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Title:
PROCESSING LINE FOR PREPARATION OF QUASI-STABLE MEDICAL AGENT AND CAVITATIONAL HYDRODYNAMICAL HOMOGENIZER
Document Type and Number:
WIPO Patent Application WO/2023/214200
Kind Code:
A1
Abstract:
The group of inventions relates to technologies of preparation of homogeneous mixtures with uniform structure, steady in time, and mixing devices used in these technologies, namely, to hydrodynamical cavitational homogenizers. The essence of inventions is that the processing line contains, at least, one basic container (1) with basic medium to be mixed, and two auxiliary containers (2, 3) with different admixed media, the pumps feeding basic and admixed media in the hydrodynamical cavitational homogenizer (11), as well as the reservoir of mixed medium (9). The output of the basic container is hydraulically connected with the nozzle of admission of basic medium of the first hydrodynamical cavitational homogenizer (11), the outlets of auxiliary containers are hydraulically connected with the inlet nozzle of admixed medium of the first homogenizer, the outlet connected with admixed medium of the second hydrodynamical cavitational homogenizer (16). The homogenizer use for the implementation of the processing line.

Inventors:
KURKAYEV ABDULA (HU)
TITULA BOHDAN (HU)
BUBENKO PETER (HU)
Application Number:
PCT/IB2022/054057
Publication Date:
November 09, 2023
Filing Date:
May 03, 2022
Export Citation:
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Assignee:
KURKAYEV ABDULA (HU)
International Classes:
B01F23/40; B01F23/41; B01F23/50; B01F25/314; B01F25/433; B01F25/434; B01F25/442; B01F25/50; B01F33/81; B01F35/71
Domestic Patent References:
WO2003006323A22003-01-23
WO2005065807A22005-07-21
WO1996014141A11996-05-17
Foreign References:
US20200239809A12020-07-30
US20170136427A12017-05-18
AT11728U12011-04-15
US4793713A1988-12-27
US20060256645A12006-11-16
US20020196702A12002-12-26
AU696262B21998-09-03
CA2203369A11996-05-17
CN1170371A1998-01-14
EP0789616A11997-08-20
EP0789616A11997-08-20
EP1249270A22002-10-16
IL115784A1999-04-11
JPS429508B1
JPS467703B1
KR100389658B12003-10-11
MX9703100A1998-04-30
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Claims:

1. The processing line for preparation of quasi-stable medical agent, containing, at least, one basic container with basic medium to be mixed, and also at least two auxiliary containers with different admixed media, the pumps feeding basic and admixed media in the hydrodynamical cavitational homogenizer, as well as the reservoir of mixed medium, the distinction is that the outlet of the basic container is hydraulically connected with the nozzle of admission of basic medium of the first hydrodynamical cavitational homogenizer, the outlets of auxiliary (smaller volume) containers are hydraulically connected with the inlet nozzle of admixed medium of said first homogenizer, the outlet of which is hydraulically connected with the inlet nozzle of basic or admixed medium of the second hydrodynamical cavitational homogenizer, the outlets of the auxiliary (bigger volume) containers are hydraulically connected with the inlet nozzle of basic or admixed medium of the second homogenizer by means of first and second controlled dispensers, the main container and, at least, a part of auxiliary containers are provided with tank-type mixers located in them, at least, a part of containers are connected with one another hydraulically by means of controlled dispensers, and the inlet of the mixed medium reservoir is hydraulically connected with the outlet of the second homogenizer.

2. The hydrodynamical cavitational homogenizer of multicomponent fluid medium, containing the blocks for treating fluid medium sequentially connected with one another along the flow of mixed medium, at that the first block of preliminary mixing contains the inlet nozzle of basic medium, the inlet nozzle of admixed medium and the outlet channel of mixed medium, through which the last one overflows in the homogenization block and then overflows in the block of controlled output of homogenized product, that in the homogenization block the cavitational mixing chamber is made with the reflector of flow mix at the output of the chamber, fulfilled in the form of narrowing along the flow chamber walls, at that in the chamber the insertion with the central channel is installed, on the external surface of the insertion the spiral groove is fulfilled, the insertion contacts with the internal wall of the chamber with possibility of forming the open-end spiral channel along the spiral groove and mixing of flows of spiral and central channels in the cavitational chamber before the reflector, organizing pulsation-wave homogenizing of treated medium, and the central channel is provided with narrowing and widening sections, at that the block of the controlled output is provided with the controlling rod of the flow medium reflector, the projection of which is located in the communication channel with the outlet of the homogenizing block, and the controlling rod is connected with the means of changing location of its projection in the communication channel.

