Chloral hydrate oral microsphere solution and preparation method thereof

Abstract

The invention discloses a preparation method of chloral hydrate oral liquid, which comprises the following steps: 1) preparation of chloral hydrate microspheres: dissolving chloral hydrate in an organic solvent, and then adding a carrier material into the solution to obtain an oil phase; adding a surfactant into deionized water to form a water phase; slowly dropwise adding the oil phase into the water phase while stirring and performing ultrasonic treatment to obtain an emulsion; continuously stirring the emulsion, removing the organic solvent, gradually solidifying the medicine and the carrier material in the oil phase to form microspheres, washing, separating and drying to obtain chloral hydrate microspheres; 2) preparation of chloral hydrate oral liquid: dissolving sorbitol in water to obtain a sorbitol aqueous solution; and adding the chloral hydrate microspheres into a sorbitol aqueous solution to obtain the chloral hydrate oral liquid. The chloral hydrate oral liquid prepared by the method has relatively high stability, and meanwhile, the acceptability of a patient is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a hydration chloral microsphere oral solution. BACKGROUND

[0002] Hydration chloral is a central sedative drug with hypnotic, sedative and anticonvulsant effects. It is mainly used for the treatment of insomnia, especially in patients with difficulty falling asleep; as a pre-anesthetic, preoperative and pre-sleep electroencephalogram examination sedative; and for the treatment of status epilepticus, and convulsions caused by high fever in children, tetanus and eclampsia. The hypnotic effect of hydration chloral is mild, does not shorten the REM sleep period, and has no obvious aftereffect. Its hypnotic mechanism may be similar to that of barbiturates, which can cause physiological sleep.

[0003] It should be noted that hydration chloral oral solution should be prepared and used immediately, because the nature of hydration chloral itself and environmental temperature, light and other factors have an impact on its stability. The quality standard of hydration chloral hospital preparation is generally lower than that of commercial products. According to literature reports, the stability of the product is very poor, and the 5% concentration product needs to be refrigerated, with a shelf life of only 30 days, and the 10% concentration product is stored at room temperature (25℃), with a shelf life of about 35 days. Literature (Song Yongxi, Li Liying, Li Qianmei. Preparation and stability prediction of hydration chloral mucilage [J]. Tianjin Pharmacy, 2002, 14(2): 48-48) reported that beta-cyclodextrin was added to hydration chloral oral solution to improve stability, but the shelf life of the product was only improved to 46.63 days, without substantial improvement. Therefore, effectively improving the stability of hydration chloral oral solution has become a problem, and no effective method has been reported. In order to solve these problems, researchers have carried out prescription screening research to improve the stability of hydration chloral oral solution and improve the taste. For example, CN116999388A adds sorbitol and sucralose to effectively ensure the stability of the oral solution, and masks the bitter, astringent and pungent taste of hydration chloral, thereby improving patient acceptance, but its stability still has room for improvement. SUMMARY

[0004] The present application provides a preparation method of hydration chloral oral solution to solve the problem of poor stability of hydration chloral oral solution.

[0005] The present application provides a preparation method of hydration chloral oral solution, comprising:

[0006] 1) Preparation of chloral hydrate microspheres: chloral hydrate is dissolved in an organic solvent, and then a carrier material is added to the above solution to obtain an oil phase; a surfactant is added to deionized water to form an aqueous phase; the oil phase is slowly added to the aqueous phase while stirring and using ultrasonic treatment to obtain an emulsion; the emulsion is continuously stirred, and the organic solvent is removed, and the drug in the oil phase and the carrier material are gradually solidified to form microspheres, which are washed, separated, dried, and then obtained as chloral hydrate microspheres;

[0007] 2) Preparation of chloral hydrate oral solution: sorbitol is dissolved in water to obtain a sorbitol aqueous solution; chloral hydrate microspheres are added to the sorbitol aqueous solution to obtain a chloral hydrate oral solution.

