A chloral hydrate solution pharmaceutical composition and a preparation method thereof

Abstract

The application discloses a kind of stable chloral hydrate solution and preparation method thereof, belong to the field of pharmaceutical technology, solve the technical problems of poor stability of chloral hydrate solution, high impurity content in prior art.The application adds special antioxidant and controls the pH value of chloral hydrate solution, and then obtains a kind of stable chloral hydrate solution capable of simultaneously controlling the content of various impurities, improves the safety of drug use, and is more easily used in clinic.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a hydrated chloral solution with high stability and low impurity content. Background Technology

[0002] Sedatives are primarily used in the treatment of mental illnesses, mainly to relieve depression and anxiety, and to treat insomnia caused by mental stress. Commonly used sedatives include phenobarbital, nitrazepam, diazepam, and benzodiazepines. However, the use of these drugs is strictly limited to pregnant women and children. Even healthy individuals may experience side effects from long-term use of benzodiazepines, such as drowsiness, poor concentration, slowed reaction time, memory loss, and dizziness.

[0003] Chloral hydrate can inhibit the ascending reticular activating system in the brainstem, inducing near-physiological sleep. It has a rapid onset of action, a long duration of action, does not shorten REM sleep, has a mild effect, does not accumulate in the body, and has few adverse reactions. Field surveys of multiple hospitals in my country show that chloral hydrate oral solution is the longest-used, most widely used, most mature, and most frequently used sedative-hypnotic drug in pediatric examinations in China. It has become the first-line drug for sedation and hypnosis in clinical pediatric examinations in my country, and there is currently no suitable alternative drug.

[0004] However, chloral hydrate has a very unpleasant taste, with a strong bitter and spicy flavor, which can cause severe crying and resistance in infants and young children when taken orally. Furthermore, chloral hydrate itself has a significant irritant effect on the gastrointestinal tract, easily causing vomiting in infants and young children, expelling the ingested medication. Since the amount vomited up is unpredictable, repeated oral administration could lead to overdose and poisoning, preventing the administration of necessary medical examinations. If enemas are used to administer medication to children, the patient must be restrained under duress before the medication can be administered, which can easily cause harm to the child and interfere with treatment. Therefore, in the development of sedative drugs, it is crucial to select medications suitable for infants and young children, considering their specific needs.

[0005] The sugar and flavorings in syrups can effectively mask the bitter, salty, or other unpleasant odors of medications, improving the taste and making them more acceptable to patients, especially children, thereby increasing medication adherence. Furthermore, as a liquid preparation, the dosage is easy to control, and unlike tablets, it does not require water to take, making it more convenient for children and the elderly with swallowing difficulties.

[0006] The prior art CN104800154A discloses a simple syrup containing chloral hydrate, which is only aimed at improving compliance in young children due to the taste problem of chloral hydrate and avoiding vomiting and gastrointestinal discomfort through oral administration, thereby improving bioavailability. However, the prior art has not systematically studied the stability of the syrup. Summary of the Invention

[0007] Based on the problems existing in the prior art, those skilled in the art urgently need to develop a hydrated chloral solution with lower impurity content and higher safety to meet the clinical needs of a large number of children.

[0008] To achieve the above-mentioned objectives, this application adopts the following technical solution:

[0009] The first objective of this application is to provide a chloral hydrate solution containing 10g of chloral hydrate per 100ml of the solution, and the solution also contains an antioxidant.

[0010] As a preferred embodiment, the antioxidant is selected from disodium edetate.

[0011] In some preferred embodiments of this application, each 100 ml of the solution contains 0.001-0.05 g of the antioxidant.

[0012] In some preferred embodiments of this application, each 100 ml of the solution contains 0.005-0.025 g of the antioxidant.

[0013] In some preferred embodiments of this application, each 100 ml of the solution contains 0.005-0.05 g of the antioxidant.

[0014] In a more preferred embodiment, each 100 ml of the solution contains 0.01 g of the antioxidant.

[0015] Furthermore, the pH value of the hydrated chloral solution is 2.0-4.2.

[0016] In some preferred embodiments of this application, the pH value is 2.5-3.6.

[0017] In some preferred embodiments of this application, the pH value is 2.5-3.3.

[0018] In some preferred embodiments of this application, the pH value is 2.7-3.3.

[0019] In some preferred embodiments of this application, the pH value is 2.7-3.0.

[0020] In some preferred embodiments of this application, the pH value is 3.0-3.3.

[0021] In some preferred embodiments of this application, the pH value is 3.0.

