Dexamethasone liposome, preparation method thereof and tablets

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dexamethasone liposome, a preparation method thereof and a preparation. The dexamethasone liposome comprises dexamethasone, phospholipid, cholesterol and sodium pyrophosphate. By preferably selecting the liposome membrane material, especially the addition of sodium pyrophosphate, the encapsulation rate of the dexamethasone liposome is significantly improved, thereby further solving the problem of light sensitivity of dexamethasone and improving the stability of the dexamethasone preparation under strong light irradiation. By optimizing the preparation process, the drug loading of the dexamethasone liposome is increased, the leakage rate is reduced, and the physical stability is significantly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dexamethasone liposome, a preparation method thereof and a preparation thereof. Background Art

[0002] Dexamethasone belongs to adrenocortical hormones. It is mainly applicable to allergic and autoimmune inflammatory diseases, such as connective tissue diseases, severe bronchial asthma, allergic diseases such as dermatitis, ulcerative colitis, acute leukemia, malignant lymphoma, etc. Dexamethasone can reduce and prevent the tissue's response to inflammation, thereby reducing the manifestation of inflammation. The hormone inhibits inflammatory cells, including macrophages and leukocytes, from aggregating at the inflammation site, and inhibits phagocytosis, the release of lysosomal enzymes, and the synthesis and release of inflammatory chemical mediators. It can reduce and prevent the tissue's response to inflammation, thereby reducing the manifestation of inflammation.

[0003] Dexamethasone is a white or off-white crystalline or crystalline powder, odorless, and slightly bitter in taste. It is readily soluble in acetone, soluble in methanol or absolute ethanol, slightly soluble in ethanol or chloroform, very slightly soluble in ether, slightly soluble in water, but it is relatively sensitive to light.

[0004] In recent years, the research on liposomes has become a very active field in the research of new drug dosage forms in the drug carrier delivery system. Liposomes are suitable for biodegradation in vivo, non-toxic and non-immunogenic, etc. Therefore, liposome-encapsulated drugs have received increasing attention and have been widely used.

[0005] Chinese Patent CN 107625727 A discloses a colloidal aqueous solution of dexamethasone nano-liposomes, a preparation method thereof and an application, which contains the following components by weight percentage: dexamethasone 0.13 wt%, glyceryl behenate 2.8 wt%, propylene glycol monocaprylate 1.2 wt%, polyoxyethylene 40 hydrogenated castor oil 3 wt%, glycerol 1.92 wt%, and the balance is water. However, the encapsulation efficiency of this dexamethasone nano-liposome is only (64.79±8.32)%, and the drug loading is (0.81±0.12)%.

[0006] Chinese Patent CN 113827738 A discloses a sialic acid-modified dexamethasone palmitate liposome, which includes a sialic acid derivative, phospholipid, cholesterol and dexamethasone palmitate. The sialic acid derivative accounts for 1%-50% of the total weight of the liposome, the phospholipid is 50-90%, the cholesterol is 0-40%, and the dexamethasone palmitate is 5-20%. The data of its encapsulation efficiency and drug loading are relatively ideal, but the stability still needs to be improved. Summary of the Invention

[0007] Overcoming the deficiencies of the prior art, the present invention provides an ornidazole liposome, preferably encapsulating the active ingredient ornidazole with a carrier membrane material, solving the problems of low encapsulation rate, high leakage rate, and unsatisfactory stability of the ornidazole liposome, improving the encapsulation rate and stability of the ornidazole liposome, preparing the ornidazole liposome by a supercritical fluid technology, solving the problem of solvent residue, and improving the drug use safety and production safety.

[0008] Specifically, the technical solution of the present invention is as follows:

[0009] The present invention provides a dexamethasone liposome, and the dexamethasone liposome includes dexamethasone, phospholipid, cholesterol, and sodium pyrophosphate.