[0008] In a specific embodiment of the present application, the above-mentioned chloral hydrate and carrier material are used in a ratio of 1:1.5 to 1:3.

[0009] In a specific embodiment of the present application, when preparing chloral hydrate microspheres, the ultrasonic power during the emulsification process is 450 to 600 W.

[0010] In a specific embodiment of the present application, when preparing chloral hydrate microspheres, the ultrasonic time during the emulsification process is 30 to 50 min.

[0011] In a specific embodiment of the present application, when preparing chloral hydrate microspheres, the amount of surfactant used accounts for 3 to 9% of the total weight of chloral hydrate microspheres.

[0012] In a specific embodiment of the present application, the carrier material can be polylactic acid-glycolic acid copolymer, gelatin, chitosan.

[0013] In a specific embodiment of the present application, the carrier material can be an organic solvent, which is ethyl acetate.

[0014] In a specific embodiment of the present application, the surfactant can be polyvinyl alcohol, Tween-80.

[0015] In a specific embodiment of the present application, when preparing a chloral hydrate oral solution, the amount of sorbitol added to chloral hydrate microspheres is in a ratio of 1.5 to 2:1.

[0016] The present application also provides a chloral hydrate oral solution prepared by the above method.

[0017] Beneficial effects:

[0018] 1) Improve the stability of chloral hydrate oral solution: the present application uses microencapsulation technology to encapsulate the active pharmaceutical ingredient in the carrier material, effectively isolating the active pharmaceutical ingredient from external light and heat, so that the active pharmaceutical ingredient remains stable in drug content for a long time and is not easily decomposed.

[0019] 2) Improved taste: Chloral hydrate has a pungent, irritating odor and a slightly bitter taste, which may cause adverse reactions such as nausea and vomiting, especially when taken orally. This invention uses microencapsulation technology to encapsulate the active pharmaceutical ingredient chloral hydrate within a carrier material, effectively masking its pungent odor and making it more palatable to patients, thus significantly improving the taste. Detailed Implementation

[0020] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0021] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0022] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0023] A method for preparing chloral hydrate oral solution, comprising:

[0024] 1) Preparation of chloral hydrate microspheres: Chloral hydrate was dissolved in an organic solvent, and then a carrier material was added to the solution to obtain an oil phase; a surfactant was added to deionized water to form an aqueous phase; the oil phase was slowly added dropwise to the aqueous phase while stirring and ultrasonic treatment to obtain an emulsion; the emulsion was stirred continuously and the organic solvent was removed. The drug and carrier material in the oil phase gradually solidified to form microspheres. After washing, separation, and drying, chloral hydrate microspheres were obtained.

[0025] 2) Preparation of chloral hydrate oral solution: Sorbitol is dissolved in water to obtain sorbitol aqueous solution; chloral hydrate microspheres are added to sorbitol aqueous solution to obtain chloral hydrate oral solution.

[0026] Preferably, the ratio of hydrated chloral to carrier material is 1:1.5 to 1:3, which can be 1:1.5, 1:2, or 1:3.

[0027] Preferably, when preparing hydrated chloral microspheres, the ultrasonic power during the emulsification process is between 450 and 600 W, which can be 450 W, 525 W, or 600 W.

[0028] Preferably, when preparing hydrated chloral microspheres, the ultrasonic time for the emulsification process is 30 to 50 minutes, which can be 30 minutes, 40 minutes, or 50 minutes.

[0029] Preferably, when preparing chloral hydrate microspheres, the amount of surfactant used accounts for 3-9% of the total weight of the chloral hydrate microspheres, which can be 3%, 6%, or 9%.

[0030] Preferably, when preparing hydrated chloral microspheres, the carrier material can be polylactic acid-glycolic acid copolymer, gelatin, or chitosan.

[0031] Preferably, when preparing hydrated chloral microspheres, the carrier material can be an organic solvent, such as ethyl acetate.

