A liposome of atenolol, a preparation method and a preparation

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a liposome of atenolol, a preparation method and a preparation. The liposome of atenolol comprises the following components: atenolol, soybean phospholipid, cholesterol, nobiletin and sesbania gum. By optimizing the excipients required in the preparation of the liposome of atenolol, the defects of low drug loading capacity of the liposome of atenolol in the prior art are overcome, the problem of low delivery efficiency of atenolol caused by low drug loading capacity of the liposome of atenolol in the prior art is solved, and the liposome of atenolol is further expanded to be prepared into a preparation. Compared with the prior art, the preparation has higher stability, and the content of related substances is lower than that of a commercial preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a liposome of atenolol, a preparation method and a preparation. BACKGROUND

[0002] Atenolol is an organic compound with the chemical formula C 14 H 22 N2O3, is a beta-adrenergic receptor blocker, is a selective beta1-adrenergic receptor blocker suitable for various causes of mild and moderate hypertension. Atenolol can affect the hemodynamic status of the fetus and cause intrauterine fetal growth restriction in early pregnancy, so it is not recommended to be selected during pregnancy. Atenolol is a selective beta-receptor blocker for the heart, has no membrane stabilizing effect, and has 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. The protein binding rate is 6-10%. The effect reaches the peak at 2-4 hours after taking, and the duration of action is long. The half-life is 6-7 hours, and it is mainly excreted in the original form from the urine. It can be removed during hemodialysis.

[0003] At present, the atenolol preparations on the market in China include atenolol tablets and atenolol injection. In the prior art, few atenolol liposomes are disclosed. Liposome technology, as a drug carrier based on lipids, not only has good biocompatibility and no immunogenicity because the main raw material phospholipid is an inherent component of human cells, but also can be prepared into nanoparticles, making it easier to penetrate biological barriers such as blood vessel walls and cell membranes.

[0004] A Chinese patent with the publication number CN115429745A discloses an atenolol flexible nanoliposome gel and a preparation method thereof. The atenolol flexible nanoliposome gel is composed of atenolol, cholesterol, phospholipid, gel matrix, surfactant, preservative, humectant, pH=7.4 PBS buffer and distilled water according to a certain mass ratio. The atenolol flexible nanoliposome gel has high encapsulation efficiency and good skin permeability, but the drug loading capacity of the atenolol flexible nanoliposome is low, which greatly reduces the delivery rate of atenolol. SUMMARY

[0005] In view of the deficiencies of the prior art, the present application provides an atenolol liposome with high drug loading capacity and high encapsulation efficiency, which overcomes the low drug loading capacity of the atenolol liposome in the prior art, solves the problem of low atenolol delivery efficiency caused by low drug loading capacity of the atenolol liposome in the prior art, and further prepares a preparation by using the atenolol liposome. Compared with the prior art, the present application has higher stability, and the related substance content is lower than that of the commercial preparation.

[0006] Specifically, the technical solutions of the present application are as follows:

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

[0008] In multiple embodiments, the components in the atenolol liposome are calculated by weight ratio as follows: 2 parts of atenolol, 2-4 parts of soybean phospholipid, 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 more preferred embodiment, the components in the atenolol liposome are calculated by weight ratio as follows: 2 parts of atenolol, 3 parts of soybean phospholipid, 1 part of cholesterol, 0.2 parts of nobiletin, and 0.2 parts of sesbania gum.

[0010] The second object of the present application is to provide a method for preparing the above-mentioned atenolol liposome, which comprises the following steps:

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

[0012] (2) Add a buffer solution containing nobiletin and sesbania gum to the phospholipid film containing atenolol obtained in step (1), and perform hydration, and then continue to perform rotary evaporation under reduced pressure in a water bath at 35-50°C, and then perform high-pressure homogenization to obtain atenolol liposomes.

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

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

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

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

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

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

[0019] In embodiments, the rotary evaporation time in step (2) is 3-7 min.

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

[0021] A third object of the present application is to provide a preparation consisting of the atenolol liposome of claim 1 and pharmaceutically acceptable adjuvants.

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

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

[0024] The present application preferably uses nobiletin and sesbania gum in the preparation of atenolol liposomes, which overcomes the 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 preparation of atenolol liposomes. Experiments show that the atenolol liposome preparation of the present application has higher stability and much lower related substance content than the commercially available preparation. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 Table 1: Average particle size of atenolol liposomes of Examples 1-3 and Comparative Examples 1-2

[0026] Figure 2 Table 2: Average particle size of atenolol liposomes of Comparative Examples 3-6

[0027] Figure 3 Figure 2: Change in related substance content of atenolol tablets of Examples 4-6 and commercially available atenolol tablets DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solutions of the present application clearer, the following embodiments are used to further illustrate the present application, but the protection scope of the present application is not limited to these embodiments, and the embodiments are only used to explain the present application. Those skilled in the art should understand that any changes or equivalent replacements without departing from the concept of the present application are included in the protection scope of the present application.

