An ambroxol hydrochloride inclusion complex, its formulation and uses

Abstract

This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an ambroxol hydrochloride inclusion complex, its formulation, and its uses. This invention utilizes inclusion complex technology and preferentially selects β-cyclodextrin and sodium cyclolactone as inclusion materials to prepare an ambroxol hydrochloride inclusion complex with high drug loading, high encapsulation efficiency, and high stability. Furthermore, this complex is combined with pharmaceutically acceptable excipients to formulate ambroxol hydrochloride tablets, solving the problem of ambroxol hydrochloride easily generating related substances under aerobic and light-exposed conditions, thus improving the stability of ambroxol hydrochloride tablets.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an ambroxol hydrochloride inclusion complex, its formulation, and its uses. Background Technology

[0002] Ambroxol hydrochloride, chemically known as trans-4-[(2-amino-3,5-dibromo-phenyl)methyl-amino]cyclohexanol, is a mucolytic agent that increases the secretion of serous glands in the respiratory mucosa and decreases the secretion of mucus glands, thereby reducing sputum viscosity. It also promotes the secretion of pulmonary surfactant, increases bronchial ciliary movement, and makes sputum easier to cough up. It can improve symptoms such as abnormal sputum secretion, poor expectoration function, thick sputum, and difficulty in expectoration. It is mainly suitable for patients with white, sticky sputum that is difficult to cough up due to acute and chronic respiratory diseases (acute and chronic bronchitis, bronchial asthma, bronchiectasis, pulmonary tuberculosis, etc.). It can also be used for neonatal respiratory distress syndrome. It has significant clinical efficacy, and ambroxol hydrochloride is well tolerated, with no drug accumulation after repeated use, and has high safety.

[0003] Ambroxol hydrochloride is unstable under aerobic, alkaline, and light-exposed conditions, which can increase the amount of related substances and affect the quality and safety of the drug. Therefore, it needs to be transported and stored in a sealed, light-protected environment.

[0004] Chinese patent CN110179764A discloses an ambroxol hydrochloride tablet and its preparation method. Specifically, the raw materials for the ambroxol hydrochloride tablet are mixed for 11-35 minutes at a relatively low rotation speed (10-18 r / min). Pregelatinized starch and colloidal silica are used in combination to improve the flowability and tablet compressibility of the raw materials, facilitating direct compression of the powder into tablets. The preparation process does not involve wet mixing or heating / drying, resulting in more stable ambroxol hydrochloride tablets. However, this method only avoids high humidity and high temperature conditions during preparation and does not substantially solve the problem of ambroxol hydrochloride easily generating related substances under aerobic and light-exposed conditions. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides an ambroxol hydrochloride inclusion complex with high drug loading, high encapsulation efficiency, and high stability, which is further formulated into ambroxol hydrochloride tablets. This solves the problem that ambroxol hydrochloride is prone to generating related substances under aerobic and light conditions, and improves the stability of ambroxol hydrochloride tablets.

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

[0007] This invention provides an ambroxol hydrochloride inclusion complex comprising ambroxol hydrochloride, β-cyclodextrin, and sodium cyclodextrin.

[0008] In several embodiments, the ambroxol hydrochloride inclusion complex comprises 10-30 parts by weight of ambroxol hydrochloride, 10-30 parts by weight of β-cyclodextrin, and 1-3 parts by weight of sodium cyclodextrin.

[0009] In a preferred embodiment, the ambroxol hydrochloride inclusion complex comprises 20 parts by weight of ambroxol hydrochloride, 20 parts by weight of β-cyclodextrin, and 2 parts by weight of sodium cyclodextrin.

[0010] A second objective of this invention is to provide a method for preparing the above-mentioned ambroxol hydrochloride inclusion complex, comprising the following steps:

[0011] Ambroxol hydrochloride and sodium cyclodextrin were dissolved in a solvent and added to a saturated aqueous solution of β-cyclodextrin at a temperature of 45℃~65℃. The solution was then evaporated at a constant temperature of 45℃~65℃ for 1~3 hours to obtain a precipitate. The precipitate was then filtered, washed, and dried to obtain the ambroxol hydrochloride inclusion complex.

