Erythromycin stearate nano-micelle oral liquid preparation and preparation method thereof

Abstract

The invention provides an erythromycin stearate nano-micelle oral liquid preparation and a preparation method thereof, and belongs to the technical field of medicine preparation, the erythromycin stearate nano-micelle oral liquid preparation comprises the following components: erythromycin stearate, ethanol, polyoxyethylene 40 hydrogenated castor oil and vitamin E succinic acid polyethylene glycol ester. The preparation method comprises the following steps: S1, stirring and mixing polyoxyethylene 40 hydrogenated castor oil and vitamin E succinic acid polyethylene glycol ester, adding ethanol, and continuously stirring; s2, keeping the temperature, adding erythromycin stearate, and stirring until erythromycin stearate is dissolved; s3, water is added under the stirring condition, and stirring is kept; s4, citric acid is added and stirred, and the pH value is adjusted; and S5, adding water to a batch, stirring, sterilizing, filtering, and canning. According to the erythromycin stearate nano-micelle oral liquid disclosed by the invention, the bitter taste can be greatly reduced, the medication compliance of old people and children with dysphagia can be improved, the stability of erythromycin in the stomach can be improved due to the fact that erythromycin is wrapped in the nano-micelle, and the micelle also has the effect of promoting body absorption and increasing the bioavailability at the same time.

Description

Technical Field

[0001] The invention relates to an oral liquid preparation, in particular to an erythromycin stearate oral liquid preparation, and belongs to the technical field of drug preparation. Background Art

[0002] Erythromycin stearate, English name: erythromycin stearate, is a macrolide antibiotic. It has certain antibacterial activity against Staphylococcus, various streptococci and Gram-positive bacilli, Haemophilus influenzae, pertussis bacteria, etc. It also has certain inhibitory effects on Legionella, Mycoplasma and Chlamydia.

[0003] Erythromycin stearate granules are easier to administer to children after dissolving than erythromycin stearate tablets and capsules. However, erythromycin stearate is a very bitter crystalline powder that is difficult to dissolve in water and is easily destroyed in gastric acid. Its bitter taste significantly affects children's medication compliance, and it is easily destroyed in gastric acid, affecting bioavailability, so the dosage of the drug needs to be increased to achieve its efficacy.

[0004] Although erythromycin stearate tablets and capsules can mask the bitter taste to a certain extent, they are not easy to administer to children and cannot avoid the risk of erythromycin degradation in gastric acid. Other structural derivatives of erythromycin, erythromycin estolate (odorless erythromycin), are odorless, acid-resistant and have high bioavailability. Existing erythromycin estolate granules are used for children's administration, but they have high hepatotoxicity and certain safety risks. Summary of the invention

[0005] In view of the above problems, the present invention provides an erythromycin stearate nano-micelle oral liquid preparation and a preparation method thereof, so as to reduce bitterness and increase medication compliance for elderly people and children with dysphagia.

[0006] To achieve the above object, the technical solution of the present invention is:

[0007] An erythromycin stearate nano-micelle oral liquid preparation comprises the following components: 0.7-1.3%wt of erythromycin stearate, 1-5%wt of ethanol, 7.5-12.5%wt of polyoxyethylene 40 hydrogenated castor oil and 0.5-1.5%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

[0008] Further, the following components are included: 0.9-1.1%wt of erythromycin stearate, 1-3%wt of ethanol, 9-11%wt of polyoxyethylene 40 hydrogenated castor oil and 0.9-1.1%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

[0009] Further, the following components are included: 1%wt of erythromycin stearate, 2%wt of ethanol, 10%wt of polyoxyethylene 40 hydrogenated castor oil and 1%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

[0010] Furthermore, the following components are included: 2.1%wt of citric acid, 0.05%wt of orange oil essence or banana oil essence, and sodium hydroxide, wherein the unit of %wt is g / 100ml.

