Atenolol liposome, preparation method and preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to atenolol liposome, a preparation method and a preparation. The atenolol liposome disclosed by the invention comprises the following components: atenolol, soybean phospholipid, cholesterol, nobiletin and sesbania gum, and by optimizing auxiliary materials required in preparation of the atenolol liposome, the defect of low drug loading capacity of the atenolol liposome in the prior art is overcome; compared with the prior art, the atenolol liposome has the advantages that the problem of low atenolol transmission efficiency caused by low drug loading capacity of the atenolol liposome in the prior art is solved, the atenolol liposome is further expanded to be prepared into the preparation, and compared with the prior art, the atenolol liposome has higher stability, and the content of related substances is lower than that of commercially available preparations.

Description

Technical Field

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

[0002] Atenolol is an organic compound with the chemical formula C 14 H 22 N2O3 is a β-adrenergic receptor blocker and a selective β1-adrenergic receptor blocker suitable for moderate and mild hypertension caused by various reasons. Atenolol can affect the hemodynamic state of the fetus and lead to intrauterine growth restriction of the fetus in early pregnancy, so it is not recommended during pregnancy. Atenolol is a cardiac selective β-receptor blocker with no membrane stabilizing effect and no endogenous sympathomimetic activity. It is generally used for sinus tachycardia and premature beats, and can also be used for hypertension, angina pectoris and glaucoma. Oral absorption is about 50%, and small doses can pass through the blood-brain barrier. Protein binding rate is 6-10%. The effect reaches its peak 2 to 4 hours after taking it, and the duration of action is longer. The half-life is 6 to 7 hours, and it is mainly excreted in the urine in its original form. It can be cleared during hemodialysis.

[0003] At present, domestically marketed atenolol preparations include atenolol tablets and atenolol injection. In the prior art, few atenolol liposomes have been disclosed. As a lipid-based drug carrier, liposome technology not only has good biocompatibility and no immunogenicity because its main raw material phospholipids are inherent components of human cells, but also liposomes can be prepared as nano-scale particles, making them easier to penetrate biological barriers such as blood vessel walls and cell membranes.

[0004] The Chinese patent with publication number CN115429745A discloses a flexible nanoliposome gel of atenolol and a preparation method thereof, wherein the flexible nanoliposome gel of atenolol is composed of atenolol, cholesterol, phospholipids, a gel matrix, a surfactant, a preservative, a moisturizer, a pH=7.4 PBS buffer and distilled water in a certain mass ratio. The flexible nanoliposome gel of atenolol has a high encapsulation rate and good skin permeability, but the drug loading of the flexible nanoliposome of atenolol is low, which greatly reduces the transfer rate of atenolol. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides an atenolol liposome with high drug loading and high encapsulation rate, which overcomes the defect of low drug loading of the atenolol liposome in the prior art, solves the problem of low atenolol delivery efficiency caused by low drug loading of the atenolol liposome in the prior art, and further utilizes the atenolol liposome to prepare a preparation, which has higher stability than the prior art, and the content of related substances is lower than that of commercially available preparations.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] The first object of the present invention is to provide an atenolol liposome, which comprises the following components: atenolol, soybean lecithin, cholesterol, nobiletin and sesbania gum.

[0008] In multiple embodiments, the components in the atenolol liposomes are calculated by weight as follows: 2 parts of atenolol, 2-4 parts of soybean lecithin, 0.5-1.5 parts of cholesterol, 0.1-0.3 parts of nobiletin, and 0.1-0.3 parts of sesbania gum.

[0009] In a preferred embodiment, the components in the atenolol liposomes are calculated by weight as follows: 2 parts of atenolol, 3 parts of soybean lecithin, 1 part of cholesterol, 0.2 parts of nobiletin, and 0.2 parts of sesbania gum.

[0010] A second object of the present invention is to provide a method for preparing the above-mentioned atenolol liposome, the method comprising the following steps:

[0011] (1) dissolving atenolol, soybean lecithin and cholesterol in an organic solvent, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0012] (2) adding a buffer solution containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) to hydrate the film, continuing to perform rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C., and homogenizing the film by high pressure emulsification to obtain atenolol liposomes.

[0013] In an embodiment, the organic solvent is ethanol and / or chloroform.

[0014] In a preferred embodiment, the organic solvent is ethanol.

[0015] In an embodiment, the buffer solution is a phosphate buffer solution or a citrate buffer solution.