Description:
PROCESSING LINE FOR PREPARATION OF QUASI-STABLE MEDICAL AGENT AND CAVITATIONAL HYDRODYNAMICAL HOMOGENIZER

TECHNICAL FIELD

The group of inventions relates to technologies of preparation of homogeneous mixtures with uniform structure, steady in time, and also to mixing devices used in these technologies, namely, to hydrodynamical cavitational homogenizers.

BACKGROUND OF THE INVENTION

From the technical level the ROTOR-TYPE MIXER is known, according to the patent USA N° US4793713A. The patent holder is Komax Systems Inc.

The mixing device is applicable for mixing two or more liquids. The driving engine is connected with the hollow shaft, which is enclosed in the mixing device housing with possibility of rotation. The hollow shaft is fulfilled with slotted grooves for reception of liquids to be mixed from the inlet openings located inside the housing. The narrow annular area of clearance is formed between the outside surface of the hollow shaft and the inside surface of the cover housing at the area of the hollow shaft not filled by the slotted grooves. The first set of openings is fulfilled in the hollow shaft, located lower in the flow from the area of the narrow annular clearance, for feeding liquids in the inner part of the hollow shaft, and the second set of openings is fulfilled in the hollow shaft, located lower in the flow from the first set of openings for delivery of liquids from the inner part of the hollow shaft and through the housing.

Patent USA N° US20060256645A1 . The patent holder is Koflo Corp.

TREATMENT OF LIQUID CONTAINING PARTICLES

The system for treatment of liquid containing particles is provided. The system contains the control means and the valve of homogenizer, at that the said control means is capable to periodically temporarily increase the clearance, determined by the valve of homogenizer, thus allowing any accumulated partial substance to pass through the valve, after that it continues to ensure homogenizing of following fluid liquid, when the valve returns to its regular operating mode.

The international application PCT/IB2003/006323 with publication N° W02005065807A2 is known. The patent holder is FRYMAKORUMA AG [CH],

ULTRASONIC DISPERSING DEVICE

The invention relates to the ultrasonic dispersing device for dispersion of mixtures of substances in liquid or viscous state. Said device contains the housing with the inlet opening for feeding dispersed substances, outlet opening for feeding dispersed substances and the oscillating body located in the housing for executing mechanical oscillations. The purpose of the invention is obtaining of average size particles in nanometer range in economically efficient way. For that, inside the housing the rotor is provided, installed with possibility of rotation, and the end face of the oscillating body lies against the end face of the rotor, forming in such a way the working chamber. The substance to be dispersed may be conducted through the working chamber for dispersing operation.

PROCESSING LINE FOR PREPARATION OF QUASI-STABLE MEDICAL AGENT is known and the most similar by its technical essence, consisting of, at least, one basic container with basic medium to be mixed, and also at least two auxiliary containers with different admixed media, the pumps feeding basic and admixed media in the hydrodynamical cavitational homogenizer, as well as the reservoir of mixed medium (US2002196702A1 , pubL, -26.12.2002).

The patents are received in the following countries:

Austria (AU696262B2), Canada CA2203369A1 ; China CN1170371A; European patent EP0789616A1 ; EP0789616A4; EP1249270A2; Israel IL115784A; Japan JP3429508B2; JP3717703B2; Korea KR100389658B1 ; Mexico MX9703100A; USA US2002196702A1 ; Publication WO9614141A1 ;

The patent holder is SHECHTER TAL [US],

From the same source of information the hydrodynamical cavitational homogenizer of multicomponent fluid medium, used in the processing line is known, containing the blocks for treating fluid medium sequentially connected with one another along the flow of mixed medium, at that the first block of preliminary mixing contains the nozzle of admission of basic medium, input nozzle of admixed medium and the output channel of mixed medium, through which the last one overflows in the block of homogenizing and then overflows in the block of controlled output of homogenized product.

