Pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a hydrate thereof, a tautomer thereof, or a stereoisomer thereof, wherein the pharmaceutical composition has a pH of no greater than 12.

Description

Pharmaceutical composition TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a pharmaceutical composition. BACKGROUND

[0002] Diazepam is a new class I small molecule drug for short-term treatment of insomnia patients, and is a partial positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptor, which selectively acts on the alpha1-subtype of GABAA receptor, can produce activation effect on the receptor and rapidly inhibit the nervous system, and can avoid excessive activation of the receptor to produce deep inhibition and induce neurological side effects.

[0003] Compared with traditional insomnia treatment drugs, diazepam has the advantages of unique metabolic pathways, significantly reduced possibility of interaction with different drugs, and suitability for insomnia patients with underlying diseases and the need to combine other drugs. Diazepam has obvious advantages in terms of movement disorders, aftereffects, tolerance, ethanol interaction, physical dependence, memory impairment and other adverse reactions.

[0004] The structural formula of diazepam is shown as formula (I). There is no disclosure of research on the stability of diazepam in the prior art. How to improve the stability of diazepam to meet the quality requirements of listed drugs is a technical problem that needs to be solved in the process of new drug development. SUMMARY

[0005] The present application provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the pH of the pharmaceutical composition is not more than 12.

[0006] In some embodiments, the pH of the pharmaceutical composition is 1-11.

[0007] In some embodiments, the pH of the pharmaceutical composition is 2-10.

[0008] In some embodiments, the pH of the pharmaceutical composition is 5-9. Specifically, the pH of the pharmaceutical composition can be 5, 6, 7, 8, or 9.

[0009] In some embodiments, the pharmaceutical composition further comprises a solvent. The solvent can be selected from one or more of water and non-aqueous solvents.

[0010] In some embodiments, the pharmaceutical composition further comprises an osmotic pressure regulator.

[0011] In some embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride and glucose.

[0012] In some embodiments, the osmotic pressure regulator is selected from sodium chloride.

[0013] The osmotic pressure of the pharmaceutical composition can be the same as that of the human body, or can be different. Preferably, the concentration of the osmotic pressure regulator sodium chloride in the pharmaceutical composition is 0.9 mg / mL.

[0014] In some embodiments, when the osmotic pressure regulator is selected from sodium chloride, the pH of the pharmaceutical composition is 1-11, preferably the pH of the pharmaceutical composition is 1.5-10, more preferably the pH of the pharmaceutical composition is 2-10.

[0015] In some embodiments, the osmotic pressure regulator is selected from glucose.

[0016] The osmotic pressure of the pharmaceutical composition can be the same as that of the human body, or can be different. Preferably, the concentration of the osmotic pressure regulator glucose in the pharmaceutical composition is 5 mg / mL.

[0017] In some embodiments, when the osmotic pressure regulator is selected from glucose, the pH of the pharmaceutical composition is 1.5-11, preferably the pH of the pharmaceutical composition is 2-10.

[0018] In some embodiments, the non-aqueous solvent is selected from one or more of an alcohol and glycerol. The alcohol can be selected from one or more of ethanol, isopropyl alcohol, and propylene glycol.

[0019] In some embodiments, the total impurity content in the pharmaceutical composition is less than or equal to 5%, preferably the total impurity content in the pharmaceutical composition is less than or equal to 3%, more preferably the total impurity content in the pharmaceutical composition is less than or equal to 2.5%.

[0020] In some embodiments, the content of the compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof in the pharmaceutical composition is 0.25 mg-25 mg.

[0021] The pharmaceutical composition provided by the present application can be a preparation product, or can be a composition involved in the preparation process, or can be a composition involved in the manufacturing process of the raw material of daridexine.

[0022] The pharmaceutical composition provided by the present application has a solid form or a liquid form. When the pharmaceutical composition is a preparation product and has a solid form, the pharmaceutical composition can be a capsule, a tablet, a solid granule, a lyophilized powder, etc. When the pharmaceutical composition is a preparation product and has a liquid form, the pharmaceutical composition can be an injection, an oral liquid, etc.

[0023] The present application also provides a preparation method of a pharmaceutical composition for preparing the pharmaceutical composition provided by the present application, the preparation method comprising:

[0024] controlling the pH of the pharmaceutical composition to be no more than 12.

[0025] In some embodiments, the controlling the pH of the pharmaceutical composition to be no more than 12 comprises: controlling the pH of the pharmaceutical composition to be 1-11, preferably controlling the pH of the pharmaceutical composition to be 2-10. The pH of the pharmaceutical composition can be controlled to be adjusted to be 5-9, and the pH can be specifically 5, 6, 7, 8, or 9.

[0026] In some embodiments, the controlling the pH of the pharmaceutical composition to be no more than 12 comprises: using a pH adjusting agent to control the pH of the pharmaceutical composition to be no more than 12.

[0027] The using a pH adjusting agent to control the pH of the pharmaceutical composition to be no more than 12 can comprise: using a pH adjusting agent to adjust the pH of a system, so that the pH of a pharmaceutical composition comprising the system and the pH adjusting agent is no more than 12, the system comprising the compound represented by formula (I) or a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof.