[0010] Furthermore, the components in the dexamethasone liposome are calculated by weight ratio as follows:

[0011] Dexamethasone 1 - 5 parts, phospholipid 2 - 10 parts, cholesterol 1 - 6 parts, sodium pyrophosphate 0.2 - 3 parts;

[0012] Preferably, dexamethasone 1 - 5 parts, phospholipid 3 - 8 parts, cholesterol 2 - 5 parts, sodium pyrophosphate 0.5 - 2 parts.

[0013] Furthermore, the phospholipid is selected from one or more of phosphatidylinositol, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, and egg yolk sphingomyelin, and preferably egg yolk sphingomyelin.

[0014] Furthermore, the components in the dexamethasone liposome are calculated by weight ratio as follows:

[0015] Dexamethasone 1 - 5 parts, egg yolk sphingomyelin 3 - 8 parts, cholesterol 2 - 5 parts, sodium pyrophosphate 0.5 - 2 parts;

[0016] Preferably, dexamethasone 3 parts, egg yolk sphingomyelin 5 parts, cholesterol 3 parts, sodium pyrophosphate 1 part.

[0017] The second object of the present invention is to provide a method for preparing the above - mentioned dexamethasone liposome, including the following steps:

[0018] (1) Dissolve the phospholipid and cholesterol in an appropriate organic solvent, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0019] (2) Dissolve the sodium pyrophosphate in a buffer solution, add dexamethasone, ultrasonicate, shake, add to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program - matically, and filter to obtain the dexamethasone liposome.

[0020] Furthermore, the organic solvent is selected from one of methanol, ethanol, chloroform, isopropane, and ether, and preferably ethanol.

[0021] Further, the buffer solution is selected from one of glycine-sodium phosphate buffer solution, glycine-tartrate buffer solution, glycine-sodium barbital buffer solution, and glycine-sodium citrate buffer solution, and preferably glycine-sodium phosphate buffer solution.

[0022] Further, the pH of the buffer solution is 5.5 - 7.5, and preferably pH = 6.2.

[0023] Further, the programmed temperature control is as follows:

[0024] The water bath temperature is 25 - 35°C for 10 - 30 min; the water bath temperature is 35 - 45°C for 10 - 30 min; the water bath temperature is 45 - 55°C for 10 - 30 min; the water bath temperature is 10 - 20°C for 10 - 30 min;

[0025] Preferably, the water bath temperature is 30°C for 20 min; the water bath temperature is 40°C for 20 min; the water bath temperature is 50°C for 20 min; the water bath temperature is 15°C for 20 min.

[0026] The third object of the present invention is to provide a dexamethasone tablet, which is characterized in that it is prepared from the above-mentioned dexamethasone liposome and pharmaceutically acceptable excipients.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] (1) The present invention preferably selects the liposome membrane material, especially the addition of sodium pyrophosphate, which significantly improves the encapsulation rate of dexamethasone liposome, thereby further solving the problem of light sensitivity of dexamethasone and improving the stability of dexamethasone preparation under strong light irradiation.

[0029] (2) The present invention optimizes the preparation process, adjusts the pH of the solution to a suitable range, improves the drug loading of dexamethasone liposome, reduces the leakage rate, and significantly improves the physical stability. Description of the Drawings

[0030] Figures 1-4 : Drug loading and encapsulation rate of dexamethasone liposome in Examples 1 - 7 and Comparative Examples 1 - 12

[0031] Figure 5 : Stability investigation of dexamethasone liposome tablets and reference preparations in high temperature and high humidity accelerated test in Examples 8 - 11

[0032] Figure 6 : Stability investigation of dexamethasone liposome tablets and reference preparations under strong light irradiation in Examples 8 - 11 Detailed Embodiments

[0033] In order to make the objectives and technical solutions of the present invention clearer and more understandable, the following further describes the present invention in conjunction with embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0034] Example 1 Dexamethasone Liposome

[0035]

[0036] Preparation Method:

[0037] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0038] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, ultrasonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature program, with the water bath temperature at 30 °C for 20 min; water bath temperature at 40 °C for 20 min; water bath temperature at 50 °C for 20 min; water bath temperature at 15 °C for 20 min, and then filter to obtain dexamethasone liposome.

