GB2455143A

GB2455143A - Preparation of emulsions using inkjet technology

Info

Publication number: GB2455143A
Application number: GB0723522A
Authority: GB
Inventors: Stephan Foerster; Stephan Hauschild
Original assignee: Centrum fuer Angewandte Nanotechnologie CAN GmbH
Current assignee: Centrum fuer Angewandte Nanotechnologie CAN GmbH
Priority date: 2007-11-30
Filing date: 2007-11-30
Publication date: 2009-06-03
Also published as: GB0723522D0; WO2009068673A1

Abstract

A method and apparatus for the manufacture of emulsions using inkjet technology. The method proceeds by printing a first immiscible substance from the printhead of an inkjet printer into a container containing the second immiscible substance such that the first immiscible substance forms an emulsion with the second immiscible substance.

Description

s FIELD OF INVENTION

[0001] The present invention is directed to the field of the preparation of emulsions using inkjet devices.

PRIOR ART

[0002] The use of inkjet devices in industrial applications is known in the literature. For example US patent 6123861 "Fabrication of Microchip drug delivery devices" inventors John T Santini, Michael J Cima and S. Langer is assigned to Massachusetts Institute of Technology, Cambridge Mass. USA. This document discloses fabrication methods of microchips that control both the rate and time of release of multiple chemical substances used in the pharmaceutical industry and allow for the release of a wide variety of molecules in either a continuous or pulsatile manner. A release system, which includes the molecules to be delivered is inserted into the reservoirs by injection, inkjet printing, or spin coating methods.

This disclosure highlights the use of medicinal compounds and their use within inkjet *: : :* technology, it is directed to the efficacy of drug administration.

[0003] Us patent publication 2004/0181 196 "Cutaneous administration system", inventors ": Ray L Pickup, Clement C Lo and William D Noonan is assigned to Hewlett-Packard Company, IP Administration, USA. This document describes the cutaneous administration of bio-active agents by a jet dispenser using inkjet technology. The dispenser propels precise * volumes of bio-active agent towards the skin, where the agents exert their effect.

*.*.*. * *

[0004] International Patent Application W02006/044695 "Inkjet dispenser for automated drug administration in a hospital management system", inventors Vitello C. John, Welkley Steve, Evans Andrew and Greeven John. This document also describes the cutaneous administration of bio-active agents by a jet dispenser using inkjet technology. The dispenser propels precise volumes of bio-active agent towards the skin, where the agents exert their effect.

[0005] -An article in Small 2005,1, No.12, 1177-1180 "Direct preparation and loading of lipid and polymer vesicles using inkjets", authors Stephan Hauschild, et al. This document discloses the direct preparation of nanometre sized, unilamellar lipid and polymer vesicles with a narrow size distribution using inkjet printers. The size of the vesicles can be controlled via the amphiphiles concentration and the cartridge type.

[00081 None of the prior art discloses a method for the synthesis of emulsions prepared using inkjet devices.

BACKGROUND OF THE INVENTION

[0009] An emulsion is a mixture of two immiscible or unblendable substances. Emulsions are part of a more general class of two-phase systems of matter called colloids, although the terms colloid and emulsion are sometimes used interchangeably, the term emulsion tends to imply that both the dispersed phase and the continuous phase are liquid.

[0010] An emulsifier (also known as an emulgent or surfactant) is a substance which stabilizes an emulsion. Examples of food emulsifiers are egg yolk (where the main emulsif'ing chemical is the phospholipid lecithin) and mustard where a variety of chemicals * .. in the mucilage surrounding the seed hull act as emulsifiers; proteins and low-molecular :::::: weight emulsifiers are also common. In some cases, particles can stabilize emulsions as well through a mechanism called Pickering stabilization. Both mayonnaise and hollandaise sauce * : * are oil-in-water emulsions stabilized with egg yolk lecithin. Detergents are another class of surfactant, and will chemically interact with both oil and water, thus stabilising the interface between oil or water droplets in suspension. This principle is exploited in soap to remove grease for the purpose of cleaning.

*..*S* [00111 Examples of emulsions include, milk (fat dispersed in water), butter (water dispersed in fat), mayonnaise (oil in water) and ice cream (fat in water which is then frozen). A huge number of emulsions exist in the cosmetic and pharmaceutical industries such as creams, lotions and ointments. Emulsions are also used as drug delivery systems such as Propofol which is a liquid anaesthetic dissolved in emulsified oil.

[0012] Emulsions are conventionally prepared by shear-induced break-up of macroscopic liquid droplets of a disperse phase into a continuous phase. Shear is provided by mechanical methods such as shaking, stirring, homogenizing or ultrasound.

[0013] Emulsions are generally unstable and thus do not form spontaneously and so for the preparation of most emulsions, high shear forces are needed with a corresponding intake of a large amount of energy which usually results in a considerable amount of damage to the immiscible substances used to prepare the emulsion, be it the dispersed phase or the continuous phase. Such damage can be mechanical and lead to denaturisation of bio-molecules, cleavage of chemical compounds or the damage can be due to a result of an increase in temperature within the immiscible substances due to the energy uptake in the emulsion forming process. - [0014] Therefore conventional methods of emulsion formation are prohibitive for the preparation of emulsions where the emulsions consist of sensitive bio-active components such as pharmaceuticals, neutraceuticals, bio- active compounds, flavourants or fragrances.

