Cibopadol fat emulsion and preparation method thereof

Abstract

The invention provides a cibopadol fat emulsion and a preparation method thereof. The cibopadol fat emulsion disclosed by the invention is prepared from 0.1 to 100 mg of cibopadol, 10 to 60 mg of a stabilizer, 20 to 300 g of oil for injection, 1 to 50 g of egg yolk lecithin, 5 to 50 g of an isoosmotic adjusting agent and the balance of water for injection. The cibopadol fat emulsion disclosed by the invention is better in solubility, better in oil phase compatibility and more stable in impurities.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a sibopadol fat emulsion and a preparation method thereof. Background Art

[0002] Sibopadol (trans-6-fluoro-4,9-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1(3H)-pyrano[3,4-b]indol]-4-amine) is an analgesic nociceptin / orphanin FQ peptide (NOP) and an opioid receptor agonist. It is currently being developed internationally by Grünenthal GmbH, Germany, and its partner, the US pharmaceutical company DepoMed, for the treatment of a number of different acute and chronic pain states. Sibopadol has demonstrated highly potent analgesic and antihypertensive effects in a variety of different animal models of pain. Notably, it has also been found to be more potent in chronic neuropathic pain models than in acute nociceptive pain, compared to selective μ-opioid receptor agonists. Relative to morphine, tolerance to the analgesic effects of sibopadol has been found to be delayed (26 days vs. 11 days of full tolerance). Furthermore, unlike morphine, sibopadol has not been found to affect motor coordination or reduce breathing in animals at or above the analgesic dose range. Therefore, it may have improved and prolonged effectiveness and greater tolerability compared with currently available opioid analgesics.

[0003] Sibopadol has poor water solubility and is difficult to inject. It must be mixed with an organic solvent to make an injection. Organic solvents themselves may have certain toxicity and interfere with the effects of drugs. Using non-toxic fat emulsions as solvents in combination with certain drugs can not only reduce the incidence rate, but also achieve the purpose of sustained release. However, unlike ordinary solution-type injections, fat emulsions are different in that their stability is affected by many factors, and improper use can cause serious consequences. The prior art Sibopadol fat emulsion preparations have low solubility and unstable impurities, which reduce bioavailability and drug safety, and affect the effect of drug treatment.

[0004] Therefore, it is necessary to develop a sibopadol fat emulsion preparation with better solubility and more stable impurities. Summary of the invention

[0005] In order to solve the above technical problems, the present invention discloses a sibopadol fat emulsion with better solubility, better oil phase compatibility and more stable impurities, and a preparation method thereof.

[0006] The invention provides a sibopadol fat emulsion. Each 500 g of the sibopadol fat emulsion comprises: 0.1-100 mg of sibopadol, 10-60 mg of a stabilizer, 20-300 g of injection oil, 1-50 g of egg yolk lecithin, 5-50 g of an isotonicity regulator, and the remainder is water for injection.

[0007] In some embodiments, every 500 g of Xibopadol fat emulsion contains: 1-100 mg of Xibopadol, 10-40 mg of stabilizer, 50-200 g of injection oil, 1-30 g of egg yolk lecithin, 10-20 g of isotonicity regulator, and the balance is water for injection.

[0008] In some embodiments, every 500 g of Xibopadol fat emulsion contains: 20-50 mg of Xibopadol, 10-40 mg of stabilizer, 50-200 g of injection oil, 1-30 g of egg yolk lecithin, 10-20 g of isotonicity regulator, and the balance is water for injection.

[0009] In some embodiments, each 500 g of Xibopadol fat emulsion contains: 20-50 mg of Xibopadol, 25 mg of stabilizer, 100 g of injection oil, 1.5-9 g of egg yolk lecithin, 11.25 g of isotonicity regulator, and the balance is water for injection.

[0010] In some embodiments, each 500 g of Xibopadol fat emulsion contains: 20-50 mg of Xibopadol, 25 mg of stabilizer, 100 g of injection oil, 6 g of egg yolk lecithin, 11.25 g of isotonicity regulator, and the balance is water for injection.

[0011] In some embodiments, the stabilizer is one or more of ethylenediaminetetraacetic acid or its salts.

[0012] In some embodiments, the stabilizer is disodium edetate.

[0013] In some embodiments, the injection oil is soybean oil or olive oil.

[0014] In some embodiments, the injection oil is soybean oil and olive oil.

[0015] In some embodiments, the isotonicity adjusting agent is one or more of glucose, sodium chloride, glycerol, and xylitol.

[0016] In some embodiments, the isotonicity adjusting agent is glycerol.

[0017] In some embodiments, the Xibopadol fat emulsion further comprises 1-50 g of poloxamer.

[0018] In some embodiments, the poloxamer is 1 to 30 g.

[0019] In some embodiments, the poloxamer is 1.5-3 g.

[0020] In some embodiments, the poloxamer is poloxamer 188.

[0021] In some embodiments, the sibopadol fat emulsion further comprises 10 to 300 mg of an emulsifier.

[0022] In some embodiments, the co-emulsifier is 50 to 250 mg.

[0023] In some embodiments, the co-emulsifier is 150 mg.

