An oral solution of ambroxol and bromhexine

Abstract

This invention relates to an ambroxol oral solution. Specifically, this invention provides an ambroxol oral solution comprising ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol, and water. The ambroxol oral solution of this invention effectively improves bitterness and its residue, has an excellent taste, and also exhibits excellent stability under light, high temperature, and high humidity, thus providing excellent storage and transportation stability and ensuring quality and safety.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more specifically to an ambroxol oral solution. Background Technology

[0002] Ambroxol hydrochloride and clenbuterol hydrochloride oral solution is used to treat cough, thick sputum, difficulty in expectoration, and wheezing caused by acute and chronic respiratory diseases (such as acute and chronic bronchitis, bronchial asthma, emphysema, etc.).

[0003] Ambroxol oral solution is widely used in clinical practice due to its convenient administration and rapid onset of action. However, existing ambroxol oral solutions suffer from bitterness and residual effects, leading to low patient compliance, especially in children, and limiting its use. Furthermore, existing ambroxol oral solutions exhibit poor stability under light, high temperature, and high humidity, requiring repackaging in brown bottles. This brown bottle repackaging makes it difficult for patients to easily and quickly observe the solution's properties, such as clarity, presence of sediment, mold, or foreign matter, when purchasing or using the solution, potentially leading to medication safety issues.

[0004] Therefore, there is a need in the art to develop an ambroxol oral solution that improves the taste and stability of the ambroxol oral solution. Summary of the Invention

[0005] The purpose of this invention is to provide an ambroxol oral solution with excellent taste and stability, thereby improving the application value of ambroxol oral solution.

[0006] In a first aspect, the present invention provides an ambroxol oral solution comprising ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol, and water.

[0007] Preferably, the ambroxol hydrochloride is 0.05-0.30 parts by weight, more preferably 0.10-0.20 parts by weight, and even more preferably 0.15 parts by weight.

[0008] Preferably, the clenbuterol hydrochloride is 0.00005-0.0005 parts by weight, more preferably 0.00005-0.0003 parts by weight, and even more preferably 0.0001 parts by weight.

[0009] Preferably, the sucralose is 0.05-0.3 parts by weight, more preferably 0.05-0.15 parts by weight, and even more preferably 0.1 parts by weight.

[0010] Preferably, the mannitol is 1-4 parts by weight, more preferably 1.5-2.5 parts by weight, and even more preferably 2.0 parts by weight.

[0011] Preferably, the trehalose is 2-6 parts by weight, more preferably 3-5 parts by weight, and even more preferably 4.0 parts by weight.

[0012] Preferably, the hydroxyethyl cellulose is 0.5-1.5 parts by weight, more preferably 0.7-0.9 parts by weight, and even more preferably 0.8 parts by weight.

[0013] Preferably, the citric acid is 0.05-0.5 parts by weight, more preferably 0.1-0.3 parts by weight, and even more preferably 0.2 parts by weight.

[0014] Preferably, the sodium citrate is 0.01-0.1 parts by weight, more preferably 0.02-0.06 parts by weight, and even more preferably 0.04 parts by weight.

[0015] Preferably, the sodium bisulfite is 0.05-0.15 parts by weight, more preferably 0.06-0.10 parts by weight, and even more preferably 0.08 parts by weight.

[0016] Preferably, the glycine is 0.5-3.0 parts by weight, more preferably 1.0-2.0 parts by weight, and even more preferably 1.5 parts by weight.

[0017] Preferably, the glycerol is 2-4 parts by weight, more preferably 2.5-3.5 parts by weight, and even more preferably 3.0 parts by weight.

[0018] Preferably, the water is 85-115 parts by weight, more preferably 90-110 parts by weight, and even more preferably 95-105 parts by weight.

[0019] Preferably, the water is purified water.

[0020] Preferably, the ambroxol oral solution comprises:

[0021] Components Dosage Ambroxol Hydrochloride 0.5-0.30 parts by weight Clenbuterol Hydrochloride 0.00005-0.0005 parts by weight Sucralose 0.05-0.3 parts by weight Mannitol 1-4 parts by weight Trehalose 2-6 parts by weight Hydroxyethyl cellulose 0.5-1.5 parts by weight Citric acid 0.05-0.5 parts by weight Sodium citrate 0.01-0.1 parts by weight Sodium bisulfite 0.05-0.15 parts by weight glycine 0.5-3.0 parts by weight glycerin 2-4 parts by weight; and Add water 95-105 parts by weight.