[0011] The preparation method of the above-mentioned erythromycin stearate nano-micelle oral liquid preparation comprises the following steps:

[0012] S1: Stir and mix polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol in a water bath, add ethanol, and continue stirring;

[0013] S2: adding erythromycin stearate to the solution obtained in step S1 while maintaining the temperature and stirring, and stirring until completely dissolved;

[0014] S3: adding water to the solution obtained in step S2 under stirring conditions and maintaining stirring;

[0015] S4: adding citric acid to the solution obtained in step S3 and stirring to adjust the pH value;

[0016] S5: Add water to the batch size, stir, sterilize and filter, and then can.

[0017] Furthermore, in step S1, the water bath condition is 55-65° C., stirring is performed for 3-8 min in the water bath condition, and stirring is performed for 2-5 min after adding ethanol.

[0018] Furthermore, in step S2, the temperature is maintained at 55-65° C.; and in step S3, stirring is maintained for 25-35 min.

[0019] Furthermore, in step S4, the pH is adjusted to 6.0-7.0 using sodium hydroxide.

[0020] Furthermore, orange oil essence or banana oil essence is added after adjusting the pH value in step S4.

[0021] Furthermore, in step S5, stirring is performed for 15-20 minutes.

[0022] The beneficial effects of the erythromycin stearate nano-micelle oral liquid preparation and the preparation method thereof of the present invention are:

[0023] The erythromycin stearate nano-micelle oral liquid of the present invention can greatly reduce bitterness and increase medication compliance of elderly people and children with dysphagia. Since erythromycin is encapsulated in nano-micelles, its stability in the stomach can be increased. The micelles also promote body absorption and increase bioavailability.

[0024] The two nonionic surfactants (polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol) of the present invention can produce a lower critical micelle concentration. After the two nonionic surfactants self-assemble in water to form micelles, the hydrophobic region inside the micelles can be loaded with erythromycin stearate. Since erythromycin stearate is wrapped inside the micelles, its bitter taste can be concealed. After taking, it can also be protected from being destroyed by gastric acid, and absorption can also be increased under the solubilization effect of the nonionic surfactant, thereby improving bioavailability.

[0025] The nonionic surfactant (polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol) of the present invention self-assembles to form micelles to encapsulate erythromycin stearate for drug loading, thereby increasing the solubility and stability of erythromycin stearate, masking its unique bitter taste, enhancing the stability of erythromycin stearate preparations, and improving the bioavailability thereof.

[0026] The combined use of the two nonionic surfactants (polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester) of the present invention can reduce the critical micelle concentration. The preferred ratio of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester can have a lower critical micelle concentration and increase the stability of the micelle.

[0027] The preferred concentration of polyoxyethylene 40 hydrogenated castor oil (7.5-12.5% ​​wt) and vitamin E succinate polyethylene glycol ester (0.5-1.5% wt) of the present invention is used for drug loading of 0.7-1.3% erythromycin stearate, with a high encapsulation rate and a good drug loading effect. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0029] An erythromycin stearate nano-micelle oral liquid preparation comprises the following components: 0.7-1.3%wt of erythromycin stearate, 1-5%wt of ethanol, 7.5-12.5%wt of polyoxyethylene 40 hydrogenated castor oil and 0.5-1.5%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

[0030] Preferably, the composition comprises the following components: 0.9-1.1%wt of erythromycin stearate, 1-3%wt of ethanol, 9-11%wt of polyoxyethylene 40 hydrogenated castor oil and 0.9-1.1%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

[0031] Further preferred components include: 1%wt erythromycin stearate, 2%wt ethanol, 10%wt polyoxyethylene 40 hydrogenated castor oil and 1%wt vitamin E succinate polyethylene glycol ester, wherein the unit of %wt is g / 100ml.

[0032] Still further preferably, the following components are also included: 2.1%wt of citric acid, 0.05%wt of orange oil flavor or banana oil flavor, and sodium hydroxide, wherein the unit of %wt is g / 100ml.

[0033] The preparation method of the above-mentioned erythromycin stearate nano-micelle oral liquid preparation comprises the following steps:

[0034] S1: Stir and mix polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol in a water bath, add ethanol, and continue stirring; preferably, the water bath is at 55-65° C., stir for 3-8 minutes in a water bath, and stir for 2-5 minutes after adding ethanol.

[0035] S2: maintaining the temperature, adding erythromycin stearate to the solution obtained in step S1 under stirring, and stirring until completely dissolved; preferably maintaining the temperature at 55-65°C.

