Chloral hydrate oral solution

Abstract

The invention provides a chloral hydrate oral solution with stable quality as well as a preparation method and application thereof. According to the oral solution, sugar sweeteners are not added, harm to teeth of children is avoided, generation of toxic substance 5-hydroxymethylfurfural is avoided, preservatives are not used, and the safety risk is reduced.

Description

1. Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a chloral hydrate oral solution with stable quality, a preparation method and an application thereof. 2. Background Art

[0002] Chloral hydrate, its chemical name: 2,2,2-trichloro-1,1-ethanediol.

[0003] The chemical structural formula is:

[0004]

[0005] In 1832, the German chemist Justus Von Liebig synthesized chloral hydrate monohydrate by chlorinating ethanol, that is, chloral hydrate. Chloral Hydrate is the first drug clinically applied to sedation and hypnosis. At present, it is considered that the central nervous system inhibitory effect of chloral hydrate mainly comes from its active metabolite trichloroethanol. The sleep-promoting mechanism of trichloroethanol is the same as that of the later developed barbiturates and benzodiazepine receptor agonist sedative-hypnotic drugs, which mainly play a role by enhancing the activity of γ-aminobutyric acid (GABA) receptors in the central nervous system. Because of its fast onset, long action time, no shortening of rapid eye movement sleep, mild action, no accumulation in the body, and few adverse reactions, it is currently widely used as a sedative-hypnotic drug for clinical pediatric examinations, and there is no suitable alternative drug yet.

[0006] Chloral hydrate is extremely easy to hydrolyze and is easily degraded under conditions such as high temperature, light, and oxidation. Its properties are unstable, especially its stability in aqueous solution is very poor. It will slowly decompose, and the decomposition will accelerate when heated, oxidized, and irradiated, generating degradation products such as chloroform, trichloroacetic acid, dichloroacetaldehyde, and hydrochloric acid. Various degradation products will affect the safety of the product and cause harm to patients. In China, before 2019, chloral hydrate was only available as hospital preparations and there were no commercial products, which could not guarantee the medication needs of the majority of small and medium-sized hospitals, especially grass-roots hospitals. Because the chloral hydrate solution is unstable and has a short shelf life, clinical use mainly involves the preparation by each hospital. Due to differences in the preparation and storage conditions, the curative effects are different, resulting in large differences in the quality of chloral hydrate hospital preparations, and it is difficult to guarantee the safety and effectiveness. There will be safety risks in children's medication. Lin Xiaofang (Discussion on the standardized management and risk prevention and control of chloral hydrate solution used in children in the hospital. China Modern Doctor. 2018, 56(16): 109) investigated the standardized management and risk control of chloral hydrate solution used in children in the hospital, and found that the risk links in children's application of chloral hydrate solution mainly include: hospital information system link, clinical physician's prescription writing link, pharmacist's dispensing link, and nurse's drug administration link; the research results also showed that the failure mode with the highest risk priority number among the risk points is calculation method error, resulting in dose error.

[0007] Chloral hydrate is often administered rectally or orally. However, due to the pungent odor of chloral hydrate, children often experience adverse reactions such as nausea and vomiting. Although rectal administration can alleviate the adverse reactions of children to a certain extent, the depth of insertion of the rectal catheter in children and the body position changes of children during the administration process will both affect the treatment effect, resulting in phenomena such as excessive or insufficient dosage. CN201910466404.2 discloses an enema containing 20-40% chloral hydrate, which has a significant improvement in stability compared with hospital preparations. However, enema administration is likely to stimulate the intestinal wall and cause children to have the urge to defecate, and the medicinal liquid overflows with exhaust or defecation, affecting the sedative effect. Generally, infants with a relatively small age are preferably considered for oral administration.

