CN115813856A - Xibopag multi-fat emulsion and preparation method thereof - Google Patents

Abstract

The invention discloses a sibopa fat emulsion and a preparation method thereof. The sibopa fat emulsion is prepared from the following raw materials in parts by mass: 0.01-1000 mg of sibopaoduo, 10-493 g of oil for injection, 1-100 g of emulsifier, 5-100 g of isoosmotic adjusting agent and the balance of water for injection. The sibopa fat emulsion has good stability, and solves the problems that the fat emulsion has poor stability and is easy to cause drug-induced diseases.

Description

Xibopag multi-fat emulsion and preparation method thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to sibopa fat emulsion and a preparation method thereof.

Background

Sibopar (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/nociceptin FQ peptide (NOP) and an opioid receptor agonist. DepoMed, a pharmaceutical company in the united states, currently developed internationally by glanta limited, germany and its partner, for the treatment of a number of different acute and chronic pain states. Sibopadox exhibits highly potent analgesic and antihypertensive effects in a variety of different animal models of pain. Notably, it has also been found to be more effective than acute nociceptive pain in a chronic neuropathic pain model than a selective mu-opioid receptor agonist. A delay in tolerance to the analgesic effect of sibopadox was found (11 days of complete tolerance on day 26) relative to morphine. Furthermore, unlike morphine, sibopadox has not been found to affect motor coordination or reduce animal respiration when analgesic dose ranges are reached or exceeded. Thus, it may have improved and prolonged effectiveness and greater tolerability than currently available opioid analgesics.

In the three-phase clinical experiment of the existing sibopadox preparation, the preparation form is tablets. The sibopadox is insoluble in water and has low bioavailability when being taken as an oral preparation. The preparation developed by the compound at present is oral liquid, capsule and tablet.

Sibopadox has poor water solubility and is difficult to inject, and can be prepared into injections by mixing with an organic solvent. The organic solvent may have certain toxicity and interfere the action of the medicine, and the non-toxic fat emulsion is used as the solvent to be combined with certain medicines, so that the morbidity can be reduced, and the purpose of sustained and controlled release can be achieved. However, unlike conventional solution-type injections, the stability of fat emulsion is affected by many factors, and improper use thereof may have serious consequences. Therefore, the stability of the fat emulsion is improved, the occurrence of drug-induced diseases is reduced, and the method is an important aspect for ensuring the reasonable application of the fat emulsion. Since the fat emulsion exists in the form of emulsion droplet particles, any change in this form has an important effect on stability (see factors affecting the stability of fat emulsion for intravenous injection, waxberry, etc., 2012).

The invention overcomes the problem of insufficient stability after the medicament is prepared into the fat emulsion, and prepares the sibopa poly-fat emulsion with good stability.

Disclosure of Invention

In order to solve the technical problems, the invention discloses the sibopar poly-fat emulsion with the content of related substances meeting the medicinal standard and good stability and the preparation method thereof.

In one technical scheme, the invention relates to a sibopa fat emulsion, wherein each 500g of the sibopa fat emulsion is prepared from the following raw materials in parts by mass: 0.01-1000 mg of sibopaoduo, 10-493 g of oil for injection, 1-100 g of emulsifier, 5-100 g of isoosmotic adjusting agent and the balance of water for injection.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 0.1-100 mg of sibopaoduo, 20-300 g of oil for injection, 1-50 g of emulsifier, 10-30 g of isoosmotic adjusting agent and the balance of water for injection.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 15-40 mg of sibopadox, 50-100 g of oil for injection, 3-9 g of emulsifier, 11.25g of isoosmotic adjusting agent and the balance of water for injection.

In another embodiment, the oil for injection is one or more of soybean oil, medium chain triglyceride, peanut oil, olive oil, fish oil, castor oil. Preferably, the oil for injection is one or more of castor oil, olive oil, castor oil/olive oil.

In another embodiment, the emulsifier is one or more of lecithin, hydrogenated phospholipid, sodium oleate, lithium macrogol dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil, and polyethylene glycol alpha-tocopheryl succinate. Preferably, the emulsifier is egg yolk lecithin, poloxamer 188.

In another technical scheme, the isotonic regulator is one or more of glucose, sodium chloride, glycerol and xylitol. Preferably, the isotonicity adjusting agent is glycerol.

