RU2847425C2 - Apparatus for producing "oil-in-water" type nanoemulsions for intravenous administration - Google Patents

Abstract

FIELD: pharmaceutical technology.

SUBSTANCE: the invention relates to the field of pharmaceutical technology and provides a device for producing oil-in-water nanoemulsions for intravenous administration. The apparatus comprises: (a) a water phase batch mixer equipped with a first heat exchange device, a mixing device and inlets for supplying purified water, glycerol and sodium oleate; (b) a discharge tank equipped with a second heat exchange device; (c) an oil phase tank mixer equipped with a third heat exchange device, a mixing device and inlets for supplying medium-chain triglycerides, lecithin and oil substance (MS); (d) an oil phase dispenser; (e) an oil phase input unit; (f) a high-pressure homogeniser, including a homogenising head, a fourth heat exchange device and a head drive and control device; (g) a bypass valve designed to direct the flow from the outlet of the supply tank to the first inlet of the oil phase input unit in emulsification mode or to the inlet of the nanoemulsion receiver in nanoemulsion discharge mode, connected to each other. In this case, the outlet of the oil phase input unit is located at a non-zero distance L from the inlet of the homogenising head, selected so that (I) the formation of a coarse-dispersed MC emulsion during the introduction of the oil phase is excluded and (II) visually noticeable separation of the combined phases along the entire length L is excluded, the installation is designed to allow for (N+K)-fold circulation in a closed loop "feed tank - oil phase inlet node - homogenising head", where N represents the number of emulsification cycles and K, if necessary, represents the number of nanoemulsion stabilisation cycles. The oil substance (OS) is selected from a group consisting of soybean oil and a combination of propofol with soybean oil.

EFFECT: ensuring improved stability of the polydispersity characteristics of different batches of nanoemulsions by eliminating the coarse-dispersed emulsion pre-treatment unit from the design of the installation.

6 cl, 3 dwg, 2 ex

Description

Field of technology to which the invention relates

The invention pertains to pharmaceutical technology and provides a system for producing oil-in-water nanoemulsions for intravenous administration. Using the invention, a propofol nanoemulsion for intravenous administration, as well as a lipid nanoemulsion for parenteral nutrition, can be prepared. The system design eliminates the need for a device for pre-preparing a coarse emulsion, which improves the stability of the polydispersity characteristics of different batches of finished nanoemulsions.

State of the art

Propofol [2,6-Di-(propan-2-yl)phenol] exhibits anesthetic and sedative activity without initial stimulation due to its nonspecific action on the lipid membranes of CNS neurons. Advantages of propofol include the rapid onset of anesthesia (30-60 seconds) and recovery (10 minutes), which is rarely accompanied by headache, nausea, and vomiting. The duration of anesthesia depends on the propofol dose and concomitant medications and ranges from 10 minutes to 1 hour, after which the patient awakens with clear consciousness. When anesthesia is maintained in the usual regimen for up to 5 hours, significant propofol accumulation is not observed.

Propofol is highly bound to plasma proteins (97%). It is metabolized primarily by conjugation in the liver, but also partially extrahepatically. Approximately 88% of inactive metabolites are excreted renally. The half-life of propofol (T _{1/2 )} after intravenous infusion ranges from 277 to 403 minutes.

Propofol is excreted into breast milk in only small amounts, allowing mothers to resume breastfeeding within a few hours of medical procedures performed under sedation or anesthesia with propofol. These advantages make propofol a valuable pharmaceutical substance for the preparation of induction anesthesia, maintenance of general anesthesia, and sedation of patients undergoing mechanical ventilation, surgical procedures, and diagnostic procedures.

The melting point of propofol is 18°C, the density is 0.955 g/ ^cm3 (Lide DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000, p. 3-252). Propofol is slightly soluble in water (0.158 g/ml; Human Metabolite Data Base; ID 0014956). The combination of physicochemical properties of propofol necessitates the preparation of its dosage forms (DF) in the form of oil-in-water emulsions.

