Ramelteon liquid preparation and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a ramelteon liquid preparation and a preparation method thereof, and the ramelteon liquid preparation comprises the following components in percentage by mass: 0.01-10% of ramelteon, 0.01-40% of a flavoring agent and the balance of a solvent. According to the technical scheme, the liquid preparation for improving ramelteon is obtained by creatively adjusting the types of solvents aiming at the defect that ramelteon is weak in light stability, and the liquid preparation does not contain organic solvents and is more environmentally friendly and safer.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a ramelteon liquid preparation and a preparation method thereof. Background Art

[0002] Ramelteon is a melatonin receptor agonist with high affinity for the MT1 and MT2 receptors and relative selectivity for the MT3 receptor. It is clinically used to improve sleep onset difficulties in insomnia. Ramelteon's activity at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, affected by endogenous melatonin, are thought to be involved in maintaining normal circadian rhythms of sleep and wake cycles. This product can improve circadian rhythm sleep disorders, has proven efficacy for chronic insomnia, and is effective for short-term insomnia. As a non-regulated hypnotic, it is not abuse- or dependency-prone, and does not cause withdrawal symptoms or rebound insomnia. It is highly safe and can be used long-term. The domestic guideline "Guidelines for the Diagnosis and Treatment of Insomnia in Adults in China (2023 Edition)" recommends ramelteon as a treatment for insomnia, stating that it can shorten sleep latency, improve sleep efficiency, and increase total sleep time. Ramelteon has been listed by the National Health Commission as one of the fourth batch of pediatric drugs encouraged for research and development. However, ramelteon has a certain degree of photosensitivity and is a photolabile drug. Under light conditions, ramelteon may undergo degradation reactions, causing changes in the chemical structure of the drug, thereby affecting the efficacy and safety of the drug; at the same time, the marketed dosage form of ramelteon is tablets, which has the disadvantage of poor compliance for children and patients with dysphagia. Summary of the Invention

[0003] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a ramelteon liquid preparation.

[0004] To achieve the above object, the technical solution adopted by the present invention is:

[0005] A ramelteon liquid preparation comprises the following components in percentage by mass: 0.01% to 10% of ramelteon, 0.01% to 40% of a flavoring agent, and a solvent to make up the difference.

[0006] The solvent is one of water, glycerol, polyethylene glycol, and propylene glycol, or a mixture of at least two of them.

[0007] The solvent is a mixture of glycerol and polyethylene glycol; preferably, the mass ratio of glycerol to polyethylene glycol in the mixed solvent is 9:1 to 2:8.

[0008] The molecular weight of the polyethylene glycol is 200-8000, preferably 200-600, more preferably one of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600, or a mixture thereof.

[0009] Preferably, the ramelteon liquid preparation comprises the following components in percentage: 0.1% to 5% of ramelteon, 0.6% to 1.5% of flavoring agent and a solvent to make up the difference.

[0010] The flavoring agent includes one or a mixture of sweeteners and flavors; preferably, the sweetener includes one or a mixture of sucralose, aspartame, sorbitol, sucrose, and saccharin sodium; preferably, the flavor includes one or a mixture of at least two of strawberry flavor, raspberry flavor, mint flavor, grape flavor, sweet orange flavor, and banana flavor.

[0011] Preferably, the ramelteon liquid preparation comprises the following percentage components: ramelteon 0.8%, sucralose 1%, flavor 0.2%, polyethylene glycol 400 10-80% and the balance glycerol, preferably ramelteon 0.8%, sucralose 1%, flavor 0.2%, polyethylene glycol 400 50% and the balance glycerol.

[0012] The ramelteon liquid preparation further comprises excipients; the excipients are antibacterial agents and / or antioxidants;

[0013] Preferably, the antibacterial agent comprises one or a mixture of at least two of hydroxypropyl methyl ester, hydroxypropyl methyl ester, benzoic acid, benzoate, sorbic acid and ascorbate;

[0014] Preferably, the antioxidant includes sodium bisulfite, sodium metabisulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, thiourea, disodium ethylenediaminetetraacetate EDTA-Na2, phosphoric acid, citric acid, butylated hydroxyanisole BHA, butylated hydroxycresol BHT, nordihydroguaiaretic acid CDGA, tocopherol, gallates, or a mixture of at least two thereof.

[0015] The mass percentage of the antibacterial agent is 0-1%, preferably 0-0.63%; the mass percentage of the antioxidant is 0-1%.

