buffer, phosphate buffer, sodium acetate-boric acid buffer; the isotonicity regulator is selected from at least one of sodium chloride, boric acid, glucose, borax, potassium chloride, glycerol; the preservative is selected from at least one of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzalkonium bromide, chlorobutanol, phenethyl alcohol, thiomersal, phenylmercuric nitrate, mercuric oxycyanide, sorbic acid, chlorhexidine.

[0021] In the embodiment of the sodium cromoglicate eye drops, the pH of the sodium cromoglicate eye drops is 6.2-7.2, preferably pH=6.7.

[0022] Compared with the prior art, the present application has the beneficial effects that:

[0023] The present application provides a kind of eye drops comprising sodium cromoglicate liposome, wherein the preparation process of sodium cromoglicate liposome preferably formula, especially adding lactic acid, so that sodium cromoglicate liposome has higher drug loading and encapsulation efficiency, further preparation into preparation foundation is consolidated.In addition, the present application sodium cromoglicate liposome eye drops does not add antioxidant, also can have very high stability, improve the safety of drug use, in sterile inspection are qualified and have higher light stability etc. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 : the content change of accelerated test sodium cromoglicate eye drops DETAILED DESCRIPTION

[0025] In order to make the purpose, technical scheme of the present application more clear, the following examples, the present application is further explained, but the protection scope of the present application is not limited to these examples, examples are only used to explain the present application. Those skilled in the art should understand that, any change or equivalent replacement without departing from the concept of the present application is included in the protection scope of the present application.

[0026] Example 1 preparation of sodium cromoglicate liposome

[0027] Dipalmitoyl phosphatidyl ethanolamine and L-lactic acid are dissolved in ethanol and water, heated in water bath under reduced pressure at 53 DEG C, rotary evaporation is obtained, the blank liposome film is obtained, sodium cromoglicate is added to the blank liposome film, the pH is adjusted to 6.8 by adding phosphate buffer solution, continue to heat in water bath under reduced pressure at 53 DEG C, rotary evaporation, filtration, washing, drying, to obtain sodium cromoglicate liposome.

[0028] The amount of sodium cromoglicate is 10g, the amount of dipalmitoyl phosphatidyl ethanolamine is 18.60g, the amount of L-lactic acid is 0.35g, and the molar ratio is 1:1.5:0.2.

[0029] The drug loading of the obtained cromolyn sodium liposome is 34.02%, and the encapsulation efficiency is 93.14%.

[0030] Example 2 Preparation of cromolyn sodium liposome

[0031] Dipalmitoyl phosphatidyl ethanolamine and L-lactic acid are dissolved in ethanol and water, and rotary evaporation is performed under reduced pressure in a water bath at 52°C to obtain a blank liposome film. Cromolyn sodium is added to the blank liposome film, and phosphate buffer solution is added to adjust the pH to 6.5. Rotary evaporation is continued under reduced pressure in a water bath at 52°C, followed by filtration, washing, and drying to obtain cromolyn sodium liposome.

[0032] The amount of cromolyn sodium is 10g, the amount of dipalmitoyl phosphatidyl ethanolamine is 12.41g, and the amount of L-lactic acid is 0.17g, and the molar ratio is 1:1:0.1.

[0033] The drug loading of the obtained cromolyn sodium liposome is 33.87%, and the encapsulation efficiency is 90.32%.

[0034] Example 3 Preparation of cromolyn sodium liposome

[0035] Dipalmitoyl phosphatidyl ethanolamine and L-lactic acid are dissolved in ethanol and water, and rotary evaporation is performed under reduced pressure in a water bath at 55°C to obtain a blank liposome film. Cromolyn sodium is added to the blank liposome film, and phosphate buffer solution is added to adjust the pH to 7.5. Rotary evaporation is continued under reduced pressure in a water bath at 55°C, followed by filtration, washing, and drying to obtain cromolyn sodium liposome.

[0036] The amount of cromolyn sodium is 10g, the amount of dipalmitoyl phosphatidyl ethanolamine is 37.23g, and the amount of L-lactic acid is 0.87g, and the molar ratio is 1:3:0.5.

[0037] The drug loading of the obtained cromolyn sodium liposome is 30.65%, and the encapsulation efficiency is 91.06%.

[0038] Example 4 Preparation of cromolyn sodium liposome

[0039] Dipalmitoyl phosphatidyl choline and L-lactic acid are dissolved in ethanol, and rotary evaporation is performed under reduced pressure in a water bath at 42°C to obtain a blank liposome film. Cromolyn sodium is added to the blank liposome film, and phosphate buffer solution is added to adjust the pH to 6.0. Rotary evaporation is continued under reduced pressure in a water bath at 42°C, followed by filtration, washing, and drying to obtain cromolyn sodium liposome.