[0029] I. Atenolol liposome and preparation method

[0030] Example 1

[0031] Formulation:

[0032] Parts by weight Atenolol 2 Soybean phospholipid 3 Cholesterol 1 Nobiletin 0.2 Sesbania gum 0.2

[0033] Preparation method:

[0034] (1) Dissolve atenolol, soybean phospholipid and cholesterol in ethanol, and evaporate under reduced pressure in a water bath at 35-50°C to obtain a phospholipid film containing atenolol;

[0035] (2) To the phospholipid film containing atenolol obtained in step (1), add the citrate buffer solution (pH = 5.8) dissolving nobiletin and sesbania gum, hydrate, continue to reduce pressure rotary evaporation in water bath at 35-50°C for 5 min, and obtain atenolol liposome by high pressure emulsification.

[0036] Example 2

[0037] Formulation:

[0038]

[0039]

[0040] Preparation method:

[0041] (1) Dissolve atenolol, soybean phospholipid and cholesterol in ethanol, and obtain phospholipid film containing atenolol by reducing pressure rotary evaporation in water bath at 35-50°C;

[0042] (2) To the phospholipid film containing atenolol obtained in step (1), add the phosphate buffer solution (pH = 6.5) dissolving nobiletin and sesbania gum, hydrate, continue to reduce pressure rotary evaporation in water bath at 35-50°C for 3 min, and obtain atenolol liposome by high pressure emulsification.

[0043] Example 3

[0044] Formulation:

[0045] Parts by weight Atenolol 2 Soybean phospholipid 4 Cholesterol 1.5 Nobiletin 0.3 Sesbania gum 0.3

[0046] Preparation method:

[0047] (1) Dissolve atenolol, soybean phospholipid and cholesterol in chloroform, and obtain phospholipid film containing atenolol by reducing pressure rotary evaporation in water bath at 35-50°C;

[0048] (2) To the phospholipid film containing atenolol obtained in step (1), add the citrate buffer solution (pH = 5.2) dissolving nobiletin and sesbania gum, hydrate, continue to reduce pressure rotary evaporation in water bath at 35-50°C for 7 min, and obtain atenolol liposome by high pressure emulsification.

[0049] Comparative example 1

[0050] Formulation:

[0051] Parts by weight Atenolol 2 Soybean phospholipid 3 Cholesterol 1 Sesbania gum 0.2

[0052] Preparation method:

[0053] (1) Atenolol, soybean phospholipid, cholesterol were dissolved in ethanol, and rotary evaporation was carried out under reduced pressure in a water bath at 35-50°C to obtain phospholipid film containing atenolol;

[0054] (2) Citrate buffer solution (pH=5.8) containing Euphorbia pekinensis was added to the phospholipid film containing atenolol obtained in step (1), and hydration was carried out. Rotary evaporation was continued under reduced pressure in a water bath at 35-50°C for 5 min, and high-pressure homogenization was carried out to obtain atenolol liposomes.

[0055] Comparative Example 2

[0056] Formulation:

[0057] Parts by weight Atenolol 2 Soybean phospholipid 3 Cholesterol 1 Nobiletin 0.2

[0058] Preparation method:

[0059] (1) Atenolol, soybean phospholipid, cholesterol were dissolved in ethanol, and rotary evaporation was carried out under reduced pressure in a water bath at 35-50°C to obtain phospholipid film containing atenolol;

[0060] (2) Citrate buffer solution (pH=5.8) containing nobiletin was added to the phospholipid film containing atenolol obtained in step (1), and hydration was carried out. Rotary evaporation was continued under reduced pressure in a water bath at 35-50°C for 5 min, and high-pressure homogenization was carried out to obtain atenolol liposomes.

[0061] Comparative Example 3

[0062] Formulation:

[0063] Sesbania gum Parts by weight 2 Atenolol 3 Soybean phospholipid 1 Cholesterol 0.5 Nobiletin 0.05

[0064] Preparation method:

[0065] (1) Atenolol, soybean phospholipid, cholesterol were dissolved in ethanol, and rotary evaporation was carried out under reduced pressure in a water bath at 35-50°C to obtain phospholipid film containing atenolol;

[0066] (2) Citrate buffer solution (pH=5.8) containing nobiletin and Euphorbia pekinensis was added to the phospholipid film containing atenolol obtained in step (1), and hydration was carried out. Rotary evaporation was continued under reduced pressure in a water bath at 35-50°C for 5 min, and high-pressure homogenization was carried out to obtain atenolol liposomes.