[0022] Another object of this application is to provide a chloral hydrate syrup, wherein each 100 ml of the solution contains 10 g of chloral hydrate, and the syrup also contains a flavoring agent and an antioxidant, wherein the flavoring agent is composed of sucrose and sucralose.

[0023] Furthermore, the sucrose content in each 100ml of the syrup is not less than 45g; and the sucralose content is 0.01g-0.1g.

[0024] More preferably, the sucrose content is 45-65g, and the sucralose content is 0.01g-0.1g.

[0025] As a preferred embodiment, the antioxidant is selected from disodium edetate.

[0026] In some preferred embodiments of this application, each 100 ml of the syrup contains 0.001-0.05 g of the antioxidant.

[0027] In some preferred embodiments of this application, each 100 ml of the syrup contains 0.005-0.025 g of the antioxidant.

[0028] In some preferred embodiments of this application, each 100 ml of the syrup contains 0.005-0.05 g of the antioxidant.

[0029] In a more preferred embodiment, each 100 ml of the syrup contains 0.01 g of the antioxidant.

[0030] Furthermore, the pH value of the hydrated chloral syrup is 2.0-4.2.

[0031] In some preferred embodiments of this application, the pH value is 2.5-3.6.

[0032] In some preferred embodiments of this application, the pH value is 2.5-3.3.

[0033] In some preferred embodiments of this application, the pH value is 2.7-3.3.

[0034] In some preferred embodiments of this application, the pH value is 2.7-3.0.

[0035] In some preferred embodiments of this application, the pH value is 3.0-3.3.

[0036] In some preferred embodiments of this application, the pH value is 3.0. In some specific embodiments, the composition of the syrup per 100 ml is as follows:

[0037] 10g chloral hydrate, 45g sucrose, 0.1g sucralose, 0.01g disodium edetate, and citric acid-sodium citrate to adjust the pH to 3.0.

[0038] In some specific embodiments, the filling volume of the solution is 5 ml, 10 ml, 50 ml or 100 ml.

[0039] In some specific embodiments, the solution with a filling volume of 10 mL consists of: 1 g chloral hydrate, 4.5 g sucrose, 0.01 g sucralose, 0.001 g disodium edetate, and citric acid-sodium citrate adjusted to pH 3.0.

[0040] A third objective of this application is to provide a method for preparing the above-mentioned solution, comprising the following steps:

[0041] Step 1: Add the flavoring agent to hot water, stir to dissolve, boil, and then cool to room temperature;

[0042] Step 2: While stirring, add an antioxidant and a pH adjuster to the solution obtained in Step 1 to adjust the pH to obtain a solution; in some preferred embodiments of this application, the pH is adjusted to 2.0-4.2; in some preferred embodiments of this application, the pH is adjusted to 2.0-3.6; in some preferred embodiments of this application, the pH is adjusted to 2.5-3.3; in some preferred embodiments of this application, the pH is adjusted to 2.7-3.0; in some preferred embodiments of this application, the pH is adjusted to 2.7-3.3; in some preferred embodiments of this application, the pH is adjusted to 3.0.

[0043] Step 3: Add chloral hydrate to the solution obtained in step 2, stir to dissolve, make up to volume and fill into containers.

[0044] Chloral hydrate is a commonly used sedative-hypnotic drug with wide applications in the medical field. However, impurities such as trichloroacetic acid, dichloroacetic acid, and chloroform are inevitably generated during the production and storage of chloral hydrate preparations.

[0045] 1) Trichloroacetic acid: Highly corrosive, primarily harmful to skin, eyes, and mucous membranes, and potentially carcinogenic. According to the CPDB (Carcinogenic Potential Database), the TD50 (median toxic dose) of trichloroacetic acid should be controlled below 0.06%.

[0046] 2) Chloroform: Primarily harmful to the central nervous system, liver, and kidneys, and potentially carcinogenic. According to product quality requirements, chloroform content must be controlled below 0.012%.

[0047] 3) Dichloroacetic acid: Primarily harms the liver and nervous system, and is potentially carcinogenic. According to the TD50 of dichloroacetic acid in the CPDB, its concentration should be controlled below 0.012%.

[0048] The beneficial effects of this application are:

[0049] Based on the applicant's long-term research and development of chloral hydrate liquid formulations, by controlling the pH value of the formulation within a certain range and adding a very small amount of disodium edetate as an antioxidant, a formulation product with extremely low contents of dichloroacetic acid, trichloroacetic acid, chloroform, and 5-hydroxymethylfurfural can be obtained. This results in a product with higher safety and easier clinical use.