[0040] The amount of cromolyn sodium is 10g, the amount of dipalmitoyl phosphatidyl choline is 19.85g, and the amount of L-lactic acid is 0.35g, and the molar ratio is 1:1.5:0.2.

[0041] The drug loading of the obtained cromolyn sodium liposome is 28.54%, and the encapsulation efficiency is 88.17%.

[0042] Example 5 Preparation of cromolyn sodium liposome

[0043] The blank liposome film is obtained by dissolving distearoyl phosphatidylcholine and L-lactic acid in chloroform and water, rotary evaporation under reduced pressure in a water bath at 58°C. The cromolyn sodium is added to the blank liposome film, and the pH is adjusted to 8.0 by adding a phosphate buffer solution. Rotary evaporation under reduced pressure in a water bath at 58°C is continued. Filtration, washing, and drying are performed to obtain the cromolyn sodium liposome.

[0044] The amount of cromolyn sodium is 10g, the amount of distearoyl phosphatidylcholine is 23.13g, and the amount of L-lactic acid is 0.35g. The molar ratio is 1:1.5:0.2.

[0045] The drug loading of the obtained cromolyn sodium liposome is 25.96%, and the encapsulation efficiency is 89.19%.

[0046] Example 6 Preparation of cromolyn sodium liposome

[0047] The blank liposome film is obtained by dissolving dipalmitoyl phosphatidylcholine and L-lactic acid in isopropyl alcohol and water, rotary evaporation under reduced pressure in a water bath at 54°C. The cromolyn sodium is added to the blank liposome film, and the pH is adjusted to 7.0 by adding a phosphate buffer solution. Rotary evaporation under reduced pressure in a water bath at 54°C is continued. Filtration, washing, and drying are performed to obtain the cromolyn sodium liposome.

[0048] The amount of cromolyn sodium is 10g, the amount of dipalmitoyl phosphatidylcholine is 21.49g, and the amount of L-lactic acid is 0.35g. The molar ratio is 1:1.5:0.2.

[0049] The drug loading of the obtained cromolyn sodium liposome is 26.71%, and the encapsulation efficiency is 88.35%.

[0050] Comparative Example 1 Preparation of cromolyn sodium liposome

[0051] The blank liposome film is obtained by dissolving phosphatidylcholine and L-lactic acid in ethanol and water, rotary evaporation under reduced pressure in a water bath at 53°C. The cromolyn sodium is added to the blank liposome film, and the pH is adjusted to 6.8 by adding a phosphate buffer solution. Rotary evaporation under reduced pressure in a water bath at 53°C is continued. Filtration, washing, and drying are performed to obtain the cromolyn sodium liposome.

[0052] The amount of cromolyn sodium is 10g, the amount of phosphatidylcholine is 2.19g, and the amount of L-lactic acid is 0.35g. The molar ratio is 1:1.5:0.2.

[0053] The obtained sodium cromoglycate liposomes had a drug loading of 18.36% and an encapsulation efficiency of 79.51%.

[0054] Comparative Example 2: Preparation of Sodium Cromoglycate Liposomes

[0055] Dimyristic phosphatidylethanolamine was dissolved in ethanol and water, and the mixture was heated in a vacuum water bath at 53°C by rotary evaporation to obtain a blank liposome membrane. Sodium cromoglycate was added to the blank liposome membrane, and the pH was adjusted to 6.8 with phosphate buffer solution. The mixture was then heated in a vacuum water bath at 53°C by rotary evaporation, filtered, washed, and dried to obtain sodium cromoglycate liposomes.

[0056] The amount of sodium cromoglycate used is 10g, and the amount of myristoyl phosphatidylethanolamine used is 18.60g, with a molar ratio of 1:1.5.

[0057] The obtained sodium cromoglycate liposomes had a drug loading of 22.24% and an encapsulation efficiency of 82.10%.

[0058] Comparative Example 3: Preparation of Sodium Cromoglycate Liposomes

[0059] Dimyristic phosphatidylethanolamine and L-lactic acid were dissolved in ethanol and water, and the mixture was heated in a vacuum water bath at 53°C by rotary evaporation to obtain a blank liposome membrane. Sodium cromoglycate was added to the blank liposome membrane, and phosphate buffer solution was added to adjust the pH to 6.8. The mixture was then heated in a vacuum water bath at 53°C by rotary evaporation, filtered, washed, and dried to obtain sodium cromoglycate liposomes.

