An empagliflozin liposome, a preparation method and a preparation
Empagliflozin liposome technology has solved the problem of slow dissolution rate, achieving high drug loading and stability, improving the dissolution rate and bioavailability of empagliflozin, and enhancing the safety of the formulation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- XINYI CITY PEOPLES HOSPITAL
- Filing Date
- 2023-10-27
- Publication Date
- 2026-06-05
AI Technical Summary
Empagliflozin is a poorly soluble drug with a slow dissolution rate, resulting in low bioavailability. Existing technologies using micronization methods suffer from high losses and high costs.
Empagliflozin liposomes were prepared using liposome technology by combining empagliflozin, egg yolk phospholipids, cholesterol, and uracil. High-pressure homogenization technology was used to improve drug loading and encapsulation efficiency, resulting in liposomes with uniform particle size and intact physical morphology.
It improved the dissolution and formulation stability of empagliflozin, reduced the content of related substances, and enhanced the bioavailability and safety of the drug.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an empagliflozin liposome, its preparation method, and its formulation. Background Technology
[0002] Diabetes is the fastest-growing prevalent chronic disease globally and a leading cause of serious illnesses such as cardiovascular disease, blindness, kidney failure, and amputation. Currently, there are 540 million adults with diabetes worldwide. Diabetes has become a major public health problem that seriously endangers health and imposes a heavy economic burden on society, making prevention and control an urgent priority.
[0003] Empagliflozin is a type 2 diabetes treatment jointly developed by Boehringer Ingelheim (Germany) and Eli Lilly (USA). It was approved for marketing in the European Union on May 22, 2014, and by the US FDA on August 1, 2014. It is the third globally marketed inhibitor of sodium-glucose cotransporter 2 (SGLT-2) to target a novel therapeutic target for diabetes. It is beneficial for blood glucose control in patients with type 2 diabetes, does not cause hypoglycemia, and has some weight-loss effects, providing patients with a better treatment option.
[0004] Empagliflozin is a white to slightly yellow powder, extremely soluble in water (very slightly soluble in aqueous media at pH 1.0, pH 4.0, and pH 7.4), slightly soluble in acetonitrile, 50% methanol, and ethanol, soluble in 50% acetonitrile, slightly soluble in methanol, and practically insoluble in toluene. Because empagliflozin is a poorly soluble drug with a slow dissolution rate, and drug dissolution directly affects drug absorption, low dissolution leads to low bioavailability and affects drug efficacy. Due to its low solubility, empagliflozin is typically improved by micronization. However, micronization requires specialized air jet milling equipment, resulting in high losses, low yields, waste, and increased costs.
[0005] Liposome drug delivery technology is now widely accepted in the industry as a novel drug delivery system, with more than ten liposome products launched, including doxorubicin, vincristine, daunorubicin, paclitaxel, irinotecan, mivaminide, cytarabine / daunorubicin, amphotericin B, bupivacaine, and acaricin. However, there are few reports on the technology of empagliflozin liposome products. Summary of the Invention
[0006] To overcome the shortcomings of existing technologies, this invention provides a liposome encapsulating empagliflozin using liposome technology, which solves the problem of slow dissolution rate of the poorly soluble drug empagliflozin, while improving the stability and safety of empagliflozin formulations and reducing the content of related substances.
[0007] The first objective of this invention is to provide an empagliflozin liposome composed of the following components: 10 parts by weight of empagliflozin, 20-30 parts by weight of egg yolk phospholipids, 2-7 parts by weight of cholesterol, and 1-4 parts by weight of uracil.
[0008] In one embodiment, the empagliflozin liposome is composed of the following components: 10 parts by weight of empagliflozin, 25 parts by weight of egg yolk phospholipids, 5 parts by weight of cholesterol, and 2 parts by weight of uracil.
[0009] A second objective of this invention is to provide a method for preparing the above-mentioned empagliflozin liposomes, the method comprising the following steps:
[0010] (1) Dissolve uracil in an appropriate amount of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep it warm and set aside for later use;
[0011] (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use;
[0012] (3) Dissolve egg yolk phospholipids and cholesterol in an appropriate amount of organic solvent, add buffer solution, place in a flask, and perform vacuum rotary evaporation in a water bath at 35~45℃ to remove organic solvent and obtain lipid film;
[0013] (4) Add the empagliflozin suspension obtained in step (2) to the lipid film in step (3) for full hydration, and then homogenize under high pressure to obtain empagliflozin liposomes.
[0014] In several embodiments, the organic solvent is selected from chloroform, methanol, and ethanol.