[0039] Example 2 Dexamethasone Liposome

[0040]

[0041] Preparation Method:

[0042] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome;

[0043] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 5.5, add dexamethasone, ultrasonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature program, with the water bath temperature at 30 °C for 20 min; water bath temperature at 40 °C for 20 min; water bath temperature at 50 °C for 20 min; water bath temperature at 15 °C for 20 min, and then filter to obtain dexamethasone liposome.

[0044] Example 3 Dexamethasone Liposome

[0045]

[0046] Preparation Method:

[0047] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0048] (2) Dissolve sodium pyrophosphate in glycine-sodium citrate buffer solution with pH = 7.5, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure with programmed temperature control. The water bath temperature is 30 °C for 20 min, 40 °C for 20 min, 50 °C for 20 min, and 15 °C for 20 min. Filter to obtain dexamethasone liposomes.

[0049] Example 4 Dexamethasone Liposomes

[0050]

[0051]

[0052] Preparation method:

[0053] (1) Dissolve phospholipids and cholesterol in an appropriate amount of methanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film.

[0054] (2) Dissolve sodium pyrophosphate in glycine-barbiturate buffer solution with pH = 5.5, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure with programmed temperature control. The water bath temperature is 35 °C for 10 min, 45 °C for 10 min, 55 °C for 10 min, and 10 °C for 10 min. Filter to obtain dexamethasone liposomes.

[0055] Example 5 Dexamethasone Liposomes

[0056]

[0057] Preparation method:

[0058] (1) Dissolve phospholipids and cholesterol in an appropriate amount of chloroform, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film.

[0059] (2) Dissolve sodium pyrophosphate in glycine-tartaric acid buffer solution with pH = 7.5, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure with programmed temperature control. The water bath temperature is 25 °C for 30 min, 35 °C for 30 min, 45 °C for 30 min, and 20 °C for 30 min. Filter to obtain dexamethasone liposomes.

[0060] Example 6 Dexamethasone Liposomes

[0061]

[0062] Preparation method:

[0063] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0064] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, ultrasonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature program, with a water bath temperature of 30 °C for 20 min; water bath temperature of 40 °C for 20 min; water bath temperature of 50 °C for 20 min; water bath temperature of 15 °C for 20 min, and then filter to obtain dexamethasone liposomes.

[0065] Example 7 Dexamethasone Liposomes

[0066]

[0067] Preparation method:

[0068] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0069] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, ultrasonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature program, with a water bath temperature of 30 °C for 20 min; water bath temperature of 40 °C for 20 min; water bath temperature of 50 °C for 20 min; water bath temperature of 15 °C for 20 min, and then filter to obtain dexamethasone liposomes.

[0070] Comparative Example 1 Dexamethasone Liposomes

[0071]

[0072] Preparation method:

[0073] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0074] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, ultrasonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature program, with a water bath temperature of 30 °C for 20 min; water bath temperature of 40 °C for 20 min; water bath temperature of 50 °C for 20 min; water bath temperature of 15 °C for 20 min, and then filter to obtain dexamethasone liposomes.

[0075] Comparative Example 2 Dexamethasone Liposomes

[0076]

[0077]

[0078] Preparation method:

[0079] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0080] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate, shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30 °C, 20 min; water bath temperature 40 °C, 20 min; water bath temperature 50 °C, 20 min; water bath temperature 15 °C, 20 min, filter to obtain dexamethasone liposomes.

[0081] Dexamethasone liposomes of Comparative Example 3

[0082]

[0083] Preparation method:

[0084] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0085] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate, shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30 °C, 20 min; water bath temperature 40 °C, 20 min; water bath temperature 50 °C, 20 min; water bath temperature 15 °C, 20 min, filter to obtain dexamethasone liposomes.

[0086] Dexamethasone liposomes of Comparative Example 4

[0087]

[0088] Preparation method:

[0089] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0090] (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate, shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30 °C, 20 min; water bath temperature 40 °C, 20 min; water bath temperature 50 °C, 20 min; water bath temperature 15 °C, 20 min, filter to obtain dexamethasone liposomes.