[0050] Furthermore, the chloral hydrate syrup provided in this application has a better taste, better compliance, and is easier for children to take.

[0051] The chloral hydrate product provided in this application, compared with commercially available simple syrup products, only requires the preparation of one solution and filling into one package, which greatly shortens the production cycle, reduces production costs, and facilitates the commercialization of the product. Detailed Implementation

[0052] The specific implementation schemes of this application are further described below with reference to specific embodiments. However, it should not be construed that the scope of this application is limited to the following examples. Based on the inventive concept and the full text of this application, the various technical features in the following examples can be appropriately combined / replaced / adjusted / modified, etc., which is obvious to those skilled in the art and still falls within the scope of protection of this application. Unless otherwise specified, all components used in this application can be purchased commercially.

[0053] The chloral hydrate solution described in this application refers to a liquid preparation of chloral hydrate. In some embodiments, the chloral hydrate solution is a chloral hydrate syrup. In some embodiments, the chloral hydrate solution is for oral administration.

[0054] The citric acid mentioned in this application refers to anhydrous citric acid or its hydrate, such as citric acid monohydrate.

[0055] The room temperature mentioned in this application refers to 10-30℃.

[0056] Examples 1-4: Screening of Prescription Flavoring Agents

[0057] Preparation: Add 30g of sucrose to hot water and stir to dissolve. Boil for no more than 30 minutes. Cool to room temperature. While stirring, add 0.005g of sodium saccharin and stir to dissolve. Add 10g of chloral hydrate and bring the volume to 100ml to obtain chloral hydrate syrup.

[0058] Filling: The above-mentioned liquid medicine can also be filled into 5ml, 10ml or 50ml specifications.

[0059] Examples 2-4 were prepared using the preparation process of Example 1, and chloral hydrate syrup was prepared sequentially according to the formulations of Examples 2-4.

[0060] Table 1. Prescriptions for Examples 1-4 of this Application

[0061]

[0062] Examples 5-7, Comparative Example 1: Screening of Antioxidant Dosage in Formulas

[0063] Preparation: Add the prescribed amount of sucrose to hot water and stir to dissolve. Boil for no more than 30 minutes, cool to room temperature, and while stirring, add anhydrous citric acid, disodium edetate, and sucralose until dissolved. Adjust the pH to 3.0 with sodium citrate, and add chloral hydrate to make up to the final volume to obtain chloral hydrate syrup.

[0064] Filling: The above-mentioned liquid medicine can also be filled into 5ml, 10ml or 50ml specifications.

[0065] The preparation process of Comparative Example 1 is the same as that of Examples 5-7, except that disodium edetate was not added.

[0066] Table 2. Prescriptions for Examples 5-7 and Comparative Example 1 of this application.

[0067]

[0068] Examples 8-13: pH screening of prescriptions

[0069] Examples 8-13 differ from Examples 5-7 only in the amount of citric acid and sodium citrate, and the pH value; the rest of the preparation process is the same.

[0070] Table 3. Prescriptions for Examples 8-13 of this Application

[0071]

[0072] Examples 15-21 Antioxidant Screening Experiments

[0073] Based on the prescription in Table 4, Examples 15-17 were prepared using the process described in Example 6.

[0074] Table 4. Prescriptions for Examples 15-21 of this Application

[0075]

[0076] Example 18

[0077] Preparation: Add the prescribed amounts of anhydrous citric acid, disodium edetate, and chloral hydrate to purified water and stir to dissolve. Adjust the pH to 3.0 with sodium citrate and bring the volume to a final volume to obtain the chloral hydrate solution.

[0078] Filling: The above-mentioned liquid medicine can also be filled into 5ml, 10ml or 50ml specifications.

[0079] Examples 19-21 were prepared in the same manner as Example 18, except that disodium edetate was replaced with glycerol, sodium bisulfite, and sodium metabisulfite.

[0080] Example 22 and Comparative Example 2

[0081] The prescription and preparation method of Example 22 are the same as those of Example 6, except that the amount of sucralose is 0.1g.

[0082] Table 5. Prescription for Example 22 of this application.

[0083]

[0084] Preparation: Add the prescribed amount of sucrose to hot water and stir to dissolve. Boil for no more than 30 minutes, cool to room temperature, and while stirring, add anhydrous citric acid, disodium edetate, and sucralose until dissolved. Adjust the pH to 3.0 with sodium citrate, and add chloral hydrate to make up to the final volume to obtain chloral hydrate syrup.

