Oral solution containing salbutamol sulfate and preparation method thereof

Abstract

According to the salbutamol sulfate-containing oral solution and the preparation method thereof provided by the invention, sucralose or acesulfame potassium is taken as a flavoring agent, so that the oral solution is relatively good in dissolvability, can relieve bitter taste and obtain a relatively good taste masking effect, is relatively good in taste, improves the medication compliance of a patient, improves the stability of the oral solution and prolongs the validity period of the medicine. The oral solution containing salbutamol sulfate provided by the invention is simple in preparation method, and has good taste masking effect and stability.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to an oral solution containing salbutamol sulfate and a preparation method thereof. Background Art

[0002] Salbutamol sulfate is a short-acting β2-adrenergic receptor agonist that selectively stimulates β2-receptors on bronchial smooth muscle, relaxing the bronchial smooth muscle and thus relieving bronchial smooth muscle spasm. It is mainly used for bronchial asthma, asthmatic bronchitis and emphysema.

[0003] The original developer of salbutamol sulfate oral solution is GlaxoSmithKline (Ireland) Limited. It was first approved for marketing in Ireland in 1975 with a specification of 2mg / 5mL and a packaging specification of 150ml / bottle.

[0004] Since the aqueous solution of salbutamol sulfate is unstable under high temperature and light conditions, the current solution preparation of salbutamol sulfate has the problem of poor stability.

[0005] Currently, most of the drugs on the market are in the form of aerosols, inhalation solutions or tablets, which have high production costs. In addition, there are problems with the coordination between hand pressing and inhalation when administering drugs by inhalation, which affects the amount of drugs that reach the effective site, especially for elderly or children.

[0006] Patent US04594359 provides a preparation composition, but the obtained composition has poor stability. Patent CN118662439 provides a composition and preparation method of salbutamol sulfate oral solution, which uses sucrose stearate as a flavoring agent and has poor taste. Summary of the Invention

[0007] The object of the present invention is to provide an oral solution containing salbutamol sulfate on the basis of the existing technology, using sucralose or acesulfame potassium as a flavoring agent, which has good solubility, can reduce bitterness, obtain good taste masking effect, have good taste, improve patient compliance with medication, and enhance the stability of the oral solution, thereby extending the shelf life of the drug.

[0008] The second object of the present invention is to provide a method for preparing the oral solution containing salbutamol sulfate.

[0009] The technical solutions of the present invention are as follows:

[0010] An oral solution containing salbutamol sulfate comprises active ingredients of salbutamol sulfate, hypromellose, citric acid, sodium citrate, a bacteriostat, sodium chloride, a flavoring agent, an essence, and a pH adjuster. The mass concentration of the salbutamol sulfate is 0.3-0.6 mg / ml; the mass concentration of the hypromellose is 3.0-6.0 mg / ml; the mass concentration of the citric acid is 3.5-6.5 mg / ml; the mass concentration of the sodium citrate is 1.0-3.0 mg / ml; the mass concentration of the bacteriostat is 1.0-3.0 mg / ml, and the bacteriostat is one or more of sodium benzoate, methylparaben, or ethylparaben; the mass concentration of the sodium chloride is 0.3-2.0 mg / ml; the mass concentration of the flavoring agent is 0.1-1.0 mg / ml, and the flavoring agent is sucralose or acesulfame potassium; and the mass concentration of the essence is 0.3-0.6 mg / ml.

[0011] For the present invention, the selected antibacterial agent is sodium benzoate.

[0012] In a preferred embodiment, the oral solution containing salbutamol sulfate mentioned in the present invention has a mass concentration of salbutamol sulfate of 0.45-0.55 mg / ml; a mass concentration of hypromellose of 4.0-5.0 mg / ml; a mass concentration of citric acid of 4.5-5.5 mg / ml; a mass concentration of sodium citrate of 1.0-3.0 mg / ml; a mass concentration of sodium benzoate of 1.5-2.5 mg / ml; a mass concentration of sodium chloride of 0.5-1.5 mg / ml; a mass concentration of sucralose or acesulfame potassium of 0.3-0.6 mg / ml; and a mass concentration of flavor of 0.4-0.5 mg / ml.

[0013] In a more preferred embodiment, the oral solution containing salbutamol sulfate mentioned in the present invention has a mass concentration of salbutamol sulfate of 0.46-0.52 mg / ml; a mass concentration of hypromellose of 4.3-4.7 mg / ml; a mass concentration of citric acid of 4.8-5.2 mg / ml; a mass concentration of sodium citrate of 1.3-1.7 mg / ml; a mass concentration of sodium benzoate of 1.8-2.2 mg / ml; a mass concentration of sodium chloride of 0.8-1.2 mg / ml; a mass concentration of sucralose or acesulfame potassium of 0.45-0.55 mg / ml; and a mass concentration of flavor of 0.44-0.48 mg / ml.