[0022] Preferably, the ambroxol oral solution comprises:

[0023] Components Dosage Ambroxol Hydrochloride 0.10-0.20 parts by weight Clenbuterol Hydrochloride 0.00005-0.0003 parts by weight Sucralose 0.05-0.15 parts by weight Mannitol 1.5-2.5 parts by weight Trehalose 3-5 parts by weight Hydroxyethyl cellulose 0.7-0.9 parts by weight Citric acid 0.1-0.3 parts by weight Sodium citrate 0.02-0.06 parts by weight Sodium bisulfite 0.06-0.10 parts by weight glycine 1.0-2.0 parts by weight glycerin 2.5-3.5 parts by weight; and Add water 95-105 parts by weight.

[0024] Preferably, the ambroxol oral solution comprises:

[0025]

[0026]

[0027] Preferably, the ambroxol oral solution comprises:

[0028] Components Dosage Ambroxol Hydrochloride 0.15g Clenbuterol Hydrochloride 0.0001g Sucralose 0.1g Mannitol 2.0g Trehalose 4.0g Hydroxyethyl cellulose 0.8g Citric acid 0.2g Sodium citrate 0.04g Sodium bisulfite 0.08g glycine 1.5g glycerin 3.0g Add water Up to 100ml.

[0029] In a second aspect, the present invention provides a method for preparing an ambroxol oral solution as described in the first aspect of the present invention, the method comprising the steps of:

[0030] The ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol, and water are mixed to obtain the ambroxol oral solution.

[0031] Preferably, the ambroxol oral solution is prepared by the following method:

[0032] Take 83-87% of the prescribed volume of water after boiling and cooling, add hydroxyethyl cellulose, stir and dissolve at 43-47℃, then add glycerol, citric acid and sodium citrate, stir and dissolve at 43-47℃, then add ambroxol hydrochloride and clenbuterol hydrochloride, stir and dissolve at 43-47℃, then add sucralose, mannitol, trehalose, sodium bisulfite and glycine, stir and dissolve at 43-47℃, then add boiled and cooled water to bring the volume to the required dosage, stir and mix, then filter successively through 0.45μm and 0.22μm microporous membranes to obtain ambroxol oral solution.

[0033] In a third aspect, the present invention provides an ambroxol medication box, the ambroxol medication box comprising an ambroxol oral solution and a transparent container as described in the first aspect of the present invention;

[0034] The ambroxol oral solution is dispensed into the transparent container.

[0035] Preferably, the transparent container includes a transparent plastic container (such as a transparent PET bottle) or a transparent glass container.

[0036] In a fourth aspect, the present invention provides the use of the ambroxol oral solution as described in the first aspect of the present invention for preparing a medicament for treating cough, thick sputum, difficulty in expectoration, and wheezing caused by acute and chronic respiratory diseases.

[0037] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Detailed Implementation

[0038] This invention develops an ambroxol oral solution comprising ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol, and water. The ambroxol oral solution of this invention, composed of these specific components, effectively improves bitterness and its residue, providing excellent palatability. It also exhibits excellent stability under light, high temperature, and high humidity, thus ensuring excellent storage and transportation stability and guaranteeing quality and safety.

[0039] the term

[0040] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0041] As used in this article, the structure of the term "ambroxol hydrochloride" is as follows:

[0042]

[0043] Ambroxol hydrochloride (CAS No.: 23828-92-4)

[0044] As used in this article, the structure of the term "clenbuterol hydrochloride" is as follows:

[0045]

[0046] Clenbuterol hydrochloride (CAS No.: 21898-19-1)

[0047] As used in this article, the CAS number for the term "impurity B" is 15942-08-2.

[0048] As used in this article, the term "PET" refers to polyethylene terephthalate, also known as polyethylene terephthalate.

[0049] As used herein, the term "parts by weight" can be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1 mg, 1 g, or 1 kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b can be a composition consisting of 1 gram of component a + 9 grams of component b, or 10 grams of component a + 90 grams of component b, etc. In the pharmaceutical composition described herein, the percentage content of a component = (the number of parts by weight of that component / the sum of the number of parts by weight of all components) × 100%. Therefore, in a composition consisting of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.

[0050] Ambroxol Oral Solution and its Preparation Method

[0051] This invention provides an ambroxol oral solution with excellent taste and stability, thereby enhancing the application value of ambroxol oral solution.

[0052] The ambroxol oral solution of the present invention may include (but is not limited to) ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol and water.

