CN110613684A

CN110613684A - Posaconazole nanoemulsion and preparation method thereof

Info

Publication number: CN110613684A
Application number: CN201910983893.9A
Authority: CN
Inventors: 李丽丽
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-10-16
Filing date: 2019-10-16
Publication date: 2019-12-27

Abstract

The invention relates to the field of medicaments, in particular to a posaconazole nanoemulsion with stable properties and a preparation method thereof. The drug is mainly prepared by dissolving the drug in an organic solvent in advance, mixing the drug with a specific oil phase, and then homogenizing the mixture with a water phase under high pressure. The nano-emulsion prepared by the invention solves the technical problems of water insolubility and poor oil solubility of posaconazole, provides a novel nano-emulsion formulation with simple process and stable property for the first time, enriches the preparation types and is suitable for industrial mass production.

Description

Posaconazole nanoemulsion and preparation method thereof

Technical Field

The invention relates to the field of medicaments, in particular to a posaconazole nanoemulsion with stable properties and a preparation method thereof.

Background

Posaconazole, CAS number: 171228-49-2, the chemical name is 4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazole-1-ylmethyl) oxa-len-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazole-3-one, which is a derivative of itraconazole, is a novel triazole antifungal drug, and the most new indications are as follows: preventing invasive aspergillus and candida infection and the like, and simultaneously having good antibacterial effect on bipolar bacteria zygomycetes, histoplasma capsulatum, saccharomycetes, coccidioidomycosis and the like and having wide antibacterial spectrum. Research shows that the effect of posaconazole is superior to that of fluconazole and itraconazole in preventing breakthrough invasive fungal infection; clinical economics analysis data of multiple countries also indicate that posaconazole has better clinical economics benefit. The original manufacturer of posaconazole is the majondo, and the currently held preparations of posaconazole such as injection, oral suspension, enteric-coated tablet, common posaconazole tablet and the like enter and mostly pass the new drug evaluation in China. Meanwhile, the domestic medicine, namely the medicament, the enterprises are not sweet and weak, and the separately held preparations of posaconazole capsules, dry suspensions, delayed release tablets, enteric-coated tablets and the like also pass new drug evaluation. Therefore, the posaconazole has a wide antibacterial spectrum and prominent antibacterial advantages, and has great economic value in the domestic market with intense competition.

However, compared with fluconazole, posaconazole is much less water-soluble and hardly soluble in water, so that the preparation on the market is usually prepared into preparations such as suspension and the like. The low water solubility limits the exertion of the drug effect. At present, in order to increase the water solubility, the Jiangjiang and the like prepare high-water-solubility posaconazole-sulfobutyl-beta-cyclodextrin inclusion compounds, however, the beta-cyclodextrin has the defect of natural instability to acid, and if the beta-cyclodextrin is prepared into an oral preparation, an enteric preparation needs to be additionally prepared, so that the preparation cost is undoubtedly increased, and the beta-cyclodextrin is not suitable for being used by diabetes patients due to the fact that the beta-cyclodextrin needs to be selected; guosliuqing and the like provide a reasonable and feasible new method for the research of insoluble drug injection by preparing posaconazole into phospholipid compound submicron emulsion injection, but the preparation process is more complex, and the change of parameters has larger influence on the physical stability of the microemulsion.

For this reason, based on and overcoming the disadvantages of the prior art formulations described above and enriching the variety of formulations, a new formulation form of posaconazole is required.

Disclosure of Invention

The invention relates to a posaconazole nanoemulsion, which belongs to a new posaconazole preparation formulation which does not appear in the prior art, and the preparation process of the posaconazole preparation formulation is simple, and the posaconazole nanoemulsion has stable property after being stored for a long time.

The invention is realized by the following preparation process:

taking a proper amount of vegetable oil, adding a surfactant, mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving the medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until the dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing the water with the formula amount and an optional cosolvent to obtain a water phase, adding the drug-containing oil into the water phase under the stirring condition, and homogenizing by a high-pressure homogenizer to obtain the posaconazole-containing nanoemulsion. The obtained preparation is used for determining the drug encapsulation efficiency by a dialysis method, and the average particle size and the particle size distribution of the preparation are determined by a TEM electron microscope.

Wherein the vegetable oil is selected from one or more of soybean oil, sesame oil, tea oil, castor oil, medium chain triglyceride and olive oil;

preferably, the vegetable oil is selected from tea oil, castor oil and olive oil.

Wherein the surfactant is selected from one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tween 80 and polyethylene glycol monolaurate;

preferably, the surfactant is selected from tween 80, glycerol monolaurate polyethylene glycol.

Wherein the high-pressure homogenizing pressure is 1000-2000bar, and the homogenizing times are 1-3 times.

The advantages of the invention are as follows:

1. provides a novel posaconazole nanoemulsion formulation with simple preparation process and composition for the first time.

2. The prepared nanoemulsion preparation has stable property, and the preparation still becomes transparent after accelerated test for 3 months without any precipitation visible to naked eyes.