[0091] Comparative Example 5 Dexamethasone Liposomes

[0092]

[0093] Preparation method:

[0094] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0095] (2) Dissolve dexamethasone in glycine-sodium phosphate buffer solution with pH = 6.2, sonicate and shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30 °C, 20 min; water bath temperature 40 °C, 20 min; water bath temperature 50 °C, 20 min; water bath temperature 15 °C, 20 min, filter to obtain dexamethasone liposomes.

[0096] Comparative Example 6 Dexamethasone Liposomes

[0097]

[0098] Preparation method:

[0099] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0100] (2) Dissolve sodium phosphate in glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate and shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30 °C, 20 min; water bath temperature 40 °C, 20 min; water bath temperature 50 °C, 20 min; water bath temperature 15 °C, 20 min, filter to obtain dexamethasone liposomes.

[0101] Comparative Example 7 Dexamethasone Liposomes

[0102]

[0103]

[0104] Preparation method:

[0105] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethyl acetate, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0106] (2) Dissolve sodium pyrophosphate in glycine-sodium phosphate buffer solution with pH = 6.2, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure, with temperature programmed control. The water bath temperature is 30 °C for 20 min; 40 °C for 20 min; 50 °C for 20 min; 15 °C for 20 min. Filter to obtain dexamethasone liposomes.

[0107] Comparative Example 8 Dexamethasone Liposomes

[0108]

[0109] Preparation method:

[0110] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0111] (2) Dissolve sodium pyrophosphate in glycine-sodium phosphate buffer solution with pH = 5.0, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure, with temperature programmed control. The water bath temperature is 30 °C for 20 min; 40 °C for 20 min; 50 °C for 20 min; 15 °C for 20 min. Filter to obtain dexamethasone liposomes.

[0112] Comparative Example 9 Dexamethasone Liposomes

[0113]

[0114] Preparation method:

[0115] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0116] (2) Dissolve sodium pyrophosphate in glycine-sodium phosphate buffer solution with pH = 8.0, add dexamethasone, ultrasonicate, shake, and emulsify it into the blank liposome film obtained in step (1). Then continue rotary evaporation under reduced pressure, with temperature programmed control. The water bath temperature is 30 °C for 20 min; 40 °C for 20 min; 50 °C for 20 min; 15 °C for 20 min. Filter to obtain dexamethasone liposomes.

[0117] Comparative Example 10 Dexamethasone Liposomes

[0118]

[0119] Preparation method:

[0120] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0121] (2) Dissolve sodium pyrophosphate in a sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature programmatically, with a water bath temperature of 30 °C for 20 min; water bath temperature of 40 °C for 20 min; water bath temperature of 50 °C for 20 min; water bath temperature of 15 °C for 20 min, and then filter to obtain dexamethasone liposomes.

[0122] Comparative Example 11 Dexamethasone Liposomes

[0123]

[0124] Preparation method:

[0125] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0126] (2) Dissolve sodium pyrophosphate in a glycine - sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Continue rotary evaporation under reduced pressure, control the temperature programmatically, with a water bath temperature of 30 °C for 20 min; water bath temperature of 40 °C for 20 min; water bath temperature of 50 °C for 20 min, and then filter to obtain dexamethasone liposomes.

[0127] Comparative Example 12 Dexamethasone Liposomes

[0128]

[0129]

[0130] Preparation method:

[0131] (1) Dissolve phospholipids and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film;

[0132] (2) Dissolve sodium pyrophosphate in a glycine - sodium phosphate buffer solution with pH = 6.2, add dexamethasone, sonicate and shake, then add it to the blank liposome film obtained in step (1) for emulsification. Rotary evaporate under reduced pressure at a water bath temperature of 40 °C, and then filter to obtain dexamethasone liposomes.

[0133] Example 8 Dexamethasone Tablets

[0134] According to the drug loading amount, take the dexamethasone liposomes of Example 1, dry them, add appropriate fillers (starch), disintegrants (crospovidone), lubricants (talc powder), granulate, and press tablets to obtain dexamethasone tablets.