As of the filing date of this application, the drug "Propofol-Lipuro" (B. Braun Melsungen, Germany) is commercially available in the form of an emulsion for intravenous administration, in which the propofol content is, in particular, 10 mg/ml. This drug has the following composition (in % w/v):

Propofol 1 Soybean oil 5 Medium chain triglycerides 5 Egg lecithin 1.2 Glycerol 2.5 Sodium oleate 0.03 Water up to 100

The description of the invention to the patent application CN 115429757 (published 06.12.2022) discloses a method for preparing an oil emulsion for injection, comprising at least the following steps:

(a) mixing an oil-soluble active substance, an oil solvent and lecithin and dissolving to obtain an oil phase;

(b) mixing glycerin, pH regulator and purified water and dissolving to obtain an aqueous phase;

(c) directly introducing the oil phase and the aqueous phase into a homogenizing device and homogenizing one to three times at a pressure of 200-500 bar to obtain an oil emulsion for injection.

Preferably, the oil-soluble active substance comprises propofol, the oil phase is 10-30%, lecithin is 1-2% and glycerol is 2-3%, the oil solvent comprises at least one substance selected from soybean oil and medium chain triglycerides.

The oil phase dissolution temperature is selected in the range of 40-80°C, and the homogenizing device is a high-pressure homogenizer. In any of the preferred embodiments, the pH of the oil emulsion for injection is 4.5-8.5, and the pH regulator is sodium oleate or sodium hydroxide.

Fig. 2 of the drawings to the said application shows a block diagram of the method, which can serve as a basis for creating an installation for its implementation.

In accordance with examples 1-7 of the known invention, emulsions with the following characteristics were prepared under the specified conditions:

The qualitative compositions of the emulsions in examples 1-7 differ from the composition of the drug "Propofol-Lipuro" in that they do not contain either medium-chain triglycerides (examples 1-3, 5 and 6) or soybean oil (examples 4 and 7).

Comparative examples 1 and 2 involve the preliminary preparation of a coarse propofol emulsion. To do this, the oil phase at 40°C is added to the aqueous phase at the same temperature, diluted with a sufficient amount of water for injection, cooled to 30°C, homogenized at 50 atm, and the pH adjusted. Obtaining the final emulsion requires two low-pressure homogenizations (80 or 50 atm) and four to five high-pressure homogenizations (700 or 500 atm). The final emulsion is characterized by an average particle size of 251 or 286 nm and a polydispersity index of 0.113 and 0.138, respectively.

The phase compositions in comparative examples 1 and 2 are identical to the phase compositions in examples 1 and 7, respectively, while the finished emulsions from the comparative examples differ in having 15-70% larger particles, and the polydispersity indices are 1.4-2.5 times higher.

The disadvantages of the known method, which involves pre-preparing a coarse propofol emulsion, include dispersion separation, a large number of homogenization cycles, and high energy consumption. Implementation of the method, in accordance with the claims of application CN 115429757, requires the use of a high-pressure homogenizer equipped with two separate phase inlets.

In 1961, A. Wretlind and O. Schubert introduced the first relatively safe fat emulsion, Intralipid, to the medical community. It contained (w/v) about 52% long-chain unsaturated fatty acids (calculated as linoleic acid), about 8% linolenic acid and about 22% oleic acid, which also made it possible to introduce nutraceutically acceptable amounts of fat-soluble vitamins, such as vitamin E (alpha-tocopherol acetate). However, already in the 1970s and 1980s, problems were identified that arose during the administration of emulsions such as Intralipid, such as facial flushing, chills, shortness of breath, hyperlipidemia, impaired pulmonary hemodynamics, overload of the pulmonary circulation in patients with respiratory failure, immunosuppression, and an increase in the concentrations of serum transaminases and bilirubin against the background of long-term infusion of FE.

Currently, preference is given to fat emulsions containing medium-chain triglycerides. The first such formulation was introduced into clinical practice in 1985 by the German company B. Braun under the trade name Lipofundin MCT/LCT, with a 50:50 ratio of medium-chain triglycerides (MCT) to long-chain triglycerides (LCT). One of the most important differences between MCTs and LCTs is their carnitine-independent transport from the cell membrane to the mitochondrial matrix, which increases the rate of MCT elimination from plasma and their absorption, energy production, and protein synthesis. An analysis of the results of using emulsions containing MCT/LCT in more than 800 patients showed their safety in patients of any age and with varying degrees of severity (Shtatnov M.K. Parenteral nutrition using fat emulsions containing fatty acids with a medium molecular length in triglycerides / Vestn. intens. terapii. No. 1 (2001). Pp. 35-42).