[0032] Preferably, the surfactant can be polyvinyl alcohol or Tween-80.

[0033] Preferably, in the preparation of chloral hydrate oral solution, the ratio of sorbitol to chloral hydrate microspheres is 1.5 to 2:1.

[0034] The above method was used to prepare chloral hydrate oral solution.

[0035] The hydrated chloral oral solution prepared using the method provided in this invention has high stability.

[0036] The present invention will be further described in detail below with reference to the embodiments. However, the present invention is not limited to the examples given.

[0037] Example 1

[0038] Information on raw and auxiliary materials is shown in Table 1:

[0039] Table 1 Raw and Auxiliary Material Information

[0040]

[0041] I. Preparation of hydrated chloral aldehyde microspheres:

[0042] 1) Drug dissolution:

[0043] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0044] 2) Aqueous phase preparation:

[0045] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0046] 3) Emulsification process:

[0047] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0048] 4) Solvent evaporation:

[0049] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0050] 5) Washing and separation:

[0051] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0052] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0053] 6) Drying:

[0054] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0055] II. Preparation of Chloral Hydrate Oral Solution

[0056] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0057] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0058] Example 2

[0059] Information on raw and auxiliary materials is shown in Table 2:

[0060] Table 2 Raw and Auxiliary Material Information

[0061]

[0062] I. Preparation of hydrated chloral aldehyde microspheres:

[0063] 1) Drug dissolution:

[0064] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0065] 2) Aqueous phase preparation:

[0066] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0067] 3) Emulsification process:

[0068] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0069] 4) Solvent evaporation:

[0070] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0071] 5) Washing and separation:

[0072] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0073] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0074] 6) Drying:

[0075] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0076] II. Preparation of Chloral Hydrate Oral Solution

[0077] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0078] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0079] Example 3

[0080] Information on raw and auxiliary materials is shown in Table 3:

[0081] Table 3 Raw and Auxiliary Material Information

[0082]

[0083]

[0084] I. Preparation of hydrated chloral aldehyde microspheres:

[0085] 1) Drug dissolution:

[0086] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0087] 2) Aqueous phase preparation:

[0088] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0089] 3) Emulsification process:

[0090] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0091] 4) Solvent evaporation:

[0092] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0093] 5) Washing and separation:

[0094] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0095] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0096] 6) Drying:

[0097] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0098] II. Preparation of Chloral Hydrate Oral Solution

[0099] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0100] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0101] Example 4

[0102] Information on raw and auxiliary materials is shown in Table 4:

[0103] Table 4 Raw and Auxiliary Material Information

[0104]

[0105] I. Preparation of hydrated chloral aldehyde microspheres:

[0106] 1) Drug dissolution:

[0107] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0108] 2) Aqueous phase preparation:

[0109] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0110] 3) Emulsification process:

[0111] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 450 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0112] 4) Solvent evaporation:

[0113] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0114] 5) Washing and separation:

[0115] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0116] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0117] 6) Drying:

[0118] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0119] II. Preparation of Chloral Hydrate Oral Solution

[0120] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0121] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0122] Example 5

[0123] Information on raw and auxiliary materials is shown in Table 5:

[0124] Table 5 Raw and Auxiliary Material Information

[0125]

[0126] I. Preparation of hydrated chloral aldehyde microspheres:

[0127] 1) Drug dissolution:

[0128] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0129] 2) Aqueous phase preparation:

[0130] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0131] 3) Emulsification process:

[0132] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 600 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0133] 4) Solvent evaporation:

[0134] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0135] 5) Washing and separation:

[0136] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0137] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0138] 6) Drying:

[0139] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0140] II. Preparation of Chloral Hydrate Oral Solution

[0141] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0142] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0143] Example 6

[0144] Information on raw and auxiliary materials is shown in Table 6:

[0145] Table 6 Raw and Auxiliary Material Information

[0146]

[0147] I. Preparation of hydrated chloral aldehyde microspheres:

[0148] 1) Drug dissolution:

[0149] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0150] 2) Aqueous phase preparation:

[0151] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0152] 3) Emulsification process:

[0153] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 30 minutes.