[0008] CN201910111983.9 discloses a preparation method of a chloral hydrate oral solution. This preparation is stored in the form of a concentrated solution. Although the problem of poor stability is improved by increasing the concentration of chloral hydrate and reducing the water consumption, it needs to be diluted in an appropriate ratio during use, which brings inconvenience to clinical use, and the compounding process may cause dosage risks due to improper operation. CN201910466210.2 discloses a diluent for compounding use with the above patent. The diluent contains a high concentration of sucrose, which has an adverse effect on children's teeth, and the pH of the diluent is low, which easily causes sucrose to degrade and produce the toxic substance 5-hydroxymethylfurfural. CN202011394079.2 reports a chloral hydrate syrup, which can be taken directly without dilution, but there are potential safety risks such as a rapid increase in the degradation impurity chloroform, the degradation of sucrose to produce the toxic substance 5-hydroxymethylfurfural, and the use of preservatives.

[0009] In view of the deficiencies of the prior art, providing a chloral hydrate oral solution that can be taken directly, has good stability, and low safety risks is a difficult problem that those skilled in the art urgently need to solve. 3. Summary of the Invention

[0010] The purpose of the present invention is to solve the problems existing in the prior art, and provide a chloral hydrate oral solution that can be taken directly and has good stability. Moreover, this solution does not add sugar sweeteners to avoid harming children's teeth, avoid producing the toxic substance 5-hydroxymethylfurfural, and does not use preservatives to reduce safety risks. In addition, another purpose of the present invention is to provide a preparation method of the chloral hydrate oral solution.

[0011] The present invention provides a chloral hydrate oral solution, which contains chloral hydrate, a pharmaceutically acceptable non-aqueous solvent, a pharmaceutically acceptable acid, and a non-sugar sweetener, wherein the concentration of the chloral hydrate is 10% - 35% (w / v), and the pH value of the chloral hydrate oral solution is 1.0 - 3.0.

[0012] The pharmaceutically acceptable non-aqueous solvents described in the present invention are selected from soybean oil, medium-chain triglycerides, corn oil, n-butanol, glycerol, triethyl glycerol, propylene glycol, peanut oil, coconut oil, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, olive oil, and any combination thereof. Preferably, the pharmaceutically acceptable non-aqueous solvent is glycerol, polyethylene glycol 400, or a combination thereof.

[0013] The pharmaceutically acceptable acid described in the present invention is an inorganic acid, and the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and any combination thereof; preferably, the pharmaceutically acceptable acid is hydrochloric acid.

[0014] The non-saccharide sweeteners described in the present invention are selected from stevioside, glycyrrhizin, glycyrrhizinate, saccharin, sodium saccharin, sucralose, aspartame, acesulfame potassium, sorbitol, maltitol, and any combination thereof; preferably, the pharmaceutically non-saccharide sweetener is sucralose.

[0015] The present invention provides a chloral hydrate oral solution, which, based on 1000 ml, comprises the following components:

[0016]

[0017] The present invention provides a chloral hydrate oral solution, which, based on 1000 ml, comprises the following components:

[0018]

[0019] In the chloral hydrate oral solution described in the present invention, the amount of glycerol is preferably 830 g, the amount of polyethylene glycol 400 is preferably 150 g, and the amount of sucralose is preferably 0.5 g.

[0020] The present invention provides a chloral hydrate oral solution, which, based on 1000 ml, comprises the following components:

[0021]

[0022] In the chloral hydrate oral solution described in the present invention, the content of dichloroacetaldehyde hydrate is ≤0.2%, the content of chloroform is ≤0.06%, and the content of trichloroacetic acid is ≤0.06%. Preferably, the content of dichloroacetaldehyde hydrate is ≤0.1%, the content of chloroform is ≤0.02%, and the content of trichloroacetic acid is ≤0.03%.

[0023] The present invention also provides a method for preparing a chloral hydrate oral solution, comprising the following steps:

[0024] (1) Sequentially add the prescribed amounts of solvents and the prescribed amount of non-saccharide sweetener into a preparation tank, stir to dissolve and make it uniform;

[0025] (2) Adjust the pH to 1.0 - 3.0 with hydrochloric acid;

[0026] (3) Control the liquid medicine temperature not exceeding 60°C, add the prescribed amount of chloral hydrate, stir to dissolve and make it uniform;

[0027] (4) Filter through a clarification filter, fill into glass bottles, seal to obtain the final product.