The current demand for oil-in-water nanoemulsions is driving interest in expanding the range of methods for their preparation and the necessary equipment with improved technological flexibility.

Disclosure of the essence of the invention

The aim of the invention is to expand the arsenal of means for preparing oil-in-water nanoemulsions.

The technical result of using the invention consists in improving the stability of the polydispersity characteristics of different batches of nanoemulsions by eliminating the unit for preliminary production of a coarse emulsion from the design of the installation.

The authors of the invention propose a device for preparing nanoemulsions for intravenous administration of the "oil in water" type, which includes:

(a) a capacitive aqueous phase mixer equipped with a first heat exchange device, a mixing device and inlets for feeding purified water, glycerin and sodium oleate;

(b) a supply tank equipped with a second heat exchange device;

(b) a capacitive oil phase mixer provided with a third heat exchange device, a mixing device and inlets for feeding medium chain triglycerides, lecithin and an oil substance (OS) selected from the group consisting of propofol and soybean oil;

(c) oil phase dispenser;

(g) oil phase input unit;

(d) a high-pressure homogenizer comprising a homogenizing head, a fourth heat exchange device, and a head drive and control device;

(e) a bypass valve configured to direct the flow from the outlet of the supply tank to the first inlet of the oil phase input unit in the emulsification mode or to the inlet of the nanoemulsion receiver in the nanoemulsion unloading mode,

at the same time

the aqueous phase mixer is connected by its outlet to the first input of the supply tank, which is connected by its outlet to the input of the bypass valve;

the bypass valve is connected with its first outlet to the first inlet of the oil phase input unit, and its second outlet is connected to the inlet of the nanoemulsion receiver;

the oil phase mixer is connected by its output to the input of the oil phase dispenser, which is connected by its output to the second input of the oil phase input unit;

the oil phase input unit is connected by its output to the input of the homogenizing head, which is connected by its output to the second input of the supply tank,

where in the proposed installation

the outlet of the oil phase input unit is located at a non-zero distance L from the inlet of the homogenizing head, selected so that (I) the formation of a coarsely dispersed emulsion MS is excluded when the oil phase is introduced and (II) a visually noticeable stratification of the combined phases along the entire length L is excluded, while the installation is designed with the possibility of carrying out (N+K)-fold circulation in the emulsification mode along the closed circuit “feed tank - oil phase input unit - homogenizing head”, where N represents the number of emulsification cycles and K, if necessary, represents the number of nanoemulsion stabilization cycles.

In the context of the disclosure of the invention, the expression "an oil substance selected from the group consisting of propofol and soybean oil" means a pharmaceutical substance of lecithin (egg yolk phospholipids) or a physiologically acceptable combination of a pharmaceutical substance of propofol and a pharmaceutical substance of lecithin.

During operation of the apparatus for the purpose of preparing propofol nanoemulsions for intravenous administration, the first heat exchange device ensures a temperature in the aqueous phase mixer in the range of 40 to 80°C, preferably equal to 70°C; the second heat exchange device ensures a temperature in the supply tank in the range of 40 to 80°C, preferably equal to 70°C in the emulsification mode and in the range of 15 to 20°C, preferably in the range of 15 to 17°C in the nanoemulsion unloading mode; the third heat exchange device ensures a temperature in the oil phase mixer in the range of 40 to 80°C, preferably equal to 70°C, and the fourth heat exchange device ensures an operating temperature of the homogenizing head in the range of 3 to 8°C, preferably equal to 6°C.

The operating pressure in the homogenizing head is in the range from 20.3 to 61.0 MPa (200-600 atm). The homogenizing head operates at a pressure of 40.5 MPa (400 atm) when introducing the oil phase, operates at a pressure of 61.0 MPa (600 atm) during N homogenization (emulsification) cycles, and operates at a pressure of 20.3 MPa (200 atm) during K cycles of stabilization of propofol nanoemulsions, where N is selected from natural numbers from 9 to 12 and K is selected from natural numbers from 2 to 4. Preferably, N = 10 and K = 2.