[0067] Comparative Example 4

[0068] Formulation:

[0069] Sesbania gum Parts by weight 2 Atenolol 3 Soybean phospholipid 1 Cholesterol 0.2 Nobiletin 0.2

[0070] Preparation method:

[0071] (1) Dissolve atenolol, soybean phospholipid, cholesterol and citrin in ethanol, and evaporate under reduced pressure in a water bath at 35-50°C to obtain a phospholipid film containing atenolol;

[0072] (2) Add citrate buffer solution (pH = 5.8) to the phospholipid film containing atenolol obtained in step (1) to hydrate, and continue to evaporate under reduced pressure in a water bath at 35-50°C for 5 min, and then pass through a high-pressure homogenizer to obtain atenolol liposomes.

[0073] Comparative Example 5

[0074] Formulation:

[0075] Sesbania gum Parts by weight 2 Atenolol 3 Soybean phospholipid 1

[0076] Preparation method:

[0077] (1) Dissolve atenolol, soybean phospholipid, and cholesterol in ethanol, and evaporate under reduced pressure in a water bath at 35-50°C to obtain a phospholipid film containing atenolol;

[0078] (2) Add citrate buffer solution (pH = 5.8) to the phospholipid film containing atenolol obtained in step (1) to hydrate, and continue to evaporate under reduced pressure in a water bath at 35-50°C for 5 min, and then pass through a high-pressure homogenizer to obtain atenolol liposomes.

[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] II. Quality evaluation of atenolol liposomes

[0082] 1. Particle size of atenolol liposomes

[0083] Cholesterol 、 Figure 1 The particle sizes of the atenolol liposomes of Examples 1-3 and Comparative Examples 1-6 were measured. The atenolol liposomes of Examples 1-3 were regular spherical in appearance and uniform in particle size. The atenolol liposomes of Comparative Examples 1-6 were irregular in shape and non-uniform in particle size, with some unformed liposomes.

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

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

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

[0087] Table 2 shows that the encapsulation efficiency of the atenolol liposomes of the present application (Examples 1-3) is comparable to that of the prior art (Comparative Example 6), but the drug loading capacity is much higher than that of the atenolol liposomes of Comparative Example 6, greatly improving the drug delivery efficiency. The drug loading capacity and the encapsulation efficiency of the atenolol liposomes of the present application are also higher than those of the atenolol liposomes of Comparative Examples 1-5.

[0088] III. Atenolol Formulations

[0089] 1. Atenolol Tablets

[0090] Example 4

[0091] The atenolol liposomes obtained in Example 1 were mixed with pharmaceutically acceptable excipients (an appropriate amount of starch, lactose, low-substitution hydroxypropyl cellulose sodium, talc), and tableting was performed by conventional means to obtain atenolol tablets.

[0092] The pharmaceutically acceptable excipients can also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc., and the tablets can also be coated.

[0093] Example 5

[0094] The atenolol liposomes obtained in Example 2 were mixed with pharmaceutically acceptable excipients (an appropriate amount of starch, lactose, low-substitution hydroxypropyl cellulose sodium, talc), and tableting was performed by conventional means to obtain atenolol tablets.

[0095] The pharmaceutically acceptable excipients can also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc., and the tablets can also be coated.

[0096] Example 6

[0097] The atenolol liposomes obtained in Example 3 were mixed with pharmaceutically acceptable excipients (an appropriate amount of starch, lactose, low-substitution hydroxypropyl cellulose sodium, talc), and tableting was performed by conventional means to obtain atenolol tablets.

[0098] The pharmaceutically acceptable excipients can also be other commonly used fillers, disintegrants, lubricants, wetting agents, flavoring agents, etc., and the tablets can also be coated.

[0099] 2. Atenolol Injection

[0100] Example 7

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

[0102] The pharmaceutically acceptable excipient can also be other commonly used antioxidants, buffers, stabilizers, bacteriostatic agents, fillers, protective agents, etc.

[0103] Example 8

[0104] The atenolol liposome obtained in Example 2 was mixed with pharmaceutically acceptable excipients (sufficient amount of sodium chloride, sodium pyrosulfite, water for injection), and prepared by conventional preparation means of injection to obtain atenolol injection.

[0105] The pharmaceutically acceptable excipient can also be other commonly used antioxidants, buffers, stabilizers, bacteriostatic agents, fillers, protective agents, etc.