[0036] S3: Add water to the solution obtained in step S2 under stirring and keep stirring; preferably, keep stirring for 25-35 minutes.

[0037] S4: adding citric acid to the solution obtained in step S3 and stirring to adjust the pH value; preferably, the pH value is adjusted to 6.0-7.0 using sodium hydroxide; further preferably, orange oil flavor or banana oil flavor is added after the pH value is adjusted.

[0038] S5: Add water to the batch, stir, sterilize and filter, and then can. Preferably, stir for 15-20 minutes.

[0039] Example 1

[0040] The invention discloses an erythromycin stearate nano-micelle oral liquid preparation. Each 100 ml of the oral liquid preparation comprises the following components by weight: 1 g of erythromycin stearate, 2 g of ethanol, 10 g of polyoxyethylene 40 hydrogenated castor oil, 1 g of vitamin E succinate polyethylene glycol ester, 2.1 g of citric acid, 0.05 g of orange oil flavor, and sodium hydroxide (pH regulator).

[0041] The preparation method of the above-mentioned erythromycin stearate nano-micelle oral liquid preparation, taking 100 ml of oral liquid preparation as an example, comprises the following steps:

[0042] S1: Stir and mix polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol in a water bath at 60°C for 5 minutes, add ethanol, and continue stirring for 2 minutes;

[0043] S2: maintaining the temperature at 60° C., adding erythromycin stearate to the solution obtained in step S1 under stirring, and stirring until completely dissolved;

[0044] S3: Add appropriate amount of water to the solution obtained in step S2 under stirring and keep stirring for 30 minutes

[0045] S4: Add citric acid to the solution obtained in step S3 and stir for 15 minutes, add sodium hydroxide to adjust the pH value to 6.5, and add orange oil flavor.

[0046] S5: Add water to 100 ml, stir for 15 minutes, sterilize and filter, and then can.

[0047] Embodiment 2-5

[0048] The types of components contained in the oral liquid preparations of Examples 2-5 and Example 1 are basically the same, the difference is that the dosage is different, and the preparation process parameters are also different, as shown in the following table:

[0049] Table 1 Components and preparation process of oral liquid preparations of Examples 2-5

[0050]

[0051] Test Example 1

[0052] Selection of the ratio of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester

[0053] The combined use of two nonionic surfactants can produce a lower critical micelle concentration. Different ratio compositions are measured and the prescription ratio with the lowest critical micelle concentration is selected. Micelles or nanomicelles refer to aggregates produced by amphiphilic nonionic surfactants when the critical micelle concentration is greater than the critical micelle concentration. The critical micelle concentration (CMC) refers to the lowest concentration at which surfactant molecules associate to form micelles in a solvent. When the concentration of surfactants in a solution reaches this concentration, the molecules will associate from single ions or molecules to colloidal aggregates, i.e., micelles, and the properties of the solution will change suddenly.

[0054] The critical micelle concentration is determined by the following method:

[0055] Determination of critical micelle concentration using iodine as probe

[0056] Nanomicelle dispersions were prepared according to different ratios of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester. The mixture (i.e., nanomicelle dispersion) was diluted with ultrapure water to obtain a series of preparations with surfactant concentrations between 0.00001 and 0.5% mg / ml. 25 μL of iodine solution containing triiodide ions (I3, 40.0 mM KI3) prepared by dissolving iodine and potassium iodide (mass ratio 0.5:1.0) in ultrapure water was added to accurately measured volumes (5.0 mL) of surfactant preparations of different concentrations. Incubate in a sealed vial in the dark for 15 h at room temperature, and then measure the absorbance at 366 nm to detect the hydrophobic I2 encapsulated in the nanomicelle core. Repeat the experiment for each diluted sample in triplicate.

[0057] C m is the surfactant concentration, A is the absorbance of the sample at 366 nm after incubation, and a curve is drawn with logC as the abscissa and A as the ordinate to determine the logC at the turning point where A suddenly increases. m , calculate C m This is the critical micelle concentration of surfactant in this ratio.