During operation of the apparatus for the purpose of preparing nanoemulsions of a fatty pharmaceutical composition for parenteral nutrition, the first heat exchange device ensures a temperature in the aqueous phase mixer in the range of 50 to 80°C, preferably equal to 70°C; the second heat exchange device ensures a temperature in the supply tank in the range of 60 to 80°C, preferably equal to 70°C in the emulsification mode and in the range of 15 to 20°C, preferably in the range of 15 to 17°C in the nanoemulsion unloading mode; the third heat exchange device ensures a temperature in the oil phase mixer in the range of 60 to 80°C, preferably equal to 70°C, and the fourth heat exchange device ensures an operating temperature of the homogenizing head in the range of 3 to 8°C, preferably equal to 6°C.

The operating pressure in the homogenizing head is in the range from 76.0 to 81.0 MPa (750-800 atm) during N homogenization (emulsification) cycles, where N is selected from natural numbers from 18 to 22.

Brief description of the drawings

Fig. 1 shows a block diagram of the proposed installation for producing oil-in-water propofol nanoemulsions.

Fig. 2 shows particle size distribution diagrams for propofol nanoemulsions (10 mg/ml) of the oil-in-water type, prepared using the proposed setup, and for the comparison drug Propofol-Lipuro, 10 mg/ml.

Fig. 3 shows particle size distribution diagrams for a fat nanoemulsion for parenteral nutrition prepared using the proposed apparatus and for the comparison drug “Lipofundin MST\LST® 20%”.

Implementation of the invention

The inventors propose a system for preparing oil-in-water nanoemulsions, the design of which is described below with reference to Figure 1 of the drawings. The system includes:

(a) a capacitive mixer 1 of the aqueous phase, equipped with a first heat exchange device 2, a mixing device 3 and inlets for feeding purified water 4, glycerin 5 and sodium oleate 6;

(b) a supply tank 7 equipped with a second heat exchange device 8;

(b) a capacitive oil phase mixer 9, equipped with a third heat exchange device 10, a mixing device 11 and inlets for feeding medium chain triglycerides 12, lecithin 13, soybean oil 14 and oil substance 15;

(c) oil phase dispenser 16;

(g) oil phase input unit 17;

(d) a high-pressure homogenizer, including a homogenizing head 18, a fourth heat exchange device 19 and a device 20 for driving and controlling the head 18;

(e) a bypass valve 21, configured to direct the flow from the outlet of the supply tank 7 to the first input of the oil phase input unit 17 in the emulsification mode or to the input of the nanoemulsion receiver 22 in the nanoemulsion unloading mode, wherein

mixer 1 is connected by its output to the first input of container 7, which is connected by its output to input 7 of valve 21;

valve 21 is connected with its first output to the first input of unit 17, and its second output is connected to the input of receiver 22;

mixer 9 is connected by its output to the input of dispenser 16, which is connected by its output to the second input of unit 17;

node 17 is connected by its output to the input of head 18, which is connected by its output to the second input of container 7.

The outlet of the oil phase input unit 17 is located at a non-zero distance L from the inlet of the homogenizing head 18. The criteria for selecting the value of L are the absence of: (1) a coarse emulsion in the combined phases at the inlet of the homogenizer, and (2) visually noticeable stratification of the combined phases along the entire length L.

Before starting the operation of the installation, the position of the oil phase input unit 17 relative to the input of the head 18 is preliminarily determined. During the test input of the oil phase, the value L is determined, satisfying criteria (1) and (2).

In the embodiment of the installation in accordance with the invention, a Donor-3 homogenizer is used with a working diameter of the homogenizing head equal to 12 mm and a piston stroke equal to 25 mm, which determines the supplied volume of combined phases equal to 2.0-2.5 ml per double piston stroke and a maximum operating pressure of 101.3 MPa (1000 atm).

An example of an oil phase inlet unit is a medical injection needle with a cannula that passes through the wall of a transparent, elastic silicone tube, with the bevel of the needle located at a distance approximately equal to the inner radius of the tube. When connecting the oil phase delivery unit to a tube with an inner diameter of 6 mm and a wall thickness of 2 mm, this distance is preferably 2.5-3 mm. The distance L, corresponding to the delivery of combined phases in a volume of 2.0-2.5 ml, is 40-50 mm. Thus, the working value of L can preferably range from 5 to 50 mm.

The value of L will also be affected by the volumetric flow rate (in ml/min) of the combined phases, which determines the volumetric linear flow rate and, as a consequence, the residence time of the supplied volume of combined phases in a section of the pipeline of length L. It is necessary to experimentally establish the relationship between the flow rate of the combined phases and the rate of formation of a coarse dispersion of the MS under operating conditions, under which the latter will not form at the entrance to the homogenizing head.