[0154] 4) Solvent evaporation:

[0155] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0156] 5) Washing and separation:

[0157] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0158] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0159] 6) Drying:

[0160] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0161] II. Preparation of Chloral Hydrate Oral Solution

[0162] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0163] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0164] Example 7

[0165] Information on raw and auxiliary materials is shown in Table 7:

[0166] Table 7 Raw and Auxiliary Material Information

[0167]

[0168]

[0169] I. Preparation of hydrated chloral aldehyde microspheres:

[0170] 1) Drug dissolution:

[0171] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0172] 2) Aqueous phase preparation:

[0173] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0174] 3) Emulsification process:

[0175] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 50 minutes.

[0176] 4) Solvent evaporation:

[0177] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0178] 5) Washing and separation:

[0179] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0180] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0181] 6) Drying:

[0182] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0183] II. Preparation of Chloral Hydrate Oral Solution

[0184] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0185] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0186] Example 8

[0187] Information on raw and auxiliary materials is shown in Table 8:

[0188] Table 8 Raw and Auxiliary Material Information

[0189]

[0190] I. Preparation of hydrated chloral aldehyde microspheres:

[0191] 1) Drug dissolution:

[0192] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0193] 2) Aqueous phase preparation:

[0194] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0195] 3) Emulsification process:

[0196] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0197] 4) Solvent evaporation:

[0198] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0199] 5) Washing and separation:

[0200] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0201] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0202] 6) Drying:

[0203] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0204] II. Preparation of Chloral Hydrate Oral Solution

[0205] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0206] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0207] Example 9

[0208] Information on raw and auxiliary materials is shown in Table 9:

[0209] Table 9 Raw and Auxiliary Material Information

[0210]

[0211] I. Preparation of hydrated chloral aldehyde microspheres:

[0212] 1) Drug dissolution:

[0213] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0214] 2) Aqueous phase preparation:

[0215] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0216] 3) Emulsification process:

[0217] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0218] 4) Solvent evaporation:

[0219] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0220] 5) Washing and separation:

[0221] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0222] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0223] 6) Drying:

[0224] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0225] II. Preparation of Chloral Hydrate Oral Solution

[0226] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0227] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0228] Comparative Example 1

[0229] Information on raw and auxiliary materials is shown in Table 10:

[0230] Table 10 Raw and Auxiliary Material Information

[0231]

[0232]

[0233] I. Preparation of hydrated chloral aldehyde microspheres:

[0234] 1) Drug dissolution:

[0235] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0236] 2) Aqueous phase preparation:

[0237] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0238] 3) Emulsification process:

[0239] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0240] 4) Solvent evaporation:

[0241] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0242] 5) Washing and separation:

[0243] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0244] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0245] 6) Drying:

[0246] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0247] II. Preparation of Chloral Hydrate Oral Solution

[0248] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0249] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0250] Comparative Example 2

[0251] Information on raw and auxiliary materials is shown in Table 11:

[0252] Table 11 Raw and Auxiliary Material Information

[0253]

[0254] I. Preparation of hydrated chloral aldehyde microspheres:

[0255] 1) Drug dissolution:

[0256] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0257] 2) Aqueous phase preparation:

[0258] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0259] 3) Emulsification process:

[0260] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0261] 4) Solvent evaporation:

[0262] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0263] 5) Washing and separation:

[0264] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0265] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0266] 6) Drying:

[0267] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0268] II. Preparation of Chloral Hydrate Oral Solution

[0269] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0270] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0271] Comparative Example 3

[0272] Information on raw and auxiliary materials is shown in Table 12:

[0273] Table 12 Raw and Auxiliary Material Information

[0274]

[0275] I. Preparation of hydrated chloral aldehyde microspheres:

[0276] 1) Drug dissolution:

[0277] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0278] 2) Aqueous phase preparation:

[0279] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0280] 3) Emulsification process:

[0281] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 420 W, set to a 30-second on-off cycle, for a total processing time of 40 minutes.