The deficiencies of the known technical solutions are low quality of mixing and weak stability of created emulsions and suspensions.

The technical task of the declared group of inventions is the elimination of above mentioned deficiencies.

SUMMARY OF THE INVENTION

The technical result is rising of degree for homogenizing of mixed media and shortening time for obtaining steady mixed state of emulsions and suspensions.

The problem is solved, and the technical result in the part of the processing line is achieved so that it contains, at least, one basic container with basic medium to be mixed, and also at least two auxiliary containers with different admixed media, the pumps feeding basic and admixed media in the hydrodynamical cavitational homogenizer, as well as the reservoir of mixed medium, at that according to the invention, the outlet of the basic container is hydraulically connected with the nozzle of admission of basic medium of the first hydrodynamical cavitational homogenizer, the outlets of auxiliary (smaller volume) containers are hydraulically connected with the inlet nozzle of admixed medium of said first homogenizer, the outlet of which is hydraulically connected with the inlet nozzle of basic or admixed medium of the second hydrodynamical cavitational homogenizer, the outlets of the auxiliary (bigger volume) containers are hydraulically connected with the inlet nozzle of basic or admixed medium of the second homogenizer by means of first and second controlled dispensers, the main container and, at least, a part of the auxiliary containers are provided with tank-type mixers located in them, at least, a part of containers are connected with one another hydraulically by means of controlled dispensers, and the inlet of the mixed medium reservoir is hydraulically connected with the outlet of the second homogenizer.

The problem is solved, and the technical result in the part of homogenizer is achieved so that it contains the blocks for treating fluid medium sequentially connected with one another along the flow of mixed medium, at that the first block of preliminary mixing contains the inlet nozzle of basic medium, the inlet nozzle of admixed medium and the outlet channel of mixed medium, through which the last one overflows in the homogenization block and then overflows in the block of controlled output of homogenized product, at that, according to the invention, in the homogenization block the cavitational mixing chamber is made with the reflector of flow mix at the output of the chamber, fulfilled in the form of narrowing along the flow chamber walls, at that in the chamber the insertion with the central channel is installed, on the external surface of the insertion the spiral groove is fulfilled, the insertion contacts with the internal wall of the chamber with possibility of forming the open-end spiral channel along the spiral groove and mixing of flows of spiral and central channels in the cavitational chamber before the reflector, and the central channel is provided with narrowing and widening sections, at that the block of the controlled output is provided with the controlling rod of the flow medium reflector, the projection of which is located in the communication channel with the outlet of the homogenizing block, and the controlling rod is connected with the means of changing location of its projection in the communication channel. The group of inventions is explained by means of the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a schematic of the described processing line in an implementation version;

Fig. 2 shows the cavitational hydrodynamical homogenizer.