[0015] In one preferred embodiment, the organic solvent is trichloromethane.
[0016] In several embodiments, the buffer solution is selected from one of citrate buffer solution, phosphate buffer solution, and acetate buffer solution.
[0017] In one preferred embodiment, the buffer solution is a phosphate buffer solution.
[0018] In several embodiments, the pH of the buffer solution is 5.5 to 6.8.
[0019] In one preferred embodiment, the buffer solution has a pH of 6.2.
[0020] The empagliflozin liposomes mentioned above can also be used in combination with other drugs in clinical practice, such as metformin.
[0021] The present invention also provides a formulation comprising the above-described empagliflozin liposomes and pharmaceutically acceptable excipients.
[0022] Furthermore, the formulation is a tablet, granule, or capsule.
[0023] The present invention also provides the use of the above-mentioned empagliflozin liposomes in the preparation of a drug for treating diabetes.
[0024] Compared with the prior art, the technical advantages of the present invention are as follows:
[0025] This invention provides empagliflozin liposomes with uniform particle size, intact physical morphology, high drug loading, high encapsulation efficiency, and high stability. Formulations prepared using empagliflozin liposomes of this invention effectively reduce the content of related substances, improve the stability of the formulation, and solve the problem of low dissolution rate of empagliflozin in water, thereby improving the dissolution rate of empagliflozin formulations. Attached Figure Description
[0026] Figure 1 Example 1: Electron micrograph of empagliflozin liposomes
[0027] Figure 2 Schematic diagram of empagliflozin liposomes
[0028] Figure 3 Impurities A and B in empagliflozin
[0029] Figure 4 Dissolution curve of empagliflozin formulation Detailed Implementation
[0030] Example 1: Empagliflozin Liposomes
[0031] formula:
[0032] Empagliflozin 1g
[0033] Egg yolk lecithin 2.5g
[0034] Cholesterol 0.5g
[0035] Uracil 0.2g
[0036] Preparation method:
[0037] (1) Dissolve uracil in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep warm and set aside for later use;
[0038] (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use;
[0039] (3) Dissolve egg yolk phospholipids and cholesterol in 30 ml of chloroform, add phosphate buffer solution with pH=6.2, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0040] (4) The empagliflozin suspension obtained in step (2) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was 32.52% and the encapsulation rate was 86.75%.
[0041] Example 2: Empagliflozin Liposomes
[0042] formula:
[0043] Empagliflozin 1g
[0044] Egg yolk lecithin 2.0g
[0045] Cholesterol 0.2g
[0046] Uracil 0.1g
[0047] Preparation method:
[0048] (1) Dissolve uracil in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep warm and set aside for later use;
[0049] (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use;
[0050] (3) Dissolve egg yolk phospholipids and cholesterol in 30 ml of methanol, add citrate buffer solution with pH=5.5, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0051] (4) The empagliflozin suspension obtained in step (2) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was measured to be 29.36% and the encapsulation rate was 87.04%.
[0052] Example 3: Empagliflozin Liposomes
[0053] formula:
[0054] Empagliflozin 1g
[0055] Egg yolk lecithin 3.0g
[0056] Cholesterol 0.7g
[0057] Uracil 0.4g
[0058] Preparation method:
[0059] (1) Dissolve uracil in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep warm and set aside for later use;
[0060] (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use;
[0061] (3) Dissolve egg yolk phospholipids and cholesterol in 30 ml of ethanol, add acetate buffer solution with pH=6.8, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvent and obtain lipid film;
[0062] (4) The empagliflozin suspension obtained in step (2) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was 30.51% and the encapsulation rate was 86.18%.
[0063] Example 4: Empagliflozin tablets (10 tablets)
[0064] The dried empagliflozin liposomes (containing 100 mg empagliflozin) from Example 1 were pulverized and mixed with pulverized 0.21 g starch, 0.04 g sodium carboxymethyl starch and 0.01 g magnesium stearate powder. The mixture was directly compressed into tablets and coated with a film to obtain empagliflozin tablets.
[0065] Example 5: Empagliflozin tablets (10 tablets)
[0066] The dried empagliflozin liposomes (containing 100 mg empagliflozin) from Example 2 were pulverized and mixed with pulverized 0.21 g starch, 0.04 g sodium carboxymethyl starch and 0.01 g magnesium stearate powder. The mixture was directly compressed into tablets and coated with a film to obtain empagliflozin tablets.