[0085] Filling: The above-mentioned liquid medicine can also be filled into 5ml, 10ml or 50ml specifications.

[0086] The preparation method of the formulation for Comparative Example 2 is as follows:

[0087] (1) Take 0.1g of anhydrous citric acid, add 3.3g of purified water, stir to dissolve, slowly and continuously add 10g of chloral hydrate while stirring, stir at a constant speed (300r / min) until completely dissolved, filter to obtain a concentrated chloral hydrate solution with a pH of 1.25;

[0088] (2) Take 0.91 mL of purified water, add 0.1 g of sodium benzoate, stir to dissolve, and obtain sodium benzoate solution. Take another 45.5 mL of purified water, heat to boiling, add 60.05 g of sucrose, 0.1 g of sucralose and 0.01 g of disodium edetate, stir to dissolve, boil for 30 minutes and then stop heating. After the temperature cools to below 80 degrees Celsius, add 0.91 g of anhydrous citric acid, sodium benzoate solution and 0.4 g of raspberry flavoring, add purified water to make up to 91 mL, stir well, and obtain diluted solution with pH 2.48;

[0089] (3) Take 1g of concentrated solution and mix it with 9.1ml of diluent to obtain Comparative Example 2 solution with pH 2.54.

[0090] Experiment 1: Taste Assessment

[0091] For Examples 1-4, a blind screening method was used, and each numbered sample was given to the subjects to smell and taste in turn. The subjects evaluated the odor, sweetness, bitterness, aftertaste, and oral retention of each sample. Each subject selected three samples with the best taste, and the results were ranked. All volunteers reported no obvious off-odor, and the odor was mild, meeting the requirements of "neutral taste (meaning no special taste or tastelessness) or generally acceptable taste" as suggested in the "Technical Guidelines for Taste Design and Evaluation of Pediatric Medication (Trial Implementation)". Example 1 had the lowest sweetness, could not suppress bitterness, and had a long bitter retention in the mouth with a slight irritation. Examples 2-3 had higher taste acceptance, but all reported aftertaste bitterness. In Example 4, 8 out of 10 participants selected this sample as having the best taste; all participants reported that this sample had moderate sweetness and no obvious aftertaste bitterness. See Table 6 for details.

[0092] Table 6

[0093]

[0094]

[0095]

[0096] Evaluation criteria: [Sweetness] Ranked by sweetness level, with moderate sweetness being the best;

[0097] [Bitterness] Ranked by degree of bitterness, with no obvious bitterness being the best;

[0098] [Aftertaste] Ranked by the degree of aftertaste, with no obvious aftertaste being the best;

[0099] [Oral retention sensation] Rank the flavors according to the duration of their retention in the oral cavity; the shorter the retention time, the better.

[0100] [Odor] Ranked by odor tolerability, with no odor being the best;

[0101] The best result is defined as ≥3 out of 5 evaluation indicators being rated 1.

[0102] Experimental Example 2: Stability Study

[0103] The stability of the syrups from Examples 5-7 and Comparative Example 1 was investigated, and dichloroacetic acid, trichloroacetic acid, and chloroform were tested. The results were statistically analyzed.

[0104] Table 7

[0105]

[0106] As shown in Table 7, in Examples 5-7, since the prescription contained disodium edetate, the trichloroacetic acid in the preparation did not show a significant increasing trend during storage; in Comparative Example 1, the trichloroacetic acid increased significantly, indicating that the stability of the syrup was significantly improved after the addition of disodium edetate.

[0107] Experimental Example 3: Effect of pH on the Stability of Syrups

[0108] Table 8

[0109]

[0110] For the syrups in Examples 6, 8-13, stability studies were conducted, and dichloroacetic acid, trichloroacetic acid, and chloroform were tested and the results were statistically analyzed. As shown in Table 8, within the pH range of 2.0-3.6, there was no significant increase in dichloroacetic acid, trichloroacetic acid, and chloroform.

[0111] Experimental Example 4: Effect of Antioxidant Type on Syrup Stability

[0112] For the syrups of Examples 6, 15-22 and Comparative Example 1, stability was investigated, and dichloroacetic acid, trichloroacetic acid, and chloroform were tested. The results were statistically analyzed.

[0113] Table 9

[0114]

[0115] As shown in Table 9, 1) in the chloral hydrate syrup, except for Examples 6 and 22, the trichloroacetic acid in Examples 15-17 and Comparative Example 1 showed a significant increase, indicating that the stability of the syrup was significantly improved after the addition of disodium edetate; 2) as can be seen from Examples 18-21, the content of dichloroacetic acid, trichloroacetic acid and chloroform in the chloral hydrate aqueous solution with added disodium edetate did not change significantly, and its stability was significantly better than that of the samples with added antioxidants.