[0016] The present invention also includes a method for preparing the ramelteon liquid preparation, comprising the following steps:

[0017] 1) adding the corrective agent and auxiliary materials in the component amount to the solvent and stirring evenly; 2) adding ramelteon until it is completely dissolved, and finally adding the essence and stirring evenly.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The technical solution of the present invention addresses the disadvantage of weak photostability of ramelteon. By creatively adjusting the type of solvent, an improved liquid preparation of ramelteon is obtained. The liquid preparation does not contain an organic solvent and is more environmentally friendly and safe. At the same time, as a liquid preparation, it is suitable for children who cannot swallow solid preparations and elderly patients with dysphagia. The oral administration dosage of the liquid preparation is more flexible than that of tablets. Furthermore, the addition of a flavoring agent to the liquid preparation improves the taste of the prepared preparation and makes it more suitable for administration to children. DETAILED DESCRIPTION

[0020] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention is further described in detail below with reference to the embodiments.

[0021] A ramelteon liquid preparation comprising 0.01% to 10% ramelteon, 0.01% to 40% flavoring agent, and a solvent to make up the difference;

[0022] The flavoring agent includes one or a mixture of sweeteners and flavors; preferably, the sweetener includes one or a mixture of sucralose, aspartame, sorbitol, sucrose, and saccharin sodium; preferably, the flavor includes one or a mixture of at least two of strawberry flavor, raspberry flavor, mint flavor, grape flavor, sweet orange flavor, and banana flavor;

[0023] The solvent is one of water, glycerol, polyethylene glycol, and propylene glycol, or a mixture of at least two of them.

[0024] Preferably, the solvent is a mixture of glycerol and polyethylene glycol with a molecular weight of 200-8000, and the molecular weight of the polyethylene glycol is preferably 200-600, more preferably one of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600, or a mixture thereof.

[0025] The auxiliary material is an antibacterial agent and / or an antioxidant;

[0026] The antibacterial agent includes one or a mixture of at least two of hydroxypropyl methyl ester, hydroxypropyl methyl ester, benzoic acid, benzoate, sorbic acid and ascorbate;

[0027] Antioxidants include sodium bisulfite, sodium metabisulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine (methionine), thiourea, disodium ethylenediaminetetraacetate (EDTA-Na2), phosphoric acid, citric acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid (CDGA), tocopherol, and gallic acid esters, or a mixture of at least two thereof.

[0028] The preparation method of the ramelteon liquid preparation comprises the following steps: 1) adding a certain amount of flavoring agent and auxiliary materials into a solvent and stirring evenly; 2) adding ramelteon until it is completely dissolved, and finally adding essence and stirring evenly.

[0029] The specific components of different embodiments are given in the form of a list below, as shown in Table 1.

[0030] Table 1

[0031] Example Example 1 Example 2 Example 3 Material Name Dosage Dosage Dosage Ramelteon 0.1g 0.8g 5g Sucralose 1.0g 1.0g 1.0g essence 0.2g 0.2g 0.2g polyethylene glycol 400 Add to 100ml Add to 100ml Add to 100ml Solution clarity Clarity and transparency Clarity and transparency Clarity and transparency

[0032] Examples 1-3 show the components of different ramelteon liquid preparations. The results show that the final solutions obtained with different ramelteon addition amounts are all clear and transparent. Since the absorption dose of ramelteon is preferably around 0.8%, subsequent solvent tests were performed with the ramelteon component amount being 0.8%, as shown in Tables 2 and 3.

[0033] Table 2

[0034] Example Example 4 Example 5 Example 6 Example 7 Material Name Dosage Dosage Dosage Dosage Ramelteon 0.8g 0.8g 0.8g 0.8g Sucralose 1.0g 1.0g 1.0g 1.0g essence 0.2g 0.2g 0.2g 0.2g polyethylene glycol 400 Add to 100ml / / / Propylene glycol / Add to 100ml / / glycerin / / Add to 100ml / water / / / Add to 100ml Solution clarity Clarity and transparency Clarity and transparency Cannot be completely dissolved Cannot be completely dissolved

[0035] Examples 4-7 show that polyethylene glycol, propylene glycol, glycerol and water are used as solvents. It was found that the solution obtained by using glycerol or water alone as the solvent could not be completely dissolved. Subsequently, the combination of different solvents was verified, and polyethylene glycol and propylene glycol and glycerol were used as combined solvents, as shown in Table 3.