The processing line for preparation of quasi-stable medical agent (see Fig. 1) contains, at least, one basic container 1 with basic mixed medium, and also the auxiliary containers 2, 3, 4 with different admixed media, the pumps 5, 6, 7 and 8, and also the reservoir 9 of the mixed medium. The output of the basic container 1 is hydraulically connected with the nozzle 10 of feeding basic medium of the first hydrodynamical cavitational homogenizer 11. The outputs of the auxiliary containers 2 and 3 (smaller volume) are hydraulically connected with the inlet nozzle 12 of admixed medium of the homogenizer 11 , the output 13 of which is hydraulically connected with the nozzle of input of basic 14 or admixed 15 medium of the second hydrodynamical cavitational homogenizer 16. The outputs of the auxiliary container 4 and the reservoir of mixed medium 9 (bigger volume) are hydraulically connected with the nozzle of input of basic 14 or admixed 15 medium of the second homogenizer 16 by means of the first 17 and second 18 controlled dispensers. The main container 1 and, at least, a part of auxiliary containers 2, 3, 4 are provided with the tank-type mixers located in them, respectively, 19, 20, 21 and 22. The containers 1 , 2 and 3 are connected with on another hydraulically by means of controlled dispenser, respectively, 23 and 24. The input of the reservoir 9 of mixed medium is hydraulically connected with the output of the second homogenizer 16. The hydrodynamical cavitational homogenizer of multicomponent fluid medium (see Fig. 2) contains sequentially connected with one another along the flow of mixed medium the blocks for treatment of fluid medium, at that the first block 25 of preliminary mixing contains the nozzle 10 of feeding basic medium, the inlet nozzle 12 of admixed medium and the output channel 26 of mixed medium, through which the last one overflows in the block 27 of cavitational homogenizing and then overflows in the block 28 of controlled output of homogenized product, exposed to pulsation-wave homogenizing. In the block 27 of homogenizing the cavitational mixing chamber 29 is made with the reflector 30 of flow mix at the output of the chamber 29, made in the form of the chamber walls narrowing along the flow. In the chamber 29 the insertion 31 with the central channel 32 is installed. On the external surface of the insertion 31 the spiral groove 33 is made. The insertion 31 contacts with the inside wall of the chamber 29 with possibility of forming the open-end spiral channel along the spiral groove 33 and mixing flows of spiral and central 32 channels in the cavitational chamber 29 before the reflector 30. The central channel 32 is provided by narrowing 34 and widening 35 sections. The block 28 of the controlled output is provided with the controlling rod 36 of the flow medium reflector, the projection 37 of which is located in the channel 38 of connection with the output of the block 27 of homogenizing. The controlling rod 36 is connected with the means of changing position of its projection in the channel 38 of connection.

The processing line ensures obtaining of highly homogenous fine- dispersed and steady emulsions, suspensions and gaseous media, including mixtures comprising a polar compound (hydrocarbon, carbohydrate and crystalline mixtures). EXAMPLES

EXAMPLE 1

The work of the processing line in production of the medical agent in form of quasi-stable hydrogel and hydrocolloidal mass is performed as follows.

In the phase 1 the following procedure is accomplished:

In the container 3 (TA-02) there are three different ingredients: liquid paraffin, Propylene Glycol and Menthol crystal. Preliminary mixing of ingredients is carried out by means of the tank-type mixer 20. This preliminarily mixed material is sufficiently uniform for more effective use in the cavitational plant 11 , for purposes of molecular homogenizing.

In the container 1 (TA-03) there are three different ingredients: NaOH, ADAM QD/T, Polysorbate 80. In this container the tank-type mixer 21 mixes these ingredients.

In the container 4 (TA-04) the mixer 22 mixes three ingredients: purified water, HPBCD (2-Hydroxypropyl)-beta-cyclodextrin) and potassium sorbate.

In the container 2 (TA-01) mixing of Natrosol 250 HHX Pharm and purified water occurs with the mixer 19. This preliminary mixture the final product viscous, that is why it is necessary to mix it carefully.

Each stage of mixing continues synchronously in total 5 minutes - the containers 1 , 2, 3, 4.

In the phase 2, since each premix is ready, it passes further in the homogenizer 11. The main material passes to the nozzle 10 of the homogenizer 11 from the container 3 (TA-02) simultaneously from the container 2 (TA-01) with mass flow rate 12.5 kg/min, and at the same time in the inlet nozzle 12 of the homogenizer 11 the dosed material passes from the container 1 (TA-03) with mass flow rate 3.64 kg/min.

From the outlet nozzle 13 of the homogenizer 11 the mixture passes into the homogenizer 16 as a dosed material in the nozzle 15 with mass flow rate 12.6 kg/min, the main material passes from the container 4 (TA-04) in the nozzle 14 of the homogenizer 16 with mass flow rate 40.24 kg/min. The obtained mixture from the homogenizer 16 passes to the container 9 (TA-05).

In the final phase 3 all the ingredients are slowly mixed by means of the scrapped wall mixer, before feeding of product for packaging.

All the process of sub molecular homogenizing, from the moment of feeding ingredients in the tanks until the ready product I hydrogel of nasal use occupies up to 30 minutes from 240 liters.

Stability in time for the product obtained in such a way is at least 5 years. Dynamic viscosity of these samples does not change considerably during storage. Colloidal stability of the product was evaluated as outstanding.