[0282] 4) Solvent evaporation:

[0283] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0284] 5) Washing and separation:

[0285] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0286] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0287] 6) Drying:

[0288] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0289] II. Preparation of Chloral Hydrate Oral Solution

[0290] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0291] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0292] Comparative Example 4

[0293] Information on raw and auxiliary materials is shown in Table 13:

[0294] Table 13 Raw and Auxiliary Material Information

[0295]

[0296] I. Preparation of hydrated chloral aldehyde microspheres:

[0297] 1) Drug dissolution:

[0298] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0299] 2) Aqueous phase preparation:

[0300] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0301] 3) Emulsification process:

[0302] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 630 W, set to a 30-second on-off cycle, for a total processing time of 40 minutes.

[0303] 4) Solvent evaporation:

[0304] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0305] 5) Washing and separation:

[0306] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0307] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0308] 6) Drying:

[0309] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0310] II. Preparation of Chloral Hydrate Oral Solution

[0311] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0312] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0313] Comparative Example 5

[0314] Information on raw and auxiliary materials is shown in Table 14:

[0315] Table 14 Raw and Auxiliary Material Information

[0316]

[0317]

[0318] I. Preparation of hydrated chloral aldehyde microspheres:

[0319] 1) Drug dissolution:

[0320] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0321] 2) Aqueous phase preparation:

[0322] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0323] 3) Emulsification process:

[0324] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a 30-second on-off cycle, for a total processing time of 20 minutes.

[0325] 4) Solvent evaporation:

[0326] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0327] 5) Washing and separation:

[0328] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0329] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0330] 6) Drying:

[0331] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0332] II. Preparation of Chloral Hydrate Oral Solution

[0333] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0334] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0335] Comparative Example 6

[0336] Information on raw and auxiliary materials is shown in Table 15:

[0337] Table 15 Raw and Auxiliary Material Information

[0338]

[0339] I. Preparation of hydrated chloral aldehyde microspheres:

[0340] 1) Drug dissolution:

[0341] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0342] 2) Aqueous phase preparation:

[0343] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0344] 3) Emulsification process:

[0345] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 60 minutes.

[0346] 4) Solvent evaporation:

[0347] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0348] 5) Washing and separation:

[0349] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0350] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0351] 6) Drying:

[0352] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0353] II. Preparation of Chloral Hydrate Oral Solution

[0354] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0355] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0356] Comparative Example 7

[0357] Information on raw and auxiliary materials is shown in Table 16:

[0358] Table 16 Raw and Auxiliary Material Information

[0359]

[0360] I. Preparation of hydrated chloral aldehyde microspheres:

[0361] 1) Drug dissolution:

[0362] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0363] 2) Aqueous phase preparation:

[0364] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0365] 3) Emulsification process:

[0366] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0367] 4) Solvent evaporation:

[0368] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0369] 5) Washing and separation:

[0370] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0371] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0372] 6) Drying:

[0373] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0374] II. Preparation of Chloral Hydrate Oral Solution

[0375] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0376] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0377] Comparative Example 8

[0378] Information on raw and auxiliary materials is shown in Table 17:

[0379] Table 17 Raw and Auxiliary Material Information

[0380]

[0381]

[0382] I. Preparation of hydrated chloral aldehyde microspheres:

[0383] 1) Drug dissolution:

[0384] The prescribed amount of chloral hydrate was dissolved in ethyl acetate to form a homogeneous solution. Then, the carrier material, polylactic acid-glycolic acid copolymer, was added to the same solution, ensuring complete dissolution, to obtain the drug / carrier solution.

[0385] 2) Aqueous phase preparation:

[0386] In another beaker, add deionized water and surfactant, and use a magnetic stirrer at 100 rpm to stir until completely dissolved to form an aqueous phase.