[0036] Table 3

[0037] Example Example 8 Example 9 Example 10 Example 11 Material Name Dosage Dosage Dosage Dosage Ramelteon 0.8g 0.8g 0.8g 0.8g Sucralose 1.0g 1.0g 1.0g 1.0g essence 0.2g 0.2g 0.2g 0.2g polyethylene glycol 400 50g 50g / 50g Propylene glycol / Add to 100ml 50g / glycerin Add to 100ml / Add to 100ml / water / / / Add to 100ml Solution clarity Clarity and transparency Clarity and transparency Clarity and transparency Clarity and transparency

[0038] The stability test was conducted on Examples 4, 5, and 8-11. The ramelteon oral solutions prepared in Examples 4, 5, and 8-11 were placed in a dark environment at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. The clarity, content, and impurity status of the solutions in each example are shown in Table 4 below.

[0039] Table 4

[0040]

[0041]

[0042] The results showed that among the solvents polyethylene glycol, propylene glycol, and the mixture of polyethylene glycol and glycerol, the mixture of propylene glycol and glycerol had good stability under light-proof conditions, and the effect of polyethylene glycol and glycerol was the best.

[0043] At the same time, this application tested different proportions of polyethylene glycol and glycerol, the proportions are shown in Table 5, and the test results are shown in Table 6.

[0044] Table 5

[0045] Example Example 12 Example 13 Example 14 Material Name Dosage Dosage Dosage Ramelteon 0.8g 0.8g 0.8g Sucralose 1.0g 1.0g 1.0g essence 0.2g 0.2g 0.2g polyethylene glycol 400 10g 30g 80g glycerin Add to 100ml Add to 100ml Add to 100ml / Solution clarity Clarity and transparency Clarity and transparency Clarity and transparency

[0046] Table 6

[0047]

[0048]

[0049] The results showed that the total impurity content of polyethylene glycol and glycerol in different proportions remained very low after being kept in the dark for 6 months, meeting the requirements.

[0050] In order to facilitate the storage of ramelteon, the photosensitivity of Examples 4, 5, and 8-14 was tested. The ramelteon oral solution was placed in a light box under an illumination of 4500 lx±500 lx for 12 days and then sampled for testing. The clarity, content, and impurity status of the solutions of each example are shown in Table 7 below.

[0051] Table 7

[0052]

[0053] It can be seen from the photosensitivity test results of Examples 4, 5, and 8-14 that ramelteon has different photostability in different solvents. Among them, although polyethylene glycol and propylene glycol alone have good stability under light-proof conditions, their photostability is poor. Therefore, brown bottles can be used for packaging liquid reagents. Mixtures of polyethylene glycol and glycerol in different proportions have a better promoting effect on the photostability of ramelteon, among which Example 8 has the best effect.

[0054] At the same time, the present application verifies the ramelteon liquid preparation with different polyethylene glycol molecular weights as solvents. The only difference from Example 8 is the molecular weight. Polyethylene glycol with molecular weights of 200, 600, and 800 were verified respectively. The results were similar to those in Example 8, but slightly inferior to those in Example 8. Therefore, polyethylene glycol 400 will still be used for subsequent research.

[0055] The formulation of Example 8 was also modified with 0.6 g of methylparaben and 0.03 g of propylparaben. The results showed that the addition of the antibacterial agent did not affect its photostability. Taste evaluation: To make the ramelteon liquid formulation of this application suitable for oral administration to children, the content and composition of the sweetener and flavoring were adjusted in this application. The corresponding examples are shown in Table 8.

[0056] Table 8

[0057] Example Example 8 Example 15 Example 16 Example 17 Comparative Example 1 Material Name Dosage Dosage Dosage Dosage Dosage Ramelteon 0.8g 0.8g 0.8g 0.8g 0.8g Sucralose 1.0g 0.1g 0.5g 2.0g / essence 0.2g 0.2g 0.2g 0.2g / polyethylene glycol 400 50g 10g 30g 80g 50g glycerin Add to 100ml Add to 100ml Add to 100ml Add to 100ml / Add to 100ml / Solution clarity Clarity and transparency Clarity and transparency Clarity and transparency Clarity and transparency Clarity and transparency

[0058] The taste of Examples 8, 15-17, and Comparative Example 1 was evaluated, and the evaluators tasted and scored according to the following table. The age of the test subjects was selected to be between 22 and 50 years old. Before the evaluation, the test subjects should rinse their mouths and then taste each solution in sequence. 10 ml of each test solution was taken and held in the mouth by the evaluator for at least 15 seconds. The evaluation criteria are shown in Table 9.