In another technical scheme, the pH value of the fat milk is 4-9. Preferably, the pH is 6.8 to 7.2. More preferably, the pH is 7.0.

In another technical scheme, the pH value regulator of the fat milk is a sodium hydroxide solution.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 15mg of sibopaoduo, 50g of castor oil, 3g of egg yolk lecithin, 11.25g of glycerol and the balance of water for injection.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 37.5mg of sibopar, 100g of olive oil, 6g of egg yolk lecithin, 188 g of poloxamer, 11.25g of glycerol and the balance of water for injection.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 40mg of sibopaoduo, 100g of castor oil, 6g of egg yolk lecithin, 2g of poloxamer, 11.25g of glycerol and the balance of water for injection.

In another technical scheme, each 500g of the sibopa fat emulsion is prepared from the following raw materials in mass: 40mg of sibopaca, 100g of castor oil, 9g of egg yolk lecithin, 3g of poloxamer, 11.25g of glycerol and the balance of water for injection.

In one technical scheme, the invention provides a preparation method of sibopa multi-fat milk, which comprises the following steps:

(1) Weighing the raw materials according to the proportion;

(2) Mixing injectable oil, heating to 60-90 deg.C, adding the fat emulsion and emulsifier, and stirring to obtain oil phase; adding isotonic regulator into water for injection, and heating to 60-90 deg.C for dissolving to obtain water phase;

(3) And (3) adding the oil phase obtained in the step (2) into the water phase, stirring, adding water, finally adjusting the pH value, filling and sealing, and sterilizing to obtain the water-soluble oil.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed description of the preferred embodiments

Example 1 solubility and compatibility of sibopadox in different oils

(1) Solubility and compatibility of sibopadox in different oils

Heating soybean oil, medium chain triglyceride, peanut oil, and castor oil to 70-80 deg.C, adding excessive sibopaodo, shearing for 30min, and centrifuging to determine solubility and related substances.

Solubility:

species of	Solubility (mg/ml)
		Soybean oil	0.005
Medium chain triglycerides	0.02
		Peanut oil	0.015
Castor oil	0.12

Compatibility:

from the results, it is found that sibopadox is less soluble in soybean oil, medium chain triglyceride, peanut oil and castor oil, and the solubility in castor oil is 0.12mg/ml at the maximum. From the viewpoint of related substances, siborpodal is the most compatible with castor oil.

(2) Solubility and compatibility of sibopadox in different oils plus egg yolk lecithin

The egg yolk lecithin is found to have a solubilizing effect on sibopar through experiments, so that the solubility and compatibility of sibopar are examined after the egg yolk lecithin is added into various oils. Heating soybean oil + lecithin (6% w/w), castor oil + lecithin (6% w/w), olive oil + lecithin (6% w/w), corn oil + lecithin (6% w/w), cottonseed oil + lecithin (6% w/w), sesame oil + lecithin (6% w/w) to 70-80 deg.C, shearing for 10min to dissolve, adding an excess of sibopaca, shearing for 30min, and centrifuging to determine the solubility and related substances.

Species of	Solubility (mg/ml)
		Soybean oil + lecithin	0.22
Castor oil + lecithin	0.37
		Olive oil + lecithin	0.74
Corn oil and lecithin	0.12
		Cottonseed oil + lecithin	0.19
Sesame oil + lecithin	0.11

Compatibility:

from the results, it was found that sibopadox has high solubility in castor oil + lecithin (6% w/w), olive oil + lecithin (6% w/w), and satisfies the solubility of fat milk prepared from the preparation. As can be seen from the relevant substances, siboperodol is better compatible in castor oil + lecithin (6% w/w), olive oil + lecithin (6%.

Example 2 formulation composition and preparation Process

The recipes were each prepared according to the composition of table 2.

