EP3773499A1

EP3773499A1 - Method for producing an oil-in-water emulsion, oil-in-water emulsion, and installation for producing an oil-in-water emulsion

Info

Publication number: EP3773499A1
Application number: EP19715451.1A
Authority: EP
Inventors: Jürgen Schmitt; Volker KRÜGER; Carsten GRUMBACH; Thorsten Braun
Original assignee: B Braun Melsungen AG
Current assignee: B Braun Melsungen AG
Priority date: 2018-04-11
Filing date: 2019-04-01
Publication date: 2021-02-17
Also published as: MX2020010336A; JP2021520993A; DE102018205493A1; KR20200143693A; RU2769322C1; WO2019197198A1; JP7335895B2; US20210100906A1; CN112367972A; CA3096704A1

Abstract

The invention relates to a method for producing an oil-in-water (O/W) emulsion, involving the following steps: a) providing an oil phase and a water phase, b) pre-mixing the oil phase and the water phase to obtain an O/W pre-emulsion, and c) homogenising the O/W pre-emulsion to obtain an O/W emulsion, with the aid of at least one counter-jet dispergator. The invention also relates to an O/W emulsion and to an installation for producing an O/W emulsion.

Description

Process for producing an O / W emulsion. O / W emulsion and plant for producing a

O / W emulsion

AREA OF APPLICATION AND PRIOR ART

The invention relates to a process for producing an O / W emulsion, an O / W emulsion and a plant for producing an O / W emulsion.

An emulsion is a finely divided mixture of two normally immiscible liquids without visible segregation. One liquid (phase) forms small drops distributed in the other liquid. The phase that forms drops is called the inner or the disperse phase. The phase in which the drops float is called outer or continuous phase. Emulsions of water and oil are distinguished in water-in-oil emulsion (W / O emulsion) and oil-in-water emulsion (O / W emulsion).

Another important component of emulsions is the emulsifier, which facilitates the formation of droplets and counteracts segregation (phase separation).

Usually, the components used to prepare an emulsion are first premixed into a coarsely dispersed preemulsion, which may also be referred to as a raw or pre-emulsion or premix. Subsequently, a homogenization, wherein a drop comminution of the disperse phase takes place (fine emulsification). The droplet size spectrum of the crude or pre-emulsion shifts significantly towards smaller droplets.

O / W emulsions for parenteral use are usually prepared by first premixing an oil phase and water phase by means of a rotor-stator agitator to a pre-emulsion and then homogenizing by means of a piston-gap homogenizer. Piston-gap homogenizers are so-called high-pressure homogenizers which are based on a high-pressure pump and a homogenizing nozzle. The high pressure pump builds up energy, which can then be used by relaxing in a Homogenisierventil for drop crushing. In a piston-gap homogenizer pressures of 100 to several hundred bar can be realized. In a piston-gap homogenizer, the pre-emulsion is usually pumped through a centric inlet bore, the pre-emulsion then passing through a radial gap between a valve seat and a valve stem. In high-pressure homogenizers, shear and expansion forces, impingement flows and, to a significant extent, cavitation forces are generally effective. Cavitation is the formation and dissolution of cavities in liquids due to pressure fluctuations. The cavitation is caused for example by very fast moving objects in the liquid (for example, by propeller or stirrer) or by rapid movement of liq fluid such as through a nozzle and by the action of ultrasound.

O / W emulsions intended for parenteral administration must meet certain specifications. For example, such emulsions for compliance with minimum medical standards should not exceed a mean drop diameter of 500 nm, preferably 350 nm.

Furthermore, such O / W emulsions should have a so-called pFAT5 value of <0.05%. This value defines the percentage of drops within an oil phase of an O / W emulsion with a diameter, in particular average diameter, of 5 pm to 50 pm. This is a safety parameter for avoiding fat embolism in patients.

A disadvantage of conventional processes for the production of O / W emulsions are long process times and in particular often only limited or insufficient process control options, in particular with regard to the quality of the O / W emulsions to be produced. For example, slight deviations from process parameters can lead to incorrect batches and consequently to batch destruction to a considerable extent.

TASK AND SOLUTION

It is an object of the invention to provide a process for the production of an O / W emulsion which avoids disadvantages occurring in connection with production processes known from the prior art for O / W emulsions and in particular by shorter ones Process times and a better process control distinguishes. It is a further object of the invention to provide an associated O / W emulsion and associated equipment for making an O / W emulsion.

These objects are achieved according to the invention by a process for producing an O / W emulsion, an O / W emulsion and by a plant according to the respective main claims. Preferred embodiments can in particular the respective Subclaims are taken. The content of the claims is made by express reference to the content of the description.

According to a first aspect, the invention relates to a process for the preparation of an oil-in-water emulsion, hereinafter abbreviated as O / W emulsion, in particular for parenteral administration. The process comprises the following steps: a) providing an oil phase and a water phase, b) premixing, i. Pre-homogenizing or pre-emulsifying the oil phase and the water phase to an oil-in-water pre-emulsion, i. an oil-in-water preemulsion, hereinafter abbreviated as O / W preemulsion (O / W preemulsion); and c) homogenizing the O / W preemulsion to an O / W emulsion by means of at least one counter jet dispersant.

For the purposes of the present invention, the term "water phase" is understood to mean water or a water-containing liquid, in particular an aqueous solution, which in the finished O / W emulsion, i. in the O / W emulsion produced by the process according to the invention, which forms an outer or continuous phase.

For the purposes of the present invention, the term "oil phase" is to be understood as meaning an oil and / or lipid and / or an oil and / or lipid-containing liquid, in particular an oil and / or lipid-containing solution, which or in the form of Drops in the finished O / W emulsion, ie in the O / W emulsion produced by the process of the invention, forming the inner or disperse phase.

For the purposes of the present invention, the term "drops" is understood to mean oil drops and / or lipid drops, ie drops consisting of at least one oil and / or at least one lipid, and / or drops containing oil and / or lipids, which are the internal or disperse Phase of the O / W preemulsion and / or O / W emulsion. Usually, the O / W preemulsion is distinguished by a broader droplet diameter distribution and / or by larger diameter drops, in particular larger average diameters, than the O / W emulsion. For the purposes of the present invention, the term "counter jet disperser" is to be understood as meaning a high pressure homogenizer in which two or more jets of a preemulsion (primary or crude emulsion) meet at least two, preferably two opposite, bores or channels in a drop comminution zone. Due to the meeting of the pre-emulsion jets, droplet comminution of drops contained in the preemulsion takes place, in particular under the action of shear forces. The aforementioned drop comminution zone can therefore also be referred to as a shear zone. The extent of drop comminution is particularly dependent on the conveying speed at which the O / W preemulsion or O / W preemulsion jets are conveyed within the counter jet disperser. The conveying speed of the O / W preemulsion or O / W preemulsion jets is controllable via a pressure which is generated by a pump, in particular a high-pressure pump, of the counter-jet disperser.