Drawings

Fig. 1 is a TEM image of posaconazole nanoemulsion prepared in example 1;

fig. 2 is a distribution diagram of the particle size of the posaconazole nanoemulsion prepared in example 1.

Detailed Description

The prior literature research shows that no nanoemulsion preparation is developed, mainly because posaconazole is different in water and poor in solubility in oil, so that the technical problem to be solved firstly is to select conditions to ensure that the solubility of posaconazole in oil meets the basic requirements of the preparation.

Selection of oil phase

First, the solubility of posaconazole in common oil for injection was tested, as shown in table 1:

table 1 degree of dissolution of posaconazole in common oil for injection (room temperature)

Kind of oil phase	Degree of dissolution (. mu.g/mL)
		Soybean oil	23.6
Sesame oil	10.9
		Tea oil	362.5
Castor oil	401.3
		Medium chain triglycerides	28.4
Olive oil	206.7

From the above table, the solubility of posaconazole in different oil phases is different, wherein the solubility in tea oil and castor oil is the best, the solubility in olive oil is slightly worse, and the solubility in common soybean oil, medium chain triglyceride and sesame oil is the worst. However, for the formulation, the above-mentioned dissolving power is apparently not sufficient for the requirement of the nanoemulsion formulation, so that a surfactant is required to further increase the solubility of the drug in the oil phase.

Selection of surfactants

Selecting common polyoxyethylene castor oil (A), polyoxyethylene hydrogenated castor oil (B), tween 80(C) and polyethylene glycol monolaurate (D) as oil phase surfactants, adding the surfactants into the castor oil according to the proportion of 30 percent of the oil, mixing, adding and dissolving the posaconazole under stirring and ultrasonic conditions, and determining the dissolution degree shown in table 2:

TABLE 2 solubility of posaconazole in castor oil after addition of different surfactants

Kind of oil phase	Degree of dissolution (mg/mL)
		Castor oil + A	6.41
Castor oil + B	5.52
		Castor oil + C	18.27
Castor oil + D	12.83

It can be seen that the solubility of posaconazole in oil is improved by 10-40 times after the oily surfactant is added, but the requirement of the nanoemulsion preparation is still difficult to meet, and only the slightly soluble level is achieved. Considering that the dissolution process is essentially a process in which a substance is dispersed in another substance in a molecular or ionic state to form a uniform dispersion system, and ultrasonic dissolution essentially belongs to a process in which solute molecules are destroyed by supplied energy from large to small and dispersed by a solvent, the efficiency thereof may not be high and the energy consumption thereof may be large. Therefore, the drug forms a molecular system from bottom to top and then is mixed with the oil containing the surfactant.

Previous researches show that the solubility of posaconazole in dichloromethane is good, so that dichloromethane is adopted for dissolving and then the posaconazole is added into an oil phase, and then the mixture is stirred to volatilize the organic solvent to the greatest extent; the inventors have surprisingly found that in this way the solubility of posaconazole is further improved, meeting the requirements of the nanoemulsion formulation, and that no significant decrease in solubility is observed after 1 month storage, and the measured degree of dissolution is shown in table 3:

TABLE 3 degree of dissolution after changing the addition mode

Kind of oil phase	Degree of dissolution (mg/mL)
		Castor oil + A	23.5
Castor oil + B	19.6
		Castor oil + C	86.9
Castor oil + D	58.4

In conclusion, the solubility of posaconazole in specific oil can meet the requirement of 'dissolving' in the Chinese pharmacopoeia by adding a specific surfactant and matching with a specific dissolving mode. So the finally determined oil is castor oil, tea oil and olive oil; the oil phase surfactant is Tween 80, polyethylene glycol monolaurate; and the process of dissolving the drug in dichloromethane, then adding the oil phase and stirring to evaporate the organic solvent is adopted when preparing the oil phase.

Third, specific preparation example

Example 1

Taking 100 parts by weight of castor oil and 30 parts by weight of tween 80, and mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving 10 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until the dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 200 parts of water and 10 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by using a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency determined by dialysis method was 92.3%; a TEM electron micrograph of the nanoemulsion formulation prepared in example 1 is shown in fig. 1, where it can be seen that the resulting nanoemulsion is good in shape, with a calculated mean particle size of the nanoemulsion of 38 nm; fig. 2 shows a particle size distribution plot of the nanoemulsion formulation prepared in example 1, which was calculated to have a PDI of 0.152. The prepared nano-emulsion is transparent, and in addition, after the prepared preparation is subjected to three-month acceleration test, the emulsion is still transparent and does not separate out obviously.

Example 2

Mechanically stirring and uniformly mixing 200 parts by weight of castor oil and 80 parts by weight of tween 80 to obtain an oil phase for later use; dissolving 30 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 500 parts of water and 20 parts of cosolvent propylene glycol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by using a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 90.1%; the average particle size was 36nm, and PDI was 0.165. The emulsion is transparent after three months of accelerated test and has no obvious precipitation.

