CN116407495A - Atenolol oral solution and preparation method and application thereof - Google Patents

Abstract

The invention relates to atenolol oral solution and a preparation method and application thereof. The atenolol oral solution provided by the invention provides an oral preparation specially used for treating infantile hemangioma, can avoid respiratory cramp and hypoglycemia adverse reaction generated when propranolol is orally taken, reduces adverse reactions such as sleep disorder, agitation of sleep and the like caused by blood brain barrier, reduces the times of administration, and is convenient to take. The atenolol oral solution overcomes the defect that the infant has narrow throat and is difficult to swallow tablets. Atenolol is dissolved in the solution as an active ingredient, and the administration dosage can be accurately controlled, so that excessive treatment or insufficient treatment is avoided.

Description

A kind of atenolol oral solution and its preparation method and application

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an atenolol oral solution for treating infantile hemangioma, a preparation method and application thereof.

Background Art

Infantile hemangioma (IH) is the most common vascular malformation or tumor in infants and young children. It is prone to occur on the head and face (about 60%), with an incidence rate of about 4% to 5%, and it is increasing year by year. The disease is more common in females, with a male-female ratio of 1:3 to 1:5. The incidence rate may be higher in low birth weight infants and premature infants. Most of them appear at birth and within 1 month after birth. The size of the tumor can reach 80% of the final size during the early proliferation period (within 3 months after birth). After 1 year old, it enters a natural regression process, which can last for 3 to 8 years or even longer. IH has limited self-regression ability, and even after 5 years, 51% have not regressed. Among IH that have regressed without treatment, about 25% to 69% have residual degenerative changes in the skin and subcutaneous tissue, including residual erythema, pigment changes, capillary dilation, atrophic scars, and fibrofatty tissue growths, which affect the appearance to varying degrees and are difficult to achieve complete or almost complete regression. In severe cases (5% to 20%), multiple complications may occur, including ulcers (16% to 23%), bleeding (41%), infection (16%), or functional impairment (vision, hearing, breathing, swallowing, etc.), disfigurement, etc., and even endanger life, thus seriously affecting the quality of life of the child. At present, hemangioma experts at home and abroad have reached a consensus on the treatment strategy of hemangioma, and early intervention should be carried out for infantile hemangioma to prevent and control the complications caused by the rapid proliferation of the tumor.