The term "at least one counter jet dispersant" can, as will be explained in more detail below, a Gegenstrahldispergator or, which is preferred, a plurality of Gegenstrahldispergatoren, i. several Gegenstrahldispergatoren mean.

The at least one counter jet disperser provided for carrying out step c) preferably has at least two, in particular two, preferably two opposite, channels or more channels. The channels have, for example, an inner diameter in the micrometer range. As a result, a particularly intense shear of drops contained in the O / W preemulsion and thus the production of O / W emulsions with a narrow or narrow droplet diameter distribution can be achieved.

The channels of the at least one counter jet disperser can furthermore have in particular a Y-shaped configuration or arrangement.

The present invention is based inter alia on the following surprising findings and advantages:

Preemulsification of an oil phase and water phase and subsequent high-pressure homogenization using at least one counter jet disperser on the one hand a significant reduction in production times for O / W emulsions and on the other hand better controllability of the quality of the O / W emulsions to be produced and in particular the production of high quality O / W emulsions achievable. Thus, a shortening of the process times by up to 75% is possible by means of the method according to the invention. As a result, production costs can be saved to a considerable extent and the number of producible emulsion batches per unit of time can be significantly increased. Overall, this leads to a significant increase in productivity.

From a productivity point of view, it is further advantageous that counter jet dispersants are typically static, i. have constant, chamber dimensions. This facilitates the implementation of scale-up processes, for example, when using multiple counter jet dispersers, the number of chambers can be upscaled linearly with the volume.

From a quality point of view, it is particularly advantageous that the use of at least one counter jet disperser results in the

Specify droplet diameter distribution in the final O / W emulsion to be produced and controlled. Thus, the inventive method allows in particular the production of O / W emulsions having a droplet diameter, in particular mean droplet diameter (determined according to

Photon correlation spectroscopy, PCS), from 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 200 nm to 300 nm, particularly preferably 240 nm to 280 nm.

Furthermore, it is advantageous that with the aid of the method according to the invention, as will be explained in more detail below, the pFAT5 value of the O / W emulsions to be produced can be better controlled and in particular significantly reduced. As a result, the risk of fatty embolism in the case of parenteral administration of a O / W emulsion produced by the O / W emulsion according to the invention can be significantly reduced.

The water phase provided according to the invention can be provided by using an emulsifier, ie by adding an emulsifier to water or a water-containing liquid. In particular, the water phase may be provided by dissolving an emulsifier in water or a liquid containing water. For this purpose, the water phase to a temperature of 40 ° C to 80 ° C, in particular 50 ° C to 70 ° C, heated. An emulsifier which can be used is a compound which is selected from the group consisting of phospholipids, phospholipids of animal origin, phospholipids of plant origin, lecithins such as egg lecithin, krill phospholipids and mixtures of at least two of the emulsifiers mentioned. Further, the water phase can be provided using an additive, ie, by adding an additive to water or a water-containing liquid. In particular, the water phase can be provided by dissolving an additive in water or a liquid containing water. As additive, a compound can be used, which is selected from the group consisting of emulsifying aid, stabilizer, Isotonisierungszusatz and mixture of at least two of said additives. As the emulsifying aid, for example, an alkali salt of a long-chain fatty acid, for example, a fatty acid having 16 to 18 carbon atoms can be used. As a stabilizer or isotonization additive, for example, a polyhydric alcohol, in particular selected from the group consisting of glycerol, glucose, xylitol and mixtures of at least two of said stabilizers or isotonization additives, are used.

The oily phase may be provided using an oil and / or lipid which is preferably selected from the group consisting of oils of vegetable origin, medium chain triglycerides (MCT), oils of animal origin, oils of marine origin and mixtures of at least two of said oils or lipids. As oils of vegetable origin, for example, safflower oil and / or soybean oil can be used. These oils are characterized by a high proportion of polyunsaturated fatty acids from the w-6 series (predominantly linoleic acid, 18: 2 co-6), while their content of w-3 fatty acids (practically exclusively as a-linolenic acid, 18: 3 co-3) is low. Mid-chain triglycerides (MCT) have a carbon chain length of 6 to 14 carbon atoms, more preferably 8 to 10 carbon atoms. As oils of marine origin, for example, fish oils and / or krill oils can be used. The fish oils derived from cold-water fish are, like Krill oils obtained from krill, characterized by a high proportion of polyunsaturated fatty acids (mainly eicosapentaenoic acid, EPA, 20: 5 co-3 and docosahexaenoic acid, DHA, 20: 6 <o-3) while their content of w-6 fatty acids is low. Suitable fish oils are, for example, those which are obtained industrially to a significant extent from cold-water fish. Fish oils generally contain triglycerides of fatty acids having 12 to 22 carbon atoms. As fish oils, for example, oils may be used which are selected from the group consisting of sardine oil, salmon oil, herring oil, mackerel oil and mixtures of at least two of the said fish oils. Alternatively or additionally, corresponding fish oil concentrates and / or krill oils can be used.

Furthermore, the oil phase can be prepared using an emulsifier, ie by adding an emulsifier to an oil or oil mixture, an oily liquid, a lipid or Lipid mixture or a lipid-containing liquid, in particular by dissolving an emulsifier in an oil or oil mixture, an oily liquid, a lipid or lipid mixture or a lipid-containing liquid, are provided. The emulsifier used in this case may be a compound which is preferably selected from the group consisting of phospholipids and mixtures of at least two phospholipids.

Furthermore, the oil phase may be prepared using an additive, i. H. by adding an additive to an oil or oil mixture, an oily liquid, a lipid or lipid mixture or a lipid-containing liquid, in particular by dissolving an additive in an oil or oil mixture, an oily liquid, a lipid or lipid mixture or a lipid-containing liquid. As an additive, for example, an antioxidant, such as a tocopherol and / or physiologically acceptable tocopherol esters, such as a-tocopherol acetate, can be used.