[0060] The dosage of sodium cromoglycate is 10g, the dosage of myristoyl phosphatidylethanolamine is 18.60g, and the dosage of L-lactic acid is 1.76g, with a molar ratio of 1:1.5:1.

[0061] The obtained sodium cromoglycate liposomes had a drug loading of 24.11% and an encapsulation efficiency of 84.39%.

[0062] Example 7: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0063]

[0064] Preparation method:

[0065] Dissolve benzalkonium chloride in water for injection, add sodium cromoglycate liposomes and sodium chloride from Example 1, adjust the pH to 6.7 using phosphate buffer, filter and add water for injection to 800 ml, sterilize and aseptically dispense.

[0066] Example 8: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0067]

[0068] Preparation method:

[0069] Dissolve benzalkonium chloride in water for injection, add sodium cromoglycate liposomes and sodium chloride from Example 2, adjust the pH to 6.2 using phosphate buffer, filter and add water for injection to 800 ml, sterilize and aseptically dispense.

[0070] Example 9: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0071]

[0072] Preparation method:

[0073] Dissolve benzalkonium chloride in water for injection, add sodium cromoglycate liposomes and sodium chloride as described in Example 3, adjust the pH to 7.2 using phosphate buffer, filter and add water for injection to 800 ml, sterilize and aseptically dispense.

[0074] Example 10: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0075]

[0076] Preparation method:

[0077] Dissolve benzalkonium bromide in water for injection, add sodium cromoglycate liposomes and glycerol as described in Example 4, adjust the pH to 6.7 using borate buffer, filter, add water for injection to 800 ml, sterilize, and aseptically dispense.

[0078] Comparative Example 4: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0079]

[0080] Preparation method:

[0081] Dissolve benzalkonium chloride in water for injection, add sodium cromoglycate liposomes and sodium chloride from Comparative Example 2, adjust the pH to 6.7 using phosphate buffer, filter and add water for injection to 800 ml, sterilize and aseptically dispense.

[0082] Comparative Example 5: Sodium cromoglycate eye drops (100 drops, 8ml each: 0.16g)

[0083]

[0084]

[0085] Preparation method:

[0086] Dissolve benzalkonium chloride in water for injection, add sodium cromoglycate and sodium chloride, adjust the pH to 6.7 using phosphate buffer, filter and add water for injection to 800 ml, sterilize and aseptically dispense.

[0087] Reference preparation: Commercially available sodium cromoglycate eye drops (National Drug Approval Number H42021***)

[0088] Verification Implementation Examples

[0089] 1. Determination of sodium cromoglycate content

[0090] Determined by ultraviolet-visible spectrophotometry (General Rule 0401).

[0091] Test solution: Accurately measure 2 ml of this product and place it in a 100 ml volumetric flask. Dilute to the mark with phosphate buffer (pH 5.8) and shake well. Accurately measure 5 ml of this product and place it in a 100 ml volumetric flask. Dilute to the mark with phosphate buffer (pH 5.8) and shake well.

[0092] Determination method: Take the test solution and measure the absorbance at a wavelength of 326 nm. (C) 23 H 14 Na2O 11 The absorption coefficient is calculated to be 164.

[0093] Accelerated testing: The samples were placed in commercial packaging at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th months of the test period to determine the content of Examples 7-10, Comparative Example 4, Comparative Example 5 and the reference preparation.

[0094] The results are as follows Figure 1 As shown, the sodium cromoglycate eye drops of Examples 7-10 of the present invention have a more stable content, and the content remains basically unchanged in the accelerated test.

[0095] 2. Aseptic examination

[0096] The presence of Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Clostridium sporogenes, Candida albicans, and Aspergillus niger was determined according to the sterility test method in item 1101 of the Chinese Pharmacopoeia 2020. Culture smears were prepared, stained, and examined under a microscope to determine the presence of bacteria.

[0097] Result Interpretation Criteria: If all test tubes are clear, or if they are turbid but confirmed to have no bacterial growth, the test sample is considered compliant; if any test tube is turbid and confirmed to have bacterial growth, the test sample is considered non-compliant, unless it can be sufficiently proven that the test result is invalid, i.e., the grown microorganisms are not contained in the test sample. A test can only be considered invalid if at least one of the following conditions is met:

[0098] (1) The microbiological monitoring results of the equipment and environment used in the sterility test do not meet the requirements of the sterility test method.

[0099] (2) Review the aseptic test process and identify factors that may cause microbial contamination.

[0100] (3) Microbial growth was observed in the negative control.