et al.Atenolol versus propranolol forthe treatment of infantile hemangiomas：A randomized controlled study[J].J AmAcad Dermatol.2014Jun；70(6):1045-9.王冠杰，等.阿替洛尔与普萘洛尔治疗婴儿血管瘤的疗效比较[J].安徽医药.2016,20(03):570-572.王琦，等.普萘洛尔与阿替洛尔治疗婴儿血管瘤的比较研究[J].中华皮肤科杂志.2016,49(10):683-687.孙龙龙，等.普萘洛尔与阿替洛尔治疗增殖期婴儿血管瘤的临床疗效及安全性对比[J].现代生物医学进展.2018,18(1):108-112.Ji Y et al.Intolerable side effects during propranolol therapyfor infantile hemangioma frequency,risk factors and management[J].ScientificReports.2018,8(1):4264.Zhao ZL et al.A survey on the application of oralpropranolol and atenolol for the management of infantile hemangiomas inmainland China:Survey on propranolol atenolol hemangiomas[J].Medicine(Baltimore).2021,100(1):e24146.)At present, the main treatment methods include laser treatment and surgical excision. Laser photocoagulation cannot stop the growth of hemangiomas and can cause ulcers, skin atrophy, and depigmentation. It is usually used as an auxiliary treatment. Surgery is mainly used to remove lesions that remain in the involution period or after treatment, such as scars, skin depressions, excess skin, fibrous fat residues, etc. Surgery is rarely used for proliferative infantile hemangiomas. Since the US FDA approved the marketing of the pediatric drug Hemangeol ^TM oral solution (propranolol hydrochloride) in March 2014, Hemangeol ^TM has become the first and only drug for the treatment of proliferative infantile hemangiomas. Propranolol has become the first-line drug for the treatment of infantile hemangiomas. Oral propranolol 2-3 mg/kg/d, taken in 3 doses, is used to treat infantile hemangiomas (Léauté-Labrèze C, et al. Infantile haemangioma [J]. Lancet. 2017; 390(10089): 85–94.). Because propranolol is highly lipid-soluble, it can be easily passed through the blood-brain barrier into the brain, and there is a high risk of adverse reactions to the central nervous system (CNS), such as drowsiness or insomnia, decreased appetite, etc. A literature review reported that the incidence of sleep disorders during propranolol treatment was about 6%, while that of placebo was 1.3% (Léaute-Labrèze C, Boccara O, Degrugillier-Chopinet C, et al. Safety of oral propranolol for the treatment of infantile hemangioma: a systematic review [J]. Pediatrics. 2016; 138: e20160353). In addition, propranolol is a non-selective β-adrenergic receptor blocker that acts on both _β1 and _β2 receptors. Blockade of _β2 receptors carries the risk of potentially serious adverse reactions, such as bronchospasm/bronchial hyperresponsiveness and hypoglycemia. Due to these side effects, some patients must stop taking the drug, resulting in a high recurrence rate of infantile hemangioma (10% to 15%). Based on the above disadvantages, propranolol has been widely promoted and applied. Compared with propranolol, atenolol is a hydrophilic selective _β1 receptor blocker. Many studies at home and abroad have confirmed that oral atenolol has the same efficacy as propranolol in the treatment of infantile hemangioma, with a lower incidence of sleep disorders and agitation, and almost no risk of airway spasm and hypoglycemia. Moreover, because atenolol has a longer half-life in the body, it can be taken once a day, avoiding the inconvenience of taking oral propranolol three times a day, and improving patient compliance. Oral atenolol has become another drug intervention option for the treatment of infantile hemangioma in China. (Alvaro

et al.Atenolol versus propranolol for the treatment of infantile hemangiomas：A randomized controlled study[J].J Am Acad Dermatol.2014Jun；70(6):1045-9. Wang Guanjie, et al. Comparison of the efficacy of atenolol and propranolol in the treatment of infantile hemangiomas[J]. Anhui Medicine.2016,20(03):570-572. Wang Qi, et al. Comparative study of propranolol and atenolol in the treatment of infantile hemangiomas[J]. Chinese Journal of Dermatology.2016,49(10):683-687. Sun Longlong, et al. Comparison of clinical efficacy and safety of propranolol and atenolol in the treatment of proliferative infantile hemangiomas[J]. Advances in Modern Biomedicine.2018,18(1):108-112. Ji Y et al. Intolerable side effects during propranolol therapyfor infantile hemangioma frequency,risk factors and management[J].ScientificReports.2018,8(1):4264.Zhao ZL et al.A survey on the application of oralpropranolol and atenolol for the management of infantile hemangiomas inmainland China:Survey on propranolol atenolol hemangiomas[J].Medicine(Baltimore).2021,100(1):e24146.)

Summary of the invention

Although atenolol is effective in treating infantile hemangiomas, there are no oral atenolol solutions for treating infantile hemangiomas on the market at home and abroad. The domestic atenolol dosage forms that have been marketed are tablets (12.5mg, 25mg, 50mg and 100mg). The dosage for infants and young children is very small and varies greatly (the patient's age is 5 to 24 weeks, and the dosage is adjusted monthly according to body weight). Usually, a tablet must be taken in multiple doses, and the dosage is difficult to accurately control; in addition, atenolol dissolves slowly in water, the tablet disintegration time is long, and the dissolution rate is low, which makes it inconvenient for infants and young children to take, affects the efficacy, and increases the risk of gastrointestinal discomfort (diarrhea); especially when used in infants of younger age, standardized medication is particularly important. At present, there are no oral atenolol preparations specifically for infants and young children in China, which cannot meet current clinical needs.

