Cyclophosphamide injection and preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a cyclopentolate injection and a preparation method thereof. The cyclopentolate injection is composed of a cyclopentolate-beta-cyclodextrin inclusion compound, Tween 80, sodium chloride and water for injection. The cyclopentolate is encapsulated by using a cyclodextrin inclusion technology, and meanwhile, the preparation method of the cyclopentolate-beta-cyclodextrin inclusion compound is optimized, so that the encapsulation rate of the cyclopentolate-beta-cyclodextrin inclusion compound is significantly improved, and the stability of the cyclopentolate injection is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a cyclophosphane injection and a preparation method thereof. BACKGROUND

[0002] The information disclosed in this Background section is for the purpose of providing an overall understanding of the application and is not intended to provide recognition of any prior art ceasing to be common general knowledge to a person in the field of technology to which the application pertains and shall not form the prior art of the application.

[0003] Cyclophosphane is a commonly used anesthetic drug, which is a white oily liquid, usually administered by intravenous injection. Cyclophosphane has the characteristics of rapid onset, short duration and rapid plasma clearance. Its main mechanism of action is to enhance the inhibitory effect of the gamma-aminobutyric acid (GABA) system to produce anesthetic and sedative effect in the central nervous system, with the characteristics of rapid induction and rapid recovery, making it one of the preferred anesthetic drugs in many surgeries, and is widely used in surgeries and other medical procedures, including but not limited to: (1) surgical anesthesia: cyclophosphane injection is widely used for induction and maintenance of anesthesia during surgery, which can quickly induce patients into unconsciousness and provide stable anesthetic effect. (2) Sedation and analgesia: cyclophosphane injection can also be used to produce sedation and analgesia, such as in some interventional procedures, endoscopy or pain management. (3) Intensive care: in intensive care centers, cyclophosphane injection can be used to sedate patients who need mechanical ventilation or other intensive treatment.

[0004] Chinese patent CN104507899A discloses cyclophosphane compounds and pharmaceutical compositions, and discloses their use in the preparation of drugs for inducing and maintaining anesthesia in animals or humans, promoting sedation and sleep in animals or humans, treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy.

[0005] Liaoning Haishike Pharmaceutical Co., Ltd. has developed a cyclophosphane injection, which is a white or white-like homogeneous emulsion liquid, the effective ingredient is cyclophosphane, the excipients are soybean oil (for injection), medium-chain triglyceride, refined egg yolk lecithin, sodium oleate, glycerol (for injection), disodium edetate, sodium hydroxide and water for injection, the indication is sedation in digestive endoscopy. Disodium edetate is used as an antioxidant to improve the antioxidant properties of oil and prevent the decomposition of cyclophosphane, but disodium edetate is a slightly toxic substance with low safety factor. SUMMARY

[0006] The person skilled in the art knows that the stability of cyclophosphane is slightly poor and is easy to be oxidized, and the prior art usually adopts oiliness components to wrap to prevent the decomposition of cyclophosphane, but the oiliness substances are also easy to be oxidized, and thus an antioxidant such as edetate disodium needs to be added. The application wraps cyclophosphane by using cyclodextrin inclusion technology, optimizes the preparation method, and provides a high-quality cyclophosphane-β-cyclodextrin inclusion compound and improves the stability of cyclophosphane injection.

[0007] Specifically, the technical scheme of the application is as follows:

[0008] The application provides a cyclophosphane injection which is composed of cyclophosphane-β-cyclodextrin inclusion compound, Tween 80, sodium chloride and water for injection; wherein the preparation method of the cyclophosphane-β-cyclodextrin inclusion compound is as follows: 1-3 moles of β-cyclodextrin is prepared into a saturated aqueous solution to obtain a β-cyclodextrin saturated aqueous solution, 1-4 moles of cyclophosphane is dissolved in a solvent and added dropwise into the β-cyclodextrin saturated aqueous solution, constant-temperature culture is carried out for 6-10 hours, a buffer solution with pH=5.2-6.0 is added, the solution is transferred to room temperature and left to stand, the product is precipitated, washed, dried, and the cyclophosphane-β-cyclodextrin inclusion compound is obtained.

[0009] It should be noted that the sodium chloride in the prescription of the cyclophosphane injection is an isotonic adjusting agent which plays a role in adjusting the osmotic pressure, and the Tween 80 is a solubilizer, and the amount of addition can be adjusted within a reasonable range according to actual needs, and the amount of addition is 0.5%-1.0%, which is a routine operation of the person skilled in the art, and the water for injection is a solvent.

[0010] In the exploration of the preparation method of the cyclophosphane-β-cyclodextrin inclusion compound, it is found that the solvent for dissolving cyclophosphane is one of the factors for stabilizing cyclophosphane, and finally the mixed solvent prepared by mixing ethanol and a poloxamer 407 aqueous solution in a volume ratio of 2-4:1 is selected to dissolve cyclophosphane, which can improve the stability of cyclophosphane to a certain extent.