Furthermore, an emulsifier-containing water phase and an emulsifier-free oil phase can be provided. This variant, referred to as the English method, for producing an O / W emulsion has the advantage over the continental method described below that often lower amounts of emulsifier are required.

Alternatively, an emulsifier-free water phase and an emulsifier-containing oil phase can be provided. This variant, referred to as a continental method, for producing an O / W emulsion has the advantage that it leads to a shortening of the process time owing to the better dispersibility of the phospholipids.

The inventive method can be operated with particular advantage, in particular without modification of the process sequence and / or without modification of a process plant, both based on the English method and based on the continental method.

In principle, the oil phase and the water phase can already be brought together before carrying out step b). In particular, the oil phase can be added to the water phase before carrying out step b).

Alternatively, the oil phase and the water phase can be brought together only when performing step b). In an embodiment of the invention, step b) is carried out by means of at least one rotor-stator-disperser, in particular rotor-stator-stirrer.

For the purposes of the present invention, the term "rotor-stator-disperser" is understood to mean a dispersant, in particular a stirrer or prehomogenizer, which operates on the rotor-stator principle, ie. a rotor and a stator (so-called rotor-stator system) has.

About the configuration of the rotor and / or the stator of the at least one rotor-stator disperser, such as over the width and / or the number and / or the mutual distance of shear slots, and / or over the speed of the rotor and / or over the flow rate at which the oil phase and the water phase are passed through the at least one rotor-stator disperser, can be with particular advantage of the specific energy input for a drop crushing, in particular drop shear, influence.

In a further embodiment of the invention, the oil phase and the water phase are spatially separated from each other supplied to the at least one rotor-stator-disperser.

In a further embodiment of the invention, the oil phase and the water phase by means of a coaxial tube, d. H. a tube-in-tube arrangement, or by means of a coaxial tube, d. H. a hose-in-hose assembly to which at least one rotor-stator disperser supplied. In this way it can be ensured with particular advantage that each drop within the at least one rotor-stator-disperser is exposed to a sufficient emulsifier concentration. If the process according to the invention is operated, for example, using the English method, it is preferred if the oil phase passes through the middle tube or the water phase through the (coaxial) outer tube surrounding the middle tube or through the middle tube surrounding it (coaxial) outer tube is performed. When using the continental method, however, it is preferred if the water phase through the middle tube or the middle tube and the oil phase through the middle tube surrounding the (coaxial) outer tube or through the middle tube surrounding (coaxial) outer tube becomes. In mixed forms of the method can be moved after the configuration of the English method.

The term "at least one rotor-stator-disperser" can, for the purposes of the present invention, a rotor-stator-disperser or a plurality of rotor-stator-dispersants, ie several rotor-stator dispersants, such as two, three, four or five rotor-stator dispersants mean.

Accordingly, step b) can basically be carried out by means of only one rotor-stator disperser.

Alternatively, the step b) can be carried out by means of a plurality of rotor-stator dispersants, in particular by means of a plurality of parallel-connected rotor-stator dispersants and / or by means of a plurality of series-connected rotor-stator dispersants. In particular, step b) can only be carried out by means of parallel-connected rotor-stator dispersants. Alternatively, step b) can only be carried out by means of series-connected rotor-stator dispersants. By a parallel and / or series connection of the rotor-stator dispersers can be increased with particular advantage, both the process productivity and the process quality, without affecting the process time. The features and advantages described in the previous paragraphs with respect to the at least one rotor-stator-disperser apply mutatis mutandis in the case of using a plurality of rotor-stator dispersants.

Step b) can be performed by commercially available under the designation ULTRA-TURRAX ^® line rotor-stator dispersers for example by means of one or a plurality.

In a further embodiment of the invention, the oil phase and the water phase, preferably exclusively, are passed through a droplet comminution zone, in particular a shear zone, of the at least one rotor-stator disperser. By the term "drop crusher zone" is meant in this context a zone, i. a region or section of the at least one rotor-stator-disperser are understood, within which takes place due to the action of the rotor and / stator, a drop crushing, in particular under the influence of shear forces. The process procedure described in this paragraph may also be referred to as forced passage of the oil phase and the water phase through the drop comminution zone, in particular shear zone, of the at least one rotor-stator disperser. As a result, it is particularly advantageous (already) during step b) to achieve a significant reduction of drops which have a diameter, in particular average diameter,> 1 μm.

In principle, the O / W preemulsion can be homogenized directly, ie without further intermediate steps, to form an O / W emulsion. As a result, another is advantageously Shortening the production time and thus achieving a further increase in process productivity.

Alternatively, the O / W preemulsion may be passed through a buffer or container prior to performing step c). The buffer or container is used with particular advantage to maintain the process flow and thus facilitates the coordination between the at least one rotor-stator-disperser and the at least one Gegenstrahldispergator.

In a further embodiment of the invention, step c) is carried out by means of a pump pressure of 500 bar to 2000 bar, in particular 800 bar to 1900 bar, preferably 1000 bar to 1500 bar. The pump pressure disclosed in this paragraph has been found to be particularly advantageous for drop crushing, in particular drop shear, and preferably for realizing a narrow or narrow droplet diameter distribution.

For the purposes of the present invention, the term "pump pressure" is to be understood as meaning a pressure generated by a pump, in particular a high-pressure pump, of the at least one counter-jet disperser. This is u.a. responsible for the conveying speed of the O / W preemulsion, in particular of O / W preemulsion jets, within the at least one counter jet disperser. Therefore, the impact pressure of O / W preemulsion jets within a droplet comminution zone, in particular shear zone, of the at least one counter jet disperser and thus the drop comminution and thus the homogenization of the O / W preemulsion to an O / W emulsion can be controlled via the pump pressure. In that regard, the pump pressure in the context of the present invention may also be referred to as homogenization pressure.