[0067] Example 6: Empagliflozin tablets (10 tablets)
[0068] The dried empagliflozin liposomes (containing 100 mg empagliflozin) from Example 3 were pulverized and mixed with pulverized 0.21 g starch, 0.04 g sodium carboxymethyl starch and 0.01 g magnesium stearate powder. The mixture was directly compressed into tablets and coated with a film to obtain empagliflozin tablets.
[0069] Example 7: Metformin empagliflozin tablets (10 tablets)
[0070] The dried empagliflozin liposomes (containing 50 mg empagliflozin) from Example 1 were pulverized and mixed with 5 g of pulverized metformin, 0.15 g of starch, 0.04 g of sodium carboxymethyl starch, and 0.01 g of magnesium stearate powder. The mixture was directly compressed into tablets and coated with a film to obtain metformin empagliflozin tablets.
[0071] Comparative Example 1: Empagliflozin Liposomes
[0072] formula:
[0073] Empagliflozin 1g
[0074] Egg yolk lecithin 2.5g
[0075] Cholesterol 0.5g
[0076] Preparation method:
[0077] (1) Dissolve empagliflozin in deionized water and disperse it to obtain an empagliflozin suspension for later use;
[0078] (2) Dissolve egg yolk phospholipids and cholesterol in 30 ml of chloroform, add phosphate buffer solution with pH=6.2, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0079] (3) The empagliflozin suspension obtained in step (1) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was 18.37% and the encapsulation efficiency was 72.61%.
[0080] Comparative Example 2: Empagliflozin Liposomes
[0081] formula:
[0082] Empagliflozin 1g
[0083] Egg yolk lecithin 2.5g
[0084] Cholesterol 0.5g
[0085] Uracil 0.6g
[0086] Preparation method:
[0087] (1) Dissolve uracil in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep warm and set aside for later use;
[0088] (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use;
[0089] (3) Dissolve egg yolk phospholipids and cholesterol in 30 ml of chloroform, add phosphate buffer solution with pH=6.2, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0090] (4) The empagliflozin suspension obtained in step (2) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was 24.06% and the encapsulation efficiency was 77.52%.
[0091] Comparative Example 3: Empagliflozin Liposomes
[0092] formula:
[0093] Empagliflozin 1g
[0094] Egg yolk lecithin 2.5g
[0095] Cholesterol 0.5g
[0096] Thymine 0.2g
[0097] Preparation method:
[0098] (1) Dissolve thymine in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of thymine, keep warm and set aside for later use;
[0099] (2) Disperse empagliflozin in the aqueous solution of thymine described in step (1) to obtain an empagliflozin suspension for later use;
[0100] (3) Dissolve egg yolk phospholipids and cholesterol in 30 ml of chloroform, add phosphate buffer solution with pH=6.2, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0101] (4) The empagliflozin suspension obtained in step (2) was added to the lipid film in step (3) and fully hydrated. Then, it was homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was 20.65% and the encapsulation rate was 73.40%.
[0102] Comparative Example 4: Empagliflozin Liposomes
[0103] formula:
[0104] Empagliflozin 1g
[0105] Egg yolk lecithin 2.5g
[0106] Cholesterol 0.5g
[0107] Uracil 0.2g
[0108] Preparation method:
[0109] (1) Dissolve uracil in 20 ml of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep warm and set aside for later use;
[0110] (2) Dissolve empagliflozin, egg yolk phospholipids and cholesterol in 30 ml of chloroform, add phosphate buffer solution with pH=6.2, place in a flask, and perform rotary evaporation under reduced pressure in a water bath at 35~45℃ to remove organic solvents and obtain lipid film;
[0111] (3) The uracil aqueous solution obtained in step (1) is added to the lipid film in step (2) for full hydration, and then homogenized under high pressure to obtain empagliflozin liposomes. The drug loading was measured to be 84.16% and the encapsulation rate was 77.54%.
[0112] Comparative Example 5: Empagliflozin Tablets (10 tablets)
[0113] The dried empagliflozin liposomes (containing 100 mg empagliflozin) of Comparative Example 1 were pulverized and mixed with pulverized 0.21 g starch, 0.04 g sodium carboxymethyl starch and 0.01 g magnesium stearate powder. The mixture was directly compressed into tablets and coated with a film to obtain empagliflozin tablets.
[0114] Commercially available preparation: Empagliflozin tablets (National Drug Approval Number HJ20201008)
[0115] Determination of empagliflozin liposome leakage rate
[0116] The empagliflozin liposomes of Examples 1-3 and Comparative Examples 1-4 were stored at 30°C for 30 days and 180 days, and the leakage rate was measured and calculated. The leakage rate was calculated as (amount of drug leaked into the medium after storage - amount of drug encapsulated in the liposomes before storage) × 100%.