[0024] In some embodiments, the co-emulsifier is one or more of palmitic acid, oleic acid, linoleic acid, stearic acid and salts thereof.

[0025] In some embodiments, the co-emulsifier is oleic acid or a salt thereof.

[0026] In some embodiments, the pH value of the fat emulsion is 4-9.

[0027] In some embodiments, the pH of the fat emulsion is 6-8.

[0028] In some embodiments, the final pH of the fat emulsion is 7.5-8, and the pH is controlled at 6-8 after sterilization.

[0029] In some embodiments, the pH adjuster of the fat emulsion is sodium hydroxide.

[0030] In some embodiments, each 500 g of Xibopadol fat emulsion contains: 20 mg of Xibopadol, 100 g of soybean oil, 6 g of egg yolk lecithin, 11.25 g of glycerol, 25 mg of disodium edetate, and the balance is water for injection.

[0031] In some embodiments, each 500 g of Xibopadol fat emulsion contains: 50 mg of Xibopadol, 100 g of olive oil, 6 g of egg yolk lecithin, 11.25 g of glycerol, 25 mg of disodium edetate, 3 g of poloxamer 188, and the balance is water for injection.

[0032] In some embodiments, each 500 g of Xibopadol fat emulsion contains: Xibopadol 20 mg, olive oil 100 g, egg yolk lecithin 6 g, glycerol 11.25 g, edetate disodium 25 mg, poloxamer 188 1.5 g, and the balance is water for injection.

[0033] In some embodiments, each 500 g of Xibopadol fat emulsion contains: 20 mg of Xibopadol, 100 g of soybean oil, 6 g of egg yolk lecithin, 11.25 g of glycerol, 150 mg of oleic acid, 25 mg of disodium edetate, and the balance is water for injection.

[0034] The present invention also provides a method for preparing Xibopadol fat emulsion, which comprises the following steps:

[0035] (1) Weigh the raw materials according to the ratio;

[0036] (2) Take the injection oil, heat it to 70-80°C, add egg yolk lecithin and mix well, add cebopadol to dissolve, and obtain the oil phase;

[0037] (3) dissolving water for injection, an isotonicity adjusting agent, a stabilizer and optionally a poloxamer and / or an optional emulsifier, and adjusting the pH;

[0038] (4) high-speed shearing and high-pressure homogenization of the oil phase and the water phase, constant volume, and pH adjustment;

[0039] (5) Filling, optionally filling with nitrogen for protection, and sterilization.

[0040] In some embodiments, the method comprises the steps of:

[0041] (1) Weigh the raw materials according to the ratio;

[0042] (2) Take the injection oil, heat it to 70-80°C, add egg yolk lecithin and mix well, add cebopadol to dissolve, and obtain the oil phase;

[0043] (3) dissolving water for injection, isotonicity regulator, stabilizer and emulsifier, and adjusting pH;

[0044] (4) high-speed shearing and high-pressure homogenization of the oil phase and the water phase, constant volume, and pH adjustment;

[0045] (5) Filling, optionally with nitrogen protection, and sterilization at 121°C for 15 minutes.

[0046] In some embodiments, the method comprises the steps of:

[0047] (1) Weigh the raw materials according to the ratio;

[0048] (2) Take the injection oil, heat it to 70-80°C, add egg yolk lecithin and mix well, add cebopadol to dissolve, and obtain the oil phase;

[0049] (3) Dissolve the water for injection, isotonicity regulator and stabilizer and adjust the pH;

[0050] (4) high-speed shearing and high-pressure homogenization of the oil phase and the water phase, constant volume, and pH adjustment;

[0051] (5) Filling, optionally with nitrogen protection, and sterilization at 121°C for 15 minutes.

[0052] In some embodiments, the method comprises the steps of:

[0053] (1) Weigh the raw materials according to the ratio;

[0054] (2) Take the injection oil, heat it to 70-80°C, add egg yolk lecithin and mix well, add cebopadol to dissolve, and obtain the oil phase;

[0055] (3) Take water for injection, add isotonicity regulator, stabilizer and poloxamer to dissolve, and adjust pH;

[0056] (4) high-speed shearing and high-pressure homogenization of the oil phase and the water phase, constant volume, and pH adjustment;

[0057] (5) Filling, optionally with nitrogen protection, and sterilization at 121°C for 15 minutes.

[0058] Obviously, according to the above contents of the present invention, according to the common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change can also be made. The above contents of the present invention are further described in detail below in conjunction with specific embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0059] Example 1 Solubility and compatibility of Xibopadol in different oils + egg yolk lecithin

[0060] Soybean oil + egg yolk lecithin (6% w / w) and olive oil + egg yolk lecithin (6% w / w) were heated to 70-80°C and sheared for 30 minutes to dissolve. Excessive amount of cebopadol was added and sheared for 60 minutes, followed by centrifugation to determine the solubility and related substances.

[0061] Table 1 Solubility of Sibopadol in different oils + egg yolk lecithin

[0062]

[0063]

[0064] a. The raw materials of Xibopado are passed through 80 sieve.