According to the "Guidelines for the Pharmaceutical Development of Children's Drugs (Chemical Drugs) (Trial)" issued by the Center for Drug Evaluation of the National Medical Products Administration on December 31, 2020, the advantage of oral liquid preparations is that the dosage is more flexible and more suitable for children who cannot swallow solid preparations. Considering the taste-masking, solubility and stability of atenolol, atenolol needs to be made into an oral solution to facilitate dosing, accurate administration and treatment of diseases.

The invention is characterized in that it provides an oral atenolol solution for treating infantile hemangioma, which is tailor-made for infants and young children, convenient and hygienic, has a good taste, high bioavailability, accurate dosing, and safe medication, and a preparation method thereof. The oral atenolol solution for treating infantile hemangioma provided by the invention solves the problem that there is currently no oral atenolol preparation specifically for treating infantile hemangioma in China. The oral atenolol solution of the invention overcomes the phenomenon that infants and young children have difficulty swallowing tablets due to narrow throats. Atenolol is dissolved in the solution as an active ingredient, and the dosage can be accurately controlled to avoid overtreatment or undertreatment.

To achieve the above purpose, the specific technical solution of the present invention is as follows:

The invention discloses an atenolol oral solution for treating infantile hemangioma. The oral solution comprises 1 to 10 parts by weight of atenolol, 1 to 5 parts by weight of saccharin sodium, 1 to 10 parts by weight of citric acid, 1 to 5 parts by weight of methylparaben sodium, 0.1 to 0.5 parts by weight of propylparaben sodium, 1 to 10 parts by weight of hydroxyethyl cellulose and 500 to 2000 parts by weight of purified water.

Preferably, an atenolol oral solution for treating infantile hemangioma comprises 2 to 10 parts by weight of atenolol, 1 to 4 parts by weight of saccharin sodium, 2 to 10 parts by weight of citric acid, 1 to 4 parts by weight of methylparaben sodium, 0.1 to 0.4 parts by weight of propylparaben sodium, 2 to 10 parts by weight of hydroxyethyl cellulose, and 800 to 1600 parts by weight of purified water.

Preferably, an atenolol oral solution for treating infantile hemangioma comprises 3 to 7 parts by weight of atenolol, 1 to 3.5 parts by weight of saccharin sodium, 3 to 7 parts by weight of citric acid, 1.5 to 3.5 parts by weight of methylparaben sodium, 0.15 to 0.35 parts by weight of propylparaben sodium, 3 to 7 parts by weight of hydroxyethyl cellulose, and 800 to 1400 parts by weight of purified water.

Preferably, an atenolol oral solution for treating infantile hemangioma comprises 3 to 5 parts by weight of atenolol, 1 to 2.5 parts by weight of saccharin sodium, 3 to 5 parts by weight of citric acid, 1.5 to 2.5 parts by weight of methylparaben sodium, 0.15 to 0.3 parts by weight of propylparaben sodium, 3 to 5 parts by weight of hydroxyethyl cellulose, and 1000 parts by weight of purified water.

Furthermore, in order to improve the taste of the oral solution, cater to the taste of infants and young children, and improve compliance, the oral solution also includes a flavoring agent, which is selected from one or a combination of milk flavor, orange flavor, cherry flavor, lemon flavor, vanilla flavor, pineapple flavor, strawberry flavor, mango flavor, and apple flavor. Preferably, the weight portion of the flavoring agent is 0.1 to 5 parts by weight.

Preferably, the oral solution further comprises a flavoring agent, and the flavoring agent is selected from one of vanilla essence and strawberry essence or a combination thereof. Preferably, the flavoring agent is selected from a combination of vanilla essence and strawberry essence, wherein the vanilla essence is 0.4-0.8 parts by weight and the vanilla essence is 0.2-0.4 parts by weight.

In another aspect, the present invention provides a method for preparing an atenolol oral solution for treating infantile hemangioma, the method comprising the following steps:

(1) Add atenolol, saccharin sodium, and citric acid to about 40% of the prescribed amount of purified water in sequence, and stir to dissolve; then add the prescribed amount of methylparaben sodium and propylparaben sodium, and stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside.