[0135] Example 9 Dexamethasone Tablets

[0136] According to the drug loading amount, take the dexamethasone liposomes of Example 2, dry them, add appropriate amounts of filler (mannitol), disintegrant (sodium carboxymethyl starch), and lubricant (microcrystalline silica), granulate, and press tablets to obtain dexamethasone tablets.

[0137] Example 10 Dexamethasone Tablets

[0138] According to the drug loading amount, take the dexamethasone liposomes of Example 3, dry them, add appropriate amounts of filler (dextrin), disintegrant (low-substituted hydroxypropyl cellulose), and lubricant (magnesium stearate), granulate, and press tablets to obtain dexamethasone tablets.

[0139] Example 11 Dexamethasone Tablets

[0140] According to the drug loading amount, take the dexamethasone liposomes of Example 5, dry them, add appropriate amounts of filler (dextrin, starch), disintegrant (low-substituted hydroxypropyl cellulose), and lubricant (magnesium stearate), granulate, and press tablets to obtain dexamethasone tablets.

[0141] Reference Preparation:

[0142] Dexamethasone Tablets (Hainan Meike Pharmaceutical Co., Ltd., National Drug Approval Number H460206**)

[0143] Verification Example

[0144] I. Quality Evaluation of Drug Loading Amount, Encapsulation Efficiency, and Leakage Rate of Dexamethasone Liposomes in Examples 1-7 and Comparative Examples 1-12 1. Encapsulation Efficiency and Drug Loading Amount of Dexamethasone Liposomes

[0145] The encapsulation efficiency and drug loading amount of dexamethasone liposomes were determined by ultrafiltration centrifugation method, and the average encapsulation efficiency and drug loading amount were calculated for 3 batches of samples.

[0146] The results are as Figures 1-4 shown, the drug loading amount and encapsulation efficiency of the dexamethasone liposomes in Examples 1-7 of the present invention are high.

[0147] 2. Stability of Dexamethasone Liposomes

[0148] The dexamethasone liposomes were stored at 25 °C, and the encapsulation efficiency was measured at 0 d and 180 d respectively, and the leakage rate of the dexamethasone liposomes was calculated.

[0149] Table 1 Leakage Rates of Dexamethasone Liposomes in Examples 1-7 and Comparative Examples 1-12

[0150] Leakage rate (%) Leakage rate (%) Example 1 0.06 Comparative Example 1 0.19 Example 2 0.08 Comparative Example 2 0.16 Example 3 0.09 Comparative Example 3 0.45 Example 4 0.12 Comparative Example 4 0.27 Example 5 0.09 Comparative Example 5 0.52 Example 6 0.13 Comparative Example 6 0.46 Example 7 0.11 Comparative Example 7 0.22 Comparative Example 10 0.36 Comparative Example 8 0.39 Comparative Example 11 0.33 Comparative Example 9 0.38 Comparative Example 12 0.32

[0151] Table 1 shows that the dexamethasone liposomes in Examples 1-7 of the present invention have high stability, and after storage at 25°C for 180 days, the leakage rate is low. The dexamethasone liposomes prepared in Comparative Examples 1-12 have poor stability. In particular, in Comparative Examples 3-6, the amount of sodium pyrophosphate was changed and sodium pyrophosphate was replaced, etc., and the leakage rate of the dexamethasone liposomes is high.

[0152] II. Stability Study of Dexamethasone Tablets

[0153] Related substances: Determined by high performance liquid chromatography (General Principles 0512).

[0154] Test solution: Take an appropriate amount of this product, weigh accurately, dissolve with methanol and quantitatively dilute to make a solution containing about 0.5 mg per 1 ml.

[0155] Control solution: Take an appropriate amount of betamethasone reference substance, weigh accurately, dissolve with methanol and quantitatively dilute to make a solution containing about 0.5 mg per 1 ml. Accurately measure 1 ml, place it in a 100-ml volumetric flask, accurately add 1 ml of the test solution, dilute to the mark with methanol, and shake well.

