Procaterol hydrochloride liquid preparation and preparation method thereof

Abstract

The invention provides a procaterol hydrochloride liquid preparation and a preparation method thereof, and relates to the technical field of medicine preparation. The procaterol hydrochloride liquid preparation provided by the invention comprises 0.001 to 0.05 mg / ml of a main drug procaterol hydrochloride, and auxiliary materials with the following concentrations: 0.0020.001 to 0.02 mg / ml of edetate disodium, 100 to 400 mg / ml of a reducing sweetening agent, and water as a solvent. According to the invention, the disodium edetate and the reducing sweetening agent are combined for use, so that the generation rate of procaterol hydrochloride related substances is synergistically reduced, the quality stability of the product is effectively ensured, meanwhile, the dosage of the disodium edetate and the reducing sweetening agent is also respectively reduced, and the clinical medication safety is further improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a liquid preparation of Procaterol hydrochloride and a preparation method thereof. Background Art

[0002] Procaterol hydrochloride is a long-acting receptor agonist and one of the commonly used long-acting β2-receptor agonists. It has the characteristics of long-lasting action, strong affinity with lung tissue, obvious bronchodilator effect, long action time, and can promote bronchial mucociliary movement, increase the clearance ability of mucociliary, relax bronchial smooth muscle, inhibit bronchial mucosal congestion and edema caused by endogenous mediators, relieve bronchospasm, improve and increase effective ventilation. It is widely used in the treatment of bronchial asthma, asthmatic bronchitis, chronic obstructive pulmonary disease (COPD) and other diseases in clinical practice. Common dosage forms include tablets, capsules, granules, oral liquid, inhalation solution, and inhalation powder.

[0003] Procaterol hydrochloride oral solution was developed by Otsuka Pharmaceutical Co., Ltd. of Japan and was launched in Japan on March 27, 1984. It can treat and relieve symptoms such as dyspnea caused by obstructive airway disorders in bronchial asthma, chronic bronchitis, emphysema, acute bronchitis, and asthma-like bronchitis. The dosage form of Procaterol hydrochloride oral solution has the advantages of easy use, accurate dosage, and good taste, and is particularly suitable for children and the elderly. However, Procaterol hydrochloride oral solution is unstable and easily affected by light, temperature, oxygen, metal ions, pH, etc. It is oxidatively degraded to form impurity III (5-formyl-8-hydroxyquinolone), which is constantly increasing during the long-term storage of the oral solution. It does not have the pharmacological effect of Procaterol, and its pharmacological activity is unknown, which may become a hidden danger in medication and bring risks. Summary of the invention

[0004] One of the purposes of the present invention is to provide a Procaterol hydrochloride oral solution, in which a reducing sweetener and edetate disodium are used to synergistically reduce the generation of related substances, ensure the stability of the Procaterol hydrochloride oral solution, and reduce the amount of the reducing sweetener and / or edetate disodium, thereby further improving the safety of clinical medication while ensuring quality stability.

[0005] Another object of the present invention is to provide a method for preparing Procaterol Hydrochloride Oral Solution, which can further improve the quality stability.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A liquid preparation of Procaterol hydrochloride comprises 0.001-0.05 mg / ml of a main drug of Procaterol hydrochloride and the following auxiliary materials in concentration: 0.001-0.02 mg / ml of disodium edetate and 100-400 mg / ml of a reducing sweetener; the solvent is water.

[0008] In a preferred embodiment of the present invention, the auxiliary materials also include 2.0-3.0 mg / ml of anhydrous citric acid and 0.4-0.5 mg / ml of sodium citrate.

[0009] In a preferred embodiment of the present invention, the auxiliary material further comprises a preservative, and the preservative consists of sodium benzoate, ethylparaben, and butylparaben, and is dissolved in ethanol.

[0010] In a preferred embodiment of the present invention, it contains 1.2-3 mg / ml of sodium benzoate, 0.01-0.1 mg / ml of ethylparaben, 0.01-0.05 mg / ml of propylparaben, and 3-5 mg / ml of ethanol.