[0012] In several embodiments, the solvent is a methanol aqueous solution with a volume fraction of 60% to 80%.

[0013] In a preferred embodiment, the solvent is a 70% (v / v) aqueous methanol solution.

[0014] In a preferred embodiment, the temperature is 55°C.

[0015] A third objective of this invention is to provide an ambroxol hydrochloride tablet comprising the above-mentioned ambroxol hydrochloride inclusion complex, wherein the ambroxol hydrochloride tablet comprises:

[0016] Contains 30 parts by weight of ambroxol hydrochloride inclusion complex

[0017] 70-190 parts by weight of microcrystalline cellulose

[0018] 10-30 parts by weight of low-substituted hydroxypropyl cellulose

[0019] Micronized silica gel 0.5-1.5 parts by weight

[0020] Remaining amount of pregelatinized starch.

[0021] In a preferred embodiment, the ambroxol hydrochloride tablets comprise:

[0022] Contains 30 parts by weight of ambroxol hydrochloride inclusion complex

[0023] 120 parts by weight of microcrystalline cellulose

[0024] 15 parts by weight of low-substituted hydroxypropyl cellulose

[0025] 0.8 parts by weight of micronized silica powder

[0026] Remaining amount of pregelatinized starch.

[0027] In a preferred embodiment, the ambroxol hydrochloride tablets comprise:

[0028] Contains 30 parts by weight of ambroxol hydrochloride inclusion complex

[0029] 170 parts by weight of microcrystalline cellulose

[0030] 25 parts by weight of low-substituted hydroxypropyl cellulose

[0031] 1.2 parts by weight of micronized silica gel

[0032] Remaining amount of pregelatinized starch.

[0033] In a preferred embodiment, the ambroxol hydrochloride tablets comprise:

[0034] 150 parts by weight of microcrystalline cellulose

[0035] 20 parts by weight of low-substituted hydroxypropyl cellulose

[0036] 1 part by weight of micronized silica

[0037] Remaining amount of pregelatinized starch.

[0038] A fourth object of the present invention is to provide the use of the above-described ambroxol hydrochloride inclusion complex or the ambroxol hydrochloride inclusion complex prepared by the above method in the preparation of medicaments for treating respiratory diseases.

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0040] This invention utilizes inclusion compound technology, and by selecting appropriate inclusion materials and optimizing preparation methods, obtains an ambroxol hydrochloride inclusion compound with high drug loading, high encapsulation efficiency, and high stability. Furthermore, this compound is combined with pharmaceutically acceptable excipients to formulate ambroxol hydrochloride tablets, thus solving the problem that ambroxol hydrochloride easily generates related substances under aerobic and light conditions, and improving the stability of ambroxol hydrochloride tablets. Attached Figure Description

[0041] Figure 1 Impurities of ambroxol hydrochloride, structural formula

[0042] Figure 2 Changes in the content of related substances in ambroxol hydrochloride tablets during light exposure tests

[0043] Figure 3 Changes in the content of related substances in ambroxol hydrochloride tablets during aerobic experiments at room temperature Detailed Implementation

[0044] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0045] I. Ambroxol Hydrochloride Inclusion Complex

[0046] Example 1 Ambroxol Hydrochloride Inclusion Complex

[0047] Dissolve 20 parts by weight of ambroxol hydrochloride and 2 parts by weight of sodium cyclodextrin in a 70% (v / v) methanol aqueous solution, add the solution to 20 parts by weight of β-cyclodextrin saturated aqueous solution at 55°C, and rotary evaporate at 55°C for 1-3 hours to obtain a precipitate. Filter, wash, and dry to obtain the ambroxol hydrochloride inclusion complex.