[0156] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler; use acetonitrile-water (28:72) as the mobile phase; the detection wavelength is 240 nm; the injection volume is 20 μl.

[0157] System suitability requirements: In the chromatogram of the control solution, the elution order of the peaks is the betamethasone peak and the dexamethasone peak in sequence, and the resolution between the two peaks should meet the requirements.

[0158] Determination method: Accurately measure the test solution and the control solution, and inject them into the liquid chromatograph respectively, and record the chromatogram until 2.5 times the retention time of the main component peak.

[0159] Limit: In the chromatogram of the test solution, if there is a chromatographic peak with the same retention time as betamethasone, calculated by the external standard method with the peak area, it shall not exceed 0.5%; the area of other individual impurity peaks shall not be greater than the area of the dexamethasone peak in the control solution (1.0%), and the sum of the areas of other impurity peaks shall not be greater than 1.5 times the area of the dexamethasone peak in the control solution (1.5%). Peaks less than 0.01 times the area of the dexamethasone peak in the control solution are ignored.

[0160] 1. Accelerated Test under High Temperature and High Humidity

[0161] Accelerated test: According to the commercial packaging, place it at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples are taken at the end of the 0th month, 1st month, 2nd month, 3rd month, and 6th month during the test period to measure the related substance content of the dexamethasone tablets in Examples 8-11 and the reference preparation.

[0162] 2. Study on Light Irradiation Experiment

[0163] The dexamethasone liposome tablets and the reference preparation prepared in Examples 8-11 were respectively placed in a light exposure device and placed for 30 days under the condition of an illuminance of 1.2×10 6 lx. The determination of the related substance content was carried out on the 0th day, 5th day, 10th day, 20th day, and 30th day to investigate the stability of the preparation under strong light irradiation.

[0164] Figure 5 It is for the stability investigation of the high temperature and high humidity accelerated test of the dexamethasone liposome tablets and the reference preparation in Examples 8-11. Figure 6 It is the result of the stability investigation of the dexamethasone liposome tablets and the reference preparation in Examples 8-11 under strong light irradiation. The results show that the dexamethasone tablets of the present invention have high stability.

Claims

1. A dexamethasone liposome, characterized in that, the formulation of the dexamethasone liposome is: 3 parts of dexamethasone, 5 parts of egg yolk phosphatidylcholine, 3 parts of cholesterol, and 1 part of sodium pyrophosphate; the preparation method of the dexamethasone liposome is: (1) Dissolve egg yolk phosphatidylcholine and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film; (2) Dissolve sodium pyrophosphate in a glycine-sodium phosphate buffer solution with a pH of 6.2, add dexamethasone, ultrasonicate, shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30°C, 20 min; water bath temperature 40°C, 20 min; water bath temperature 50°C, 20 min; water bath temperature 15°C, 20 min, filter to obtain dexamethasone liposome.

2. A dexamethasone liposome, characterized in that, the formulation of the dexamethasone liposome is: 5 parts of dexamethasone, 8 parts of egg yolk phosphatidylcholine, 5 parts of cholesterol, and 2 parts of sodium pyrophosphate; the preparation method of the dexamethasone liposome is: (1) Dissolve egg yolk phosphatidylcholine and cholesterol in an appropriate amount of ethanol, and remove the organic solvent by rotary evaporation under reduced pressure to obtain a blank liposome film; (2) Dissolve sodium pyrophosphate in a glycine-sodium citrate buffer solution with a pH of 7.5, add dexamethasone, ultrasonicate, shake, add it to the blank liposome film obtained in step (1) for emulsification, continue rotary evaporation under reduced pressure, control the temperature program, water bath temperature 30°C, 20 min; water bath temperature 40°C, 20 min; water bath temperature 50°C, 20 min; water bath temperature 15°C, 20 min, filter to obtain dexamethasone liposome.

3. A dexamethasone tablet, characterized in that, it is prepared from the dexamethasone liposome according to claim 1 or 2 and pharmaceutically acceptable excipients.

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