A method for acidifying glycerol, acidified glycerol and application thereof

Abstract

The present invention relates to the field of medical technology, and specifically to a method for acidifying glycerol, acidified glycerol and applications thereof. The method for acidifying glycerol comprises first treating activated carbon with hydrochloric acid and drying; then adding the activated carbon treated in step (1) to the glycerol, heating, and filtering. The acidified glycerol prepared by the acidifying method of the present invention has a significant effect on improving drug stability. The present invention further adds a certain proportion of hydroxypropyl methylcellulose (E3), which can further improve the stability of the drug at high temperature of 60°C and light conditions, and has good application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, and in particular to a method for acidifying glycerol, acidified glycerol and applications thereof. Background Art

[0002] Lomefloxacin hydrochloride is a third-generation broad-spectrum quinolone antibacterial drug with high antibacterial activity against Enterobacteriaceae such as Escherichia coli, Shigella, Klebsiella, Proteus, and Enterobacter; Haemophilus influenzae and Neisseria gonorrhoeae are also highly sensitive to this drug; it also has certain antibacterial effects against Pseudomonas species such as Acinetobacter and Pseudomonas aeruginosa, Staphylococcus, Pneumococcus, and hemolytic Streptococcus.

[0003] Lomefloxacin hydrochloride has a long half-life, lasting effects, and good permeability. Marketed lomefloxacin hydrochloride ear drops typically contain ethanol to increase drug solubility and permeability, helping the drug target areas of inflammation. While somewhat irritating, glycerin mitigates ethanol's irritation to mucosal membranes and prolongs the drug's local retention time. Lomefloxacin hydrochloride ear drops are weakly acidic, and the China New Drug Standard (No. WS1-(X-034)-2002Z) stipulates a pH of 4.5-6.0 for excellent stability and safety, meeting all quality requirements for ear drops. Research on domestically marketed lomefloxacin hydrochloride ear drops revealed that they are packaged in low-density polyethylene medicinal eye drop bottles, shielded from light, and stored sealed, with a shelf life of 24 months.

[0004] After searching literature from many countries, it was found that there were only optimization of prescription process and quality research, but no research on improvement of product stability.

[0005] Chinese invention patent application CN109260152A from Yuzhou Traditional Chinese Medicine Hospital discloses a lomefloxacin hydrochloride ear drop solution that uses hydrogenated castor oil and polyethylene glycol as cosolvents, glycerol as a penetration enhancer, and disodium ethylenediaminetetraacetic acid as a buffer. This solution allows the lomefloxacin hydrochloride ear drop solution to self-aggregate and form a micellar solution, which reduces the irritation of the ear drop solution, reduces patient discomfort, and prolongs its retention time in the ear. However, these ingredients are all commonly used functional excipients, and the product stability needs further improvement. Summary of the Invention

[0006] In view of the deficiencies in the prior art, the present invention provides a method for acidifying glycerol, acidified glycerol and applications.

[0007] The purpose of the present invention is achieved through the following technical solutions:

[0008] A method for acidifying glycerol comprises the following steps:

[0009] (1) Add hydrochloric acid to the activated carbon and dry it;

[0010] (2) Add the activated carbon treated in step (1) to glycerol, heat, and filter to obtain the product.

[0011] Preferably, the concentration of the hydrochloric acid in step (1) is 0.05-2 mol / L, and the mass volume ratio of the activated carbon to the hydrochloric acid is 1-1.5 g:10 mL.

[0012] Preferably, the treatment in step (1) is first boiling and then stirring at 70-80°C.

[0013] Preferably, the boiling time is 10-15 minutes.

[0014] Preferably, the stirring time is 40-60 minutes.

[0015] Preferably, cooling and filtration are performed before drying in step (1).

[0016] Preferably, the glycerol in step (2) is 0.3%-0.5% of the mass of the activated carbon treated in step (1).

[0017] Preferably, the heating in step (2) is heating to 80°C-100°C and then stirring for 15-20 minutes.

[0018] Another object of the present invention is to provide acidified glycerol prepared by the above-mentioned acidification treatment method.

[0019] The third object of the present invention is to provide a lomefloxacin hydrochloride ear drop composition, which comprises lomefloxacin hydrochloride, acidified glycerol, disodium edetate, hypromellose and ethanol.

[0020] Preferably, the mass ratio of lomefloxacin hydrochloride to hypromellose is 3-4:5-12; more preferably 3.3:5-3.3:12.