[0058] The results are shown in the following table:

[0059] Table 2 Critical micelle concentration of surfactants at different ratios

[0060]

[0061] The preferred ratio of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester is 91:9 to form mixed nano micelles. The mixed nano micelles of the present invention refer to mixed micelles composed of at least two or more nonionic surfactants.

[0062] The above-mentioned ratio of 91:9 of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester was further studied to obtain the dosage range of the two surfactants that can maintain the minimum critical micelle concentration. The results are shown in the following table:

[0063] Table 3 Critical micelle concentration of surfactants at different ratios

[0064]

[0065] From Table 3, it can be seen that the optimal ratio range of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester is: 8.09 (89 / 11) to 13.3 (93 / 7).

[0066] Test Example 2

[0067] On the basis of Test Example 1, the prescription amount of erythromycin stearate is 10 mg / ml, the ratio of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester is selected as 10:1, and the preferred dosage of the two substances in the oral solution is screened, and the encapsulation rate of erythromycin stearate in the final product is used as the screening index. The specific test is as follows:

[0068] Determination of the encapsulation efficiency of erythromycin stearate by different concentrations of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol. Determination method: After the preparation is completed according to the preparation method of Example 1, take an appropriate amount of sample and centrifuge at 10000rpm, take the supernatant to determine the erythromycin stearate content, which is the drug loading of erythromycin stearate. The results are shown in the following table.

[0069]

[0070] The content of erythromycin stearate was determined by high performance liquid chromatography, the chromatographic conditions were Waters XBridge C18 column, 250 mm × 4.6 mm, 5 μm, the mobile phase was acetonitrile-phosphate buffer (60:40), and the flow rate was 1.0 mL·min －1 , detection wavelength 215nm, injection volume 50μL. Reference substance: Accurately weigh an appropriate amount of erythromycin reference substance, add an appropriate amount of methanol (2mg in 1mL of methanol) to dissolve, and then dilute with diluent to 1mg·mL －1 Erythromycin reference solution. Test sample: Dilute 10 times with methanol before measurement.

[0071] Table 4 Comparison of encapsulation efficiency of surfactants at different concentrations

[0072]

[0073] It can be seen from the above table that to achieve an encapsulation rate of more than 95%, the concentration of polyoxyethylene 40 hydrogenated castor oil needs to be maintained above 7.5%wt. According to the optimal ratio of polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol ester obtained in Experimental Example 1, the optimal concentration of vitamin E succinate polyethylene glycol ester should be 0.74%wt.

[0074] Test Example 3: Stability Study

[0075] The samples were prepared according to the recipe and process of Example 1 and placed at 25°C ± 2°C / 60% RH ± 5% RH for stability. The detection methods of various indicators are as follows:

[0076] The micelle particle size and PDI were measured using a Zetasizer Nano nanoparticle size potentiometer;

[0077] The pH value was measured using a pH meter;

[0078] Erythromycin B, C components and related substances were determined by high performance liquid chromatography. The chromatographic conditions were as follows: octadecylsilane bonded silica gel was used as the filler; phosphate solution (8.7 g of potassium dihydrogen phosphate, 1000 ml of water, and the pH was adjusted to 8.2 with 20% phosphoric acid)-acetonitrile (40:60) was used as the mobile phase; the column temperature was 35°C; the wavelength was 215 nm; and the injection volume was 20 μl.

[0079] Table 5 Stability results of products placed at 25℃ / 60%RH

[0080]

[0081] It can be seen from the above table that the erythromycin stearate nano-micelle oral liquid preparation prepared by the present invention has strong stability. The above stability test was also performed on the products obtained in Examples 2-5, and the results were basically the same as those in the above table, indicating that the erythromycin stearate nano-micelle oral liquid preparations prepared within the parameter range of the present invention all have strong storage stability.