EXAMPLE 2

The work of the processing line in production of the medical agent in quasi-stable state on the base of suspension, crystals of a special class Quantum Dots (QD)

Receipt: In the phase 1 the following occurs:

In the container 3 (TA-02) water for injection (WFI) 40 I with added stuff TiO2 (powder), preliminary mixing by means of the mixer (USM 60) built into the tank, after that the homogenous suspension is fed to the cavitational plant 11 as basic stuff.

In the container 2 (TA-01) water for injection (WFI) 10 I with added reagent, pharmaceutically acceptable acid (acetic acid, citric acid, ascorbic acid, benzenesulfonic acid, benzoic acid, boric acid, diatrizoic acid, edetic acid, formic acid, gentisic acid, hydrochloric acid, hydroxyethylpiperazine ethane sulfonic acid, lactic acid, lactobionic acid, maleic acid, metaphosphoric acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid), 0.182 kg, preliminary mixing by means of the mixer (USM 60) built into the container, at temperature up to 70°C, the obtained homogenous mass is fed to the cavitational plant 11 as a dosed reagent for basic stuff.

Mixing from two containers 2 (TA-01) and 3 (TA-02) is performed realized simultaneously and proportionally to the volume of each container in one cycle, during 3-5 minutes.

In the phase 2 the following occurs:

The suspension for homogenizing is fed to the container 1 (TA- 03).

For specified structuring of crystals with developed surface and dimensionality in variations cyclicity of passage of treated suspension in the cavitational plant 11 is foreseen. From the container 1 (TA-03) suspension is fed to the cavitational plant 11 and at the output comes into the container 3 (TA-02) and so, on closed circle depending on requirements of necessary result in granulometric composition of crystals in suspension, where content of TiO2 in suspension is from 0.0001 up to 10 mass% WFI.

According to results of suspension readiness with specified parameters of crystals, in the container 1 (TA-03) the suspension is warmed up to the boiling point of water from 100 °C up to total evaporation of acid and water, then the dehydrated powder is filled with WFI up to volume 50 liters, is mixed in the mixer (USM 60) built into the container, the obtained homogenous mass is fed to the cavitational plant 11 , as dosed 12.

In the phase 3 the following occurs:

From the container 4 (TA-04), 190 I are fed into the inlet 14, as basic mass WFI and is homogenized in one cycle.

The obtained ready suspension is fed to the reservoir 9 (TA-05) 240 I with regulated option of content from 0.0001-10 mass%, the crystals of special class QD TiCh with WFI, then it is sterilized at temperature 121 °C and is fed to dispensing in sterile conditions.

The size of particles EP 2.9.31 min 90.0 vol % < 250 nm, dynamical viscosity is 0.94 - 1.14 mPas.

EXAMPLE 3

The work of the processing line in production of the medical agent in quasi-stable state.

The medical agent is prepared on the base of oil extracts in ready form as hydrogel for vaginal and rectal use, in commercial packing and dosing devices.

In the phase 1 the following occurs: In the container 4 (TA-04) there are three different ingredients: liquid substance ADAM QD/ T, liquid substance ADAM QD/ S and Pure Vanilla Extract.

In the container 2 (TA-01) there are three different ingredients: purified water (PW), Natrosol 250 HHX Pharm, Dexolve (Sulfobutylated beta-cyclodextrin).

In the container 3 (TA-02) with mixer 8 ingredients are mixed: Vaseline (pharma grade), Cacao Butter, Rose Oil Extract, Pumpkin Seed Oil Extract, Griffonia Simplicifolia Oil Extract, Celandine Oil Extract, Chamomile Extract, Liquorice Extract.

Preliminary, separate mixing of ingredients is executed in the containers 2, 4 and 3 (TA-01 , TA-04 and TA-02) by means of the mixer (USM60). These preliminary mixed materials are sufficiently uniform for more effective use in the cavitational plant 11 for purposes of sub molecular homogenizing.

Simultaneous process of mixing in each separate container 4, 2 and 3 continues up to 5 minutes.

In the phase 2 the following occurs:

When each premix is ready, the mixture passes to the cavitational homogenizer 11.

By means of the dosing pump the main material passes into the homogenizer 11 from the container 3 (TA-02) with mass flow rate 12.6 kg/min, and at the same time through the nozzle 10 the dosed material passes in the homogenizer 11 from the container 2 (TA-01) with mass flow rate 2.4 kg/min.