[0048] Example 2 Ambroxol Hydrochloride Inclusion Complex

[0049] Dissolve 10 parts by weight of ambroxol hydrochloride and 1 part by weight of sodium cyclodextrin in a 60% (v / v) methanol aqueous solution, add the solution to 10 parts by weight of β-cyclodextrin saturated aqueous solution at 45°C, and rotary evaporate at 45°C for 1-3 hours to obtain a precipitate. Filter, wash, and dry to obtain the ambroxol hydrochloride inclusion complex.

[0050] Example 3 Ambroxol Hydrochloride Inclusion Complex

[0051] Dissolve 30 parts by weight of ambroxol hydrochloride and 3 parts by weight of sodium cyclodextrin in an 80% (v / v) methanol aqueous solution, and add the solution to 30 parts by weight of β-cyclodextrin saturated aqueous solution at 65°C. The solution is then evaporated at a constant temperature of 65°C for 1–3 h to obtain a precipitate. The precipitate is filtered, washed, and dried to obtain the ambroxol hydrochloride inclusion complex.

[0052] Comparative Example 1: Ambroxol Hydrochloride Inclusion Complex

[0053] Dissolve 20 parts by weight of ambroxol hydrochloride in a 70% (v / v) methanol aqueous solution, add it to 20 parts by weight of a saturated aqueous solution of β-cyclodextrin at 55°C, and rotary evaporate at 55°C for 1-3 hours to obtain a precipitate. Filter, wash, and dry to obtain the ambroxol hydrochloride inclusion complex.

[0054] Comparative Example 2: Ambroxol Hydrochloride Inclusion Complex

[0055] Dissolve 20 parts by weight of ambroxol hydrochloride and 0.5 parts by weight of sodium cyclodextrin in a 70% (v / v) methanol aqueous solution, and add the solution to 20 parts by weight of β-cyclodextrin saturated aqueous solution at 55°C. The solution is then evaporated at a constant temperature of 55°C for 1–3 h to obtain a precipitate. The precipitate is filtered, washed, and dried to obtain the ambroxol hydrochloride inclusion complex.

[0056] II. Quality Evaluation of Ambroxol Hydrochloride Inclusion Complex

[0057] This invention evaluates the ambroxol hydrochloride inclusion complexes of Examples 1-3 and Comparative Examples 1-2 based on three indicators: drug loading, encapsulation efficiency, and leakage rate.

[0058] The storage conditions for evaluating leakage rate are a temperature of 40±2℃ and a relative humidity of 75%±5% for one month.

[0059] Table 1. Drug loading, encapsulation efficiency, and leakage rate of ambroxol hydrochloride inclusion complex.

[0060] Drug loading (%) Encapsulation rate (%) Leakage rate (%) Example 1 Ambroxol Hydrochloride Inclusion Complex 38.6 92.7 0.17 Example 2 Ambroxol Hydrochloride Inclusion Complex 37.2 91.4 0.19 Example 3 Ambroxol Hydrochloride Inclusion Complex 37.9 91.0 0.20 Comparative Example 1: Ambroxol Hydrochloride Inclusion Complex 30.4 80.3 0.52 Comparative Example 2: Ambroxol Hydrochloride Inclusion Complex 32.5 83.4 0.49

[0061] Table 1 shows the drug loading, encapsulation efficiency, and leakage rate of the ambroxol hydrochloride inclusion complexes of Examples 1-3 and Comparative Examples 1-2. It shows that the ambroxol hydrochloride inclusion complex of the present invention has a high drug loading, high encapsulation efficiency, and low leakage rate, and has higher stability compared with the ambroxol hydrochloride inclusion complexes of the comparative examples.

[0062] III. Ambroxol Hydrochloride Tablets

[0063] Example 4: Ambroxol Hydrochloride Tablets

[0064] formula:

[0065] Contains 30g of ambroxol hydrochloride inclusion complex

[0066] 120g of microcrystalline cellulose

[0067] Low-substituted hydroxypropyl cellulose 15g

[0068] Micronized silica gel 0.8g

[0069] Remaining amount of pregelatinized starch.

[0070] Preparation method: Dry compression tableting.