(2) Add hydroxyethyl cellulose to about 40% of the prescribed amount of purified water, heat at 40°C to 80°C and stir to dissolve, cool to room temperature, then add the prescribed amount of flavoring agent, mix well, and obtain solution ②;

(3) Add solution ① cooled to room temperature to solution ② and mechanically stir for 3 to 10 minutes to obtain solution ③;

(4) Add purified water to the above solution ③ to make up the total amount, stir evenly, and fill it.

Preferably, the mechanical stirring speed of the high-speed shearing machine is 200-500r/min.

The preferred preparation method described in the present invention is obtained through a large number of experiments, reasonable coordination and comparative summary. The preparation process is simple and the process is short. The obtained oral solution is colorless and transparent, has moderate viscosity and good stability.

Combined with all the above technical solutions, the positive effects of the atenolol oral solution of the present invention are as follows: (1) The atenolol oral solution of the present invention can be used to treat infantile hemangioma, can avoid the adverse reactions of respiratory spasm and hypoglycemia caused by oral propranolol, reduce the adverse reactions such as sleep disorders and sleep agitation that occur through the blood-brain barrier, and reduce the number of medications, making it easier to take. (2) The atenolol oral solution of the present invention can reduce gastrointestinal reactions and improve bioavailability, thereby reducing the dosage of infants and young children; (3) After a large number of experiments, the oral solution of this formula has been obtained, and the drug is evenly dispersed, the viscosity is moderate, and the stability is good; (4) The oral solution overcomes the phenomenon that infants and young children have difficulty taking tablets due to narrow throats. Atenolol is dissolved in the solution as an active ingredient, and the dosage can be accurately controlled to avoid overtreatment or undertreatment. It can also be prepared into a fruity flavor that infants and young children like, which caters to children's psychology and reduces the difficulty of taking medicine for infants and young children; (5) The preparation process is simple, the process is short, the source of raw materials is easy to obtain and the cost is low, and it has a broad market prospect.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

Example 1

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, and stir mechanically for 3 minutes to obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 2

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, and stir mechanically for 3 minutes to obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 3

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, and stir mechanically for 3 minutes to obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 4

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, aspartame and hydrochloric acid to about 40% of the prescription amount of purified water in turn, stir to dissolve, filter to obtain solution ①, cool to room temperature and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat to 80℃ and stir to dissolve, cool to room temperature to obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 5

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, sodium cyclamate, and citric acid to about 40% of the prescription amount of purified water in turn, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add methylcellulose to about 40% of the prescription amount of purified water, heat and stir to dissolve at 70°C, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, and stir mechanically for 5 minutes to obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 6

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, sorbitol, and citric acid to about 40% of the prescription amount of purified water in turn, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add xanthan gum to about 40% of the prescription amount of purified water, heat and stir to dissolve at 80°C, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, and stir mechanically for 3 minutes to obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 7

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium silicate and lauric acid, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 8

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium benzoate, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 9

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium propylparaben, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 10

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium methylparaben, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Embodiment 11

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of methylparaben sodium and propylparaben sodium, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to dissolve at 80℃, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 12

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium methylparaben and sodium propylparaben, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to 80℃ to dissolve, cool to room temperature, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 13

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in sequence, stir and dissolve; then add the prescription amount of sodium methylparaben and sodium propylparaben, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to dissolve at 80°C, cool to room temperature, then add the prescription amount of strawberry essence and vanilla essence, mix and mix well, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Embodiment 14

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in turn, stir and dissolve; then add the prescription amount of sodium methylparaben and sodium propylparaben, stir and dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to dissolve at 40°C, cool to room temperature, then add the prescription amount of strawberry essence and vanilla essence, mix and mix well, and obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 10 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Embodiment 15

An atenolol oral solution for treating infantile hemangioma is composed of the following components in parts by weight:

Preparation method: According to the above formula, add atenolol, saccharin sodium, and citric acid to about 40% of the prescription amount of purified water in turn, stir to dissolve, filter to obtain solution ①, cool to room temperature, and set aside. Add hydroxyethyl cellulose to about 40% of the prescription amount of purified water, heat and stir to dissolve at 80°C, cool to room temperature, then add the prescription amount of strawberry flavor and vanilla flavor, mix and mix well to obtain solution ②; add solution ① cooled to room temperature to solution ②, stir mechanically for 3 minutes, and obtain solution ③; add purified water to the above solution ③ to the full amount, stir evenly, and fill.