[0016] In a preferred embodiment, the buffer solution is a citrate buffer solution.

[0017] In an embodiment, the pH of the buffer solution is 5.2-6.5.

[0018] In a preferred embodiment, the pH of the buffer solution is 5.8.

[0019] In an embodiment, the time of rotary evaporation in step (2) is 3 to 7 minutes.

[0020] In a preferred embodiment, the time of rotary evaporation in step (2) is 5 minutes.

[0021] The third object of the present invention is to provide a preparation consisting of the atenolol liposomes according to claim 1 and pharmaceutically acceptable excipients.

[0022] In an embodiment, the preparation is a tablet or an injection.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention optimizes the components required for the preparation of atenolol liposomes, especially adds a certain proportion of nobiletin and sesbania gum, overcomes the defect of low drug loading of atenolol liposomes in the prior art, solves the problem of low atenolol delivery efficiency caused by low drug loading of atenolol liposomes in the prior art, and further expands the atenolol liposomes to prepare preparations. Experiments show that the atenolol liposome preparation of the present invention has higher stability than the prior art, and the content of related substances is much lower than that of commercially available preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The average particle size of the atenolol liposomes in Examples 1 to 3 and the atenolol liposomes in Comparative Examples 1 to 2

[0026] Figure 2 The average particle size of the atenolol liposomes in Comparative Examples 3 to 6

[0027] Figure 3 The graph showing the changes in the contents of related substances in the atenolol tablets of Examples 4 to 6 and the commercially available atenolol tablets is shown in FIG. DETAILED DESCRIPTION

[0028] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art 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.

[0029] 1. Atenolol liposomes and preparation method

[0030] Example 1

[0031] formula:

[0032] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1 Nobiletin 0.2 Sesbania gum 0.2

[0033] Preparation method:

[0034] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0035] (2) adding a citrate buffer solution (pH=5.8) containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and homogenizing by high pressure emulsification to obtain atenolol liposomes.

[0036] Example 2

[0037] formula:

[0038]

[0039]

[0040] Preparation method:

[0041] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0042] (2) adding a phosphate buffer solution (pH=6.5) containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 3 min, and homogenizing by high pressure emulsification to obtain atenolol liposomes.

[0043] Example 3

[0044] formula:

[0045] Weight Atenolol 2 Soybean lecithin 4 cholesterol 1.5 Nobiletin 0.3 Sesbania gum 0.3

[0046] Preparation method:

[0047] (1) dissolving atenolol, soybean lecithin and cholesterol in chloroform, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0048] (2) adding a citrate buffer solution (pH=5.2) containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 7 min, and homogenizing by high pressure emulsification to obtain atenolol liposomes.

[0049] Comparative Example 1

[0050] formula:

[0051] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1 Sesbania gum 0.2

[0052] Preparation method:

[0053] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0054] (2) adding a citrate buffer solution (pH=5.8) containing sesbania gum to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and homogenizing by high pressure emulsification to obtain atenolol liposomes.

[0055] Comparative Example 2

[0056] formula:

[0057] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1 Nobiletin 0.2

[0058] Preparation method:

[0059] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0060] (2) adding a citrate buffer solution (pH=5.8) containing nobiletin to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and obtaining atenolol liposomes by high pressure homogenization.

[0061] Comparative Example 3

[0062] formula:

[0063] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1 Nobiletin 0.5 Sesbania gum 0.05

[0064] Preparation method:

[0065] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0066] (2) adding a citrate buffer solution (pH=5.8) containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) for hydration, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and homogenizing by high pressure emulsification to obtain atenolol liposomes.

[0067] Comparative Example 4

[0068] formula:

[0069] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1 Nobiletin 0.2 Sesbania gum 0.2

[0070] Preparation method:

[0071] (1) dissolving atenolol, soybean lecithin, cholesterol, nobiletin, and sesbania gum in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0072] (2) adding a citrate buffer solution (pH=5.8) to the phospholipid film containing atenolol obtained in step (1) to hydrate it, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and obtaining atenolol liposomes by high pressure homogenization.

[0073] Comparative Example 5

[0074] formula:

[0075] Weight Atenolol 2 Soybean lecithin 3 cholesterol 1

[0076] Preparation method:

[0077] (1) dissolving atenolol, soybean lecithin and cholesterol in ethanol, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol;

[0078] (2) adding a citrate buffer solution (pH=5.8) to the phospholipid film containing atenolol obtained in step (1) to hydrate it, and continuing to perform reduced pressure rotary evaporation in a water bath at 35° C. to 50° C. for 5 min, and obtaining atenolol liposomes by high pressure homogenization.