[0011] In the present invention, ethanol is used as the solvent for the preservative. Compared with other solvents such as propylene glycol, the preservative can be dissolved more quickly, which can effectively improve the efficiency of industrial production.

[0012] In a preferred embodiment of the present invention, the reducing sweetener is sucrose.

[0013] In a preferred embodiment of the present invention, the liquid preparation is an oral solution.

[0014] In a preferred embodiment of the present invention, it comprises:

[0015] Procaterol hydrochloride 0.001~0.05mg / ml

[0016] Sucrose 150~300mg / ml

[0017] Edetate disodium 0.001~0.01mg / ml

[0018] Sodium benzoate 1.5~2.5mg / ml

[0019] Ethyl paraben 0.02~0.08mg / ml

[0020] Butylparaben 0.02~0.04mg / ml

[0021] Anhydrous citric acid 2.4~2.8mg / ml

[0022] Sodium citrate 0.4~0.45mg / ml

[0023] Ethanol 3.6~4.2mg / ml.

[0024] In a preferred embodiment of the present invention, it comprises:

[0025] Procaterol hydrochloride 0.005mg / ml

[0026] Sucrose 300mg / ml

[0027] Edetate disodium 0.005mg / ml

[0028] Sodium benzoate 2mg / ml

[0029] Ethyl paraben 0.05mg / ml

[0030] Butylparaben 0.025mg / ml

[0031] Anhydrous citric acid 2.614mg / ml

[0032] Sodium citrate 0.404mg / ml

[0033] Ethanol 4mg / ml.

[0034] A method for preparing a liquid preparation of Procaterol hydrochloride comprises the following steps:

[0035] 50-70% of the amount of the prescription amount of purified water is measured, and the reducing sweetener is added and stirred to dissolve to obtain a first solution;

[0036] adding sodium benzoate, sodium citrate and anhydrous citric acid to the first solution and stirring to dissolve to obtain a second solution;

[0037] Add ethylparaben and butylparaben to ethanol, stir and dissolve, and then add to the second solution to obtain a third solution;

[0038] Add disodium edetate and Procaterol hydrochloride to the third solution, stir and dissolve, and add the remaining water to make up to volume to obtain the solution.

[0039] The beneficial effects of the present invention are:

[0040] The present invention provides a Procaterol hydrochloride oral solution with low edetate disodium and sweetener content. Edetate disodium is a commonly used food and drug additive. Compared with the similar calcium disodium edetate, its toxicity is relatively low. However, when used in excess or not in accordance with regulations, edetate disodium will also affect people's health, such as causing the loss of trace elements required in the human body, causing symptoms such as vomiting and diarrhea, and even causing temporary renal dysfunction, blood pressure reduction and hypocalcemia. Therefore, the use of edetate disodium should be avoided or reduced as much as possible in food or medicine. In the field of medicine, edetate disodium usually complexes metal ions to avoid metal ions catalyzing API to generate related substances, thereby improving the stability of the medicine. As mentioned above, edetate disodium itself also has certain risks. Therefore, how to ensure quality stability under the premise of reducing the amount of edetate disodium as much as possible has become a difficulty in the field of medicine.

[0041] The oral solution of Procaterol hydrochloride provided by the present invention uses disodium edetate and a reducing sweetener in combination to synergistically reduce the generation rate of related substances of Procaterol hydrochloride, thereby effectively ensuring the quality stability of the product, and at the same time, respectively reducing the dosage of disodium edetate and the reducing sweetener, thereby further improving the safety of clinical medication. DETAILED DESCRIPTION

[0042] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0043] Example 1

[0044] This embodiment provides different prescription compositions of Procaterol hydrochloride oral solution, as shown in Table 1.

[0045] Table 1 Prescription composition of different Procaterol hydrochloride oral solutions

[0046]

[0047] Example 2

[0048] The compositions of prescriptions 1-10 were used to prepare Procaterol oral solution according to the following method to obtain samples ①~ .