In a further embodiment of the invention, the step c) at a temperature of the O / W pre-emulsion of 30 ° C to 80 ° C, in particular 40 ° C to 77.5 ° C, preferably 40 ° C to 75 ° C, particularly preferred 40 ° C to 65 ° C, is performed. In other words, it is preferred if the at least one counter jet disperser at a temperature of the O / W preemulsion of 30 ° C to 80 ° C, in particular 40 ° C to 77.5 ° C, preferably 40 ° C to 75 ° C, particularly preferably 40 ° C to 65 ° C, is operated, or, in other words, the O / W preemulsions when performing section c) a temperature of 30 ° C to 80 ° C, in particular 40 ° C to 77.5 ° C, preferably 40 ° C to 75 ° C, more preferably 40 ° C to 65 ° C, having. The temperature disclosed in this paragraph can therefore also be referred to as homogenizing temperature in the sense of the present invention. The ones in this attachment revealed temperature has (also) been found to be particularly advantageous for drop crushing, especially drop shear, and preferably for the realization of a narrow or narrow droplet diameter distribution.

For example, the at least one counter jet disperser may be operated to perform step c) at a pump pressure of 1900 bar and at a temperature of the O / W preemulsion of 40 ° C.

Furthermore, the at least one counter jet disperser for carrying out step c) can be operated, for example, at a pump pressure of 1500 bar and at a temperature of the O / W preemulsion of 50 ° C.

Furthermore, the at least one counter jet disperser for carrying out step c) can be operated, for example, at a pump pressure of 1000 bar and at a temperature of the O / W preemulsion of 60 ° C.

In a further embodiment of the invention, the O / W preemulsion when performing step c) is passed through the at least one counter jet disperser several times, in particular twice, three times, four times or five times. By passing the O / W preemulsion through the at least one counter jet disperser several times, an increase in the process quality, in particular with regard to the mean droplet diameter and / or the pFAT5 value, can be achieved with particular advantage.

In a further embodiment of the invention, the step c) by means of a plurality of Gegenstrahldispergatoren, in particular by means of two, three, four or five Gegenstrahldispergatoren performed. Preferably, step c) is carried out by means of a plurality of parallel jet counter-jet dispersers and / or by means of a plurality of counter-jet jet dispersers connected in series. By using a plurality of counter jet dispersers, in particular by a parallel and / or series connection of the counter jet dispersers, a significant improvement in the process quality, in particular with respect to the mean droplet diameter and / or the pFAT5 value, can also be achieved. In addition, this procedural measure (s) can increase process productivity. Thus, the process time does not change in the case of a series connection of the counter jet dispersers. In the case of a parallel connection, the process time is reduced linearly. Overall, therefore, there is a considerable time savings, whereby a significant increase in the number of producible O / W emulsion batches per unit time and thus a significant increase in process productivity is achievable. In particular, step c) can only be carried out by means of parallel jet counter-jet dispersers.

Alternatively, step c) can only be carried out by means of counter-jet dispersers connected in series.

In a further embodiment of the invention, step c) is carried out at least by means of two counter-jet dispersers connected in series, in particular only by means of two counter-jet dispersers connected in series. Preferably, the first counter jet disperser is operated at a higher pump pressure than the second, i. downstream, Gegenstrahldispergator. Particularly preferred is the first Gegenstrahldispergator with a pump pressure of at most 1900 bar, preferably at most 1500 bar, in particular at a pump pressure of 800 bar to 1400 bar, preferably 1000 bar to 1200 bar, and the second, i. downstream, Gegenstrahldispergator with a pump pressure <1000 bar, in particular from 500 bar to 800 bar, preferably from 500 bar operated.

The present invention is further based on the surprising finding that drops with a diameter, in particular average diameter, of 1 pm to 50 pm at a pump pressure of <1000 bar, in particular from 500 bar to 800 bar, preferably from 500 bar, preferably crush to let. As a result, controllability of the pFAT5 value, which is important for parenterally administered O / W emulsions, can be realized with particular advantage.

Furthermore, the present invention is based on the surprising finding that the first counter jet disperser is operated at a higher pump pressure than the second (downstream) counter jet disperser by means of a pressure cascade, in particular by means of at least two counter jet mixers connected in series, as described in the penultimate paragraph , Produce drops with a diameter, in particular average diameter, <500 nm, in particular <400 nm, preferably <350 nm, in particular from 200 nm to 320 nm, preferably 200 nm to 300 nm, particularly preferably 240 nm to 280 nm, via the pump pressure of the first counter jet disperser, and also the proportion of drops with a diameter, in particular average diameter,> 1 pm, in particular from 1 pm to 50 pm, significantly and in particular reproducibly reduced, via the pump pressure of the second Gegenstrahldispergators.

For example, the first counter jet disperser can be operated at a pump pressure of 1900 bar and the second counter jet disperser at a pump pressure of 500 bar. Furthermore, for example, the first Gegenstrahldispergator at a pump pressure of 1500 bar and the second Gegenstrahldispergator be operated at a pump pressure of 500 bar.

Furthermore, for example, the first Gegenstrahldispergator at a pump pressure of 1200 bar and the second Gegenstrahldispergator be operated at a pump pressure of 500 bar.

Furthermore, the first counter jet disperser and the second counter jet disperser may each be operated at a same temperature of the O / W preemulsion. In that regard, reference is made to the homogenization temperatures disclosed in the previous description in connection with the O / W preemulsion. For example, both the first counter jet disperser and the second counter jet disperser may be operated at a 50 ° C O / W preemulsion temperature.

As Gegenstrahldispergator, for example, one or a plurality of under the name Nanojet or Microfluidizer ^® commercially available Gegenstrahldispergatoren be used.

In a further embodiment, the at least one Gegenstrahldispergator downstream of a pressure reducer. The pressure reducer is preferably configured to generate a backpressure to a pressure generated by the at least one counter jet disperser, in particular pump pressure. For example, the pressure reducer may be adapted to generate a back pressure of 10 bar to 100 bar, in particular 30 bar to 70 bar. By using a pressure reducer, a process stability can be achieved with particular advantage. In particular, outgassing phenomena can be avoided by means of a pressure reducer. In the case of a plurality of Gegenstrahldispergatoren each Gegenstrahldispergator a pressure reducer can be followed.

Preferably, an O / W emulsion having a droplet diameter, in particular average droplet diameter (determined by photon correlation spectroscopy, PCS), of 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 240 nm to 280 nm, is produced by means of the method according to the invention.

Further preferred by the method according to the invention is an O / W emulsion having a pFAT5 <0.05%, in particular <0.04%, preferably <0.03%, more preferably <0.02%, particularly preferably <0 , 01%, in particular <0.01%. For example, can an O / W emulsion having a pFAT5 value of 0.001% to 0.01% can be produced by means of the process according to the invention.