[0028] In some embodiments, after the controlling the pH of the pharmaceutical composition to be no more than 12, the preparation method further comprises:

[0029] sterilizing the pH-adjusted pharmaceutical composition.

[0030] There are various sterilization methods, such as overkill method, residual probability method, sterile filtration method, aseptic dispensing method, etc.

[0031] In some embodiments, the present application provides a preparation method of a pharmaceutical composition, comprising:

[0032] dissolving the compound represented by formula (I) or a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof in a solvent to obtain a didaxini solution;

[0033] using a pH adjusting agent to adjust the pH of the didaxini solution, so that the pH of the adjusted didaxini solution is no more than 12.

[0034] The pH-adjusted didanosine solution is sterilized.

[0035] Optionally, before the dissolving the compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof in a solvent, the method can further comprise: dissolving an osmotic pressure regulator in the solvent. At this time, the dissolving the compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof in a solvent comprises: dissolving the compound represented by formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof in a solvent containing an osmotic pressure regulator to obtain a didanosine solution.

[0036] In some embodiments, the using a pH regulator to adjust the pH of the didanosine solution so that the pH of the adjusted didanosine solution is not more than 12 comprises: using a pH regulator to adjust the pH of the didanosine solution so that the pH of the adjusted didanosine solution is 1-11, preferably so that the pH of the adjusted didanosine solution is 2-10. The pH of the didanosine solution can be adjusted to be 5-9, and the pH can be specifically 5, 6, 7, 8, or 9.

[0037] The present application also provides a quality control method of a pharmaceutical composition, for quality control of the pharmaceutical composition provided in the above of the present application, the quality control method comprising: controlling the pH of the pharmaceutical composition to be not more than 12.

[0038] In some embodiments, the controlling the pH of the pharmaceutical composition to be not more than 12 comprises: controlling the pH of the pharmaceutical composition to be 1-11, preferably controlling the pH of the pharmaceutical composition to be 2-10. The pH of the pharmaceutical composition can be controlled to be 5-9, and the pH can be specifically 5, 6, 7, 8, or 9.

[0039] In some embodiments, the controlling the pH of the pharmaceutical composition to be not more than 12 comprises: using a pH regulator to control the pH of the pharmaceutical composition to be not more than 12.

[0040] The present application also provides an impurity control method of a pharmaceutical composition, for impurity control of the pharmaceutical composition provided in the above of the present application, the impurity control method comprising: controlling the pH of the pharmaceutical composition to be not more than 12.

[0041] In some embodiments, the controlling the pH of the pharmaceutical composition to be no more than 12 comprises: controlling the pH of the pharmaceutical composition to be 1-11, preferably controlling the pH of the pharmaceutical composition to be 2-10. The pH of the pharmaceutical composition can be controlled to be 5-9, and the pH can be 5, 6, 7, 8, or 9.

[0042] In some embodiments, the controlling the pH of the pharmaceutical composition to be no more than 12 comprises: using a pH regulator to control the pH of the pharmaceutical composition to be no more than 12.

[0043] The pH regulator mentioned above in the present application can be selected from an acid or a base, wherein the acid can be selected from one or more of phosphoric acid, hydrochloric acid, citric acid (citric acid), and glacial acetic acid; the base can be selected from one or more of sodium hydroxide, potassium hydroxide, and sodium phosphate. The pH regulator can be an acid itself, or an acid solution, which can be an aqueous solution of the acid, such as an aqueous solution of phosphoric acid, an aqueous solution of hydrochloric acid, an aqueous solution of citric acid, an aqueous solution of glacial acetic acid, etc.; the pH regulator can be a base itself, or a base solution, which can be an aqueous solution of the base, such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of sodium phosphate, etc. Specific embodiments

[0044] The present application will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present application.

[0045] Example 1

[0046] Under the stirring of a magnetic stirrer (stirring speed 50-800 rpm), the raw material of digoxin represented by formula (1) was respectively dissolved in water, an aqueous solution containing sodium chloride, and an aqueous solution containing glucose to prepare solutions with concentrations of 0.25 mg / mL, 1 mg / mL, 2 mg / mL, 1 mg / mL (containing sodium chloride), 1 mg / mL (containing glucose), 10 mg / mL, 15 mg / mL, and 20 mg / mL. The material usage relationship of the prepared digoxin solution is shown in Table 1.

[0047] Table 1. Material usage relationship of digoxin solution

[0048] The prepared digoxin solution was adjusted in pH value using a pH regulator, the pH of the digoxin solution was adjusted to be in the range of 1-13, and then sterilized at 121℃ for 15 min, and the related substances of digoxin were detected.

[0049] Example 2

[0050] The pH of solution 2 was adjusted to 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 using aqueous glacial acetic acid, aqueous citric acid, aqueous hydrochloric acid, and adjusted to 7.0, 8.0, 9.0, 10.0, 11.0 using aqueous potassium hydroxide, aqueous sodium phosphate according to the method in Example 1. The pH-adjusted solutions were sterilized at 121 °C for 15 min, and the related substances of digoxin were detected. The detection results of the related substances of digoxin in this example are shown in Table 2.