[0014] In a particularly preferred embodiment, the oral solution containing salbutamol sulfate mentioned in the present invention has a mass concentration of salbutamol sulfate of 0.48-0.49 mg / ml; a mass concentration of hypromellose of 4.4-4.6 mg / ml; a mass concentration of citric acid of 4.9-5.1 mg / ml; a mass concentration of sodium citrate of 1.4-1.6 mg / ml; a mass concentration of sodium benzoate of 1.9-2.1 mg / ml; a mass concentration of sodium chloride of 0.9-1.1 mg / ml; a mass concentration of sucralose or acesulfame potassium of 0.49-0.51 mg / ml; and a mass concentration of flavor of 0.45-0.47 mg / ml.

[0015] For example, in the oral solution containing salbutamol sulfate mentioned in the present invention, the mass concentration of salbutamol sulfate in the oral solution is 0.482 mg / ml; the mass concentration of hypromellose is 4.5 mg / ml; the mass concentration of citric acid is 5.0 mg / ml; the mass concentration of sodium citrate is 1.5 mg / ml; the mass concentration of sodium benzoate is 2.0 mg / ml; the mass concentration of sodium chloride is 1.0 mg / ml; the mass concentration of sucralose is 0.5 mg / ml; and the mass concentration of flavor is 0.46 mg / ml.

[0016] For example, the oral solution containing salbutamol sulfate mentioned in the present invention has a mass concentration of salbutamol sulfate of 0.482 mg / ml; a mass concentration of hypromellose of 4.5 mg / ml; a mass concentration of citric acid of 5.0 mg / ml; a mass concentration of sodium citrate of 1.5 mg / ml; a mass concentration of sodium benzoate of 2.0 mg / ml; a mass concentration of sodium chloride of 1.0 mg / ml; a mass concentration of acesulfame potassium of 0.5 mg / ml; and a mass concentration of flavor of 0.46 mg / ml.

[0017] The present invention also provides a method for preparing the oral solution containing salbutamol sulfate, comprising the following steps:

[0018] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, antibacterial agent, sodium chloride, flavoring agent and essence, and stir until dissolved;

[0019] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make up to volume, sterilize and filter, and fill to obtain the product.

[0020] In the present invention, in step (1), the selected antibacterial agent is sodium benzoate.

[0021] Adopt the technical scheme of the present invention, the advantages are as follows:

[0022] The present invention provides an oral solution containing salbutamol sulfate. Sucralose or acesulfame potassium is used as a flavoring agent. The solution has good solubility, can reduce bitterness, achieves a good taste-masking effect, and has a good taste. This improves patient compliance with medication, enhances the stability of the oral solution, and extends the shelf life of the drug. The oral solution containing salbutamol sulfate provided by the present invention has a simple preparation method and exhibits good taste-masking and stability. DETAILED DESCRIPTION

[0023] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0024] Example 1

[0025] An oral solution containing salbutamol sulfate, comprising the following components by weight:

[0026]

[0027] The preparation method of the oral solution containing salbutamol sulfate comprises the following steps:

[0028] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, sodium benzoate, sodium chloride, sucralose, and flavor, and stir until dissolved;

[0029] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make the volume to 1 ml, sterilize and filter, and fill.

[0030] Example 2

[0031] An oral solution containing salbutamol sulfate, comprising the following components by weight:

[0032]

[0033] The preparation method of the oral solution containing salbutamol sulfate comprises the following steps:

[0034] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, sodium benzoate, sodium chloride, acesulfame potassium, and flavor, and stir until dissolved;

[0035] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make the volume to 1 ml, sterilize and filter, and fill.

[0036] Comparative Example 1

[0037] An oral solution containing salbutamol sulfate, comprising the following components by weight:

[0038]

[0039] The preparation method of the oral solution containing salbutamol sulfate comprises the following steps:

[0040] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, sodium benzoate, sodium chloride, saccharin sodium, and flavoring, and stir until dissolved;

[0041] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make the volume to 1 ml, sterilize and filter, and fill.

[0042] Comparative Example 2

[0043] An oral solution containing salbutamol sulfate, comprising the following components by weight:

[0044]

[0045] The preparation method of the oral solution containing salbutamol sulfate comprises the following steps:

[0046] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, sodium benzoate, sodium chloride, sucrose stearate, and flavor, and stir until dissolved;

[0047] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make the volume to 1 ml, sterilize and filter, and fill.