Example 16

The atenolol oral solution for treating infantile hemangioma prepared in Examples 1 to 6 was used for partial prescription compatibility study. The solution was placed at high temperature (60°C) and light (4500lx) for 30 days respectively, and compared with the initial placement to preliminarily screen the prescription. The examination items included the properties, related substances and content of the oral solution. The screening results are shown in Table 1

Properties: It should be a colorless transparent liquid.

Related substances: Refer to the test method for Atenolol Tablets in Part II of the 2020 edition of the Chinese Pharmacopoeia, and set the limit as: the total amount of impurities shall not exceed 1.0%.

Content determination: Refer to the test method for atenolol tablets in Part II of the Chinese Pharmacopoeia 2020 edition, and the limit is set at 94.0% to 106.0% of the labeled amount of atenolol (C ₁₄ H ₂₂ N ₂ O ₃ ).

Table 1. Compatibility test results of some prescriptions

As shown in Table 1, the atenolol oral solution for treating infantile hemangioma provided by Examples 1 to 3 of the present invention is stable to high temperature and strong light; the samples are all colorless transparent liquids, and the uniformity of the drug content is conducive to accurate medication; Example 4 adjusts the sweetener from saccharin sodium to aspartame on the basis of Examples 1 to 3, and the pH adjuster is adjusted from citric acid to hydrochloric acid, which has a certain impact on product quality, the solution is easy to change color, and the content of atenolol is slightly reduced. The difference between Examples 5 and 6 and Examples 1 to 3 is that the components of the thickener or sweetener are different. It can be seen that the stability of the oral solution is reduced after the adjustment, from a colorless transparent liquid to a light yellow transparent liquid, the content of atenolol is also reduced, and all related substances are increased.

Embodiment 17

Antibacterial efficacy test

The samples of Examples 1 to 3 and 7 to 15 were taken to test their antibacterial efficacy, with specific reference to the antibacterial efficacy test method in 1121 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition. The results are shown in Table 2.

Table 2. Antibacterial efficacy test results

Note: NI has not increased, which means that the increase in the number of test bacteria does not exceed 0.5lg compared with the previous measurement time.

In the test results, the atenolol oral solution prepared in Examples 1 to 3 and 15 did not add an antibacterial agent, which did not meet the criteria for "oral preparations" in Table 2-3 of the 2020 edition of the Chinese Pharmacopoeia General Rules 1121 Antibacterial Efficacy Test Method. In the range of 1 to 5 and 0.1 to 0.6 parts by weight of sodium methylparaben and sodium propylparaben (Example 11 to Example 14), effective antibacterial efficacy can be maintained. Sodium propylparaben (Example 9) alone did not meet the antibacterial efficacy judgment standard. Sodium methylparaben (Example 10) alone can meet the antibacterial efficacy judgment standard, but the antibacterial effect is relatively weak. The difference between Examples 7 and 8 and Examples 11 to 14 is that the components of the antibacterial agent are different, which can meet the antibacterial efficacy, but the antibacterial effect is relatively weak. The test results show that the oral solution in the present invention needs to be added with an antibacterial agent, especially sodium methylparaben and sodium propylparaben, to ensure the quality stability during the storage period and ensure the safe use of the patient.

Embodiment 18

Taste evaluation test

The prepared atenolol oral solution was tested for taste using a blind method. 2 points indicate good taste, 1 point indicates good taste, 0 points indicate average taste, -1 point indicates poor taste, and -2 points indicate relatively poor taste. After tasting, the subjects gave corresponding scores. Each sample was evaluated by 5 healthy subjects, and the evaluation score was taken as the average value (one decimal point exposed) as the final score (range -2 to 2). The higher the score, the better the acceptance. The taste of Examples 7 to 8 and Examples 11 to 14 was evaluated, and the results are shown in Table 3.