[0079] Comparative Example 6

[0080] The atenolol liposomes were prepared according to the method of Example 1 in the specification of Chinese patent CN115429745A.

[0081] 2. Quality evaluation of atenolol liposomes

[0082] 1. Particle size of atenolol liposomes

[0083] Figure 1 , Figure 2 The particle sizes of the atenolol liposomes of Examples 1 to 3 and Comparative Examples 1 to 6 are shown in Table 1. The atenolol liposomes of Examples 1 to 3 have regular spherical appearances and relatively uniform particle sizes; the atenolol liposomes of Comparative Examples 1 to 6 have irregular shapes, uneven particle sizes, and are accompanied by unformed liposomes.

[0084] 2. Drug loading and encapsulation efficiency of atenolol liposomes

[0085] Table 2 Drug loading and encapsulation efficiency of atenolol liposomes (%)

[0086] Drug loading (%) Encapsulation rate (%) Example 1 26.34 93.36 Example 2 20.63 91.27 Example 3 21.15 92.05 Comparative Example 1 15.25 80.62 Comparative Example 2 14.76 78.24 Comparative Example 3 17.53 82.39 Comparative Example 4 14.05 76.40 Comparative Example 5 15.32 77.31 Comparative Example 6 12.14 93.04

[0087] As shown in Table 2, compared with the prior art (Comparative Example 6), the encapsulation efficiency of the atenolol liposomes in Examples 1 to 3 of the present invention is comparable thereto, but the drug loading is much higher than that of the atenolol liposomes in Comparative Example 6, which greatly improves the drug delivery efficiency; the drug loading is also higher than that of the atenolol liposomes in Comparative Examples 1 to 5, and the encapsulation efficiency is high.

[0088] 3. Atenolol preparations

[0089] 1. Atenolol tablets

[0090] Example 4

[0091] The atenolol liposomes obtained in Example 1 were mixed with pharmaceutically acceptable excipients (appropriate amounts of starch, lactose, low-substituted hydroxypropyl cellulose sodium, and talc), and tablets were pressed by conventional tablet preparation methods to obtain atenolol tablets.

[0092] The pharmaceutically acceptable excipients may also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc. in pharmacy, and coating may also be performed.

[0093] Example 5

[0094] The atenolol liposomes obtained in Example 2 were mixed with pharmaceutically acceptable excipients (appropriate amounts of starch, lactose, sodium low-substituted hydroxypropyl cellulose, and talc), and tablets were compressed by conventional tablet preparation methods to obtain atenolol tablets.

[0095] The pharmaceutically acceptable excipients may also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc. in pharmacy, and coating may also be performed.

[0096] Example 6

[0097] The atenolol liposomes obtained in Example 3 were mixed with pharmaceutically acceptable excipients (appropriate amounts of starch, lactose, sodium low-substituted hydroxypropyl cellulose, and talc), and tablets were compressed by conventional tablet preparation methods to obtain atenolol tablets.

[0098] The pharmaceutically acceptable excipients may also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc. in pharmacy, and coating may also be performed.

[0099] 2. Atenolol injection

[0100] Example 7

[0101] The atenolol liposomes obtained in Example 1 were mixed with pharmaceutically acceptable excipients (appropriate amounts of sodium chloride, sodium pyrosulfite, and water for injection), and prepared by conventional preparation methods for injections to obtain atenolol injection.

[0102] The pharmaceutically acceptable excipients may also be other antioxidants, buffers, stabilizers, antibacterial agents, fillers, protective agents, etc. commonly used in pharmacy.

[0103] Example 8

[0104] The atenolol liposomes obtained in Example 2 were mixed with pharmaceutically acceptable excipients (appropriate amounts of sodium chloride, sodium pyrosulfite, and water for injection), and prepared by conventional preparation methods for injections to obtain atenolol injection.

[0105] The pharmaceutically acceptable excipients may also be other antioxidants, buffers, stabilizers, antibacterial agents, fillers, protective agents, etc. commonly used in pharmacy.

[0106] Example 9

[0107] The atenolol liposomes obtained in Example 3 were mixed with pharmaceutically acceptable excipients (appropriate amounts of sodium chloride, sodium pyrosulfite, and water for injection), and prepared by conventional preparation methods for injections to obtain atenolol injection.