In a further embodiment of the invention, a parenterally administered O / W emulsion is prepared by the method according to the invention.

According to a second aspect, the invention relates to an oil-in-water emulsion, hereinafter abbreviated as O / W emulsion, which is prepared or preparable by a process according to the first aspect of the invention.

Alternatively or in combination, the invention according to a second aspect relates to an oil-in-water emulsion, hereinafter abbreviated as O / W emulsion, which has a pFAT5 value <0.04%, in particular <0.03%, preferably <0 , 02%, more preferably <0.01%, in particular <0.01%. For example, the O / W emulsion may have a pFAT5 value of 0.001% to 0.01%.

Furthermore, it is preferred if the O / W emulsion has a drop diameter, in particular average drop diameter (determined by photon correlation spectroscopy, PCS), from 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 200 nm to 300 nm, particularly preferably 240 nm to 280 nm.

With regard to further features and advantages of the O / W emulsion, reference is made to the statements made in the context of the first aspect of the invention. The features and advantages described there in connection with the method according to the invention also apply mutatis mutandis to the O / W emulsion according to the second aspect of the invention.

According to a third aspect, the invention relates to a plant for producing an oil-in-water emulsion, hereinafter abbreviated as O / W emulsion, and / or for carrying out a process according to the first aspect of the invention.

The plant has at least one pre-mix disperser, i. Prehomogenizing or pre-emulsifying, an oil phase and a water phase to an oil-in-water pre-emulsion (hereinafter abbreviated as O / W pre-emulsion), and at least one preferably downstream jet disperser for homogenizing the O / W Preemulsion to an oil-in-water emulsion, hereinafter abbreviated as O / W emulsion, on.

The at least one dispersant (for premixing the O / W preemulsion) is preferably designed as a rotor-stator-disperser, in particular rotor-stator. The system may comprise a rotor-stator-disperser or a plurality of rotor-stator-dispersers, ie several rotor-stator-dispersers, such as two, three, four or five, rotor-stator-dispersers.

In particular, the system may comprise a plurality of parallel-connected rotor-stator dispersers and / or a plurality of rotor-stator dispersers connected in series.

Furthermore, the plant may comprise a counter jet disperser or a plurality of counter jet dispersants, i. several counter jet dispersers, such as two, three, four or five Gegenstrahldispergatoren exhibit.

In particular, the system may comprise a plurality of parallel jet counter-jet dispersers and / or a plurality of counter-jet jet dispersers connected in series.

The plant preferably has at least two counter jet dispersers connected in series.

Furthermore, an intermediate container can be connected between the at least one disperser (for premixing the O / W pre-emulsion) and the at least one counter jet disperser. The intermediate container facilitates with particular advantage by buffering the process flow, the coordination between the at least one rotor-stator-disperser and the at least one Gegenstrahldispergator.

Furthermore, the at least one Gegenstrahldispergator downstream of a pressure reducer. Further features and advantages of the invention will become apparent from the following description of preferred embodiments in the form of figure descriptions and the accompanying figures and examples. In this case, individual features can be realized individually or in combination with each other. The embodiments described below represent the present invention by way of example only, without limiting it thereto. BRIEF DESCRIPTIONS

The figures show schematically the following:

1: a microchannel structure of a counter jet disperser usable according to the invention,

2 shows a flow chart of a method according to the invention,

3 shows a further flowchart of a method according to the invention and

4 shows a further flow chart of a method according to the invention.

1 shows a channel structure 1 of a counter jet disperser usable according to the invention. The channel structure 1 shown has a Y-shaped arrangement and may for example have an inner diameter d in the micrometer range. Via the inlets 2 and 3, an O / W preemulsion can be passed through the channel structure 1 by means of a pressure generated by a pump (high pressure pump) of the counter jet disperser. Due to the oppositely disposed channels 4 and 6, jets of the O / W preemulsion collide in a drop comminution zone 5. In particular under the influence of shear forces, comminution of drops contained in the O / W preemulsion occurs there. The resulting O / W emulsion can leave the channel structure 1 via an outlet 7.

Fig. 2 shows schematically a flow chart of a method according to the English method.

To provide a water phase, a pre-disperser 10 with a rotor-stator system 11 is used. This makes it possible to disperse an emulsifier, such as egg lecithin, in water, especially in water for injection (WFI). In addition to an emulsifier, the water may also be admixed with a stabilizer or isotonizing additive, such as, for example, glycerol, and with an emulsifying aid, such as, for example, sodium oleate. Subsequently, the mixture can be heated or tempered for example over a period of 60 minutes to a temperature of 55 ° C to 75 ° C.

The provision of an oil phase can take place in a container 20, which can be designed as a pre-tempering container, with a stirring element 21. For example, soybean oil and medium-chain triglycerides (MCT) and a-tocopherol can be used to provide the oil phase. The mixture produced in the container 20 can also be heated or tempered to a temperature of for example 55 ° C to 75 ° C. The oil phase and water phase provided in this way are then fed into a rotor-stator disperser 30. Here, the oil phase and the water phase are preferably spatially separated from each other fed into the rotor-stator-disperser 30. This can be done, for example, by means of a coaxial tube or a coaxial tube. This can ensure that the oil drops are exposed to a sufficient emulsifier concentration.

The oil phase and the water phase are preferably conducted through a shearing zone 32 of the rotor-stator disperser 30. As a result, an effective comminution of oil droplets with a diameter, in particular average diameter,> 1 pm can already be achieved at this process stage. In the rotor-stator disperser 30, premixing of the oil phase and the water phase to an O / W preemulsion occurs.

Via an outlet 34 of the rotor-stator-disperser, the O / W preemulsion can be fed via a buffer 40 to at least one counter jet disperser 50. The buffer or container is used with particular advantage to maintain the process flow and thus facilitates the coordination between the rotor-stator-disperser 30 and the at least one Gegenstrahldispergator 50th

The counter jet disperser 50 is operated by means of a high pressure pump, which in particular can generate a pressure in the range from 500 bar to 1900 bar. By means of the pump pressure generated within the counter jet disperser 50, the O / W preemulsion is pumped through a microchannel structure having preferably opposite channels. At this time, jets of the O / W preemulsion in the drop comminution zone meet, whereby drops contained in the O / W preemulsion are crushed, especially under the action of shear forces. In this case, droplets can be produced with particular advantage which have a diameter, in particular average diameter (determined by photon correlation spectroscopy, PCS), from 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 240 nm to 280 nm.