[0028] The present invention also provides a preparation method of chloral hydrate oral solution, comprising the following steps:

[0029] (1) Sequentially add the prescribed amounts of glycerol and polyethylene glycol 400 into a preparation tank, add the prescribed amount of sucralose, stir to dissolve and make it uniform;

[0030] (2) Adjust the pH to 1.0 - 2.0 with hydrochloric acid;

[0031] (3) Control the liquid medicine temperature not exceeding 60°C, add the prescribed amount of chloral hydrate, stir to dissolve and make it uniform;

[0032] (4) Filter through a clarification filter, fill into glass bottles, seal to obtain the final product.

[0033] The present invention also provides the use of chloral hydrate oral solution in the preparation of sedative and hypnotic pharmaceutical preparations.

[0034] The beneficial technical effects of the present invention are as follows:

[0035] (1) The chloral hydrate oral solution of the present invention does not add sugar sweeteners, avoiding harm to children's teeth;

[0036] (2) The chloral hydrate oral solution of the present invention avoids the generation of the toxic substance 5 - hydroxymethylfurfural. After being placed at 60°C for 30 days, 5 - hydroxymethylfurfural is not detected, while the content of 5 - hydroxymethylfurfural in the commercially available chloral hydrate syrup is 1.44% after being placed at 60°C for 30 days; and after being placed at 60°C for 30 days, the amount of chloroform is significantly lower than that of the commercially available chloral hydrate syrup and chloral hydrate enema;

[0037] (3) The chloral hydrate oral solution of the present invention does not use preservatives, which can reduce the safety risk, and the antibacterial efficacy inspection meets the requirements of the Chinese Pharmacopoeia after being placed for 28 days;

[0038] (4) The chloral hydrate oral solution of the present invention has a good taste, meeting the clinical needs of children's medication;

[0039] (5) The chloral hydrate oral solution of the present invention has good stability. After being placed at 40°C ± 2°C and 25% ± 5% RH for 2 months, the contents of the related substances dichloroacetaldehyde hydrate, chloroform, and trichloroacetic acid do not increase significantly;

[0040] (6) The chloral hydrate oral solution of the present invention controls related substances. The content of dichloroacetaldehyde hydrate is ≤0.1%, the content of chloroform is ≤0.02%, and the content of trichloroacetic acid is ≤0.03%, ensuring the safety of clinical medication.

[0041] (7) The chloral hydrate oral solution of the present invention is convenient to use. Compared with the commercially available syrup, it does not need to be diluted and can be taken directly, making clinical use more convenient and safe. 4. Specific implementation manners

[0042] The following details the specific embodiments of the present invention. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as a limitation to the present invention.

[0043] Control Example 1 Chloral Hydrate / Syrup Combination Package

[0044] Product name: Chloral Hydrate / Syrup Combination Packaging, Trade name: Jiajia, Manufacturer: Tefeng Pharmaceutical Co., Ltd.

[0045] Control Example 2 Chloral Hydrate Enema

[0046] Product name: Chloral Hydrate Enema, Trade name: Jiajia, Manufacturer: Tefeng Pharmaceutical Co., Ltd.

[0047] Prescription:

[0048]

[0049]

[0050] Note: This prescription is excerpted from CN201910466404.2.

[0051] Example 1 Preparation Method of Chloral Hydrate Oral Solution

[0052] The preparation method is as follows:

[0053] (1) Add the prescribed amount of solvent and non-saccharide sweetener to the preparation tank in sequence, stir and dissolve evenly.

[0054] (2) Adjust the pH to 1.0 - 2.0 with hydrochloric acid.

[0055] (2) Control the liquid medicine temperature not exceeding 60°C, add the prescribed amount of chloral hydrate, stir and dissolve evenly.