[0021] Preferably, the composition comprises, by weight, 1-10 parts of lomefloxacin hydrochloride, 150-350 parts of acidified glycerol, 0.1-2 parts of disodium edetate, 1-15 parts of hypromellose and 150-400 parts of ethanol.

[0022] Preferably, the composition comprises, by weight, 3-7 parts of lomefloxacin hydrochloride, 150-350 parts of acidified glycerol, 0.5-1 part of disodium edetate, 5-12 parts of hypromellose and 150-400 parts of ethanol.

[0023] Preferably, the hypromellose is hypromellose E3.

[0024] A fourth object of the present invention is to provide a method for preparing the lomefloxacin hydrochloride ear drop composition, comprising the following steps:

[0025] (1) Heat water, add lomefloxacin hydrochloride to dissolve, then add disodium edetate and hypromellose to dissolve;

[0026] (2) mixing acidified glycerol and ethanol and adding the mixture to the solution system of step (1);

[0027] (3) Add water to make the solution contain 3.3-6.7 mg / ml of lomefloxacin hydrochloride, and filter to obtain the solution.

[0028] Preferably, the solution is heated to 40-50° C. in step (1), and water is added to the solution to a constant volume in step (3) so that the solution contains 3.3-6.7 mg / ml of lomefloxacin hydrochloride.

[0029] A fifth object of the present invention is to provide the use of the acidified glycerol prepared by the above-mentioned acidification treatment method in improving the stability of drugs.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) After extensive research, the inventor unexpectedly discovered that special acidification of glycerol and then adding it to drugs can significantly improve the stability of the drugs.

[0032] (2) The present invention further adds a certain proportion of hypromellose (E3) to further improve the stability of the product. Glycerin may contain some metal ions or impurities that affect the stability of the product. Through this treatment, the stability is greatly improved. The addition of hypromellose can increase the viscosity and increase the retention time at the administration site. At the same time, due to the increased viscosity, it can also reduce the transmittance of light. Under these dual effects, the stability of the product under light and high temperature can be increased at the same time. However, similar excipients cannot achieve similar effects.

[0033] (3) The stability of the product prepared by the present invention is greatly improved, and the stability is significantly improved under high temperature of 60°C and light conditions; the safety of the product is improved, and the patient compliance is improved.

[0034] (4) The present invention can also reduce storage and transportation conditions, increase the shelf life, and thus reduce costs. DETAILED DESCRIPTION

[0035] The present invention will be further described below in conjunction with specific embodiments.

[0036] The following raw materials are all conventional raw materials in the art. Among them, the models and manufacturers of the raw and auxiliary materials of lomefloxacin hydrochloride ear drops are shown in Table 1.

[0037] Table 1 Information on raw and auxiliary materials used in each example

[0038] Name of raw materials Manufacturer Lomefloxacin hydrochloride Yichang Renfu Pharmaceutical Co., Ltd. glycerin Jilin Aodong Biotechnology Co., Ltd. ethanol Nanjing Chemical Reagent Co., Ltd. Edetate disodium Hunan Erkang Pharmaceutical Co., Ltd. Hydroxypropyl methylcellulose E3 Hunan Erkang Pharmaceutical Co., Ltd. Povidone K30 BASF New Materials Co., Ltd. Hydroxypropyl methylcellulose E5 Hunan Erkang Pharmaceutical Co., Ltd. hydrochloric acid Nanjing Chemical Reagent Co., Ltd. activated carbon Zhejiang Xingda Activated Carbon Co., Ltd.

[0039] Example 1

[0040] Acidification method of glycerol:

[0041] (1) Activated carbon treatment: Add 10g activated carbon to 100ml 0.1mol / L hydrochloric acid, boil for 15 minutes, stir at 75℃ for 40 minutes, cool, filter, and dry for later use;

[0042] (2) Add 0.3% of the weight of glycerol to the treated activated carbon while stirring the glycerol, heat to 85±2°C, stir for 15 minutes, cool and filter to obtain acidified glycerol for later use.

[0043] The composition formula of lomefloxacin hydrochloride ear drops is as shown in Table 2:

[0044] Table 2 Example 1 Lomefloxacin hydrochloride ear drops composition formula

[0045]

[0046] Preparation method of lomefloxacin hydrochloride ear drops composition:

[0047] (1) Weigh an appropriate amount of water (100g) and heat it to 45°C. Add the prescribed amount of lomefloxacin hydrochloride and stir to dissolve. Then add the prescribed amount of edetate disodium and hypromellose in sequence and dissolve for later use.