When the system operates in emulsification mode, circulation occurs in a closed loop (container 7 - unit 17 - head 18), which ensures the required number N of emulsification cycles and, if necessary, the number K of nanoemulsion stabilization cycles. After this, valve 21 is switched to nanoemulsion discharge mode. The need for nanoemulsion stabilization is dictated by the nature of the nanoemulsion. In the case of propofol, K stabilization cycles are required to ensure the established shelf life of the dosage form. In the case of the nanoemulsion, which is soybean oil, this requirement is not met, but this does not mean that stabilization cannot be performed at the discretion of a specialist in the field, taking into account other factors.

The heat exchange device 2 ensures a temperature in the mixer 1 in the range from 40 to 80°C, preferably equal to 70°C. The heat exchange device 10 ensures a temperature in the mixer 9 in the range from 40 to 80°C, preferably equal to 70°C. The heat exchange device 8 ensures a temperature in the tank 7 in the range from 40 to 80°C, preferably equal to 70°C, in the emulsification mode and a temperature in the range from 15 to 20°C upon its completion. The heat exchange device 19 ensures an operating temperature of the head 18 in the range from 3 to 8°C, preferably at a temperature of 6°C.

The operating pressure in the homogenizing head 18 is in the range from 20.3 to 81.0 MPa (200-800 atm). For the MS represented by propofol, the head 18 preferably operates at a pressure of 40.5 MPa (400 atm) when introducing the oil phase, at a pressure of 61.0 MPa (600 atm) during N cycles of homogenization (emulsification) of propofol and at a pressure of 20.3 MPa (200 atm) during K cycles of stabilization of the propofol nanoemulsion. Preferably, N=10 and K=2. When the MS is soybean oil, the operating pressure in the homogenizing head 18 is in the range from 76.0 to 81.0 MPa (750-800 atm) during N cycles of homogenization (emulsification), where N=22 is preferable.

The apparatus according to the invention may be part of a complete process plant for the preparation of the dosage form "Propofol emulsion 10 mg/ml for intravenous administration." In this case, the receiver 22 is connected downstream of the finished propofol nanoemulsion to a sterilizing filtration unit, which preferably comprises sequentially connected filters or blocks of parallel-connected filters with a pore size of 0.45 and 0.22 μm, which is connected downstream of the sterile propofol nanoemulsion to a dosage form packaging unit, which has devices for filling the emulsion into sterile vials, autoclaving them, capping them, applying labels, and packaging them in secondary packaging, such as, for example, a cardboard box.

The operation of the installation will be further illustrated by preferred examples of the preparation of two nanoemulsions, given solely to confirm industrial applicability and not limiting the scope of the invention claims.

Example 1. Operation of the unit during the preparation of the dosage form “Propofol emulsion (10 mg/ml) for intravenous administration”

The dosage form "Propofol emulsion (10 mg/ml) for intravenous administration" has the following composition in % (w/v):

Propofol 1.00 Soybean oil 5.00 Medium chain triglycerides 5.00 Egg yolk phospholipids (Lecithin) 1.20 Glycerol 2.25 Sodium oleate 0.03 Water for injection up to 100

Water for injection is added to tank mixer 1 through inlet 4, mixing device 3 is turned on, and glycerin and sodium oleate are successively added through inlets 5 and 6, respectively. Using heat exchanger 2, the contents of the mixer are heated to 70°C, mixed using mixing device 3 for 15 minutes, and maintained at this temperature until the aqueous phase is added to tank 7.

Medium-chain triglycerides are added to tank mixer 9 through inlet 12, and lecithin is added through inlet 13. Mixer 11 is turned on, and the contents of mixer 9 are heated to 70°C using heat exchanger 10. The mixture is mixed using mixer 11 for 15 minutes, and soybeans and propofol are added through inlets 14 and 15, respectively, and mixed using mixer 11 for another 10 minutes.

The aqueous phase is transferred to the container 7, the temperature in it is set and maintained at 70°C, after which the direction of flow from the outlet of the container 7 to the first inlet of the unit 17 is set for the valve 21, the device 20 is turned on and the circuit “container 7 - unit 17 - head 18” is filled with the aqueous phase.