[0065] The results show that Sibopadol has a high solubility in soybean oil + egg yolk lecithin (6% w / w) and olive oil + egg yolk lecithin (6% w / w), which can meet the solubility requirements for preparing fat emulsions.

[0066] Table 2 Compatibility of Xibopadol in soybean oil + egg yolk lecithin

[0067]

[0068] Table 3 Compatibility of Sibopadol in olive oil + egg yolk lecithin

[0069]

[0070] Note: RRT refers to relative retention time.

[0071] According to the relevant substances, it can be seen that Xibopadol has good compatibility in soybean oil + egg yolk lecithin (6% w / w) and olive oil + egg yolk lecithin (6% w / w).

[0072] Example 2 Prescription composition and stability study

[0073] (1)Soybean oil+egg yolk lecithin+stabilizer

[0074] According to the composition in Table 4, prepare the prescriptions respectively.

[0075] Table 4 Prescription composition and preparation process of Scheme 1 to Scheme 3

[0076]

[0077] The results of stability tests of each scheme of Sibopadol fat emulsion after sterilization, placement at high temperature of 60°C for 5 days, 60°C for 10 days, 60°C for 30 days, 40°C for 5 days, 40°C for 10 days, 40°C for 30 days, 25°C for 1 month, 25°C for 2 months, and 25°C for 3 months are shown in Table 5.

[0078] Table 5 Stability study of schemes 1 to 3

[0079]

[0080]

[0081] The results show that the addition of the stabilizer disodium ethylenediaminetetraacetate in Schemes 1 and 3 has better impurity stability.

[0082] (2) Olive oil + egg yolk lecithin + stabilizer

[0083] According to the composition in Table 6, prepare the prescriptions respectively.

[0084] Table 6 Prescription composition and preparation process of Scheme 4 to Scheme 7

[0085]

[0086]

[0087] The results of stability study of each regimen of Xibopadol fat emulsion at 0 day, after sterilization, high temperature 60℃ for 5 days, 60℃ for 10 days, 60℃ for 30 days, 40℃ for 5 days, 40℃ for 10 days, 40℃ for 30 days, light for 5 days, light for 10 days, light for 30 days, and 25℃ for 1 month are shown in Table 7.

[0088] Table 7 Stability study of schemes 4 to 7

[0089]

[0090] The results showed that the stabilizer disodium edetate was added in schemes 4 and 7, and the impurity stability was better. The impurity stability of scheme 6 was also good, but the colostrum properties were not good.

[0091] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

Claims

1. A sibopadol fat emulsion, characterized in that: Each 500g of Xibopadol fat emulsion contains: Xibopadol 0.1-100mg, stabilizer 10-60mg, injection oil 20-300g, egg yolk lecithin 1-50g, isotonic regulator 5-50g, and the balance is water for injection.

2. The Xibopadoo fat emulsion according to claim 1, characterized in that Each 500g of Xibopadol fat emulsion contains: 1-100mg of Xibopadol, 10-40mg of stabilizer, 50-200g of injection oil, 1-30g of egg yolk lecithin, 10-20g of isotonic regulator, and the balance is water for injection.

3. The Xibopadoo fat emulsion according to claim 1 or 2, characterized in that The stabilizer is one or more of ethylenediaminetetraacetic acid or its salts; preferably, the stabilizer is disodium ethylenediaminetetraacetic acid.

4. The Xibopadoo fat emulsion according to claim 1 or 2, characterized in that The injection oil is soybean oil and / or olive oil.

5. The Xibopadoo fat emulsion according to claim 1 or 2, characterized in that: The isotonicity regulator is one or more of glucose, sodium chloride, glycerol and xylitol; preferably, the isotonicity regulator is glycerol.

6. The Xibopadoo fat emulsion according to claim 1 or 2, characterized in that: The sibopadol fat emulsion further comprises 1-50 g of poloxamer; preferably, the poloxamer is 1-30 g; preferably, the poloxamer is poloxamer 188.

7. The Xibopadoo fat emulsion according to claim 1 or 2, characterized in that: The sibopadol fat emulsion further comprises 10 to 300 mg of an emulsifier; preferably, the emulsifier is 50 to 250 mg.

8. The Xibopadoo fat emulsion according to claim 7, characterized in that: The co-emulsifier is one or more of palmitic acid, oleic acid, linoleic acid, stearic acid and salts thereof; preferably, the co-emulsifier is oleic acid or a salt thereof.

9. The Xibopadol fat emulsion according to claim 1 or 2, characterized in that: The pH value of the sibopadol fat emulsion is 4-9; preferably, the pH value is 6-8.

10. A method for preparing the sibopadol fat emulsion according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: (1) Weigh the raw materials according to the ratio; (2) Take the injection oil, heat it to 70-80°C, add egg yolk lecithin and mix well, add cebopadol to dissolve, and obtain the oil phase; (3) dissolving water for injection, an isotonicity adjusting agent, a stabilizer and optionally a poloxamer and / or an optional emulsifier, and adjusting the pH; (4) high-speed shearing and high-pressure homogenization of the oil phase and the water phase, constant volume, and pH adjustment; (5) Filling, optionally filling with nitrogen for protection, and sterilization.

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