Table 3. Taste evaluation test results

Note: The total score is the mean of the data of 5 healthy subjects. >1.5-2 points indicate good taste, >0.5-1.5 points indicate good taste, -0.5-0.5 points indicate average taste, <-0.5--1.5 points indicate poor taste, and <-1.5--2 points indicate relatively poor taste.

In the test results, 5 subjects accepted Example 13 and Example 14 with added flavoring agents better, which increased palatability and facilitated medication. In the oral solution without added flavoring agents, the subjects believed that Example 11 and Example 12 with added sodium methylparaben and sodium propylparaben antibacterial agents had good taste, which was better than Example 7 and Example 8 with added other antibacterial agents. The test results show that after adding flavoring agents, the taste is sweet and without bitterness, and the acceptance among the population is high, which is conducive to infants and young children taking medicine.

Embodiment 19

Stability test

In order to further clarify the superiority of the prescription, atenolol oral solution for the treatment of infantile hemangioma was subjected to a stability test to examine the properties, related substances, content and microbial limits of the oral solution.

Properties: It should be a colorless transparent liquid.

Related substances: Refer to the test method for Atenolol Tablets in Part II of the 2020 edition of the Chinese Pharmacopoeia. Combined with the relevant requirements of ICHQ3B (R2), the limits are set as follows: Impurity G shall not exceed 0.5%, other individual impurities shall not exceed 0.25%, and the total impurities shall not exceed 1.0%.

Content determination: Refer to the test method for atenolol tablets in Part II of the Chinese Pharmacopoeia 2020 edition, and the limit is set at 94.0% to 106.0% of the labeled amount of atenolol (C ₁₄ H ₂₂ N ₂ O ₃ ).

Microbial limits: The test is carried out in accordance with the general rules 1105 and 1106 of the fourth volume of the Chinese Pharmacopoeia 2020 edition. In accordance with the general rules 1107 of the fourth volume of the Chinese Pharmacopoeia 2020 edition, the microbial limits of this product are set as follows: the total number of aerobic bacteria in each 1ml of the test sample shall not exceed ¹⁰² cfu; the total number of molds and yeasts in each 1ml of the test sample shall not exceed ¹⁰¹ cfu; Escherichia coli shall not be detected in each 1ml of the test sample.

The stability of Examples 11 to 14 was investigated respectively, with an accelerated period of 6 months and a long-term period of 18 months. The results of the stability investigations are shown in Tables 3 and 4:

Table 3. Accelerated test (40℃±2℃, RH: 75%±5%)

Table 4. Long-term study (25℃±2℃, RH: 60%±5%)

Note: “—” indicates that no relevant inspection is set at that time point.

It can be seen from the combination of accelerated test and long-term test that the atenolol oral solution of the present invention has good stability, and meets the requirements in the accelerated stability study of 6 months and the long-term stability study of 18 months. The chemical stability of Example 11 is better than that of Example 12, which shows that the increase of the antibacterial dose is conducive to the improvement of stability. The formula of the atenolol oral solution for treating infantile hemangioma provided in Example 13 is the optimal formula.

Embodiment 20

Treatment Effects

The atenolol oral solution embodiments 13-14 of the present invention were used for trial use, and the therapeutic effect was significant with few adverse reactions. The technical effects of the present invention are described in detail below in conjunction with the experiment. We selected 20 children aged 5 to 20 weeks with infantile hemangioma, all of whom were informed and permitted by their parents, and randomly divided them into 2 groups, 10 in each group. A preliminary clinical trial of the preparations of embodiments 13-14 was conducted, with an oral dose of atenolol of 1 mg/kg/d, once a day, and the efficacy was evaluated by the visual analog scale. The duration was 2 months or 6 months.