[0051] Table 2. Detection results of the related substances of digoxin

[0052] Example 3

[0053] The pH of solution 1 was adjusted to 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 using aqueous phosphoric acid, and adjusted to 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0 using aqueous sodium hydroxide according to the method in Example 1. The pH-adjusted solutions were sterilized at 121 °C for 15 min, and the related substances of digoxin were detected. The detection results of the related substances of digoxin in this example are shown in Table 3.

[0054] Table 3. Detection results of the related substances of digoxin

[0055] Example 4

[0056] The pH of solution 3 was adjusted to 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 using aqueous phosphoric acid, and adjusted to 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0 using aqueous sodium hydroxide according to the method in Example 1. The pH-adjusted solutions were sterilized at 121 °C for 15 min, and the related substances of digoxin were detected. The detection results of the related substances of digoxin in this example are shown in Table 4.

[0057] Table 4. Detection results of the related substances of digoxin

[0058] Example 5

[0059] The pH of solution 4 was adjusted to 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 using aqueous phosphoric acid solution, and to 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0 using aqueous sodium hydroxide solution according to the method of Example 1. The solution after pH adjustment was sterilized at 121°C for 15 min, and the related substances of didanosine were detected. The results of detection of the related substances of didanosine in this example are shown in Table 5.

[0060] Table 5. Results of detection of the related substances of didanosine

[0061] Example 6

[0062] The pH of solution 5 was adjusted to 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 using aqueous phosphoric acid solution, and to 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0 using aqueous sodium hydroxide solution according to the method of Example 1. The solution after pH adjustment was sterilized at 121°C for 15 min, and the related substances of didanosine were detected. The results of detection of the related substances of didanosine in this example are shown in Table 6.

[0063] Table 6. Results of detection of the related substances of didanosine

[0064] Example 7

[0065] The pH of solution 6 was adjusted to 1.0, 1.5, 2.0, 3.0, 4.0 using aqueous phosphoric acid solution, the pH of solution 7 was adjusted to 1.0, 1.5, 2.0, 3.0 using aqueous phosphoric acid solution, and the pH of solution 8 was adjusted to 1.0, 1.5, 2.0, 3.0, 4.0 using aqueous phosphoric acid solution according to the method of Example 1. The solution after pH adjustment was sterilized at 121°C for 15 min, and the related substances of didanosine were detected. The results of detection of the related substances of didanosine in this example are shown in Table 7.

[0066] Table 7. Results of detection of the related substances of didanosine

[0067] In the present application, the structural formula of impurity 1 is as follows:

[0068] The structural formula of impurity 2 is as follows:

[0069] The structural formula of impurity 3 is as follows:

[0070] The structural formula of impurity 4 is as follows:

[0071] The research results of the present application show that: 1. In order to improve the stability of gedatinsini, the pH value of the system in which gedatinsini is located needs to be controlled to be not more than 12;

[0072] 2. The content of gedatinsini in the system has little effect on the stability of gedatinsini, and the stability of gedatinsini is mainly affected by the pH value of the system;

[0073] 3. The pharmaceutical composition in example 4 and example 5 of the present application contains an osmotic pressure regulator, but the stability of gedatinsini is mainly affected by the pH value of the system.

Claims

1. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the pH of the pharmaceutical composition is no more than 12; 2. The pharmaceutical composition of claim 1, wherein, The pH of the pharmaceutical composition is 1-11, preferably the pH of the pharmaceutical composition is 2-10.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition further comprises a solvent selected from one or more of water and non-aqueous solvent.

4. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition further comprises an osmotic pressure adjusting agent.

5. The pharmaceutical composition of claim 4, wherein, The osmotic pressure adjusting agent is selected from one or more of sodium chloride and glucose.

6. The pharmaceutical composition of claim 5, wherein, The osmotic pressure adjusting agent is selected from sodium chloride, and the pH of the pharmaceutical composition is 1-11, preferably the pH of the pharmaceutical composition is 1.5-10.

7. The pharmaceutical composition of claim 5, wherein, The osmotic pressure adjusting agent is selected from glucose, and the pH of the pharmaceutical composition is 1.5-11, preferably the pH of the pharmaceutical composition is 2-10.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The total impurity content of the pharmaceutical composition is less than or equal to 5%, preferably the total impurity content of the pharmaceutical composition is less than or equal to 3%, more preferably the total impurity content of the pharmaceutical composition is less than or equal to 2.5%.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The pharmaceutical composition is an injection.

10. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 9, characterized in that, The preparation method comprises: controlling the pH of the pharmaceutical composition to be no more than 12.

11. A method for quality control of a pharmaceutical composition according to any one of claims 1 to 9, characterized in that, The quality control method comprises: controlling the pH of the pharmaceutical composition to be no more than 12.

12. A method for controlling impurities of a pharmaceutical composition according to any one of claims 1 to 9, characterized by, The impurity control method comprises: controlling the pH of the pharmaceutical composition to be no more than 12.

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