[0071] Example 5 Ambroxol Hydrochloride Tablets

[0072] formula:

[0073] Contains 30g of ambroxol hydrochloride inclusion complex

[0074] 170g of microcrystalline cellulose

[0075] Low-substituted hydroxypropyl cellulose 25g

[0076] Micronized silica gel 1.2g

[0077] Remaining amount of pregelatinized starch.

[0078] Preparation method: Dry compression tableting.

[0079] Example 6 Ambroxol Hydrochloride Tablets

[0080] formula:

[0081] Contains 30g of ambroxol hydrochloride inclusion complex

[0082] 150g of microcrystalline cellulose

[0083] Low-substituted hydroxypropyl cellulose 20g

[0084] 1g of micronized silica

[0085] Remaining amount of pregelatinized starch.

[0086] Preparation method: Dry compression tableting.

[0087] Example 7 Ambroxol Hydrochloride Tablets

[0088] formula:

[0089] Contains 30g of ambroxol hydrochloride inclusion complex

[0090] 70g of microcrystalline cellulose

[0091] 10g of low-substituted hydroxypropyl cellulose

[0092] Micronized silica gel 0.5g

[0093] Remaining amount of pregelatinized starch.

[0094] Preparation method: Dry compression tableting.

[0095] Example 8 Ambroxol Hydrochloride Tablets

[0096] formula:

[0097] Contains 30g of ambroxol hydrochloride inclusion complex

[0098] 190g of microcrystalline cellulose

[0099] Low-substituted hydroxypropyl cellulose 30g

[0100] Micronized silica gel 1.5g

[0101] Remaining amount of pregelatinized starch.

[0102] Preparation method: Dry compression tableting.

[0103] Comparative Example 3 (Ambroxol Hydrochloride Tablets H20150082)

[0104] IV. Quality Evaluation of Ambroxol Hydrochloride Tablets

[0105] Determination of related substances content

[0106] The relevant substances were determined by high performance liquid chromatography (General Rule 0512). Test solution: Take an appropriate amount of this product, dissolve and dilute with the mobile phase to prepare a solution containing approximately 1 mg per ml. Reference solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with the mobile phase, and mix well. System suitability solution: Dissolve approximately 5 mg of ambroxol hydrochloride in 0.2 ml of methanol, then add 40 μl of formaldehyde solution (1→100), mix well, heat in a 60℃ water bath for 5 minutes, and dry under nitrogen. Dissolve the residue in 5 ml of water, dilute to 20 ml with the mobile phase, and mix well. Chromatographic conditions: Use octadecylsilane-bonded silica gel as the stationary phase; use 0.01 mol / L diammonium hydrogen phosphate solution (adjusted to pH 7.0 with phosphoric acid)-acetonitrile (50:50) as the mobile phase; the detection wavelength is 248 nm; the injection volume is 20 μl. System suitability requirements: In the chromatogram of the system suitability solution, the resolution between the ambroxol peak and impurity I peak (relative retention time approximately 0.8) should be greater than 4.0. Assay method: Accurately measure the test solution and control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to twice the retention time of the main component peak. Limit: If impurity peaks are present in the chromatogram of the test solution, the sum of the areas of all impurity peaks should not exceed 0.3 times (0.3%) the area of ​​the main peak in the control solution.

[0107] 1. Study on the photostability of ambroxol hydrochloride tablets

[0108] Ambroxol hydrochloride tablets from Examples 4-8 and Comparative Example 3 were used as test samples. The tablets were placed in an illumination box with fluorescent lamps and kept at an illuminance of 4500 lx ± 500 lx for 90 days. Samples were taken on days 0, 10, 30, 60 and 90, and the content of impurity I in the ambroxol hydrochloride tablets was determined by high performance liquid chromatography.

[0109] 2. Study on the antioxidant stability of ambroxol hydrochloride tablets

[0110] Ambroxol hydrochloride tablets from Examples 4-8 and Comparative Example 3 were used as test samples. The tablets were placed in open containers at a temperature of 20±2℃ and a relative humidity of 65±20%rh for 90 days. Samples were taken on days 0, 10, 30, 60 and 90, and the content of impurity I in the ambroxol hydrochloride tablets was determined by high performance liquid chromatography.