TABLE 2

Scheme(s)	Scheme one	Scheme two	Scheme three	Scheme four
					Sibopaduo	15mg	40mg	40mg	75mg
Castor oil	50g	100g	100g	/
					Olive oil	/	/	/	200g
Egg yolk lecithin	3g	6g	6g	12g
					Poloxamer 188	/	2g	3g	6g
Glycerol	11.25g	11.25g	11.25g	22.5g
					Sodium hydroxide	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Water (W)	To 500g	To 500g	Adding to 500g	Adding to 1000g

The preparation process comprises the following steps:

(1) Weighing castor oil/olive oil according to the prescription amount, heating to 70-80 ℃, adding egg yolk lecithin, shearing and dissolving, adding sibopadox, shearing and dissolving, and finishing oil phase preparation;

(2) Weighing glycerol and poloxamer 188 with the prescription amount, 40% of injection water with the prescription amount at 70-80 ℃, shearing and dissolving, adjusting the pH to 9.0-9.5 by using 1mol/L sodium hydroxide solution, and finishing the preparation of a water phase;

(3) Slowly adding the oil phase into the water phase, washing the oil phase container with about 20% of water for injection, adding the water for washing into the water phase, shearing for 20min, adding the water for injection to 100% of the prescription amount, and shearing for 5min to complete the preparation of primary emulsion;

(4) Homogenizing at 200bar for 1 time and 800bar for 3 times. The pH of the final emulsion was measured and adjusted to the above pH range using 1mol/L sodium hydroxide solution if it was not in the range of 6.8 to 7.2. And (5) filling and sterilizing.

Example 3 Simbopag milk stability study

The results of stability test of sibopar fat milk at 0 day after sterilization, 10 days at 60 ℃, 30 days at 60 ℃,1 month after acceleration, and 2 months after sterilization are shown in table 3. The results show that the long-term stability of protocol one to protocol four is good.

TABLE 3

It should be understood that the above-mentioned embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. The simbopag fat emulsion is characterized in that every 500g of the simbopag fat emulsion is prepared from the following raw materials in parts by mass:

0.01-1000 mg of sibopaoduo, 10-493 g of oil for injection, 1-100 g of emulsifier, 5-100 g of isoosmotic adjusting agent and the balance of water for injection.

2. The sibopar crepidat milk of claim 1, wherein each 500g of sibopar crepidat milk is prepared from the following raw materials in mass:

0.1-100 mg of sibopaoduo, 20-300 g of oil for injection, 1-50 g of emulsifier, 10-20 g of isoosmotic adjusting agent and the balance of water for injection.

3. The sibopar crepidat milk of claim 2, wherein each 500g of sibopar crepidat milk is made from:

15-40 mg of sibopadox, 50-100 g of oil for injection, 3-9 g of emulsifier, 11.25g of isoosmotic adjusting agent and the balance of water for injection.

4. The sibopaca fatty emulsion according to any one of claims 1 to 3, wherein the oil for injection is one or more of soybean oil, medium chain triglyceride, peanut oil, olive oil, fish oil, castor oil;

preferably, the oil for injection is one or more of castor oil and/or olive oil.

5. The siborpan polylol emulsion according to any one of claims 1 to 3, wherein the emulsifier is one or more of lecithin, hydrogenated phospholipids, sodium oleate, lithium macrogol dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil, polyethylene glycol alpha-tocopheryl succinate;

preferably, the emulsifier is egg yolk lecithin or poloxamer 188.

6. The sibopar fat emulsion according to any of claims 1 to 3, wherein the isotonicity adjusting agent is one or more of glucose, sodium chloride, glycerol, xylitol;

preferably, the isotonicity adjusting agent is glycerol.

7. The sibopar poly-fat milk according to any of claims 1 to 3, wherein the pH of the fat milk is 4 to 9; preferably, the pH is 6.8 to 7.2; more preferably, the pH is 7.0.

8. The sibopar fatly milk of claim 7, wherein: the pH value regulator of the fat emulsion is sodium hydroxide solution.

9. A method of preparing sibopar poly-fat milk according to any one of claims 1 to 8, characterized in that: the method comprises the following steps:

(1) Weighing the raw materials according to the proportion;

(2) Mixing injectable oil, heating to 60-90 deg.C, adding Ceripop lipid emulsion and emulsifier, and stirring to obtain oil phase; adding isotonic regulator into water for injection, and heating to 60-90 deg.C for dissolving to obtain water phase;

(3) And (3) adding the oil phase obtained in the step (2) into the water phase, stirring, adding water, finally adjusting the pH value, filling and sealing, and sterilizing to obtain the water-soluble oil.