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CN-121987601-A - Diphenhydramine hydrochloride composition and preparation method and application thereof

CN121987601ACN 121987601 ACN121987601 ACN 121987601ACN-121987601-A

Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a diphenhydramine hydrochloride composition and a preparation method thereof. The invention adopts carbon dioxide to adjust the pH of the diphenhydramine hydrochloride solution and performs terminal sterilization on the diphenhydramine hydrochloride solution, thereby improving the sterility assurance level of diphenhydramine hydrochloride injection and greatly improving the safety of clinical use.

Inventors

  • DU YOUGUO
  • GONG JIAHUI
  • ZHU LEI
  • JIA YUANCHAO
  • CHEN LIN

Assignees

  • 南京唯创远医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241029

Claims (10)

  1. 1. The diphenhydramine hydrochloride composition is characterized by comprising diphenhydramine hydrochloride, a pH regulator, water for injection and protective gas, wherein the protective gas is CO 2 , and the pH of a solution of the composition is 5.5-6.5.
  2. 2. The diphenhydramine hydrochloride composition according to claim 1, wherein the pH adjuster is selected from one or more of sodium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, naOH, sodium carbonate, and sodium bicarbonate, preferably one or more of NaOH, sodium carbonate, and sodium bicarbonate, further preferably the pH adjuster is selected from one or a combination of NaOH and sodium carbonate, and still further preferably the pH adjuster is selected from NaOH.
  3. 3. Diphenhydramine hydrochloride composition according to any one of claims 1-2, wherein the prescription of diphenhydramine hydrochloride composition is selected from the group consisting of: Prescription composition Dosage of Diphenhydramine hydrochloride 50g PH regulator Adjusting the pH to 7.0-8.0 CO 2 Proper amount of Water for injection To 1000ml And Prescription composition Dosage of Diphenhydramine hydrochloride 20g PH regulator Adjusting the pH to 7.0-8.0 CO 2 Proper amount of Water for injection To 1000ml 。
  4. 4. A diphenhydramine hydrochloride composition according to any one of claims 1-3, wherein the diphenhydramine hydrochloride composition does not contain any further excipients.
  5. 5. Diphenhydramine hydrochloride composition according to any one of claims 1-4, wherein the composition is prepared according to the following steps: (1) Taking 60% -80% of water for injection according to a prescription, controlling the water temperature to be 15-30 ℃, adding diphenhydramine hydrochloride, and stirring until the diphenhydramine hydrochloride is dissolved; (2) Dropwise adding an aqueous solution of sodium hydroxide into the solution to adjust the pH to 7.0-8.0; (3) Controlling the water temperature to be 15-30 ℃, continuously introducing CO 2 gas until the liquid medicine is clear, and finally controlling the pH to be 5.5-6.5; (4) Adding water for injection, and fixing volume to full volume.
  6. 6. The diphenhydramine hydrochloride composition of claim 5, wherein the preparation further comprises the steps of: (5) Filling protective gas into the headspace of the glass bottle, controlling the headspace oxygen to be less than 5%, filling the solution obtained in the step (4) into the glass bottle, and immediately sealing the glass bottle after filling; (6) And (3) carrying out damp heat sterilization, wherein the sterilization temperature is controlled to be 121 ℃, and the sterilization time is 12-15 min.
  7. 7. The diphenhydramine hydrochloride injection is characterized by comprising diphenhydramine hydrochloride, a pH regulator, water for injection and CO 2 , wherein the pH of the injection is 5.5-6.5.
  8. 8. The diphenhydramine hydrochloride injection according to claim 7, wherein the pH adjuster is selected from one or more of NaOH, sodium carbonate and sodium bicarbonate, preferably the pH adjuster is selected from one or a combination of NaOH and sodium carbonate, further preferably the pH adjuster is selected from NaOH.
  9. 9. Diphenhydramine hydrochloride injection according to any one of claims 7-8, wherein the injection is formulated from a formulation selected from the group consisting of Prescription composition Dosage of Diphenhydramine hydrochloride 50g PH regulator Adjusting the pH to 7.0-8.0 CO 2 Proper amount of Water for injection To 1000ml Or (b) Prescription composition Dosage of Diphenhydramine hydrochloride 20g PH regulator Adjusting the pH to 7.0-8.0 CO 2 Proper amount of Water for injection To 1000ml 。
  10. 10. Diphenhydramine hydrochloride injection according to any one of claims 7-9, wherein the injection is prepared by the steps of: (1) Taking 60% -80% of water for injection according to a prescription, controlling the water temperature to be 15-30 ℃, adding diphenhydramine hydrochloride, and stirring until the diphenhydramine hydrochloride is dissolved; (2) Dropwise adding an aqueous solution of a pH regulator into the solution to regulate the pH of the liquid medicine to 7.0-8.0; (3) Keeping the temperature of the solution at 15-30 ℃, continuously introducing CO 2 gas until the liquid medicine is clear, and keeping the final pH at 5.5-6.5; (4) Adding water for injection, and fixing the volume to the full volume; (5) Filling protective gas into the headspace of the glass bottle, controlling the headspace oxygen to be less than 5%, filling the solution obtained in the step (4) into the glass bottle, and immediately sealing the glass bottle after filling; (6) And (3) carrying out damp heat sterilization, wherein the sterilization temperature is controlled to be 121 ℃, and the sterilization time is 12-15 min.