[0011] Especially, the mixed solvent prepared by mixing ethanol and a poloxamer 407 aqueous solution with a mass fraction of 15% in a volume ratio of 3:1 can not only improve the stability of cyclophosphane, but also slightly improve the encapsulation rate of the cyclophosphane-β-cyclodextrin inclusion compound.

[0012] Further, the buffer solution in the method is a sodium phosphate dibasic-citric acid buffer solution with pH of 5.6. It is found that the timing of adding the buffer solution is one of the key factors affecting the stability of cyclophosphane and the encapsulation rate of the inclusion compound.

[0013] Further, the culture temperature in the method is 10-15°C, and preferably 12°C. The culture step in the scheme is also one of the key factors affecting the stability of cyclophosphane and the encapsulation rate of the inclusion compound, and the temperature environment of culture can further affect the encapsulation rate of the cyclophosphane-β-cyclodextrin inclusion compound.

[0014] The room temperature refers to 25℃±2℃.

[0015] The present invention also provides a method for preparing the aforementioned cyclopropofol injection, the method comprising:

[0016] After grinding the cyclopropanol-β-cyclodextrin inclusion complex, it was dissolved in Tween 80 and an appropriate amount of water for injection. Sodium chloride was added to adjust the osmotic pressure, and water for injection was added to the prescribed volume. The mixture was stirred, filtered through a 0.2 μm filter membrane, filled, and sterilized.

[0017] Compared with the prior art, the technical advantages of the present invention are as follows:

[0018] This invention utilizes cyclodextrin inclusion technology to encapsulate propofol, while optimizing the preparation method of the propofol-β-cyclodextrin inclusion complex. First, a mixed solvent of ethanol and an aqueous solution of 15% poloxamer 407 at a volume ratio of 2-4:1 is preferred. Second, the timing of adding the buffer solution is optimized. Finally, a low-temperature culture procedure is added and the temperature is controlled. The optimization of these three technologies significantly improves the encapsulation efficiency of the propofol-β-cyclodextrin inclusion complex and enhances the stability of the propofol injection solution. Attached Figure Description

[0019] Figure 1 DSC curve of the cyclopofol-β-cyclodextrin inclusion complex in Example 1.

[0020] Figure 2 DSC curve of the control group sample.

[0021] Figure 3 Accelerated test curves of propofol content changes in Examples 1-3, Comparative Examples 1-5, and commercially available propofol injections. Detailed Implementation

[0022] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0023] Example 1: Povidone-iodine injection (20ml: 50mg)

[0024] Formula:

[0025]

[0026] Preparation method:

[0027] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 3:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 12℃ for 6-10 h. Then add a pH=5.6 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0028] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0029] Example 2: Povidone-iodine injection (20ml: 50mg)

[0030] Formula:

[0031]

[0032] Preparation method:

[0033] (1) Prepare a saturated aqueous solution of 1 mole of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 1 mole of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 2:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 10℃ for 6-10 h. Then add a pH=5.2 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0034] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0035] Example 3: Povidone-iodine injection (20ml: 50mg)

[0036] Formula:

[0037]

[0038] Preparation method:

[0039] (1) Prepare a saturated aqueous solution of 3 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 4 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 4:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 15℃ for 6-10 h. Then add a pH=6.0 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0040] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0041] Comparative Example 1: Cycloprophenin Injection (20ml: 50mg)

[0042] Formula:

[0043]

[0044] Preparation method:

[0045] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in ethanol solvent and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 12℃ for 6-10 h. Then add a pH=5.6 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0046] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0047] Comparative Example 2: Cycloprophenin Injection (20ml: 50mg)

[0048] Formula:

[0049]

[0050]

[0051] Preparation method:

[0052] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 1:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 12℃ for 6-10 h. Then add a pH=5.6 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0053] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0054] Comparative Example 3: Cyclopofol Injection (20ml: 50mg)

[0055] Formula:

[0056]

[0057] Preparation method:

[0058] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 3:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 12℃ for 6-10 h. Transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0059] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0060] Comparative Example 4: Cyclopofol Injection (20ml: 50mg)

[0061] Formula:

[0062]

[0063] Preparation method:

[0064] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 3:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Add a pH=5.6 disodium hydrogen phosphate-citric acid buffer solution and incubate at a constant temperature of 12℃ for 6-10 h. Then transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0065] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0066] Comparative Example 5: Cyclopofol Injection (20ml: 50mg)

[0067] Formula:

[0068]

[0069] Preparation method:

[0070] (1) Prepare a saturated aqueous solution of 2 moles of β-cyclodextrin to obtain a saturated aqueous solution of β-cyclodextrin. Dissolve 3 moles of propofol in a mixed solvent of ethanol and 15% poloxamer 407 in a volume ratio of 3:1 and add it dropwise to the saturated aqueous solution of β-cyclodextrin. Incubate at a constant temperature of 25℃ for 6-10 h. Then add a pH=5.6 disodium hydrogen phosphate-citric acid buffer solution, transfer to room temperature and let stand to precipitate the product. Wash and dry to obtain the propofol-β-cyclodextrin inclusion complex.