[0056] (3) Filter through a clarification filter, fill into glass bottles, and seal to obtain the final product.

[0057] Example 2 Comparison of the Stability of Chloral Hydrate Oral Solutions in Different Solvent Systems

[0058] According to the preparation method described in Example 1, prepare the chloral hydrate solution according to the prescription in Table 1, place it at 60 °C for 30 days with the product of the control example, and check it by GC method (General Rule 0521 of the Chinese Pharmacopoeia 2020 Edition). At the same time, compare the stability data of Patent CN202011394079.2. The results are shown in Table 3.

[0059] Table 1 Prescription Design Table for Different Solvent Systems

[0060] Prescription Active Ingredient Solvent 1 Solvent 2 Sweetener Adjust pH with Hydrochloric Acid Prescription 1 Chloral Hydrate 333.3 g Polyethylene Glycol 400 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5 Prescription 2 Chloral Hydrate 333.3 g Glycerol 830.0 g Purified Water 134.0 g Sucralose 0.5 g 1.5 Prescription 3 Chloral Hydrate 333.3 g Glycerol 830.0 g Soybean Oil 124.0 g Sucralose 0.5 g 1.5 Prescription 4 Chloral Hydrate 333.3 g Glycerol 830.0 g Peanut Oil 122.0 g Sucralose 0.5 g 1.5 Prescription 5 Chloral Hydrate 333.3 g Polyethylene Glycol 400 150.0 g Propylene Glycol 664.0 g Sucralose 0.5 g 1.5 Prescription 6 Chloral Hydrate 333.3 g Polyethylene Glycol 1000 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5 Prescription 7 Chloral Hydrate 333.3 g Propylene Glycol 150.0 g Glycerol 816.0 g Sucralose 0.5 g 1.5 Prescription 8 Chloral Hydrate 333.3 g n-Butanol 150.0 g Glycerol 765.0 g Sucralose 0.5 g 1.5 Prescription 9 Chloral Hydrate 333.3 g Triethyl Glycerate 150.0 g Glycerol 836.0 g Sucralose 0.5 g 1.5 Prescription 10 Chloral Hydrate 333.3 g Polyethylene Glycol 400 150.0 g Coconut Oil 593.0 g Sucralose 0.5 g 1.5 Prescription 10 Chloral Hydrate 333.3 g Polyethylene Glycol 300 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5

[0061] Table 2 Stability Results of Chloral Hydrate Solutions in Different Solvent Systems

[0062]

[0063]

[0064] Note: The data of the samples of Patent CN202011394079.2, the hospital preparations of West China Second University Hospital, and the hospital preparations of West China Hospital are taken from Patent CN202011394079.2.

[0065] The results show that: the product described in the present invention uses a non-aqueous solvent, and the toxic impurity chloroform produced by the degradation of the product is much lower than that of the samples with aqueous solvent prescriptions, the control example, and other hospital preparations. It has good stability, 5-hydroxymethylfurfural is not detected, and no preservatives are used, so its safety is better than that of the comparative products. At the same time, considering palatability and reducing adverse reactions, glycerol and polyethylene glycol 400 are preferably used in this product.

[0066] Example 3 Comparison of the Stability of Chloral Hydrate Oral Solutions with Different Specifications and Concentrations

[0067] According to the preparation method described in Example 1, prepare the chloral hydrate solution according to the prescription in Table 3, place it at 60 °C for 30 days with the product of the control example, and check it by GC method (General Rule 0521 of the Chinese Pharmacopoeia 2020 Edition). At the same time, compare the stability data of Patent CN202011394079.2. The results are shown in Table 4.