[0111] Figure 2 , Figure 3 The graphs show the changes in the content of related substances in ambroxol hydrochloride tablets during light exposure and during room temperature aerobic tests, respectively. They show that the content of related substances in the ambroxol hydrochloride tablets of the present invention is low and remains basically unchanged during the experiments. In contrast, the ambroxol hydrochloride tablets of Comparative Example 3 showed a significant increase in related substances after 10 days in both light exposure and room temperature aerobic tests, indicating lower stability.

Claims

1. An ambroxol hydrochloride inclusion complex, characterized in that, The ambroxol hydrochloride inclusion complex comprises 20 parts by weight of ambroxol hydrochloride, 20 parts by weight of β-cyclodextrin, and 2 parts by weight of sodium cyclodextrin; the preparation method of the ambroxol hydrochloride inclusion complex includes the following steps: Ambroxol hydrochloride and sodium cyclodextrin were dissolved in a solvent and added to a saturated aqueous solution of β-cyclodextrin at a temperature of 45℃~65℃. The solution was then evaporated at a constant temperature of 45℃~65℃ for 1~3 hours to obtain a precipitate. The precipitate was then filtered, washed, and dried to obtain the ambroxol hydrochloride inclusion complex.

2. A method for preparing the ambroxol hydrochloride inclusion complex according to claim 1, characterized in that, The method includes the following steps: Ambroxol hydrochloride and sodium cyclodextrin were dissolved in a solvent and added to a saturated aqueous solution of β-cyclodextrin at a temperature of 45℃~65℃. The solution was then evaporated at a constant temperature of 45℃~65℃ for 1~3 hours to obtain a precipitate. The precipitate was then filtered, washed, and dried to obtain the ambroxol hydrochloride inclusion complex.

3. The method according to claim 2, characterized in that, The solvent is a methanol aqueous solution with a volume fraction of 60% to 80%.

4. The method according to claim 2, characterized in that, The solvent is a 70% (v / v) aqueous methanol solution.

5. The method according to claim 3, characterized in that, The temperature is 55°C.

6. An ambroxol hydrochloride tablet comprising the ambroxol hydrochloride inclusion complex of claim 1, characterized in that, The ambroxol hydrochloride tablets contain: 30 parts by weight of ambroxol hydrochloride inclusion complex 70-190 parts by weight of microcrystalline cellulose 10-30 parts by weight of low-substituted hydroxypropyl cellulose Micronized silica gel 0.5~1.5 parts by weight Remaining amount of pregelatinized starch.

7. The ambroxol hydrochloride tablets according to claim 6, characterized in that, The ambroxol hydrochloride tablets contain: 30 parts by weight of ambroxol hydrochloride inclusion complex 120 parts by weight of microcrystalline cellulose 15 parts by weight of low-substituted hydroxypropyl cellulose 0.8 parts by weight of micronized silica gel Remaining amount of pregelatinized starch.

8. The ambroxol hydrochloride tablets according to claim 6, characterized in that, The ambroxol hydrochloride tablets contain: 30 parts by weight of ambroxol hydrochloride inclusion complex 170 parts by weight of microcrystalline cellulose 25 parts by weight of low-substituted hydroxypropyl cellulose 1.2 parts by weight of micronized silica gel Remaining amount of pregelatinized starch.

9. The ambroxol hydrochloride tablets according to claim 6, characterized in that, The ambroxol hydrochloride tablets contain: 30 parts by weight of ambroxol hydrochloride inclusion complex 150 parts by weight of microcrystalline cellulose 20 parts by weight of low-substituted hydroxypropyl cellulose 1 part by weight of micronized silica Remaining amount of pregelatinized starch.

10. Use of the ambroxol hydrochloride inclusion complex according to claim 1 or the ambroxol hydrochloride inclusion complex prepared by the method according to claim 2 in the preparation of a medicament for treating respiratory diseases.

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