[0053] In the ambroxol oral solution described in this invention, the combined effect of the components gives the ambroxol oral solution excellent taste and stability, thereby improving the application value of the ambroxol oral solution.

[0054] In the ambroxol oral solution of the present invention, the amount of ambroxol hydrochloride can be 0.05-0.30 parts by weight, preferably 0.10-0.20 parts by weight, and more preferably 0.15 parts by weight.

[0055] In the ambroxol oral solution of the present invention, the amount of clenbuterol hydrochloride can be 0.00005-0.0005 parts by weight, preferably 0.00005-0.0003 parts by weight, and more preferably 0.0001 parts by weight.

[0056] In the ambroxol oral solution of the present invention, the amount of sucralose can be 0.05-0.3 parts by weight, preferably 0.05-0.15 parts by weight, and more preferably 0.1 parts by weight.

[0057] In the ambroxol oral solution of the present invention, the amount of mannitol can be 1-4 parts by weight, preferably 1.5-2.5 parts by weight, and more preferably 2.0 parts by weight.

[0058] In the ambroxol oral solution of the present invention, the amount of trehalose can be 2-6 parts by weight, preferably 3-5 parts by weight, and more preferably 4.0 parts by weight.

[0059] In the ambroxol oral solution of the present invention, the amount of hydroxyethyl cellulose can be 0.5-1.5 parts by weight, preferably 0.7-0.9 parts by weight, and more preferably 0.8 parts by weight.

[0060] In the ambroxol oral solution of the present invention, the amount of citric acid can be 0.05-0.5 parts by weight, preferably 0.1-0.3 parts by weight, and more preferably 0.2 parts by weight.

[0061] In the ambroxol oral solution of the present invention, the amount of sodium citrate can be 0.01-0.1 parts by weight, preferably 0.02-0.06 parts by weight, and more preferably 0.04 parts by weight.

[0062] In the ambroxol oral solution of the present invention, the amount of sodium bisulfite can be 0.05-0.15 parts by weight, preferably 0.06-0.10 parts by weight, and more preferably 0.08 parts by weight.

[0063] In the ambroxol oral solution of the present invention, the amount of glycine used can be 0.5-3.0 parts by weight, preferably 1.0-2.0 parts by weight, and more preferably 1.5 parts by weight.

[0064] In the ambroxol oral solution of the present invention, the amount of glycerol used can be 2-4 parts by weight, preferably 2.5-3.5 parts by weight, and more preferably 3.0 parts by weight.

[0065] In the ambroxol oral solution of the present invention, the amount of water used can be 85-105 parts by weight, preferably 90-110 parts by weight, and more preferably 95-105 parts by weight.

[0066] Representatively, the ambroxol oral solution of the present invention comprises:

[0067]

[0068]

[0069] Typically, the ambroxol oral solution comprises:

[0070] Components Dosage Ambroxol Hydrochloride 0.15g Clenbuterol Hydrochloride 0.0001g Sucralose 0.1g Mannitol 2.0g Trehalose 4.0g Hydroxyethyl cellulose 0.8g Citric acid 0.2g Sodium citrate 0.04g Sodium bisulfite 0.08g glycine 1.5g glycerin 3.0g Add water Up to 100ml.

[0071] The ambroxol oral solution of the present invention can be prepared by a mixing method. For example, the ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol and water are mixed to obtain the ambroxol oral solution.

[0072] The main superior technical effects of this invention include:

[0073] This invention develops an ambroxol oral solution that effectively improves bitterness and residue, providing excellent palatability and high patient compliance. The ambroxol oral solution also exhibits excellent stability under light, high temperature, and high humidity, thus ensuring excellent storage and transportation stability and guaranteeing quality and safety.

[0074] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions.

[0075] Example 1 Ambroxol Oral Solution

[0076] The formulation of the ambroxol oral solution in Example 1 is shown in Table 1:

[0077] Table 1. Formulation of Ambroxol Oral Solution

[0078] Components Dosage Ambroxol Hydrochloride 0.15g Clenbuterol Hydrochloride 0.0001g Sucralose 0.1g Mannitol 2.0g Trehalose 4.0g Hydroxyethyl cellulose 0.8g Citric acid 0.2g Sodium citrate 0.04g Sodium bisulfite 0.08g glycine 1.5g glycerin 3.0g Add purified water Up to 100ml.