Example 3

Uniformly mixing 100 parts by weight of tea oil and 40 parts by weight of tween 80 by mechanical stirring to obtain an oil phase for later use; dissolving 10 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until the dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 300 parts of water with 15 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 92.6 percent; the average particle diameter was 37nm, and PDI was 0.158. The emulsion is transparent after three months of accelerated test and has no obvious precipitation.

Example 4

Mechanically stirring and uniformly mixing 200 parts by weight of castor oil and 100 parts by weight of polyethylene glycol monolaurate to obtain an oil phase for later use; dissolving 30 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 700 parts of water and 30 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by using a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 93.1%; the average particle diameter was 37nm, and PDI was 0.147. The emulsion is transparent after three months of accelerated test and has no obvious precipitation.

Example 5

Taking 100 parts by weight of tea oil and 40 parts by weight of polyethylene glycol monolaurate, and mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving 10 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until the dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 300 parts of water with 15 parts of cosolvent ethanol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 89.9%; the average particle diameter was 40nm, and PDI was 0.164. The emulsion is transparent after three months of accelerated test, and basically has no obvious precipitation.

Example 6

Taking 200 parts by weight of olive oil and 100 parts by weight of polyethylene glycol monolaurate, and mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving 30 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 700 parts of water and 30 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by using a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 87.4%; the average particle size was 38nm and PDI was 0.152. After three months of accelerated test, the emulsion is semitransparent as a whole, but obvious substances are separated out from the bottom.

Comparative example 1

Taking 100 parts by weight of soybean oil and 40 parts by weight of tween 80, and mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving 10 parts of medicine in a proper amount of dichloromethane, adding the medicine into the oil phase under the stirring condition, continuously stirring and carrying out ultrasonic treatment until the dichloromethane is completely removed to obtain a medicine-containing oil phase; and then mixing 300 parts of water with 15 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 71.3%; the average particle size was 35nm, and PDI was 0.152. After three months of accelerated test, the emulsion is semi-turbid, and obvious substances are separated out from the bottom.

Comparative example 2

Taking 100 parts by weight of soybean oil and 40 parts by weight of tween 80, and mechanically stirring and uniformly mixing to obtain an oil phase for later use; adding 10 parts of medicine into the oil phase under the stirring condition to obtain a medicine-containing oil phase; and then mixing 300 parts of water with 15 parts of cosolvent glycerol to obtain a water phase, adding the medicine-containing oil into the water phase under the stirring condition, and homogenizing for 2 times under the pressure of 1500bar by a high-pressure homogenizer to obtain the nanoemulsion. The drug encapsulation efficiency is 60.3%; the average particle size was 36nm, and PDI was 0.158. The prepared emulsion is semitransparent, the bottom of the emulsion is visible with precipitation, the emulsion is semi-turbid after three-month accelerated test, and substances are obviously separated out from the bottom of the emulsion.

The invention solves the problem of poor solubility of posaconazole in water and oil phases, and prepares a novel posaconazole preparation, namely a nanoemulsion preparation, which has simple raw material composition, simpler preparation process and stable properties of the obtained nanoemulsion. Can be used for preparing injection and other dosage forms. The above examples are only for explaining the present invention and do not limit the technical solution of the present invention.

Claims

1. A posaconazole nanoemulsion, which consists of posaconazole, vegetable oil, a surfactant, water and an optional cosurfactant.

2. The nanoemulsion according to claim 1, wherein the nanoemulsion consists of 1-50 parts of posaconazole, 20-500 parts of vegetable oil, 3-500 parts of surfactant, 40-1000 parts of water and 1-50 parts of cosurfactant.

3. The nanoemulsion as claimed in claim 1, wherein the nanoemulsion comprises, by weight, 10-30 parts of posaconazole, 100-200 parts of vegetable oil, 30-100 parts of surfactant, 200-700 parts of water and 10-30 parts of cosurfactant.

4. The nanoemulsion of claim 1, wherein the vegetable oil is selected from one or more of soybean oil, sesame oil, tea oil, castor oil, medium chain triglycerides, olive oil; preferably, the vegetable oil is selected from tea oil, castor oil and olive oil.

5. The nanoemulsion of claim 1, wherein the surfactant is selected from one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tween 80, polyethylene glycol monolaurate; preferably, the surfactant is selected from tween 80, glycerol monolaurate polyethylene glycol.

6. A process for preparing a nanoemulsion according to any one of claims 1 to 5, comprising the following steps:

taking the vegetable oil according to the formula amount, adding a surfactant, mechanically stirring and uniformly mixing to obtain an oil phase for later use; dissolving the drug in dichloromethane, adding into the oil phase under stirring, continuously stirring and performing ultrasonic treatment until dichloromethane is removed completely to obtain a drug-containing oil phase; and then mixing the water with the formula amount and an optional cosolvent to obtain a water phase, adding the drug-containing oil into the water phase under the stirring condition, and homogenizing by a high-pressure homogenizer to obtain the posaconazole-containing nanoemulsion.

7. The method according to claim 6, wherein the high-pressure homogenization pressure is 1000-2000bar, and the number of homogenization times is 1-3.