[0049] Step (1): Measure 60% of the prescribed amount of purified water, add sucrose, stir and dissolve, and obtain a first solution.

[0050] Step (2): Weigh the prescribed amount of sodium benzoate, sodium citrate and anhydrous citric acid, add them to the first solution, stir and dissolve them, and obtain a second solution.

[0051] Step (3): taking prescribed amounts of ethylparaben, butylparaben and ethanol, adding ethylparaben and butylparaben to ethanol, stirring and dissolving, and then adding them to the second solution to obtain a third solution.

[0052] Step (4): add edetate disodium (if contained in the prescription) and Procaterol hydrochloride to the third solution in sequence, stir to dissolve, and add the remaining water to make up to volume.

[0053] Example 3

[0054] Using the composition of prescription 8, Procaterol oral solution was prepared according to the following method to obtain samples ⑧′.

[0055] Step (1): 60% of the prescribed amount of purified water is measured, and the prescribed amount of sodium benzoate, sodium citrate, anhydrous citric acid, and disodium edetate are added, stirred and dissolved to obtain a first solution.

[0056] Step (2): taking prescribed amounts of ethylparaben, butylparaben and ethanol, adding ethylparaben and butylparaben into ethanol and stirring to dissolve, and then adding the mixture into the first solution to obtain a second solution.

[0057] Step (3): Weigh the prescribed amount of Procaterol hydrochloride, add it to the second solution, stir and dissolve, and obtain a third solution.

[0058] Step (4): Add the prescribed amount of sucrose to the third solution, stir to dissolve, and add the remaining water to make up to volume.

[0059] Example 4

[0060] Using the composition of prescription 8, Procaterol oral solution was prepared according to the following method to obtain samples ⑧″.

[0061] Step (1): 60% of the prescribed amount of purified water is measured, and disodium edetate is added and stirred to dissolve, and then citric acid, sodium citrate, sodium benzoate and sucrose are added and stirred to dissolve to obtain a first solution.

[0062] Step (2): taking prescribed amounts of ethylparaben, butylparaben and ethanol, adding ethylparaben and butylparaben into ethanol and stirring to dissolve, thereby obtaining a second solution.

[0063] Step (3): Weigh the prescribed amount of Procaterol hydrochloride, dissolve the Procaterol hydrochloride in 10% of the prescribed amount of purified water, stir and dissolve, and obtain a bulk drug solution.

[0064] Step (4): Mix the first solution and the second solution, add the raw material drug solution, stir to dissolve, and add the remaining water to make up to volume.

[0065] Test example

[0066] The Procaterol hydrochloride oral solution samples ①~ The mouthfeel and / or stability of the Procaterol hydrochloride oral solution sample ①′ obtained in Example 3 and the Procaterol hydrochloride oral solution sample ①″ obtained in Example 4 were compared, and the specific results are shown below.

[0067] Taste

[0068] Table 2 Sample taste statistics

[0069]

[0070]

[0071] The results in Table 2 show that when sucrose is not added, the sample of Procaterol Hydrochloride Oral Solution tastes sour and astringent, and the mouthfeel compliance is low. With the addition of sucrose, the taste of the sample improves. When the amount of sucrose is not less than 150 mg / ml, the sweetness of the sample is close to that of the local original research (Mepuqing) and the reference preparation (Meptin), and there is no sour taste.

[0072] stability

[0073] 1. Effect of preparation method on related substances

[0074] Sample ⑧ obtained in Example 2, sample ⑧′ obtained in Example 3, and sample ⑧″ obtained in Example 4 were tested to determine the content of impurity III therein. The results are shown in Table 3.