[0108] The pharmaceutically acceptable excipients may also be other antioxidants, buffers, stabilizers, antibacterial agents, fillers, protective agents, etc. commonly used in pharmacy.

[0109] IV. Quality inspection of atenolol tablets

[0110] The appearance, weight difference, hardness and friability, disintegration time, dissolution and related substances of Examples 4 to 6 and commercially available atenolol tablets (National Medicine Standard H37020215) were investigated and all met the requirements of the Pharmacopoeia. Only the investigation results of the related substances are shown here.

[0111] The detection method for relevant substances is determined in accordance with the high performance liquid chromatography method (General Chapter 0512) of the "Chinese Pharmacopoeia".

[0112] Test solution: Take about 10 mg of this product, place it in a 100 ml volumetric flask, add an appropriate amount of mobile phase, dissolve it by ultrasound and dilute it to the scale, and shake it well. Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute it to the scale with the mobile phase, and shake it well. Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler; use phosphate buffer (take 6.8 g of potassium dihydrogen phosphate, 1.3 g of sodium octane sulfonate, dissolve it in water and dilute it to 1000 ml, and adjust the pH value to 3.0 with phosphoric acid)-methanol (70:30) as the mobile phase; the detection wavelength is 226 nm; the injection volume is 20 μl. System suitability requirements: The number of theoretical plates calculated based on the atenolol peak is not less than 2000. The separation between the atenolol peak and the adjacent impurity peak should meet the requirements. Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 3 times the retention time of the main component peak. Limit: If there are impurity peaks in the chromatogram of the test solution, the sum of the areas of the impurity peaks shall not be greater than the main peak area of ​​the control solution (1.0%).

[0113] The atenolol tablets of Examples 4 to 6 and commercially available atenolol tablets (National Medicine Standard H37020215) were used as test samples and placed at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 0th month, 1st month, 3rd month, and 6th month during the test to test the changes in the content of related substances in the atenolol tablets.

[0114] Figure 3 The graphs of the changes in the contents of related substances of the atenolol tablets of Examples 4 to 6 and commercially available atenolol tablets show that the atenolol tablets prepared by the present invention have high stability, and when stored in a high temperature and high humidity environment, the related substances increase slowly, and the content of related substances remains low, which is lower than that of commercially available preparations.

Claims

1. An atenolol liposome, characterized in that, The atenolol liposome comprises the following components: atenolol, soybean lecithin, cholesterol, nobiletin and sesbania gum.

2. The atenolol liposome according to claim 1, characterized in that The components in the atenolol liposome are calculated by weight as follows: 2 parts of atenolol, 2-4 parts of soybean lecithin, 0.5-1.5 parts of cholesterol, 0.1-0.3 parts of nobiletin, and 0.1-0.3 parts of sesbania gum.

3. The atenolol liposome according to claim 2, characterized in that The components in the atenolol liposome are calculated by weight as follows: 2 parts of atenolol, 3 parts of soybean lecithin, 1 part of cholesterol, 0.2 parts of nobiletin, and 0.2 parts of sesbania gum.

4. A method for preparing the atenolol liposome according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: (1) dissolving atenolol, soybean lecithin and cholesterol in an organic solvent, and performing rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C. to obtain a phospholipid film containing atenolol; (2) adding a buffer solution containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1) to hydrate the film, continuing to perform rotary evaporation under reduced pressure in a water bath at 35° C. to 50° C., and homogenizing the film by high pressure emulsification to obtain atenolol liposomes.

5. The method according to claim 4, characterized in that The organic solvent is ethanol and / or chloroform. Preferably, the organic solvent is ethanol.

6. The method according to claim 4, characterized in that The buffer solution is a phosphate buffer solution or a citrate buffer solution. Preferably, the buffer solution is a citrate buffer solution.

7. The method according to claim 4, characterized in that The pH of the buffer solution is 5.2-6.5, and preferably, the pH of the buffer solution is 5.

8.

8. The method according to claim 4, characterized in that The time of rotary evaporation in step (2) is 3 to 7 minutes. Preferably, the time of rotary evaporation in step (2) is 5 minutes.

9. A preparation, characterized in that The invention is composed of the atenolol liposome according to claim 1 and pharmaceutically acceptable excipients.

10. The preparation according to claim 9, characterized in that The preparation is a tablet or an injection.

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