[0059] Table 9

[0060] level standard score 1 Poor experience, obvious bitterness or strange smell 1～2 2 Average experience, slight bitterness or odor 3～4 3 Average experience, no bitterness or slight odor 5～6 4 The experience is good, no bitterness or weak odor 7～8 5 Good experience, no bitterness or odor 9～10

[0061] The test results are shown in Table 10;

[0062] Table 10

[0063] Group score Example 8 9.6 Example 15 9.2 Example 16 9.5 Example 17 9.3 Comparative Example 1 3.1

[0064] The results show that after adding the flavoring agent, the taste test of the present invention is good and significantly better than that of the comparative example. At the same time, the research results show that when the solvent ratio remains unchanged, the addition of the flavoring agent in the range of 0.6% to 1.5% can play a good seasoning role without affecting the temperature, heat, and light stability of ramelteon.

[0065] In summary, the technical solution of the present invention addresses the shortcoming of weak photostability of ramelteon, and obtains a liquid preparation of improved ramelteon through creative adjustment of the type of solvent. The liquid preparation does not contain organic solvents, which is more environmentally friendly and safer. At the same time, as a liquid preparation, it is suitable for children who cannot swallow solid preparations and elderly patients with dysphagia, and the oral liquid preparation dosage is more flexible than tablets. Furthermore, flavoring agents are added to the liquid preparation, and the prepared preparation has a better taste and is more suitable for children's administration. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A ramelteon liquid preparation, characterized in that, The invention comprises the following components in percentage by weight: 0.01% to 10% of ramelteon, 0.01% to 40% of a flavoring agent and a solvent to make up the difference.

2. The ramelteon liquid preparation according to claim 1, wherein The solvent is one of water, glycerol, polyethylene glycol, and propylene glycol, or a mixture of at least two of them.

3. The ramelteon liquid preparation according to claim 1, wherein The solvent is a mixture of glycerol and polyethylene glycol; preferably, the mass ratio of glycerol to polyethylene glycol in the mixed solvent is 9:1 to 2:

8.

4. The ramelteon liquid preparation according to claim 2 or 3, wherein The molecular weight of the polyethylene glycol is 200-8000, preferably 200-600, more preferably one of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600, or a mixture thereof.

5. The ramelteon liquid preparation according to claim 1, wherein The invention comprises the following components in percentage: 0.1% to 5% of ramelteon, 0.6% to 1.5% of flavoring agent and solvent to make up the difference.

6. The ramelteon liquid preparation according to claim 1, wherein The flavoring agent includes one or a mixture of sweeteners and flavors; preferably, the sweetener includes one or a mixture of sucralose, aspartame, sorbitol, sucrose, and saccharin sodium; preferably, the flavor includes one or a mixture of at least two of strawberry flavor, raspberry flavor, mint flavor, grape flavor, sweet orange flavor, and banana flavor.

7. The ramelteon liquid preparation according to claim 1, wherein The composition comprises the following percentages: 0.8% ramelteon, 1% sucralose, 0.2% flavor, 10-80% polyethylene glycol and the balance glycerol; preferably 0.8% ramelteon, 1% sucralose, 0.2% flavor, 50% polyethylene glycol and the balance glycerol.

8. The ramelteon liquid preparation according to claim 1, wherein Also includes auxiliary materials; the auxiliary materials are antibacterial agents and / or antioxidants; Preferably, the antibacterial agent comprises one or a mixture of at least two of hydroxypropyl methyl ester, hydroxypropyl methyl ester, benzoic acid, benzoate, sorbic acid and ascorbate; Preferably, the antioxidant includes sodium bisulfite, sodium metabisulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, thiourea, disodium ethylenediaminetetraacetate EDTA-Na2, phosphoric acid, citric acid, butylated hydroxyanisole BHA, butylated hydroxycresol BHT, nordihydroguaiaretic acid CDGA, tocopherol, gallates, or a mixture of at least two thereof.

9. The ramelteon liquid preparation according to claim 8, characterized in that The mass percentage of the antibacterial agent is 0-1%, preferably 0-0.63%; the mass percentage of the antioxidant is 0-1%.

10. A method for preparing the ramelteon liquid preparation according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: 1) adding a certain amount of flavoring agent and auxiliary materials into a solvent and stirring the mixture evenly; 2) adding ramelteon until the mixture is completely dissolved, and finally adding essence and stirring the mixture evenly.

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