After filling the circuit with the aqueous phase, the operating pressure in head 18 is set to 400 atm, and the oil phase is introduced at a flow rate of 300 ml/h, regulated by dispenser 16. This circulates the homogenized mass, enriched with the oil phase. Upon completion of the oil phase loading, the operating pressure in head 18 is increased to 600 atm, and 10 homogenization cycles are performed. The duration of one homogenization cycle is measured as follows: in operating mode, using a graduated cylinder, measure the volume of emulsion processed by the homogenizer in 10 seconds, and calculate the time it takes for the homogenizer to process 200 ml of emulsion. This time is considered the duration of one homogenization cycle.

The operating pressure is then reduced to 200 atm, and two nanoemulsion stabilization cycles are performed, each lasting the time it takes for 200 ml of emulsion to pass through the homogenizer. The prepared propofol nanoemulsion is discharged into receiver 22.

As follows from Fig. 2, the nanoemulsion prepared using the proposed setup is characterized by a unimodal particle size distribution close to the distribution obtained for the commercially available drug Propofol-Lipuro under the same measurement conditions.

Example 2. Operation of the installation for the preparation of fat nanoemulsions for parenteral nutrition

The fat nanoemulsion for parenteral nutrition has a composition (in % w/v) completely identical to the drug “Lipofundin MST\LST® 20%” (B. Braun, Germany):

Soybean oil 10.00 Medium chain triglycerides 10.00 Egg yolk phospholipids (Lecithin) 1.20 Glycerol 2.50 Vitamin E (alpha-tocopherol acetate) 0.02 Sodium oleate 0.03 Water for injection up to 100

Water for injection is added to tank mixer 1 through inlet 4, mixing device 3 is turned on, and glycerin and sodium oleate are successively added through inlets 5 and 6, respectively. Using heat exchanger 2, the contents of the mixer are heated to 70°C, mixed using mixing device 3 for 15 minutes, and maintained at this temperature until the aqueous phase is added to tank 7.

Medium-chain triglycerides are loaded into tank mixer 9 through inlet 12, and vitamin E is loaded through inlet 13. Mixer 11 is turned on, and the contents of mixer 9 are heated to 70°C using heat exchanger 10. The mixture is mixed using mixer 11 for 15 minutes, and soybean oil and lecithin are loaded through inlets 14 and 15, respectively, and mixed using mixer 11 for another 15 minutes.

The aqueous phase is transferred to the container 7, the temperature in it is set and maintained at 70°C, after which the direction of flow from the outlet of the container 7 to the first inlet of the unit 17 is set for the valve 21, the device 20 is turned on and the circuit “container 7 - unit 17 - head 18” is filled with the aqueous phase.

After filling the circuit with the aqueous phase, the operating pressure in head 18 is set to 800 atm, and the oil phase is introduced at a flow rate of 300 ml/h, regulated by dispenser 16. This circulates the homogenized mass, enriched with the oil phase. After completing the oil phase loading, 20 homogenization cycles are performed. The duration of one homogenization cycle is measured as follows: in operating mode, the volume of emulsion processed by the homogenizer in 10 seconds is measured using a graduated cylinder, and the time it takes for the homogenizer to process 200 ml of emulsion is calculated. This time is considered the duration of one homogenization cycle. The prepared propofol nanoemulsion is discharged into receiver 22.

As follows from Fig. 3, the nanoemulsion prepared using the proposed setup is characterized by a unimodal particle size distribution close to the distribution obtained for the commercially available drug “Lipofundin MST\LST® 20%” under the same measurement conditions.

Thus, the invention makes it possible to prepare analogues of known drugs that have the following particle size distribution characteristics:

The above characteristics, together with the distribution graphs presented in Fig. 2, show that, using the proposed invention, a propofol nanosuspension can be prepared having a particle size distribution close to that of the drug "Propofol-Lipuro".

The above characteristics, together with the distribution graphs presented in Fig. 3, show that, using the proposed invention, a fat nanosuspension for parenteral nutrition can be prepared that has a narrower and essentially symmetrical particle size distribution, which can be considered as an advantage of the prepared preparation in relation to the preparation “Lipofundin MST\LST® 20%” of the same composition.