Description

Diphenhydramine hydrochloride composition and preparation method and application thereof Technical Field The invention belongs to the field of chemical pharmaceutical preparations, and relates to a preparation method of a diphenhydramine hydrochloride composition. More particularly, the invention relates to diphenhydramine hydrochloride injection resistant to terminal sterilization and a preparation method thereof. Background The diphenhydramine hydrochloride injection original grinding preparation is developed by MCNEIL CONSUMER HEALTHCARE, is marketed in 1947 at the earliest, and is mainly used for improving anaphylactic reaction of blood or blood plasma and treating other simple immediate anaphylactic diseases, motion sickness and anti-parkinsonism. Currently, the original formulation was returned to the market, and West-Ward Pharmaceuticals International Ltd diphenhydramine hydrochloride injection (1 mL:50 mg) marketed in the U.S. in 1972 was FDA listed as a reference formulation for imitation. The drug was identified as an internationally recognized homogeneous drug and was also listed in the reference formulation catalogue by the national food and drug administration drug review Center (CDE). Diphenhydramine hydrochloride injection cannot be subjected to terminal sterilization generally because of its chemical structure and its aqueous solution is easily degraded at high temperature, and a sterile filtration production process is adopted. Ward Pharmaceuticals International Ltd diphenhydramine hydrochloride injection (1 mL:50 mg) on the market has a pH of 4.0-6.5 and contains 100 micrograms of benzethonium chloride (Benzethonium Chloride) per bottle of the formulation. The diphenhydramine hydrochloride injection produced by the company is subjected to damp-heat sterilization, and related substances are obviously increased after sterilization, which indicates that the reference preparation is not subjected to damp-heat sterilization, and the reference preparation does not select a terminal sterilization process with the highest sterility assurance level. In addition, the lower content of benzethonium chloride in the reference formulation, however, has a definite toxicity to cells, and there are also some potential drawbacks such as the possibility of allergic reactions to it by the individual patient. Therefore, the application of benzethonium chloride existing in diphenhydramine hydrochloride injection to human bodies has potential safety risks. Diphenhydramine hydrochloride injection is also approved in China to be marketed, wherein a certain amount of benzyl alcohol is added as a bacteriostatic agent to control the sterility level. Chen Li in "high performance liquid chromatography to determine the benzyl alcohol content of diphenhydramine hydrochloride injection (strait pharmaceutical, volume 25, 12 th 2013, P121-123)" it is also reported that "benzyl alcohol is often added to diphenhydramine injection as a bacteriostatic agent", and the national drug administration has also been prescribed in "notification about enhanced benzyl alcohol injection administration", such as prescription or solvent containing benzyl alcohol, should be explicitly noted in the specification, and prohibited from being used for intramuscular injection in children. It can be seen that the use of benzyl alcohol also brings a certain risk to the clinical use of diphenhydramine hydrochloride injection. Diphenhydramine hydrochloride has better solubility under acidic conditions, but is easy to hydrolyze to generate the diphenyl methanol which is difficult to dissolve in water. The skilled person in the present invention has found through a number of experiments that the rate of hydrolysis of diphenhydramine hydrochloride in aqueous solutions is affected by temperature and acid-base level, diphenhydramine hydrochloride being difficult to withstand sterilization temperatures under low acidic conditions. In the prior art, diphenhydramine hydrochloride injection can degrade at high temperature to produce impurity A (2- (diphenylmethoxy) -N-methylethylamine) and impurity D (benzhydrol). The technical personnel of the invention also find that the improvement of the pH can obviously improve the heat stability of the diphenhydramine hydrochloride injection, so that the diphenhydramine hydrochloride injection is expected to resist damp and heat sterilization by improving the pH of the liquid medicine to a neutral or alkaline level, but after the pH level is improved, the solubility of diphenhydramine hydrochloride is obviously reduced, and the diphenhydramine hydrochloride can be separated out in the room temperature preparation process. The terminal sterilization can not be realized on the premise of ensuring the properties of the liquid medicine by improving the pH adjustment under the existing prescription. In conclusion, diphenhydramine hydrochloride aqueous solution is dissolved under acidic conditions, but cannot withstand terminal