The O / W emulsion produced in the counter jet disperser 50 can then be transferred to a filling container 70 for further filling in suitable packaging sizes.

Fig. 3 shows schematically another flow diagram of a method according to the invention, which is operated by the English method. The illustrated method differs from the method illustrated in FIG. 1 in that it is operated with two counter jet dispersers 50 and 60 connected in series.

In this case, in the first counter jet disperser 50, preferably drops with a diameter, in particular average diameter (determined by photon correlation spectroscopy, PCS), of 180 nm to 340 nm, in particular 200 nm to 320 nm, preferably 200 nm to 300 nm, particularly preferably 240 nm to 280 nm, while in the second, d. H. downstream, Gegenstrahldispergator 60 preferably a reduction of the proportion of drops with a diameter, in particular average diameter, of> 1 pm, and thus takes place a reduction of the pFAT5 value. For this purpose, the first counter jet disperser 50 can be operated, for example, at a pump pressure of 1500 bar, wherein the O / W preemulsion within the counter jet disperser 50 preferably has a temperature of 50 ° C. The second Gegenstrahldispergator 60 is preferably operated at a pump pressure of 500 bar, wherein the O / W emulsion within the Gegenstrahldispergators 60 preferably has a temperature of 50 ° C.

Otherwise, the method sequence and the reference numbers correspond to the method sequence shown in FIG. 2 as well as the reference numbers shown in FIG.

4 shows schematically a further flowchart of a method according to the invention. In this case, however, the method is based on the continental method.

For this purpose, a water phase is provided by means of a container 15, which may be designed as Vortemperierbehälter, and the oil phase by means of a pre-disperser 25 with a rotor-stator system 23 is provided.

To provide the water phase, water, in particular water for injection purposes (WFI), for example, mixed with sodium hydroxide solution and glycerol and the resulting mixture with stirring by means of a stirrer element 13, for example, heated to a temperature of 55 ° C to 75 ° C or tempered. To provide the oil phase, for example, oleic acid, soybean oil and medium chain triglycerides with an emulsifier, such as egg lecithin, and an antioxidant, such as a-tocopherol, and the resulting mixture also with stirring to a temperature of 55 ° C to 75 ° C. heated or tempered. Otherwise, the method sequence and the reference numbers correspond to the method sequence shown in FIG. 2 as well as the reference numbers shown in FIG.

EXAMPLE PART

1. Preparation of Parenteral Fat Emulsion (Lipofundin MCT / LCT 20%)

The manufacturing process was divided into the following three process steps.

In a first step, the production of the oil phase and water phase took place. The water phase was prepared in a stirred tank reactor for crushing and dissolving the emulsifier. The preparation of the oil phase was carried out by simple temperature control of the oil phase on a magnetic stirrer.

In a second step, preparing an O / W-pre-emulsion was made by means of a dispersant under the designation ULTRA-TURRAX ^® Inline (Ytron-Z) commercially available rotor-stator. In contrast to conventional methods, the oil phase and the water phase were guided by means of a forced passage through the shear zone of the rotor-stator disperser. This ensured that every part of the oil phase also passed through the homogenization zone. In the classical stirred tank reactors, the introduction of the oil phase into the rotor-stator-stirrer can only be considered statistically and, according to experience, leads to an undesirably broad and only partially controllable particle distribution.

In a third step, the final fine emulsion was prepared by means of a PSI-40 high pressure homogenizer designed as a counter jet disperser. In contrast to the piston-gap homogenizers used in conventional processes, which use a dynamic valve for droplet breakup, the counter jet disperser had a static microchannel structure for droplet breakup.

1.1 Rotor-stator-Disperqator (Inline-Rotor-Stator, Ytron-Z)

The used rotor-stator-disperser (Ytron-Z) consisted of eleven main components. The raw materials (oil phase and water phase) could be fed to the system via two feed funnels, which could each be closed or opened via a disk valve. From there, the raw materials flowed directly into the inlet of two diaphragm motor metering pumps (ProMinent ^® Sigma / 1 control type S1 Cb). These two pumps operated on the principle of an oscillating positive displacement pump, which were driven by an electric motor. This transmitted by means of a push rod a lifting movement on a dosing membrane. The stroke movement of the displacer was continuously recorded and regulated, so that the stroke could be carried out according to a predetermined metering profile and thus could be adapted accordingly to the properties of the raw materials (viscosity and / or outgassing property). In order for each oil drop to be exposed to a direct emulsifier concentration, the metering was carried out via a metering head with a tube-in-tube structure. While the oil phase was centered through the inner tube, the water phase was passed in a surrounding outer tube. The raw materials were pumped by means of the two metering pumps directly into a reactor head and ran there by means of a forced passage directly into a rotating rotor / stator set. This was driven by means of a three-phase motor (ATB Motorenwerke GmbH, IM B3, 1, 5 kW).

The product passed through the rotor / stator and exited the reactor head via a product outlet which was necked by a pressure air driven guetsch valve (KVT GmbH).

The gate valve served as a technically obligatory backpressure valve for the correct functionality of the two diaphragm metering pumps, as well as a reduction unit of the product outlet, to ensure that the reactor head reached its working volume and could not run empty in the process. The system was controlled via a control cabinet by means of a programmable logic controller (PLC, SIMATIC, Siemens AG). The proportions of the two metering pumps and the speed of the rotor-stator disperser could be entered via a touch panel mounted in the control cabinet door and started simultaneously. The shaft of the rotor-stator disperser was sealed by means of a product-lubricated mechanical seal.

The rotor disk was stretched by means of a key on the rotary shaft of the three-phase motor and was fixed by means of a rotor screw with an O-ring seal on this. The stator was bolted firmly to the reactor lid and was displaced contactlessly against the rotor disk when the reactor head was closed. The reactor head was closed by a clamp connection with an O-ring seal.

1.2 Formulation of a Model Emulsion (Lipofundin MCT / LCT 20%; Parenteral Fat Emulsion ^' )

To prepare an exemplary O / W emulsion, the recipe given in Table 1 below was used:

Table 1: Formulation of a model emulsion (parenteral fat emulsion)

1.3 Procedure:

The preparation of the water phase was carried out in a 10 l stirred tank, which was tempered by means of a tempering unit via a double jacket to 65 ° C process temperature. This process step essentially served the comminution and hydration of the emulsifier in the water phase. For this process step egg lecithin (emulsifier), glycerol and sodium oleate were placed in a stirred tank and filled with tempered (65 ° C) water for injections (Wfl) to a volume of 10 I.