[0075] Table 3 Content of impurity III in samples obtained by different preparation processes

[0076] sample Impurity III% Sample ⑧ Not detected Sample ⑧′ 0.11 Sample ⑧″ 0.08

[0077] From the results in Table 3, it can be seen that the same preparation formula has different contents of impurity III when different preparation methods are used. When the preparation methods of Example 3 and Example 4 are used, a trace amount of impurity III will be generated during the process. However, when the preparation method of Example 2 is used, the generation of impurity III during the sample preparation process can be completely avoided.

[0078] 2. Effect of sucrose dosage on related substances

[0079] Table 4 Effect of different sucrose contents on impurity III

[0080]

[0081] The results in Table 4 show that when the amount of sucrose increases from 0 mg / ml to 400 mg / ml, the growth rate of impurity III slows down, indicating that sucrose in the prescription has a delayed effect on the degradation of Procaterol hydrochloride. When the sucrose concentration is 150 mg / ml, the content of impurity III in the sample can reach the level of localized original research, and is slightly better than the localized original research. When the sucrose concentration is 300 mg / ml, the content of impurity III in the sample is lower than the reference preparation, and the quality is significantly better than the localized original research and reference preparation. On this basis, further increasing the sucrose content significantly reduces the efficiency of inhibiting the generation of impurity III.

[0082] 3. Effect of metal ion chelating agent dosage on related substances

[0083] Table 5 Effect of different edetate disodium contents on impurity III

[0084]

[0085] As shown in Table 5, compared with the sample without edetate disodium, the generation rate of impurity III of the sample with edetate disodium added is effectively controlled under different conditions. When the content of edetate disodium is 0.001-0.008mg / ml, the generation rate of impurity III continues to decline, especially, when the content of edetate disodium is not less than 0.002mg / ml, the generation rate of impurity III is less than 0.5%. When the content of edetate disodium is higher than 0.01mg / ml, the generation rate of impurity III no longer has obvious decline, and the content tends to be stable.

[0086] The above only exemplifies a limited number of implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A liquid preparation of Procaterol hydrochloride, characterized in that: The invention comprises a main drug of Procaterol hydrochloride at 0.001-0.05 mg / ml, and auxiliary materials with the following concentrations: edetate disodium at 0.001-0.02 mg / ml, a reducing sweetener at 100-400 mg / ml, and the solvent is water.

2. The liquid preparation of Procaterol hydrochloride according to claim 1, characterized in that: The auxiliary materials also include 2.4-3.0 mg / ml of anhydrous citric acid and 0.4-0.45 mg / ml of sodium citrate.

3. The liquid preparation of Procaterol hydrochloride according to claim 2, characterized in that: The auxiliary material also includes a preservative, which consists of sodium benzoate, ethylparaben and butylparaben and is dissolved in ethanol.

4. The liquid preparation of Procaterol hydrochloride according to claim 3, characterized in that: It contains sodium benzoate 1.2-3 mg / ml, ethylparaben 0.01-0.1 mg / ml, propylparaben 0.01-0.05 mg / ml, and ethanol 3-5 mg / ml.

5. The liquid preparation of Procaterol hydrochloride according to any one of claims 1 to 4, characterized in that: The reducing sweetener is sucrose.

6. The liquid preparation of Procaterol hydrochloride according to claim 5, characterized in that: The liquid preparation is an oral solution.

7. The liquid preparation of Procaterol hydrochloride according to claim 6, characterized in that: It includes:

8. The liquid preparation of Procaterol hydrochloride according to claim 7, characterized in that: It includes:

9. A method for preparing a liquid preparation of Procaterol hydrochloride, characterized in that: It includes the following steps: 50-70% of the amount of the prescription amount of purified water is measured, and the reducing sweetener is added and stirred to dissolve to obtain a first solution; adding sodium benzoate, sodium citrate and anhydrous citric acid to the first solution and stirring to dissolve to obtain a second solution; Add ethylparaben and butylparaben to ethanol, stir and dissolve, and then add to the second solution to obtain a third solution; Add disodium edetate and Procaterol hydrochloride to the third solution, stir and dissolve, and add the remaining water to make up to volume to obtain the solution.

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