[0387] 3) Emulsification process:

[0388] The drug / carrier solution (oil phase) was slowly added dropwise to the aqueous phase while simultaneously stirring with a magnetic stirrer at a speed of 500 rpm. The emulsion was then treated with an ultrasonic processor at a power of 525 W, set to a cycle of 30 seconds on and 30 seconds off, for a total processing time of 40 minutes.

[0389] 4) Solvent evaporation:

[0390] Continue stirring the emulsion and use a rotary evaporator with the temperature set to 79°C to evaporate for 100 minutes to remove the organic solvent.

[0391] 5) Washing and separation:

[0392] After the organic solvent has completely evaporated, the mixture is cooled to room temperature, allowing the drug and carrier material in the oil phase to gradually solidify and form microspheres. The microspheres are then separated using a centrifuge set at 25°C, 400 rpm, and 20 min.

[0393] Wash the microspheres several times with an appropriate amount of water to remove residual surfactants and other impurities.

[0394] 6) Drying:

[0395] The washed microspheres were transferred to a freeze dryer for freeze drying. The freeze dryer was set to -20°C for 8 hours, then freeze-dried at 0°C and 600Pa for 6-8 hours. The temperature was then raised to 60°C and 600Pa for 3 hours to continue drying until completely dry, thus obtaining hydrated chloral microspheres.

[0396] II. Preparation of Chloral Hydrate Oral Solution

[0397] 1) Add 100g of sorbitol to 60g of water, heat to dissolve, cool to room temperature and make up to 200ml to prepare a 50% sorbitol aqueous solution;

[0398] 2) Add 60g of chloral hydrate microspheres to 100ml of the above sorbitol solution and stir to dissolve. Then, bring the volume of the above sorbitol solution to 200ml to obtain a chloral hydrate oral solution with a concentration of 10%.

[0399] Table 18 provides a summary of the experimental variables for each embodiment and comparative example.

[0400] Table 18. Summary of experimental variables in Examples 1-9 and Comparative Examples 1-8

[0401]

[0402] Stability tests were performed on the hydrated chloral oral solutions prepared in Examples 1-9 and Comparative Examples 1-8.

[0403] The hydrated chloral aldehyde oral solutions prepared in Examples 1-9 and Comparative Examples 1-8 were placed at 60°C under light (4500 lx ± 500 lx) for 0, 30, 90, and 180 days, respectively. The contents of hydrated chloral aldehyde and known impurities in the hydrated chloral aldehyde oral solutions prepared in Examples 1-9 and Comparative Examples 1-8 under different conditions were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Detailed data are shown in Table 19. Known impurities include formic acid, dichloroacetic acid, dichloroacetaldehyde hydrate, trichloroacetic acid, and trichloroethanol.

[0404] Table 19 shows the content data of each substance in the hydrated chloral oral solution prepared in Examples 1-9 and Comparative Examples 1-8 after being placed at 60°C under light irradiation (4500 lx ± 500 lx) for 0 days, 30 days, 90 days, and 180 days.

[0405]

[0406]

[0407]

[0408]

[0409] Observing Table 19, the following conclusions can be drawn:

[0410] Comparing Examples 1-3 and Comparative Examples 1-2, it is evident that when the drug-to-carrier ratio is between 1:1.5 and 1:3 in the preparation of chloral hydrate microspheres, the resulting chloral hydrate oral solution exhibits better stability, more stable content, and less variation in impurities. Conversely, when the drug-to-carrier ratio is less than or greater than 1:1.5-1:3, the resulting chloral hydrate oral solution exhibits poorer stability and greater variations in content and impurities. Therefore, under the same conditions, controlling the drug-to-carrier ratio to 1:1.5-1:3 during the preparation of chloral hydrate microspheres leads to better stability of the resulting chloral hydrate oral solution.