[0048] (2) Mix the prescribed amount of acidified glycerin and the prescribed amount of ethanol, then add the solution obtained in (1) and stir evenly;

[0049] (3) Add purified water to make up to 1000 ml;

[0050] (4) Filtration: 0.45 μm membrane filtration;

[0051] (5) Filling: 5ml / tube;

[0052] (6) Seal.

[0053] Example 2

[0054] Acidification method of glycerol:

[0055] (1) Activated carbon treatment: Add 10g activated carbon to 100ml 0.1mol / L hydrochloric acid, boil for 10 minutes, stir at 80℃ for 60 minutes, cool, filter, and dry for later use;

[0056] (2) Add 0.5% of the treated activated carbon to the glycerol while stirring, heat to 95±2°C, stir for 20 minutes, cool and filter to obtain acidified glycerol for later use.

[0057] The composition formula of lomefloxacin hydrochloride ear drops is as shown in Table 3:

[0058] Table 3 Example 2 Lomefloxacin hydrochloride ear drops composition formula

[0059]

[0060] Preparation method of lomefloxacin hydrochloride ear drops composition:

[0061] (1) Weigh an appropriate amount of water (about 100g) and heat it to 50℃. Add the prescribed amount of lomefloxacin hydrochloride and stir to dissolve. Then add the prescribed amount of edetate disodium and hypromellose in sequence and dissolve for later use.

[0062] (2) Mix the prescribed amount of acidified glycerin and the prescribed amount of ethanol, then add the solution obtained in (1) and stir evenly;

[0063] (3) Add purified water to make up to 1000 ml;

[0064] (4) Filtration: 0.45 μm membrane filtration;

[0065] (5) Filling: 5ml / tube;

[0066] (6) Seal.

[0067] Example 3

[0068] Acidification method of glycerol:

[0069] (1) Activated carbon treatment: Add 10g activated carbon to 100ml 0.1mol / L hydrochloric acid, boil for 10 minutes, stir at 70℃ for 60 minutes, cool, filter, and dry for later use;

[0070] (2) Add 0.5% of the treated activated carbon to the glycerol while stirring, heat to 95±2°C, stir for 20 minutes, cool and filter to obtain acidified glycerol for later use;

[0071] The composition formula of lomefloxacin hydrochloride ear drops is as shown in Table 4:

[0072] Table 4 Example 3 Lomefloxacin hydrochloride ear drops composition formula

[0073]

[0074] Preparation method of lomefloxacin hydrochloride ear drops composition:

[0075] (1) Weigh an appropriate amount of water (about 100g) and heat it to 40℃, add the prescribed amount of lomefloxacin hydrochloride, stir to dissolve, then add the prescribed amount of edetate disodium and hypromellose in sequence and dissolve for later use;

[0076] (2) Mix the prescribed amount of acidified glycerin and the prescribed amount of ethanol, then add the solution obtained in (1) and stir evenly;

[0077] (3) Add purified water to make up to 1000 ml;

[0078] (4) Filtration: 0.45 μm membrane filtration;

[0079] (5) Filling: 5ml / tube;

[0080] (6) Seal.

[0081] Example 4

[0082] Acidification method of glycerol:

[0083] (1) Activated carbon treatment: Add 15g activated carbon to 100ml 0.1mol / L hydrochloric acid, boil for 10 minutes, stir at 75℃ for 60 minutes, cool, filter, and dry for later use;

[0084] (2) Add 0.5% of the treated activated carbon to the glycerol while stirring, heat to 95±2°C, stir for 20 minutes, cool and filter to obtain acidified glycerol for later use;

[0085] The composition formula of lomefloxacin hydrochloride ear drops is as shown in Table 5:

[0086] Table 5 Example 4 Lomefloxacin hydrochloride ear drops composition formula

[0087]

[0088] Preparation method of lomefloxacin hydrochloride ear drops composition:

[0089] (1) Weigh an appropriate amount of water (about 100g) and heat it to 45°C. Add the prescribed amount of lomefloxacin hydrochloride and stir to dissolve. Then add the prescribed amount of edetate disodium and hypromellose in sequence and dissolve for later use.