To disperse an IKA T 50 under the name ULTRA-TURRAX ^® available rotor-stator stirrer was used (10,000 U / min) at maximum speed. The dispersion was carried out for 1 h in a stirred tank on the rotor-stator-stirrer with simultaneous temperature control by means of the jacket temperature of the stirred tank at 65 ° C.

Then the water phase to a process temperature of 75 ° C, was preliminarily heated further for use in the in-line ULTRA-TURRAX ^®, on a magnetic stirrer and transferred to a first feed tank of the in-line rotor-stator reactor. This also had a jacket tempering, which the water phase during emulsification tempered to process temperature. The preparation of the water phase was completed with this step.

To prepare the oil phase soybean oil, MCT and alpha-tocopherol were added to a beaker and then, heated to a process temperature of 75 ° C on a magnetic stirrer, preparatory to use in-line ULTRA-TURRAX ^® and in a second receiving vessel of the inline rotor Stator reactor transferred. This reservoir also had a jacket temperature, which tempered the oil phase during the emulsification to process temperature. The preparation of the oil phase was completed with this step.

A rotor with a slot width of 1 mm and a stirrer circumference of 33 mm was used for an innermost sprocket, a stirrer circumference of 44 mm for a middle sprocket and a stirrer circumference of 55 mm for an outer sprocket.

The tooth spacing of the stator was 0.5 mm. The circumference of the three sprockets was 38 mm for an inner sprocket, 49 mm for a middle sprocket and 60 mm for an outer sprocket.

Before starting the emulsification, the process parameters for the metering as well as for the rotor-stator speed were set on the PLC of the control unit of the inline rotor stator according to Table 2 below:

Table 2: Process parameters of the inline rotor stator

After starting the system, the pressure at the product outlet was set to a back pressure of 2 bar. The O / W pre-emulsion was collected at the product outlet in a beaker while constantly stirring.

Subsequently, the O / W emulsion was finely emulsified in a three-pass PSI-40 type high-pressure homogenizer designed as a counter jet disperser. Instead of a conventional dynamic valve, this high-pressure homogenizer used a static micrometer-sized channel structure in which the droplet break-up took place. Due to the much narrower and unchangeable channel dimension, a more intensive shear and a lower and reproducible flow distribution with resulting narrow droplet distributions took place. Furthermore, such high pressure homogenizers are easier to scale due to their static chamber geometry. Drop breakage took place in an interaction chamber (shear chamber) consisting of a diamond core buried in a 316L stainless steel jacket. The diamond core was designed with the above-mentioned microstructured channels in which the drops were accelerated and broken at high process pressure. For emulsification so-called Y-chambers were used. The microchannels formed the shape of a wye in such chambers. In this case, process pressures of 500 bar to 2,000 bar were possible.

In order to protect the interaction chamber from damage due to cavitation at high process pressures, the interaction chamber was followed by an APM (auxiliary processing module) (secondary chamber). This secondary chamber acted as a pressure reducer and produced a low back pressure on the outlet side (outlet) of the primary chamber. A relaxation of the interaction chamber against the direct atmospheric pressure with induced cavitation was so prevented. In practice, the APM module was a stainless steel core with a specially dimensioned bore in a stainless steel jacket.

The following process parameters and chamber configurations have been defined for the high-pressure homogenizer:

Table 3: Process Parameters and Chamber Configurations of the High Pressure Homogenizer

The chamber E101 D was a single-slot Y-chamber and delivered flow rates up to 20 L / h.

The APM module delivered a back pressure of about 50 bar for the primary chamber E101 D.

By further optimizing the chamber configuration, an additional improved emulsion quality could be achieved with the PSI-40 high pressure homogenizer. This configuration has been defined with the following process parameters:

Table 4: further optimized process parameters and chamber configurations of the

high-pressure homogenizer

The APM module (reduced backpressure) provided backpressure for the primary chamber E101 D, but with a reduced backpressure near 50 bar.

The information regarding the generated back pressures was based on manufacturer information.

To characterize the O / W emulsions produced, the following particle analysis was used. a) Photon Correlation Spectroscopy (PCS):

In this method, the Brownian motion is quantified with the aid of an autocorrelation function of the scattered light signal of disperse particles. For the measurement, a light beam with a defined wavelength is passed through a sample by means of a laser, which results in a scattering of the laser light. The scattered light intensity is subject to time-dependent fluctuations due to the non-directional diffusion of molecules surrounding the particles. These time-dependent interference phenomena depend on the size of the scattering particles.

The mean particle diameter or droplet diameter in nanometers [nm] is used as the output parameter. b) Microscopic image acquisition (microimage):

For microscopic image acquisition, one drop at a time (about 10 l of sample) was observed on a microscope slide under a light microscope with an x100 immersion oil objective. From this sample, an image sample was taken at five points (top left, bottom left, bottom right, top right, center) of the slide, which were then evaluated by software counting the droplets from a size of 2 pm.

As output parameter, the microimage was led with the unit [drop]. The microimage corresponded to the number of drops of five image samples of a considered sample volume.

2. Preparation of O / W emulsions at different Homoaenisiertemperaturen and

-to press

The fat emulsion prepared according to 1 was prepared using various homogenizing temperatures and pressures. A PSI-40 counter jet disperser was used. From a description of the company Microfluidics (Chamber User Guide, 12/30/14) is known how the process temperature changes with the pressure during homogenization (2.5 ° C per 100 bar). This temperature is to be added to the respective test temperature T _{H of} the O / W preemulsion, ie the temperature of the O / W preemulsion before it enters the at least one counter jet disperser, and gives the homogenization temperature for the purposes of the present invention. For example, for an O / W preemulsion which has a temperature of 20 ° C. prior to its entry into the at least one counter jet disperser, a temperature of O / O is calculated for a counter jet disperser which is operated at a homogenization pressure (pump pressure) of 1000 bar. W preemulsion within the counter jet disperser of 45 ° C.