[0048] Comparative Example 3

[0049] An oral solution containing salbutamol sulfate, comprising the following components by weight:

[0050]

[0051] The preparation method of the oral solution containing salbutamol sulfate comprises the following steps:

[0052] (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, sodium benzoate, sodium chloride, aspartame, and flavor, and stir until dissolved;

[0053] (2) Add the remaining purified water to the mixed solution obtained in step (1) to make the volume to 1 ml, sterilize and filter, and fill.

[0054] The effect data of embodiment and comparative example are as follows:

[0055] The stability of the oral solutions in the examples and comparative examples was investigated, and the test results are shown in Table 1 below.

[0056] Table 1 Stability results

[0057]

[0058] The present invention is an oral solution and a true solution. The solubility of the flavoring agents in the examples and comparative examples was investigated, and the results are shown in Table 2 below.

[0059] Table 2 Solubility results

[0060]

[0061]

[0062] As shown in Table 1, the oral solutions prepared in the examples of the present invention, in Example 1, using sucralose as a flavoring agent, have low levels of related substances. Under conditions of illumination, 40°C, and 60°C for 30 days, and under accelerated conditions, the increase in related substances is small, resulting in the best stability effect, improved stability of the oral solution, and extended shelf life of the drug. In Example 2, using acesulfame potassium as a flavoring agent, the stability is slightly worse than that of Example 1. In Comparative Example 1, using saccharin sodium as a flavoring agent, and in Comparative Example 3, using aspartame as a flavoring agent, under conditions of illumination, 40°C, and 60°C for 30 days, the increase in related substances is large, and the stability is significantly worse than that of the examples.

[0063] As shown in Table 2, the flavoring agents in Examples 1 and 2 dissolved rapidly. In Comparative Example 2, sucrose stearate was used as the flavoring agent, and in Comparative Example 3, aspartame was used as the flavoring agent. Both were very slightly soluble in water. Sucrose stearate floated on the liquid surface, while aspartame, suspended in the solution, failed to dissolve in the solution and remained clear. The solubility was significantly worse than that of the Examples.

[0064] The taste of the oral solutions in the Examples and Comparative Examples was investigated, and the results of the taste investigation on adults and children are shown in Tables 3 and 4 below.

[0065] Adult evaluation criteria: 10 tasters were asked to compare and rate the bitterness of each sample. The taste rating range was 1-10, with very bad taste (0 points), bad taste (1-3 points), acceptable taste (4-6 points), good taste (7-9 points), and very good taste (10 points).

[0066] Table 3 Results of the survey on adults' perception

[0067]

[0068] Children's evaluation criteria: 20 tasters were asked to compare and score the bitterness of each sample (VAS score). The taste score range was 0-100 points, with very bad taste (0 points), bad taste (20 points), neither good nor bad taste (50 points), good taste (80 points), and very good taste (100 points).

[0069] Table 4 Results of children's taste test

[0070]

[0071] As shown in Tables 3 and 4, the oral solutions prepared with sucralose and acesulfame potassium in the examples of the present invention have good palatability and are acceptable to children. They have a similar taste to the flavoring agent saccharin sodium in Comparative Example 1 of the original study. The sucrose stearate in Comparative Example 2 did not provide any flavor correction.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oral solution containing salbutamol sulfate, characterized in that: The oral solution comprises active ingredients of salbutamol sulfate, hypromellose, citric acid, sodium citrate, an antibacterial agent, sodium chloride, a flavoring agent, an essence and a pH regulator, wherein the mass concentration of the salbutamol sulfate is 0.3-0.6 mg / ml; the mass concentration of the hypromellose is 3.0-6.0 mg / ml; the mass concentration of the citric acid is 3.5-6.5 mg / ml; the mass concentration of the sodium citrate is 1.0-3.0 mg / ml; the mass concentration of the antibacterial agent is 1.0-3.0 mg / ml, and the antibacterial agent is one or more of sodium benzoate, methylparaben or ethylparaben; the mass concentration of the sodium chloride is 0.3-2.0 mg / ml; the mass concentration of the flavoring agent is 0.1-1.0 mg / ml, and the flavoring agent is sucralose or acesulfame potassium; and the mass concentration of the essence is 0.3-0.6 mg / ml.

2. The oral solution containing salbutamol sulfate according to claim 1, characterized in that The antibacterial agent is sodium benzoate.