[0082] Comparative Example 1

[0083] Comparative Example 1 is a comparative test of Example 1, except that vitamin E succinate polyethylene glycol ester is not added, and 11g of polyoxyethylene 40 hydrogenated castor oil is added instead. The remaining components and preparation process are the same as those of Example 1. The appearance of the obtained oral liquid preparation is grayish white and turbid, and the encapsulation efficiency of erythromycin stearate is 96%. However, the results of stability investigation (refer to Test Example 3) are shown in the following table:

[0084] Table 6 Stability results of comparative example 1 at 25°C / 60%RH

[0085]

[0086] Comparative Example 2

[0087] Comparative Example 2 is a comparative test of Example 1, except that polyoxyethylene 40 hydrogenated castor oil is not added, and 11g of vitamin E succinate polyethylene glycol is added instead. The remaining components and preparation process are the same as those of Example 1. The appearance of the obtained oral liquid preparation is milky white and turbid, and the encapsulation rate of erythromycin stearate is 97%. However, the results of stability investigation (refer to Test Example 3) are shown in the following table:

[0088] Table 7 Stability results of comparative example 2 at 25°C / 60%RH

[0089]

[0090]

[0091] Comparative Example 3

[0092] The oral liquid preparation of the present invention also has strong stability in the gastric acid environment. The comparative example conducted a 6-hour stability test on erythromycin stearate granules and erythromycin stearate nano-micelle oral liquid 100 mg in 250 ml pH 1.2 medium. The results are shown in the following table:

[0093] Table 8

[0094]

[0095] Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. An erythromycin stearate nano-micelle oral liquid preparation, characterized in that: The invention comprises the following components: 0.7-1.3%wt of erythromycin stearate, 1-5%wt of ethanol, 7.5-12.5%wt of polyoxyethylene 40 hydrogenated castor oil and 0.5-1.5%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

2. The erythromycin stearate nano-micelle oral liquid preparation according to claim 1, characterized in that: The invention comprises the following components: 0.9-1.1%wt of erythromycin stearate, 1-3%wt of ethanol, 9-11%wt of polyoxyethylene 40 hydrogenated castor oil and 0.9-1.1%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

3. The erythromycin stearate nano-micelle oral liquid preparation according to claim 1, characterized in that: The invention comprises the following components: 1%wt of erythromycin stearate, 2%wt of ethanol, 10%wt of polyoxyethylene 40 hydrogenated castor oil and 1%wt of vitamin E succinate polyethylene glycol, wherein the unit of %wt is g / 100ml.

4. The erythromycin stearate nano-micelle oral liquid preparation according to any one of claims 1 to 3, characterized in that: Also includes the following components: 2.1% wt of citric acid, 0.05% wt of orange oil essence or banana oil essence, and sodium hydroxide, wherein the unit of % wt is g / 100 ml.

5. A method for preparing an erythromycin stearate nano-micelle oral liquid preparation according to claims 1-4, characterized in that: The steps include: S1: Stir and mix polyoxyethylene 40 hydrogenated castor oil and vitamin E succinate polyethylene glycol in a water bath, add ethanol, and continue stirring; S2: adding erythromycin stearate to the solution obtained in step S1 while maintaining the temperature and stirring until it is completely dissolved; S3: adding water to the solution obtained in step S2 under stirring conditions and maintaining stirring; S4: adding citric acid to the solution obtained in step S3 and stirring to adjust the pH value; S5: Add water to the batch size, stir, sterilize and filter, and then can.

6. The method for preparing the erythromycin stearate nano-micelle oral liquid preparation according to claim 5, characterized in that: In step S1, the water bath condition is 55-65° C., stirring is performed for 3-8 min in the water bath condition, and stirring is performed for 2-5 min after adding ethanol.

7. The method for preparing an erythromycin stearate nano-micelle oral liquid preparation according to claim 5, characterized in that: In step S2, the temperature is maintained at 55-65°C; in step S3, stirring is maintained for 25-35 minutes.

8. The method for preparing the erythromycin stearate nano-micelle oral liquid preparation according to claim 5, characterized in that: In step S4, the pH is adjusted to 6.0-7.0 using sodium hydroxide.

9. The method for preparing an erythromycin stearate nano-micelle oral liquid preparation according to claim 5, characterized in that: In step S4, after adjusting the pH value, orange oil essence or banana oil essence is added.

10. The method for preparing an erythromycin stearate nano-micelle oral liquid preparation according to claim 5, characterized in that: In step S5, the mixture is stirred for 15-20 min.

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