[0090] (2) Mix the prescribed amount of acidified glycerin and the prescribed amount of ethanol, then add the solution obtained in (1) and stir evenly;

[0091] (3) Add purified water to make up to 1000 ml;

[0092] (4) Filling: 10ml / tube;

[0093] (5) Seal.

[0094] Example 5

[0095] Acidification method of glycerol:

[0096] (1) Activated carbon treatment: Add 15g activated carbon to 100ml 0.1mol / L hydrochloric acid, boil for 10 minutes, stir at 80℃ for 60 minutes, cool, filter, and dry for later use;

[0097] (2) Add 0.5% of the treated activated carbon to the glycerol while stirring, heat to 95±2°C, stir for 20 minutes, cool and filter to obtain acidified glycerol for later use.

[0098] The composition formula of lomefloxacin hydrochloride ear drops is as shown in Table 6:

[0099] Table 6 Example 5 Lomefloxacin hydrochloride ear drops composition formula

[0100]

[0101] Preparation method of lomefloxacin hydrochloride ear drops composition:

[0102] (1) Weigh an appropriate amount of water (about 100g) and heat it to 50℃. Add the prescribed amount of lomefloxacin hydrochloride and stir to dissolve. Then add the prescribed amount of edetate disodium and hypromellose in sequence and dissolve for later use.

[0103] (2) Mix the prescribed amount of acidified glycerin and the prescribed amount of ethanol, then add the solution obtained in (1) and stir evenly;

[0104] (3) Add purified water to make up to 1000 ml;

[0105] (4) Filtration: 0.45 μm membrane filtration;

[0106] (5) Filling: 10ml / tube;

[0107] (6) Seal.

[0108] Comparative Example 1

[0109] The only difference from Example 1 is that the glycerol is not acidified.

[0110] Comparative Example 2

[0111] The difference from Example 1 is that in the acidification treatment method of glycerol, the activated carbon treatment in step (1) is boiled for 5 minutes.

[0112] Comparative Example 3

[0113] The difference from Example 1 is that in the acidification treatment method of glycerol, step (1) the activated carbon treatment is boiled for 20 minutes;

[0114] Comparative Example 4

[0115] The difference from Example 1 is that in the acidification treatment method of glycerol, the activated carbon in step (1) is 6 g.

[0116] Comparative Example 5

[0117] The difference from Example 1 is that in the acidification treatment method of glycerol, the amount of activated carbon in step (1) is 18 g.

[0118] Comparative Example 6

[0119] The only difference from Example 1 is that in the acidification treatment method of glycerol, in step (1), stirring is performed at 65° C. for 40 minutes, and filtering is performed after cooling.

[0120] Comparative Example 7

[0121] The only difference from Example 1 is that in the acidification treatment method of glycerol, in step (1), stirring is performed at 85° C. for 40 minutes, and filtering is performed after cooling.

[0122] Comparative Example 8

[0123] The only difference from Example 1 is that 0.2% treated activated carbon is added in step (2) of the acidification treatment method of glycerol.

[0124] Comparative Example 9

[0125] The only difference from Example 1 is that 0.6% of treated activated carbon is added in step (2) of the acidification treatment method of glycerol.

[0126] Comparative Example 10

[0127] The difference from Example 1 is that in the acidification treatment method of glycerol, the stirring time after adding activated carbon in step (2) is 10 minutes.

[0128] Comparative Example 11

[0129] The difference from Example 1 is that in the acidification treatment method of glycerol, the stirring time after glycerol treatment of activated carbon in step (2) is 25 minutes.

[0130] Comparative Example 12

[0131] The only difference from Example 1 is that in the acidification treatment method of glycerol, the heating temperature during stirring after glycerol treatment of activated carbon in step (2) is 75°C.

[0132] Comparative Example 13

[0133] The only difference from Example 1 is that in the acidification treatment method of glycerol, the heating temperature during stirring after glycerol treatment of activated carbon in step (2) is 105°C.

[0134] Comparative Example 14

[0135] The only difference from Example 1 is that hypromellose E3 is replaced with povidone K30.

[0136] Comparative Example 15

[0137] The only difference from Example 1 is that hypromellose E3 is replaced by hypromellose E5.

[0138] Comparative Example 16

[0139] The only difference from Example 1 is that the amount of hypromellose E3 is 4 g, and the weight ratio of lomefloxacin hydrochloride to hypromellose is 3.3:4.

[0140] Comparative Example 17

[0141] The only difference from Example 4 is that the amount of hypromellose E3 is 13 g, and the weight ratio of lomefloxacin hydrochloride to hypromellose is 3.3:13.