[0411] Comparing Examples 1, 4, and 5 with Comparative Examples 3 and 4, it is evident that when the ultrasonic power during the emulsification process of preparing chloral hydrate microspheres is between 450 and 600 W, the resulting chloral hydrate oral solution exhibits better stability, more stable content, and less variation in impurities. Conversely, when the ultrasonic power is below 450 W or above 600 W, the stability of the resulting chloral hydrate oral solution is poorer, with greater variations in content and impurities. Therefore, under the same conditions, controlling the ultrasonic power during the emulsification process to between 450 and 600 W during the preparation of chloral hydrate microspheres leads to better stability of the resulting chloral hydrate oral solution.

[0412] Comparing Examples 1, 6, and 7 with Comparative Examples 5 and 6, it is evident that when the ultrasonic emulsification process for preparing chloral hydrate microspheres is between 30 and 50 minutes, the resulting chloral hydrate oral solution exhibits better stability, more stable content, and less variation in impurities. Conversely, when the ultrasonic time is less than 30 minutes or more than 50 minutes, the stability of the resulting chloral hydrate oral solution is poorer, with greater variations in content and impurities. Therefore, under the same conditions, controlling the ultrasonic emulsification process to between 30 and 50 minutes during the preparation of chloral hydrate microspheres leads to better stability of the resulting chloral hydrate oral solution.

[0413] Comparing Examples 1, 8, and 9 with Comparative Examples 7 and 8, it is evident that when the surfactant content accounts for 3-9% of the total weight of the chloral hydrate microspheres during preparation, the resulting chloral hydrate oral solution exhibits better stability, more stable content, and less variation in impurities. Conversely, when the surfactant content is less than 3% or more than 9% of the total weight of the chloral hydrate microspheres, the resulting chloral hydrate oral solution shows poorer stability and greater variation in content and impurities. Therefore, under the same conditions, controlling the surfactant content to 3-9% of the total weight of the chloral hydrate microspheres during preparation yields a more stable chloral hydrate oral solution.

[0414] It is understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A method for preparing a hydrated chloral aldehyde oral solution, characterized in that, include: 1) Preparation of chloral hydrate microspheres: Chloral hydrate was dissolved in an organic solvent, and then a carrier material was added to the solution to obtain an oil phase; a surfactant was added to deionized water to form an aqueous phase; the oil phase was slowly added dropwise to the aqueous phase while stirring and ultrasonic treatment to obtain an emulsion; the emulsion was stirred continuously and the organic solvent was removed. The drug and carrier material in the oil phase gradually solidified to form microspheres. After washing, separation, and drying, chloral hydrate microspheres were obtained. 2) Preparation of chloral hydrate oral solution: Sorbitol is dissolved in water to obtain sorbitol aqueous solution; chloral hydrate microspheres are added to sorbitol aqueous solution to obtain chloral hydrate oral solution.

2. The preparation method of hydrated chloral oral solution according to claim 1, characterized in that, The ratio of hydrated chloral to carrier material is 1:1.5 to 1:

3.

3. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, During the preparation of hydrated chloral microspheres, the ultrasonic power during the emulsification process is between 450 and 600 W.

4. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, When preparing hydrated chloral microspheres, the ultrasonic time for the emulsification process is 30-50 min.

5. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, In the preparation of hydrated chloral microspheres, the amount of surfactant used accounts for 3-9% of the total weight of the hydrated chloral microspheres.

6. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, The carrier material can be polylactic acid-glycolic acid copolymer, gelatin, or chitosan.

7. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, The carrier material can be an organic solvent, such as ethyl acetate.

8. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, The surfactant may be polyvinyl alcohol or Tween-80.

9. The method for preparing chloral hydrate oral solution according to claim 1, characterized in that, In the preparation of the chloral hydrate oral solution, the ratio of sorbitol to chloral hydrate microspheres is 1.5 to 2:

1.

10. A hydrated chloral oral solution, prepared by any one of the methods in claims 1-9.

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