The percentage of emulsion droplets greater than 5 microns (pFat5), the mean droplet size (MDS) as measured by photon correlation spectroscopy (PCS), the number of drops by microsopic counting and the pH were measured. .1 20 ° C study

Tab. 5 Examination of emulsion parameters after preparation of a fat emulsion at 20 ° C

(Test temperature) and different homogenization pressures

.2 30 ° C study

Tab. 6 Examination of emulsion parameters after preparation of a fat emulsion at 30 ° C

(Test temperature) and different homogenization pressures

.3 40 ° C study

Tab. 7 Examination of emulsion parameters after preparation of an emulsion at 40.degree

(Test temperature) and different homogenization pressures

.4 50 ° C study

Tab. 8 Investigation of emulsion parameters after preparation of an emulsion at 50 ° C

(Test temperature) and different homogenization pressures

.5 60 ° C study

Tab. 9 Examination of emulsion parameters after preparation of an emulsion at 60 ° C

(Test temperature) and different homogenization pressures

2.6 70 ° C study

Tab.10 Examination of emulsion parameters after preparation of an emulsion at 70 ° C

(Test temperature) and different homogenization pressures

The experimental results presented in Tables 5 to 10 show that the minimum medical standard assumed for the parenteral administration of O / W emulsions, according to which the mean drop diameter of the O / W emulsions should not exceed a value of 500 nm, of all O produced / W emulsions is fulfilled. Furthermore, the results tabulated in Tables 5 to 10 show that the average droplet diameter can be reduced with increasing pressure and / or as the number of homogenization cycles increases.

In addition, the test results obtained show that drops having a diameter, in particular average diameter, above 1 pm, in particular between 1 pm and 5 pm, preferably at a homogenization pressure below 1000 bar, in particular at a homogenization pressure of 500 bar, are comminuted. This makes it possible, in particular in the case of two counter-jet dispersers connected in series, to control the mean droplet diameter of the O / W emulsions to be produced via the first counterjet disperser and the pFAT5 value of the O / W emulsions to be produced via the second, ie downstream, counterjet disperser. In this way, therefore, both the targeted in relation meets the minimum standard existing on the mean droplet diameter as well as the minimum standard assumed in relation to the pFAT5 value, and consequently the process quality is significantly increased.

3. Production of O / W emulsions by means of homogenization with different pressure levels

The fat emulsion prepared according to 1. was prepared using two series-connected counter jet dispersers (each of type PSI-40). The results obtained are shown in the following Tables 1 1 to 13.

2.7 First pressure level 1900 bar

Tab. 1 1 Examination of the emulsion drop diameter after preparation of an emulsion with two different microfluidizer pressures 2.8 First pressure level 1500 bar

Tab. 12 Investigation of the emulsion drop diameter after preparation of an emulsion with two different microfluidizer pressures

2.9 First pressure level 1000 bar

Tab. 13 Investigation of the emulsion drop diameter after preparation of an emulsion with two different microfluidizer pressures

The tabulated results show that the minimum medical standard required for parenterally administered O / W emulsions in terms of mean drop diameter is met by all O / W emulsions produced. Furthermore, the results show that the average droplet diameter can be additionally reduced by the use of a second series-connected counter jet disperser. If the second counter jet disperser is also at a homogenizing pressure (pump pressure) <1000 bar, operated in particular at a homogenization pressure of 500 bar, the pFAT5 value valid for parenterally administered O / W emulsions can be clearly undershot. Overall, therefore, a significant increase in the process quality, in particular with respect to the mean droplet diameter and the pFAT5 value of the O / W emulsions to be produced, can be achieved.

Claims

claims

A process for producing an O / W emulsion, in particular for parenteral administration, comprising the following steps:

a) providing an oil phase and a water phase,

b) premixing the oil phase and the water phase into an O / W preemulsion; and c) homogenizing the O / W preemulsion to an O / W emulsion by means of at least one counter jet dispersant.

2. The method according to claim 1, characterized in that the step b) is carried out by means of at least one rotor-stator disperser.

3. The method according to claim 2, characterized in that the oil phase and the water phase spatially separated from each other are supplied to the at least one rotor-stator disperser.

4. The method according to claim 2 or 3, characterized in that the oil phase and the water phase are supplied by means of a tube-in-tube arrangement to the at least one rotor-stator-disperser

5. The method according to any one of claims 2 to 4, characterized in that the oil phase and the water phase are passed through a droplet comminution zone, in particular shear zone, of the at least one rotor-stator disperser.

6. The method according to any one of the preceding claims, characterized in that the step c) by means of a pump pressure of 1000 bar to 1900 bar, in particular 1000 bar to 1500 bar, preferably 1200 bar to 1500 bar, is performed.

7. The method according to any one of the preceding claims, characterized in that the step c) at a temperature of the O / W pre-emulsion of 30 ° C to 80 ° C, in particular 40 ° C to 77.5 ° C, preferably 40 ° C. to 75 ° C, more preferably 40 ° C to 65 ° C is performed.

8. The method according to any one of the preceding claims, characterized in that the O / W preemulsion in performing step c) is passed several times through the at least one Gegenstrahldispergator.

9. The method according to any one of the preceding claims, characterized in that the step c) is carried out by means of a plurality of Gegenstrahldispergatoren.

10. The method according to any one of the preceding claims, characterized in that the step c) is carried out at least by means of two counter-jet dispersers connected in series.

1 1. A method according to claim 10, characterized in that the first Gegenstrahldispergator is operated at a higher pump pressure than the second Gegenstrahldispergator.

12. The method of claim 10 or 1 1, characterized in that the first Gegenstrahldispergator at a pump pressure of at most 1500 bar, in particular 800 bar to 1400 bar, preferably 1000 bar to 1200 bar, and the second Gegenstrahldispergator at a pump pressure <1000 bar, in particular from 500 bar to 800 bar, preferably of 500 bar, is operated.

13. The method according to any one of the preceding claims, characterized in that the at least one Gegenstrahldispergator a pressure reducer is connected downstream.

14. O / W emulsion, prepared or preparable according to one of the preceding claims and / or having a pFAT5 value <0.04%, in particular <0.03%, preferably <0.02%, particularly preferably <0.01 %.

15. Plant for producing an O / W emulsion and / or for carrying out a method according to any one of claims 1 to 13, characterized in that the system comprises at least one dispersant for premixing an oil phase and a water phase to an O / W pre-emulsion and at least one downstream Gegenstrahldispergator for homogenizing the O / W preemulsion to an O / W emulsion.