[0068] Table 3 Prescription Design Table for Different Specifications and Concentrations

[0069] Specification Concentration Active Ingredient Solvent 1 Solvent 2 Sweetener Adjust pH with Hydrochloric Acid 33％ Chloral Hydrate 333.3 g Polyethylene Glycol 400 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5 10％ Chloral Hydrate 100.0 g Polyethylene Glycol 400 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5 25％ Chloral Hydrate 250.0 g Polyethylene Glycol 400 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5 40％ Chloral Hydrate 400.0 g Polyethylene Glycol 400 150.0 g Glycerol 830.0 g Sucralose 0.5 g 1.5

[0070] Table 4 Stability Results of Chloral Hydrate Solutions with Different Specifications and Concentrations

[0071]

[0072] Note: The data of the samples of Patent CN202011394079.2, the hospital preparations of West China Second University Hospital, and the hospital preparations of West China Hospital are taken from Patent CN202011394079.2.

[0073] The results show that: for prescriptions with different specifications and concentrations, as the specification and concentration increase, the degradation of chloroform decreases, but it is far lower than that of the control example and other hospital preparations, and it has good stability, so its safety is superior to that of the comparative products. Considering the palatability and the intake volume of infants, the preferred specification of this product is 33%.

[0074] Example 4 Comparison of the Stability of Chloral Hydrate Oral Solutions with Different pH Values

[0075] According to the preparation method described in Example 1 and Prescription 1 of Example 2, chloral hydrate solutions with pH values of 1.0, 1.5, and 2.0 were prepared. Additionally, samples were prepared by adjusting the pH to 1.5 with sulfuric acid, nitric acid, and phosphoric acid instead of hydrochloric acid. They were placed at 60°C for 10 days and examined by GC method (General Rule 0521 of the Chinese Pharmacopoeia 2020 Edition) to investigate the stability of chloral hydrate solutions with different pH values and different pH regulators. The results are shown in Table 5.

[0076] Table 5 Stability Results of Chloral Hydrate Solutions with Different pH Values

[0077]

[0078] The results show that: for samples with different pH values adjusted by hydrochloric acid and samples with pH adjusted by different regulators, after being placed at 60°C for 30 days, the appearance, pH, and content showed no obvious changes compared with those at day 0. The chloroform content increased slightly with the increase of pH, but still met the ICH limit (600 μg / g). Among them, the increase of samples with pH values from 1.0 to 2.0 was relatively small. Therefore, the pH value of the chloral hydrate solution is preferably 1.0 - 2.0. At the same time, considering the administration route and administration safety, hydrochloric acid is preferably used as the pH regulator.

[0079] Example 5 Comparison of the Palatability of Chloral Hydrate Oral Solutions with Different Sweeteners

[0080] According to the preparation method described in Example 1, chloral hydrate oral solutions containing different sweeteners were prepared according to Table 6, and a taste (sweetness, bitterness) comparison was made with the control example. The basic taste is the taste felt at the beginning of ingestion, and the aftertaste is the taste remaining after oral administration. Both are important for the evaluation of taste. The scoring basis is shown in Table 7, and the scoring results of 6 taste judges for the taste are shown in Table 8.

[0081] Table 6 Prescription Design Table of Different Sweeteners

[0082]

[0083]

[0084] Table 7 Scoring Basis

[0085] Flavor Grade 0 to 1 1.1 to 3 3.1 to 6 6 to 9 9 to 12.5 ＞12.5 Description Very Slight; Almost Indistinguishable Slight Slight to Moderate Moderate Moderate to High High

[0086] Table 8 Comparison Results of the Taste of the Product Described in the Invention and the Control Example

[0087]

[0088]

[0089]

[0090] The results show that the product of the present invention uses non-saccharide sweeteners. Sucralose has a higher sweetness level than other sweetener formulations. It is in the same grade as each flavor in the control example, with no significant difference, good palatability, easy to be accepted, and can meet the clinical compliance.

[0091] Example 6 Study on the Bacteriostatic Efficacy of Chloral Hydrate Oral Solution

[0092] The chloral hydrate oral solution of the present invention does not use preservatives. To investigate the microbial safety of the product, according to the antibacterial efficacy test method in General Principles 1121 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition), the antibacterial efficacy of the chloral hydrate oral solution in Prescription 1 of Example 1 of the present invention was determined. The judgment criteria and results are shown in Table 9 and Table 10 respectively.