[0142] Comparative Example 18

[0143] The difference from Example 1 is that in the acidified glycerol preparation method, hydrochloric acid in step (1) is replaced with phosphoric acid.

[0144] Evaluation of drug stability results in each example

[0145] The lomefloxacin hydrochloride ear drops obtained in Examples 1 to 5 and Comparative Examples 1 to 17 were placed under high temperature conditions of 60°C for 10 days, 30 days, and 60 days, and under light conditions (total illumination of not less than 1.2×10 6 lux·hr, near-ultraviolet energy not less than 200w·hr / m 2 ) conditions for 10 days and 15 days, and observe the changes in product shape and related substances. The test results are shown in Tables 7 and 8.

[0146] Table 7 Results of high temperature 60℃ inspection of finished products of each preparation

[0147]

[0148]

[0149]

[0150]

[0151] For Comparative Examples 1-14 and 18, the high temperature for 60 days exceeded the limit. For Comparative Examples 15-17, the high temperature for 60 days met the requirement, but the light intensity did not meet the requirement.

[0152] Table 8 Investigation results of finished preparations under lighting conditions

[0153]

[0154]

[0155]

[0156] Examples 1-5 are the best examples, and both high temperature and light stability are better than the control preparation. The control preparation meets the requirements at a high temperature of 60°C for 30 days, but exceeds the limit at 60 days. Examples 1-5 still meet the requirements at a high temperature of 60°C for 60 days.

[0157] Comparative Examples 1-13 are glycerol treatments that are not within the scope of the patent claims, and high temperature of 60°C for 60 days has exceeded the limit. Comparative Example 18 is glycerol treatment with a hydrochloric acid analogue, and high temperature of 60°C for 60 days has exceeded the limit. Comparative Examples 14-15 are analogues of hydroxypropyl methylcellulose E3, and high temperature of 60°C for 60 days and light exposure for 15 days have exceeded the limit.

[0158] In Comparative Examples 16-17, the weight ratio of the active ingredient to the hydroxypropyl methylcellulose was outside the range of the patent claims, and the light exposure for 15 days exceeded the limit.

[0159] The above results show that the embodiments within the scope of the claims can achieve beneficial effects, while the comparative examples and control preparations outside the scope cannot achieve good stability effects.

[0160] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A lomefloxacin hydrochloride ear drop composition, characterized in that: The raw materials of the composition are composed of the following components: lomefloxacin hydrochloride, acidified glycerol, disodium edetate, hypromellose and ethanol; the mass ratio of lomefloxacin hydrochloride to hypromellose is 3-4:5-12, and the hypromellose is hypromellose E3; The acidified glycerol is prepared by the following acidification treatment method: (1) Add hydrochloric acid to the activated carbon and dry it to obtain the treated activated carbon; (2) Add treated activated carbon to glycerol, heat, and filter to obtain; The mass volume ratio of the activated carbon to the hydrochloric acid in step (1) is 1-1.5 g:10 mL; The treatment in step (1) is to first boil for 10-15 minutes and then stir at 70-80° C. for 40-60 minutes; In step (2), 0.3% to 0.5% by mass of glycerol of treated activated carbon is added to the glycerol.

2. The lomefloxacin hydrochloride ear drop composition according to claim 1, characterized in that The concentration of the hydrochloric acid in step (1) is 0.05-2 mol / L.

3. The lomefloxacin hydrochloride ear drop composition according to claim 1, characterized in that The heating in step (2) is heating to 80°C-100°C and then stirring for 15-20 minutes.

4. The lomefloxacin hydrochloride ear drop composition according to claim 1, characterized in that The composition comprises, by weight, 1-10 parts of lomefloxacin hydrochloride, 150-350 parts of acidified glycerol, 0.1-2 parts of disodium edetate, 1-15 parts of hypromellose and 150-400 parts of ethanol.

5. A method for preparing the lomefloxacin hydrochloride ear drop composition according to any one of claims 1 to 4, characterized in that: The steps include: (1) Heat water to 40-50°C, add lomefloxacin hydrochloride to dissolve, and then add edetate disodium and hypromellose to dissolve; (2) mixing acidified glycerol and ethanol, and adding the mixture to the solution system of step (1); (3) Add water to make up the volume so that the solution contains 3.3-6.7 mg / ml of lomefloxacin hydrochloride, and filter to obtain the solution.

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