[0106] Example 9

[0107] The atenolol liposome obtained in Example 3 was mixed with pharmaceutically acceptable excipients (sufficient amount of sodium chloride, sodium pyrosulfite, water for injection), and prepared by conventional preparation means of injection to obtain atenolol injection.

[0108] The pharmaceutically acceptable excipient can also be other commonly used antioxidants, buffers, stabilizers, bacteriostatic agents, fillers, protective agents, etc.

[0109] IV. Quality investigation of atenolol tablets

[0110] The appearance, tablet weight difference, hardness and friability, disintegration time, dissolution, and related substances of the atenolol tablets obtained in Examples 4-6 and commercially available atenolol tablets (Guojiazhunzi H37020215) were investigated, all of which met the requirements of the Pharmacopoeia. Herein, only the results of the investigation of related substances are shown.

[0111] The detection method of related substances was determined according to the High Performance Liquid Chromatography method (General Rule 0512) of the Chinese Pharmacopoeia.

[0112] Test solution: about 10 mg of the product was taken into a 100 ml flask, and the mobile phase was added to dissolve and dilute to the mark. The control solution was prepared by accurately measuring 1 ml of the test solution into a 100 ml flask and diluting to the mark with the mobile phase. Chromatographic conditions: octadecylsilane-bonded silica gel was used as the filler; the mobile phase was phosphate buffer (6.8 g of potassium dihydrogen phosphate and 1.3 g of sodium octanesulfonate were dissolved and diluted to 1000 ml with water, and the pH value was adjusted to 3.0 with phosphoric acid)-methanol (70:30); the detection wavelength was 226 nm; the injection volume was 20 μl. System suitability requirements: the theoretical plate number calculated according to the atenolol peak was not less than 2000. The separation degree between the atenolol peak and the adjacent impurity peak should meet the requirements. Determination method: the test solution and the control solution were accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded until the main component peak retention time was 3 times. Limit: if there were impurity peaks in the chromatogram of the test solution, the sum of the areas of the impurity peaks should not be greater than the area of the main peak of the control solution (1.0%).

[0113] The atenolol tablets of Examples 4-6 and commercially available atenolol tablets (Guojiazhunzi H37020215) were used as the test products, and were placed at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 0th month, the 1st month, the 3rd month and the 6th month during the test period, and the content change of the related substances of the atenolol tablets was tested.

[0114] Comparative Example 6 Figure 3 The content change of the related substances of the atenolol tablets of Examples 4-6 and commercially available atenolol tablets is shown in the figure. The atenolol tablets prepared by the present application have high stability, and the content of the related substances increases slowly when stored in a high-temperature and high-humidity environment. Moreover, the content of the related substances is lower than that of the commercially available preparation.

Claims

1. A liposome of atenolol, characterized by, The components in the atenolol liposome are calculated by weight ratio as follows: 2 parts of atenolol, 2-4 parts of soybean phospholipid, 0.5-1.5 parts of cholesterol, 0.1-0.3 parts of nobiletin, and 0.1-0.3 parts of mesquite gum. The preparation method of the atenolol liposome comprises the following steps: (1) dissolving atenolol, soybean phospholipid and cholesterol in an organic solvent, and performing rotary evaporation under reduced pressure in a water bath at 35-50°C to obtain a phospholipid film containing atenolol; (2) adding a buffer solution containing nobiletin and mesquite gum to the phospholipid film containing atenolol obtained in step (1) to perform hydration, and continuing to perform rotary evaporation under reduced pressure in a water bath at 35-50°C, and then performing high-pressure homogenization to obtain atenolol liposome.

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

3. The liposomal atenolol according to claim 1, characterized in that, The organic solvent is ethanol and / or trichloromethane.

4. The liposomal atenolol according to claim 1, characterized in that, The organic solvent is ethanol.

5. The liposomal atenolol according to claim 1, wherein The buffer solution is a phosphate buffer solution or a citrate buffer solution.

6. The liposomal atenolol according to claim 1, wherein The buffer solution is a citrate buffer solution.

7. The liposomal atenolol according to claim 1, wherein The pH of the buffer solution is 5.2-6.

5.

8. The liposomal atenolol according to claim 1, wherein The pH of the buffer solution is 5.

8.

9. The liposomal atenolol according to claim 1, wherein The rotary evaporation time in step (2) is 3-7 min.

10. The liposomal atenolol according to claim 1, wherein The rotary evaporation time in step (2) is 5 min.

11. A formulation characterized in that, The atenolol liposome of claim 1 and pharmaceutically acceptable excipients.

12. The formulation of claim 11, wherein, The preparation is a tablet or an injection solution.

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