[0093] Table 9 Antibacterial Efficacy Judgment Criteria for Oral Preparations, Oral Mucosa Preparations, and Rectal Administration Preparations

[0094]

[0095] Note: NI means no increase, indicating that for the previous measurement time, the increase in the number of test bacteria does not exceed 0.5 lg value.

[0096] Table 10 Results of the Antibacterial Efficacy of Chloral Hydrate Oral Solution (lg value reduction of the test product at each interval)

[0097] Time Staphylococcus aureus Pseudomonas aeruginosa Escherichia coli Candida albicans Aspergillus niger 14d >4.7 >4.8 >4.8 >4.7 >4.7 28d NI NI NI NI NI

[0098] The results show that the product of the present invention can still meet the antibacterial efficacy requirements of the antibacterial efficacy test method in General Principles 1121 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition) without using preservatives, indicating that the product of the present invention has a low risk of microbial safety.

[0099] Example 7 Study on the Stability of the Chloral Hydrate Oral Solution of the Present Invention

[0100] The stability of the chloral hydrate oral solution in Prescription 1 of Example 2 of the present invention and the chloral hydrate syrup in the control example was investigated under the conditions of 40°C ± 2°C and 25% ± 5% RH. The test results are shown in Table 11 and Table 12. The results show that the chloral hydrate oral solution of the present invention has good stability after being placed at 40°C ± 2°C and 25% ± 5% for 2 months.

[0101] Table 11 Results of the Accelerated Stability Test of the Oral Solution of the Present Invention (40°C ± 2°C, 25% ± 5% RH)

[0102]

[0103] Table 12 Stability test results of Comparative Example 1 (40°C ± 2°C, 25% ± 5% RH)

[0104]

Claims

1. A chloral hydrate oral solution, characterized in that, It includes chloral hydrate, a pharmaceutically acceptable non-aqueous solvent, a pharmaceutically acceptable acid, and a non-saccharide sweetener. The concentration of the chloral hydrate is 10% - 35% (w / v), and the pH value of the chloral hydrate oral solution is 1.0 - 3.

0.

2. The chloral hydrate oral solution according to claim 1, wherein The pharmaceutically acceptable non-aqueous solvent is selected from soybean oil, medium-chain triglycerides, corn oil, n-butanol, glycerol, triethyl glycerol, propylene glycol, peanut oil, coconut oil, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, olive oil, and any combination thereof.

3. The chloral hydrate oral solution according to claim 1, wherein The pharmaceutically acceptable acid is an inorganic acid, and among them, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and any combination thereof.

4. The chloral hydrate oral solution according to claim 1, characterized in that, The non-saccharide sweetener is selected from stevioside, glycyrrhizin, glycyrrhizinate, saccharin, sodium saccharin, sucralose, aspartame, acesulfame potassium, sorbitol, maltitol, and any combination thereof.

5. The chloral hydrate oral solution according to claim 1, wherein, The pharmaceutically acceptable non-aqueous solvent is glycerol, polyethylene glycol 400, or a combination thereof; the pharmaceutically non-saccharide sweetener is sucralose; the pharmaceutically acceptable acid is hydrochloric acid.

6. The chloral hydrate oral solution according to claim 5, wherein Calculated by 1000 ml, it includes the following components:

7. The chloral hydrate oral solution according to claim 6, characterized in that, Calculated by 1000 ml, it includes the following components:

8. The chloral hydrate oral solution according to claim 7, wherein Calculated by 1000 ml, it includes the following components:

9. The chloral hydrate oral solution according to claims 1 to 8, characterized in that, The content of dichloroacetaldehyde hydrate is ≤0.2%, the content of chloroform is ≤0.06%, and the content of trichloroacetic acid is ≤0.06%.

9. Use of the chloral hydrate oral solution according to claims 1 - 8 in the preparation of sedative and hypnotic pharmaceutical preparations.

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