In Example 13, 10 patients had a tumor color lighter by more than one grade at 8 weeks of treatment, 9 patients had complete regression at 24 weeks, and 1 patient had a tumor color lighter by more than 2 grades, and no adverse reactions occurred during the treatment. In Example 14, 9 patients had a tumor color lighter by more than one grade at 8 weeks of treatment, 7 patients had complete regression at 24 weeks, and 3 patients had a tumor color lighter by more than 2 grades, and no adverse reactions occurred during the treatment. Oral administration of the atenolol oral solution of the present invention has a better therapeutic effect in the treatment of infantile hemangioma, and there are few adverse reactions during the treatment.

Claims (10)

1. The atenolol oral solution is characterized by comprising 1-10 parts by weight of atenolol, 1-5 parts by weight of saccharin sodium, 1-10 parts by weight of citric acid, 1-5 parts by weight of sodium methylparaben, 0.1-0.5 part by weight of sodium propylparaben, 1-10 parts by weight of hydroxyethyl cellulose and 500-2000 parts by weight of purified water.

2. The atenolol oral solution of claim 1 wherein said oral solution comprises 2 to 10 parts by weight atenolol, 1 to 4 parts by weight sodium saccharin, 2 to 10 parts by weight citric acid, 1 to 4 parts by weight sodium methylparaben, 0.1 to 0.4 parts by weight sodium propylparaben, 2 to 10 parts by weight hydroxyethyl cellulose, 800 to 1600 parts by weight purified water.

3. The atenolol oral solution of claim 1 wherein said oral solution comprises 3 to 7 parts by weight atenolol, 1 to 3.5 parts by weight saccharin sodium, 3 to 7 parts by weight citric acid, 1.5 to 3.5 parts by weight sodium methylparaben, 0.15 to 0.35 parts by weight sodium propylparaben, 3 to 7 parts by weight hydroxyethyl cellulose, 800 to 1400 parts by weight purified water.

4. The atenolol oral solution of claim 1 wherein said oral solution comprises 3 to 5 parts by weight atenolol, 1 to 2.5 parts by weight saccharin sodium, 3 to 5 parts by weight citric acid, 1.5 to 2.5 parts by weight sodium methylparaben, 0.15 to 0.3 parts by weight sodium propylparaben, 3 to 5 parts by weight hydroxyethyl cellulose, 1000 parts by weight purified water.

5. The atenolol oral solution of any one of claims 1-4 further comprising 0.1-5 parts by weight of a flavoring agent selected from one or more of milk essence, orange essence, cherry essence, lemon essence, vanilla essence, pineapple essence, strawberry essence, mango essence, apple essence.

6. The atenolol oral solution of claim 5 wherein the flavoring agent is selected from one or a combination of vanilla, strawberry flavor.

7. The atenolol oral solution of claim 5 wherein the flavoring agent is selected from the group consisting of vanilla, strawberry flavor, wherein the vanilla is 0.4 to 0.8 parts by weight and the vanilla is 0.2 to 0.4 parts by weight.

8. A process for the preparation of an oral solution of atenolol according to any one of claims 5 to 7, characterized in that it comprises the steps of:

(1) Sequentially adding atenolol, saccharin sodium and citric acid into purified water with about 40% of the prescription amount, stirring and dissolving; adding prescription amount of sodium methylparaben and sodium propylparaben, stirring for dissolving, filtering to obtain solution (1), and cooling to room temperature for standby.

(2) Adding hydroxyethyl cellulose into purified water with about 40% of the prescription amount, heating, stirring and dissolving at 40-80 ℃, cooling to room temperature, adding the prescription amount of the flavoring agent, mixing and uniformly mixing to obtain a solution (2);

(3) Adding the solution (1) cooled to room temperature to the solution (2), and mechanically stirring for 3-10 min to obtain a solution (3);

(4) Adding purified water to the solution (3) to the full amount, stirring uniformly, and filling to obtain the final product.

9. The method of claim 8, wherein the high speed shears have a mechanical stirring speed of 200-500r/min.

10. Use of an atenolol oral solution according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of infantile hemangiomas.