[0079] Preparation method

[0080] Take 85% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of hydroxyethyl cellulose, stir and dissolve at 45°C, then add the prescribed amounts of glycerol, citric acid, and sodium citrate, stir and dissolve at 45°C, then add the prescribed amounts of ambroxol hydrochloride and clenbuterol hydrochloride, stir and dissolve at 45°C, then add the prescribed amounts of sucralose, mannitol, trehalose, sodium bisulfite, and glycine, stir and dissolve at 45°C, then add the boiled and cooled purified water to bring the volume to the required dosage. After stirring and mixing, filter sequentially through 0.45μm and 0.22μm microporous membranes to obtain ambroxol hydrochloride oral solution, which is dispensed into transparent PET bottles. The ambroxol hydrochloride specification is 1.5mg / ml, and the clenbuterol hydrochloride specification is 1μg / ml.

[0081] Example 2 Ambroxol Oral Solution

[0082] The formulation of the ambroxol oral solution in Example 2 is shown in Table 2:

[0083] Table 2. Formulation of Ambroxol Oral Solution

[0084]

[0085]

[0086] Preparation method

[0087] Take 85% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of hydroxyethyl cellulose, stir and dissolve at 45°C, then add the prescribed amounts of glycerol, citric acid, and sodium citrate, stir and dissolve at 45°C, then add the prescribed amounts of ambroxol hydrochloride and clenbuterol hydrochloride, stir and dissolve at 45°C, then add the prescribed amounts of sucralose, mannitol, trehalose, and sodium bisulfite, stir and dissolve at 45°C, then add the boiled and cooled purified water to bring the volume to the required dosage. After stirring and mixing, filter sequentially through 0.45μm and 0.22μm microporous membranes to obtain ambroxol hydrochloride oral solution, which is dispensed into transparent PET bottles. The ambroxol hydrochloride strength is 1.5mg / ml, and the clenbuterol hydrochloride strength is 1μg / ml.

[0088] Example 3 Ambroxol Oral Solution

[0089] The formulation of the ambroxol oral solution in Example 3 is shown in Table 3:

[0090] Table 3. Formulation of Ambroxol Oral Solution

[0091] Components Dosage Ambroxol Hydrochloride 0.15g Clenbuterol Hydrochloride 0.0001g Sucralose 0.1g Mannitol 4.0g Trehalose 1.0g Hydroxyethyl cellulose 0.8g Citric acid 0.2g Sodium citrate 0.04g Sodium bisulfite 0.08g glycine 1.5g glycerin 3.0g Add purified water Up to 100ml.

[0092] Preparation method

[0093] Take 85% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of hydroxyethyl cellulose, stir and dissolve at 45°C, then add the prescribed amounts of glycerol, citric acid, and sodium citrate, stir and dissolve at 45°C, then add the prescribed amounts of ambroxol hydrochloride and clenbuterol hydrochloride, stir and dissolve at 45°C, then add the prescribed amounts of sucralose, mannitol, trehalose, sodium bisulfite, and glycine, stir and dissolve at 45°C, then add the boiled and cooled purified water to bring the volume to the required dosage. After stirring and mixing, filter sequentially through 0.45μm and 0.22μm microporous membranes to obtain ambroxol hydrochloride oral solution, which is dispensed into transparent PET bottles. The ambroxol hydrochloride specification is 1.5mg / ml, and the clenbuterol hydrochloride specification is 1μg / ml.

[0094] Example 4 Ambroxol Oral Solution

[0095] The formulation of the ambroxol oral solution in Example 4 is shown in Table 4:

[0096] Table 4. Formulation of Ambroxol Oral Solution

[0097] Components Dosage Ambroxol Hydrochloride 0.15 g Clenbuterol Hydrochloride 0.0001g Sucralose 0.1 g Mannitol 2.0 g Trehalose 4.0 g Hydroxyethyl cellulose 1.0 g Citric acid 0.2 g Sodium citrate 0.04 g Sodium bisulfite 0.08 g glycine 1.5 g glycerin 1.0 g Add purified water Up to 100 ml.

[0098] Preparation method

[0099] Take 85% of the prescribed amount of purified water after boiling and cooling, add the prescribed amount of hydroxyethyl cellulose, stir and dissolve at 45°C, then add the prescribed amounts of glycerol, citric acid, and sodium citrate, stir and dissolve at 45°C, then add the prescribed amounts of ambroxol hydrochloride and clenbuterol hydrochloride, stir and dissolve at 45°C, then add the prescribed amounts of sucralose, mannitol, trehalose, sodium bisulfite, and glycine, stir and dissolve at 45°C, then add the boiled and cooled purified water to bring the volume to the required dosage. After stirring and mixing, filter sequentially through 0.45μm and 0.22μm microporous membranes to obtain ambroxol hydrochloride oral solution, which is dispensed into transparent PET bottles. The ambroxol hydrochloride strength is 1.5 mg / ml, and the clenbuterol hydrochloride strength is 1 μg / ml.