[0117] Table 1. Leakage rate (%) of empagliflozin liposomes in Examples 1-3 and Comparative Examples 1-4
[0118]
[0119] As shown in Table 1, the empagliflozin liposomes of the present invention have high stability and do not leak after being stored at 30°C for a period of time. In contrast, the empagliflozin liposomes prepared in Comparative Examples 1-4 have high leakage rates and poor stability.
[0120] Stability testing of empagliflozin formulations
[0121] Accelerated stability tests were conducted on empagliflozin tablets of Examples 4-6, metformin empagliflozin tablets of Example 7, empagliflozin tablets of Comparative Example 5, and commercially available formulations. The above formulations were placed in a constant temperature and humidity chamber at high temperature (40°C) and high humidity (75±5% relative humidity) for accelerated testing. Samples were taken at month 0 and month 6 to determine the content of related substances (impurity A, impurity B) and total impurities.
[0122] Table 2. Content of related substances in accelerated test of empagliflozin formulations
[0123]
[0124] As shown in Table 2, the empagliflozin formulation of this invention has high stability, and its content of related substances remains basically unchanged during high temperature and high humidity storage.
[0125] Empagliflozin formulation dissolution
[0126] According to the method of Dissolution and Release Determination (General Rule 0931, Method II) in Part IV of the 2020 edition of the Chinese Pharmacopoeia, dissolution tests were performed on empagliflozin tablets of Examples 4-6, metformin empagliflozin tablets of Example 7, empagliflozin tablets of Comparative Example 5, and commercially available formulations. The temperature was 37°C ± 0.5°C, the dissolution medium was 0.1 mol / L hydrochloric acid solution, the medium volume was 900 ml, the rotation speed was 50 rpm, and samples were taken after 5, 10, 15, and 30 minutes. The solutions were filtered through a 0.45 μm microporous membrane, and the corresponding dissolution medium at the same temperature was replenished in the operating container in a timely manner. The detection method was HPLC.
[0127] Figure 4 The invention demonstrates that the empagliflozin tablets of this invention have high dissolution rate, solving the problem of slow dissolution rate of the poorly soluble drug empagliflozin.
Claims
1. An empagliflozin liposome, characterized in that, The empagliflozin liposomes are composed of the following components: 10 parts by weight of empagliflozin, 20-30 parts by weight of egg yolk phospholipids, 2-7 parts by weight of cholesterol, and 1-4 parts by weight of uracil. The method for preparing the empagliflozin liposomes is as follows: (1) Dissolve uracil in an appropriate amount of deionized water at 45~55℃ to obtain an aqueous solution of uracil, keep it warm and set aside for later use; (2) Disperse empagliflozin in the uracil aqueous solution described in step (1) to obtain an empagliflozin suspension for later use; (3) Dissolve egg yolk phospholipids and cholesterol in an appropriate amount of organic solvent, add buffer solution, place in a flask, and perform vacuum rotary evaporation in a water bath at 35~45℃ to remove organic solvent and obtain lipid film; (4) Add the empagliflozin suspension obtained in step (2) to the lipid film in step (3) for full hydration, and then homogenize under high pressure to obtain empagliflozin liposomes.
2. The empagliflozin liposome as described in claim 1, characterized in that, The empagliflozin liposomes are composed of the following components: 10 parts by weight of empagliflozin, 25 parts by weight of egg yolk phospholipids, 5 parts by weight of cholesterol, and 2 parts by weight of uracil.
3. The empagliflozin liposome as described in claim 1, characterized in that, The organic solvent is selected from one of chloroform, methanol, and ethanol.
4. The empagliflozin liposome as described in claim 3, characterized in that, The organic solvent is trichloromethane.
5. The empagliflozin liposome as described in claim 1, characterized in that, The buffer solution is selected from one of citrate buffer solution, phosphate buffer solution, and acetate buffer solution.
6. The empagliflozin liposome as described in claim 5, characterized in that, The buffer solution is a phosphate buffer solution.
7. The empagliflozin liposome as described in claim 1, characterized in that, The pH of the buffer solution is 5.5 to 6.
8.
8. The empagliflozin liposome as described in claim 7, characterized in that, The pH of the buffer solution is 6.
2.
9. The empagliflozin liposome as described in claim 1, characterized in that, The empagliflozin liposomes can also be used in combination with other drugs in clinical practice.
10. A formulation, characterized in that, The formulation comprises empagliflozin liposomes as described in claim 1 and pharmaceutically acceptable excipients.
11. The formulation of claim 10, characterized in that, The preparations are tablets, granules, or capsules.