[0101] (4) The microorganisms growing in the test sample tube are confirmed to be caused by improper items and / or aseptic techniques used in the aseptic test.

[0102] If a test is deemed invalid after evaluation, it should be repeated. During the retest, the same amount of test sample should be taken again and examined according to law. If no bacterial growth is observed, the test sample is deemed compliant; if bacterial growth is observed, the test sample is deemed non-compliant.

[0103] Accelerated testing: The samples were placed in commercial packaging at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 6th month of the test period to perform sterility tests on Examples 7-10, Comparative Example 4, Comparative Example 5, and the reference preparation.

[0104] Table 1. Results of sterility tests for formulations in Examples 7-10, Comparative Example 4, and Reference Formulation.

[0105]

[0106] The results showed that Comparative Examples 4 and 5 failed the sterility test, while Examples 7-10 passed the sterility test.

[0107] 3. Strong light irradiation test

[0108] The formulations of Examples 7-10, Comparative Example 4, and Reference Formulation were used as test samples. They were placed in an illumination box equipped with fluorescent lamps and kept at an illuminance of 4500 lx ± 500 lx for 30 days. Samples were taken on the 10th and 30th days to detect the content of sodium cromoglycate, related substances, and changes in appearance.

[0109] Table 2. Results of strong light irradiation tests on formulations of Examples 7-10, Comparative Example 4, and Reference Formulation.

[0110]

[0111]

[0112] Table 2 shows that the sodium cromoglycate eye drops of Examples 7-10 of this invention have solved the problem of sodium cromoglycate easily changing color when exposed to light, and have good photostability, with better stability than the reference preparation.

Claims

1. A sodium cromoglycate eye drop, characterized in that, The sodium cromoglycate eye drops comprise: sodium cromoglycate liposomes and pharmaceutically acceptable excipients; The method for preparing the sodium cromoglycate liposomes is as follows: Phospholipids and L-lactic acid were dissolved in a solvent and rotary evaporated under reduced pressure in a water bath to obtain a blank liposome membrane. Sodium cromoglycate was added to the blank liposome membrane, and a buffer solution was added to adjust the pH. The membrane was then rotary evaporated under reduced pressure in a water bath, filtered, washed, and dried to obtain sodium cromoglycate liposomes. The phospholipid is selected from at least one of dipalmitoylphosphatidylcholine, distearylphosphatidylcholine, dimyristoylphosphatidylcholine, and dimyristoylphosphatidylethanolamine; the sodium cromoglycate, phospholipid, and L-lactic acid are calculated in a molar ratio of 1:1-3:0.1-0.

5.

2. The sodium cromoglycate eye drops according to claim 1, characterized in that, The phospholipid is dimyristoyl phosphatidylethanolamine.

3. The sodium cromoglycate eye drops according to claim 1, characterized in that, The pH is adjusted to 6.0-8.

0.

4. The sodium cromoglycate eye drops according to claim 3, characterized in that, The pH is adjusted to 6.5-7.

5.

5. The sodium cromoglycate eye drops according to claim 1, characterized in that, The water bath heating temperature is 42℃-58℃.

6. The sodium cromoglycate eye drops according to claim 5, characterized in that, The water bath heating temperature is 52-55℃.

7. The sodium cromoglycate eye drops according to claim 1, characterized in that, The solvent is selected from at least one of ethanol, isopropanol, water, and chloroform.

8. The sodium cromoglycate eye drops according to claim 7, characterized in that, The solvents are ethanol and water.

9. The sodium cromoglycate eye drops according to claim 1, characterized in that, The sodium cromoglycate, phospholipids, and L-lactic acid are calculated in a molar ratio of 1:1.5:0.

2.

10. The sodium cromoglycate eye drops according to claim 1, characterized in that, The additives are pH adjusters, isotonic adjusters, and preservatives.

11. The sodium cromoglycate eye drops according to claim 10, characterized in that, The pH adjuster is selected from at least one of borate buffer, phosphate buffer, and sodium acetate-borate buffer; the isotonic adjuster is selected from at least one of sodium chloride, boric acid, glucose, borax, potassium chloride, and glycerol; the preservative is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, benzalkonium bromide, chlorobutanol, phenethyl alcohol, thimerosal, phenylmercuric nitrate, mercuric oxycyanide, sorbic acid, and chlorhexidine.

12. The sodium cromoglycate eye drops according to claim 1, wherein the pH of the sodium cromoglycate eye drops is 6.2-7.

2.

13. The sodium cromoglycate eye drops according to claim 12, wherein the pH of the sodium cromoglycate eye drops is 6.7.

Images