[0100] Formulation Study

[0101] 1. Taste test

[0102] Twenty subjects orally administered the ambroxol oral solutions from Examples 1-4. The taste of the ambroxol oral solutions was evaluated, with evaluation indicators including initial bitterness and bitter residue. The scoring criteria were as follows: 0 points (none, pleasant taste); 1 point (mild, no impact on taste); 2 points (present, impact on taste); 3 points (relatively severe, still acceptable); 4 points (severe, unacceptable). A single-blind method was used to evaluate the taste of the ambroxol oral solutions, and subjects were not allowed to make prior judgments about the possible tastes of the ambroxol oral solutions they were to taste. The taste evaluation results of the ambroxol oral solutions are shown in Table 5.

[0103] Table 5. Taste evaluation of the ambroxol oral solutions prepared in Examples 1-4

[0104]

[0105] As can be seen from Table 5, the ambroxol oral solution prepared in this embodiment can effectively improve the bitterness and residue of ambroxol, and improve the oral compliance of ambroxol oral solution.

[0106] 2. Stability assessment

[0107] 2.1 Light stability test

[0108] The stability of ambroxol oral solutions prepared in Examples 1-4 and packaged in transparent PET bottles was investigated under light conditions (4500 lx, 25 °C) for 0 days, 10 days, and 30 days. The properties and impurity content (%) of the ambroxol oral solutions at different time points were determined by high performance liquid chromatography.

[0109] The results of the ambroxol oral solutions prepared in Examples 1-4 and packaged in transparent PET bottles under different light conditions for different durations are shown in Table 6.

[0110] Table 6. Stability test results of the ambroxol oral solutions prepared in Examples 1-4 under light conditions (4500 lx, 25 °C).

[0111]

[0112] As can be seen from Table 6, the ambroxol oral solution prepared in Example 1 has the best light stability and can be dispensed into transparent containers for storage.

[0113] 2.2 Accelerated Stability Assessment

[0114] The stability of the ambroxol oral solution prepared in Example 1 and packaged in transparent PET bottles was investigated according to the guidelines for stability testing of Chinese Pharmacopoeia preparations at 0 days, 1, 3 and 6 months. The properties and impurity content (%) of the ambroxol oral solution at different test time points were determined by high performance liquid chromatography.

[0115] The results of the ambroxol oral solution prepared in Example 1 and packaged in transparent PET bottles at different testing times at a temperature of 40±2℃ and a relative humidity of RH 75±5% are shown in Table 7.

[0116] Table 7. Stability test results of the ambroxol oral solution prepared in Example 1 at a temperature of 40±2℃ and a relative humidity of RH 75±5%.

[0117]

[0118] As can be seen from Table 7, the ambroxol oral solution prepared in Example 1 has excellent high temperature and high humidity stability, which can reduce storage and transportation costs, ensure the stability of the ambroxol oral solution during transportation and storage, and ensure quality and safety.

[0119] The above description is an implementation scheme designed for one case of the present invention. It should be noted that for those skilled in the art, several improvements can be made without departing from the principle of the present invention, and these improvements should also be considered within the scope of protection of the present invention.

Claims

1. An ambroxol oral solution, characterized in that, The ambroxol oral solution is composed of the following components:

2. The ambroxol oral solution as described in claim 1, characterized in that, The ambroxol oral solution is composed of the following components:

3. A method for preparing the ambroxol oral solution as described in claim 1, characterized in that, The method includes the following steps: The ambroxol hydrochloride, clenbuterol hydrochloride, sucralose, mannitol, trehalose, hydroxyethyl cellulose, citric acid, sodium citrate, sodium bisulfite, glycine, glycerol, and water are mixed to obtain the ambroxol oral solution.

4. An ambroxol medication kit, characterized in that, The ambroxol medicine box includes the ambroxol oral solution as described in claim 1 and a transparent container; The ambroxol oral solution is dispensed into the transparent container.

5. The use of the ambroxol oral solution as described in claim 1, characterized in that, This is used to prepare medicines for treating cough, thick sputum, difficulty in expectoration, and wheezing caused by acute and chronic respiratory diseases.

Images