Claims (25)

1. A device for preparing nanoemulsions for intravenous administration of the “oil in water” type, which includes: (a) a capacitive aqueous phase mixer equipped with a first heat exchange device, a mixing device and inlets for feeding purified water, glycerin and sodium oleate; (b) a supply tank equipped with a second heat exchange device; (b) a capacitive oil phase mixer provided with a third heat exchange device, a mixing device and inlets for feeding medium chain triglycerides, lecithin and an oil substance (OS) selected from the group consisting of soybean oil and a combination of propofol with soybean oil; (c) oil phase dispenser; (g) oil phase input unit; (d) a high-pressure homogenizer comprising a homogenizing head, a fourth heat exchange device, and a head drive and control device; (e) a bypass valve, the first output of which is connected to the first input of the oil phase input unit, and the second output of which is connected to the input of the nanoemulsion receiver and is configured to direct the flow from the output of the supply tank to the first input of the oil phase input unit in the emulsification mode, and in the nanoemulsion unloading mode - to the input of the nanoemulsion receiver, at the same time the aqueous phase mixer is connected by its outlet to the first input of the supply tank, which is connected by its outlet to the input of the bypass valve; the oil phase mixer is connected by its output to the input of the oil phase dispenser, which is connected by its output to the second input of the oil phase input unit; the oil phase input unit is connected by its output to the input of the homogenizing head, which is connected by its output to the second input of the supply tank, and the installation is characterized by the fact that the outlet of the oil phase input unit is located at a non-zero distance L from the inlet of the homogenizing head, selected so that (I) the formation of a coarsely dispersed emulsion MS is excluded when the oil phase is introduced and (II) a visually noticeable stratification of the combined phases along the entire length L is excluded, while the installation is designed with the possibility of carrying out (N+K)-fold circulation in the emulsification mode along the closed circuit "feed tank - oil phase input unit - homogenizing head", where N represents the number of emulsification cycles and K, if necessary, represents the number of nanoemulsion stabilization cycles. 2. The installation according to paragraph 1, characterized in that the MS is a combination of propofol with soybean oil, the first heat exchange device is designed with the possibility of providing a temperature in the aqueous phase mixer in the range from 40 to 80°C, preferably equal to 70°C; the second heat exchange device is designed with the possibility of providing in the supply tank a temperature in the range from 40 to 80°C, preferably equal to 70°C in the emulsification mode and in the range from 15 to 20°C, preferably in the range from 15 to 17°C in the nanoemulsion unloading mode; the third heat exchange device is configured to provide a temperature in the oil phase mixer in the range from 40 to 80°C, preferably equal to 70°C, and the fourth heat exchange device is configured to provide an operating temperature of the homogenizing head in the range from 3 to 8°C, preferably equal to 6°C. 3. The installation according to paragraph 2, characterized in that the homogenizing head is designed with the ability to provide a working pressure in the range from 20.3 to 61.0 MPa (200-600 atm). 4. The installation according to paragraph 3, characterized in that the homogenizing head is designed with the possibility of providing a working pressure of 40.5 MPa (400 atm) when introducing the oil phase, providing a working pressure of 61.0 MPa (600 atm) during N cycles of homogenization (emulsification) and providing a working pressure of 20.3 MPa (200 atm) during K cycles of stabilization of propofol nanoemulsions, where N is selected from natural numbers from 9 to 12 and K is selected from natural numbers from 2 to 4. 5. The installation according to paragraph 1, characterized in that the MS is soybean oil, the first heat exchange device is designed with the possibility of providing a temperature in the aqueous phase mixer in the range from 50 to 80°C, preferably equal to 70°C; the second heat exchange device is designed with the possibility of providing in the supply tank a temperature in the range from 60 to 80°C, preferably equal to 70°C in the emulsification mode, and in the range from 15 to 20°C, preferably in the range from 15 to 17°C in the nanoemulsion unloading mode; the third heat exchange device is configured to provide a temperature in the oil phase mixer in the range from 60 to 80°C, preferably equal to 70°C, and the fourth heat exchange device is configured to provide an operating temperature of the homogenizing head in the range from 3 to 8°C, preferably equal to 6°C. 6. The installation according to paragraph 5, characterized in that the homogenizing head is designed with the possibility of providing a working pressure in the range from 76.0 to 81.0 MPa (750-800 atm) during N homogenization (emulsification) cycles, where N is selected from natural numbers from 18 to 22.