From the output nozzle 13 (the) oil mixture passes into the container 1 (TA-03).

This process occupies no more than 5 minutes. In the phase 3 the following occurs:

From the container 1 (TA-03) the oil mixture passes to the homogenizer 16 in the nozzle 15 as dosed ingredient with mass dosing 3 kg/min, at the same time in the nozzle 14 as a main ingredient the suspension from the container 4 (TA-04) is fed with mass expense 15 kg/min, this process of sub molecular homogenizing continues no more than 14 minutes, the total obtained volume of hydrogel is from 240000 ml.

The water-oil mixture (hydrogel, where more than 80% is WFI) from the cavitational homogenizer 16 passes into the container 9 (TA- 05), since that the ready product (hydrogel) is fed to the line of final commercial packing.

The hydrodynamical cavitational homogenizer (see Fig. 2) works as follows. The main flow of stuff from 70 up to 99.99% passes into the nozzle 10 of feeding basic medium of the block 25. In the case if that substance is passed in the closed contour with each cycle of repeated mixing, then the substance is fed 100%. Through the input nozzle 12 of admixed (dosed) medium of the block 26 the auxiliary medium passes by delivery under pressure from 10-30% higher than pressure of basic medium fed in the nozzle 10. Both media, being mixed in the output channel 26 of the block 25, pass into the cavitational chamber 34 of the block 27 for further sub molecular cavitational homogenizing.

The fluid product fed to the block 28 is twisted in the spiral channel formed by the spiral groove 33 and forms the pulsing intensive vortical layer, not breaking and not disturbing the jet coming from the opening of the central channel 32, but partially wavily unites with it in the cavitational chamber 29 of sub molecular pulsation-wave homogenizing and strikes in the form of two flows on the narrow spot of the regulated reflector 30.

On the external surface of the rod 36 output of ready product (emulsion, suspension) is provided.

Through the nozzle 13 output of ready product in the block 28 is executed.

Regulation of the reflector 30 is ensured at the expense of the pump 39 with external fastening 40 for the rod 36.

Depending on the components characteristics and quantity of product for homogenizing in one fed fluid medium the reflector 30 is regulated for approach or moving away manually or automatically.

In the chamber 29 the intensive vortical layer is formed on the jet surface, which at breaking on the reflector 30 induces the turbulent wave pulsations considering thermo physic processes from impact, where the temperature of the treated fluid medium (product) rises from 10%.

INDUSTRIAL APPLICABILITY

Thereby, the described processing line and plant are destined for obtaining of emulsion, suspension, dispersion by means of deagglomeration of powder and homogenizing in a fluid medium.

The principal characteristics of the device/instrument are: high force of displacement for solubilization and homogenizing of poorly soluble materials, viscous oil media.

Using the inventions ensures raised degree of homogenizing of different media thanks to possibility of ensuring cyclicity on the closed contour, i.e. treatment of different compositions for obtaining homogenous mixtures. The processing line and plant provide forming of persistently stable suspensions, hydrogels and viscoplastic mixtures, where content of solid particles varies from 0.0001 up to 150 mg/ml, destined for alimentary, cosmetic and pharmaceutical productions, forming of quasi-stable different forms of crystals of ceramic, nonorganic and polymeric materials, potentially applicable both independently and in combinations of different compositions of medical agents.

The crystals and particles TiO2 and SiO2 acquire biological activity due to modelling by means of the cavitational homogenizer, forming special structures with developed lattice surface. That is why the surface of crystals and particles in the breaks of the developed surface of lattices of a number of ionic groups of ligands ensures forming of excitonic structures, ionic bindings and a range of other areas of local energy overheating, i.e. quantum dots (QD), where O2 is in metastable electronically-excited triplet state 302 (T3+) and makes up to 80% of the crystal or particles structure.

A particular feature of 302 (T3+) oxygen is ensured thanks to catalytic properties of crystals and particles under influence, photonic, electromagnetic - wavelike and thermal, the controlled synthesis of the active forms of oxygen (AFO) occurs, 302 (S1-3).