[0116] Experimental Example 5: Prescription Comparison Study

[0117] The stability of the 5 mL, 10 mL and 50 mL formulations of Examples 6 and 22, as well as Comparative Example 2, was investigated. Dichloroacetic acid, trichloroacetic acid, chloroform and 5-hydroxymethylfurfural were detected and the results were statistically analyzed.

[0118] Table 10

[0119]

[0120] As shown in Table 10, the hydrated chloral solution of this application has extremely low levels of all impurities, and the levels of trichloroacetic acid and 5-hydroxymethylfurfural are better than those of Comparative Example 2.

[0121] After being placed under long-term stability test conditions (25℃±2℃, 60%±5%RH) for 18 months, the test results showed that the content of each impurity in Examples 6 and 22 was extremely low. For example, the content of chloroform was lower than the amount of chloroform after 30 days under accelerated conditions (40℃).

[0122] Test Example 6: Examination of the antibacterial efficacy of the prescription

[0123] For the 5ml, 10ml, 50ml, and 100ml formulations of Examples 6 and 22, refer to the General Rules, Part IV, of the 2020 edition of the Chinese Pharmacopoeia. <1121> The antibacterial efficacy test method was used to determine the antibacterial efficacy against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus niger. In addition, the antibacterial efficacy against Saccharomyces rouxii was also tested.

[0124] The test results showed that the Ig values ​​at 28 days in Examples 6 and 22 were extremely low, and the antibacterial test results were both NI (according to the pharmacopoeia, this means no increase, that is, the increase in the number of test bacteria at the previous test time does not exceed 0.5 Ig), which meets the requirements of the Chinese Pharmacopoeia. This indicates that the formulation of this application can still guarantee antibacterial efficacy even without the addition of antibacterial agents.

[0125] The embodiments described above are merely preferred embodiments of this application and are not intended to limit the scope of this application. Any modifications and improvements made by those skilled in the art to the technical solutions of this application without departing from the spirit of this application should fall within the protection scope defined by the claims of this application.

Claims

1. A chloral hydrate solution, wherein each 100 ml of the solution contains 10 g of chloral hydrate, characterized in that: The solution also contains an antioxidant selected from disodium edetate; preferably, each 100 ml of the solution contains 0.001-0.05 g of the antioxidant.

2. The solution according to claim 1, characterized in that: The pH value of the solution is 2.0 to 4.2, preferably 2.5 to 3.3, more preferably 2.7 to 3.0, and even more preferably 3.

0.

3. The solution according to claim 1, characterized in that: The solution contains 0.005-0.05g of the antioxidant per 100ml; preferably, the solution contains 0.005-0.025g of the antioxidant per 100ml.

4. The solution according to claim 1, characterized in that, The solution is chloral hydrate syrup, and the syrup also contains a flavoring agent composed of sucrose and sucralose.

5. The solution according to claim 4, characterized in that, The syrup contains not less than 45g of sucrose per 100ml, preferably 45-65g; and the sucralose content is 0.01g-0.1g.

6. The solution according to claim 4 or 5, characterized in that, Each 100 ml of the syrup contains 0.01 g of the antioxidant.

7. The solution according to claim 4 or 5, characterized in that, The composition of the syrup per 100ml is as follows: 10g chloral hydrate, 45g sucrose, 0.1g sucralose, 0.01g disodium edetate, and citric acid-sodium citrate to adjust the pH to 3.

0.

8. The solution according to claim 7, characterized in that, The solution is filled in volumes of 5 ml, 10 ml, 50 ml, or 100 ml.

9. The solution according to claim 8, characterized in that, The solution, in a 10 mL volume, consists of: 1 g chloral hydrate, 4.5 g sucrose, 0.01 g sucralose, 0.001 g disodium edetate, and citric acid-sodium citrate adjusted to pH 3.

0.

10. A method for preparing the solution according to any one of claims 4-9, characterized in that, Includes the following steps: Step 1: Add the flavoring agent to hot water, stir to dissolve, boil, and then cool to room temperature; Step 2: While stirring, add antioxidants and pH adjusters to the solution obtained in Step 1 to obtain a solution with a pH of 2.0~4.2; Step 3: Add chloral hydrate to the solution obtained in step 2, stir to dissolve, make up to volume and fill into containers.

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