3. The oral solution containing salbutamol sulfate according to claim 2, characterized in that The oral solution has a mass concentration of salbutamol sulfate of 0.45-0.55 mg / ml, a mass concentration of hypromellose of 4.0-5.0 mg / ml, a mass concentration of citric acid of 4.5-5.5 mg / ml, a mass concentration of sodium citrate of 1.0-2.0 mg / ml, a mass concentration of sodium benzoate of 1.5-2.5 mg / ml, a mass concentration of sodium chloride of 0.5-1.5 mg / ml, a mass concentration of sucralose or acesulfame potassium of 0.3-0.6 mg / ml, and a mass concentration of flavor of 0.4-0.5 mg / ml.

4. The oral solution containing salbutamol sulfate according to claim 3, characterized in that The oral solution has a mass concentration of salbutamol sulfate of 0.46-0.52 mg / ml, a mass concentration of hypromellose of 4.3-4.7 mg / ml, a mass concentration of citric acid of 4.8-5.2 mg / ml, a mass concentration of sodium citrate of 1.3-1.7 mg / ml, a mass concentration of sodium benzoate of 1.8-2.2 mg / ml, a mass concentration of sodium chloride of 0.8-1.2 mg / ml, a mass concentration of sucralose or acesulfame potassium of 0.45-0.55 mg / ml, and a mass concentration of flavor of 0.44-0.48 mg / ml.

5. The oral solution containing salbutamol sulfate according to claim 3, characterized in that The oral solution has a mass concentration of salbutamol sulfate of 0.48-0.49 mg / ml, a mass concentration of hypromellose of 4.4-4.6 mg / ml, a mass concentration of citric acid of 4.9-5.1 mg / ml, a mass concentration of sodium citrate of 1.4-1.6 mg / ml, a mass concentration of sodium benzoate of 1.9-2.1 mg / ml, a mass concentration of sodium chloride of 0.9-1.1 mg / ml, a mass concentration of sucralose or acesulfame potassium of 0.49-0.51 mg / ml, and a mass concentration of flavor of 0.45-0.47 mg / ml.

6. The oral solution containing salbutamol sulfate according to claim 5, characterized in that The mass concentration of salbutamol sulfate in the oral solution is 0.482 mg / ml; the mass concentration of hypromellose is 4.5 mg / ml; the mass concentration of citric acid is 5.0 mg / ml; the mass concentration of sodium citrate is 1.5 mg / ml; the mass concentration of sodium benzoate is 2.0 mg / ml; the mass concentration of sodium chloride is 1.0 mg / ml; the mass concentration of sucralose is 0.5 mg / ml; and the mass concentration of flavor is 0.46 mg / ml.

7. The oral solution containing salbutamol sulfate according to claim 5, characterized in that The mass concentration of salbutamol sulfate in the oral solution is 0.482 mg / ml; the mass concentration of hypromellose is 4.5 mg / ml; the mass concentration of citric acid is 5.0 mg / ml; the mass concentration of sodium citrate is 1.5 mg / ml; the mass concentration of sodium benzoate is 2.0 mg / ml; the mass concentration of sodium chloride is 1.0 mg / ml; the mass concentration of acesulfame potassium is 0.5 mg / ml; and the mass concentration of flavor is 0.46 mg / ml.

8. The method for preparing the oral solution containing salbutamol sulfate according to claim 1, characterized in that: The steps include: (1) In a dark environment, stir and disperse hypromellose at 50-80° C., cool the resulting dispersion to 20-30° C., add salbutamol sulfate, hypromellose, citric acid, sodium citrate, antibacterial agent, sodium chloride, flavoring agent and essence, and stir until dissolved; (2) Add the remaining purified water to the mixed solution obtained in step (1) to make up to volume, sterilize and filter, and fill to obtain the product.

9. The method for preparing an oral solution containing salbutamol sulfate according to claim 8, wherein: The pH regulator is sodium citrate; the antibacterial agent is sodium benzoate.

10. The method for preparing an oral solution containing salbutamol sulfate according to claim 8, wherein: The oral solution has a mass concentration of salbutamol sulfate of 0.45-0.55 mg / ml, a mass concentration of hypromellose of 4.0-5.0 mg / ml, a mass concentration of citric acid of 4.5-5.5 mg / ml, a mass concentration of sodium citrate of 1.0-2.0 mg / ml, a mass concentration of sodium benzoate of 1.5-2.5 mg / ml, a mass concentration of sodium chloride of 0.5-1.5 mg / ml, a mass concentration of sucralose or acesulfame potassium of 0.3-0.6 mg / ml, and a mass concentration of flavor of 0.4-0.5 mg / ml.

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