[0071] (2) After grinding the cyclopropanol-β-cyclodextrin inclusion complex, dissolve it in Tween 80 and an appropriate amount of water for injection, add sodium chloride to adjust the osmotic pressure, add water for injection to the prescribed amount, stir well, filter through a 0.2μm filter membrane, fill and sterilize.

[0072] Commercially available podophyllin injection: National Drug Approval Number H20220017

[0073] Validation and quality evaluation of cyclopophenol-β-cyclodextrin inclusion complex

[0074] 1. Validation using Differential Scanning Calorimetry (DSC)

[0075] Differential scanning calorimetry (TAQ20) was used to verify whether cyclopropanol and β-cyclodextrin form a compound. Cyclopropanol and β-cyclodextrin were physically mixed and ground at a molar ratio of 2:3 to obtain a control group sample, and its DSC curve was tested. The cyclopropanol-β-cyclodextrin inclusion complex from Example 1 was ground, and its DSC curve was tested for comparison.

[0076] Figure 1 The image shows the DSC curve of the cyclopofol-β-cyclodextrin inclusion complex in Example 1. Figure 2 The DSC curves of the control group samples show that the physically mixed cyclopofol and β-cyclodextrin exhibit two endothermic peaks during the heating process, while the DSC curve of the cyclopofol-β-cyclodextrin inclusion complex in Example 1 shows only one endothermic peak, indicating that the cyclopofol-β-cyclodextrin inclusion complex prepared in this invention can be confirmed to have formed an inclusion complex.

[0077] 2. Encapsulation efficiency of the cyclopophenol-β-cyclodextrin inclusion complex

[0078] Table 1. Encapsulation efficiency of cyclopofol-β-cyclodextrin inclusion complexes in the examples and comparative examples.

[0079]

[0080]

[0081] Table 1 shows that the encapsulation efficiency of the cyclopofol-β-cyclodextrin inclusion complexes in Examples 1-3 of the present invention is higher than that of the cyclopofol-β-cyclodextrin inclusion complexes in the comparative examples. This indicates that the contact area between cyclopofol and the inclusion material β-cyclodextrin in Examples 1-3 is small, resulting in greater stability and longer shelf life, making them suitable for industrial production.

[0082] Stability evaluation of podophenol injection

[0083] The cyclopropofol injection solutions of Examples 1-3, Comparative Examples 1-5, and commercially available cyclopropofol injection solutions were used as test samples to conduct accelerated tests to verify their stability. The experimental conditions were: the solution was placed at a temperature of 40±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd, and 6th months of the test period to determine the cyclopropofol content and plot the cyclopropofol content change curve.

[0084] Figure 3 The figures show accelerated testing curves of propofol content changes in Examples 1-3 (propofol injection), Comparative Examples 1-5 (propofol injection), and commercially available propofol injection. The results indicate that the propofol injections in Examples 1-3 of this invention exhibit high stability; after being stored in a high-temperature and high-humidity environment for 6 months, the content of the active ingredient propofol remains essentially unchanged.

Claims

1. A cyclopropofol injection solution, characterized in that, The cyclopofol injection solution is composed of cyclopofol-β-cyclodextrin inclusion complex, Tween 80, sodium chloride, and water for injection. The preparation method of the cyclopropanol-β-cyclodextrin inclusion complex is as follows: 2 moles of β-cyclodextrin are prepared into a saturated aqueous solution to obtain a β-cyclodextrin saturated aqueous solution. 3 moles of cyclopropanol are dissolved in the solvent and added dropwise to the β-cyclodextrin saturated aqueous solution. The mixture is incubated at a constant temperature for 6-10 h. Then, a buffer solution with pH = 5.2-6.0 is added, and the mixture is transferred to room temperature and allowed to stand. The product is precipitated, washed, and dried to obtain the cyclopropanol-β-cyclodextrin inclusion complex. The solvent is a mixed solvent of ethanol and 15% poloxamer 407 aqueous solution with a volume ratio of 3:

1.

2. The cyclopropofol injection solution according to claim 1, characterized in that, The buffer solution is a disodium hydrogen phosphate-citric acid buffer solution.

3. The cyclopropofol injection solution according to claim 1, characterized in that, The pH of the buffer solution is 5.

6.

4. The cyclopropofol injection solution according to claim 1, characterized in that, The culture temperature is 10℃~15℃.

5. The cyclopropofol injection solution according to claim 1, characterized in that, The culture temperature is 12℃.

6. The cyclopropofol injection solution according to claim 1, characterized in that, The specifications of the cyclopropofol injection are 20ml:50mg.

7. A method for preparing the cyclopropofol injection solution according to claim 1, characterized in that, The method is as follows: After grinding the cyclopropanol-β-cyclodextrin inclusion complex, it was dissolved in Tween 80 and an appropriate amount of water for injection. Sodium chloride was added to adjust the osmotic pressure, and water for injection was added to the prescribed volume. The mixture was stirred, filtered through a 0.2 μm filter membrane, filled, and sterilized.

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