[0015] Current inkjet technology provides a means to generate very small substance droplets with droplet volumes down to picolitres (l02 litres). A jet of these substance droplets can be * *. injected into a liquid to produce emulsions with droplets which have diameters in a typical :::::: I...

*:h1 [0016) Such a method of emulsion manufacture avoids the use of the harsh mechanical methods outlined above and thus provides a means to produce emulsions that contain sensitive compounds in a gentle environment, such that the sensitive compounds are not damaged by conventional emulsion forming methods.

* ..S I.

SUMMARY OF THE INVENTION

[0017] The present invention teaches a method and apparatus for the manufacture of emulsions, preferably but not limited to bio-active emulsions.

[0018] The method comprises providing a first immiscible substance of the bio-active component in at least one inkjet cartridge and a second immiscible substance in a container as well as an emulsifier in either the inkjet cartridge or the container. The first immiscible substance is printed through the inkjet printhead to emerge as a droplet jet from the inkjet printhead into the container where the second immiscible substance is present. The first immiscible substance forms the emulsion with the second immiscible substance in the container.

[0019] The method allows for the formation of a wide range of emulsions that would usually prove problematic. The invention allows the use of co-solvents that are used to reduce the viscosity of the immiscible substances and also allows the preparation of emulsions at various temperatures to aid the manufacture of the emulsions. Where co-solvents are used, they are removed from the manufactured emulsion by a dialysis apparatus.

[0020] The invention provides for the manufacture of emulsions without affecting the chemical properties of either the first immiscible substance or the second immiscible substance. For example, the method allows bio-active emulsions to be made efficiently, quickly and in large quantities without affecting their chemical properties. The advantages are that the use of a continuous manufacture method allow large quantities of emulsion to be manufactured, which may not be have been previously possible by using co-solvents, warming means and dialysis of the prepared emulsions where needed. * **

DESCRIPTION OF DRAWINGS *

[0021] FIGURE 1. Depicts the manufacture of emulsions using inkjet devices in a batch preparation system. S... S...

e:o.: FIGURE 2. Depicts the manufacture of emulsions using inkjet devices in a continuous flow system.

FIGURE 3. Depicts a schematic flow diagram for the manufacture of emulsions using inkjet devices (300).

FIGURE 4. Shows a size distribution by intensity of soy bean oil (A) emulsion.

FIGURE 5. Shows a size distribution by intensity of soy bean oil (A) emulsion after 3 weeks.

FIGURE 6. Shows a size distribution by intensity of soy bean oil emulsions with various concentrations (15% -A, 3% -B, 1% -C) of soy bean oil in the cartridge.

FIGURE 7. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised io by SDS after preparation (A) and after 5 weeks (B).

FIGURE 8. Shows a size distribution by intensity of soy bean oil (5%) emulsion stabilised by SDS after preparation (A) and after 5 weeks (B).

FIGURE 9. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised with various surfactants, sodium dodecyl sulfate (A), egg lecithine (B) and cetyltriinethylammonium bromide (C) (each 3%) -after preparation.

FIGURE 10. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by sodium dodecyl sulfate (A), sodium laureth sulfate (B) and sodium dodecyl benzene sulfonate (C) (each 3%) after preparation.

* *. FIGURE 11. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised with various surfactants, sodium dodecyl sulfate (A), sodium laureth sulfate (B) and sodium * W dodecyl benzene suLfonate (C) (each 3%) -after 3-5 weeks. *

S... S. * S FIGURE 12. Shows a size distribution by intensity of soy bean oil (15%) emulsion at various temperatures, stabilised by lecithin (3%) at 6 °C (A), 15 °C (B) and 35 °C (C) -after S. 55 *..: preparation.

*S.*.* FIGURE 13. Shows a size distribution by intensity of soy bean oil (15%) emulsion at various temperatures stabilised by lecithin (3%) at 6 °C (A), 15 °C (B) and 35 °C (C) -3-5 weeks after preparation.

FIGURE 14. Shows a size distribution by intensity of various oil emulsions, of linseed oil (A), sweet almond oil (B) and fish oil (C) each 15% -stabilised by lecithin (3%) after preparation.

FIGURE 15. Shows a size distribution by intensity of various oils -(15%) stabilised by lecithin (3%) and equipped with coriander oil (A), orange oil (B) and menthol (C) (1%) after preparation.

FIGURE 16. Shows a size distribution by intensity of fragrant emulsions of soy bean oil io (15%) stabilised by lecithin (3%) and equipped with coriander oil (A), carnation oil (B) and cayenne pepper extract (C) (1%) after preparation.

FIGURE 17. Shows a size distribution by intensity of emulsions containing various active ingredients with soy bean oil (15%) stabilised by lecithin (3%) equipped with tocopherol (A), clotrimazol (B) arid piroxicam (C) -(1%) after preparation.

FIGURE 18. Shows size distribution by intensity of emulsions with concentrations of 15% (A), 5% (B) and 2% (C) of paraffin oil in the cartridge stabilised by SDS (3%) after preparation FIGURE 19. Shows a size distribution by intensity of paraffin oil (15%) emulsion stabilised by -SDS (A), SDBS (B) and SLES (C) (3%) after preparation. * .*

FIGURE 20. Shows a size distribution by intensity of paraffin oil (5%) emulsion stabilised by -SDS with concentrations of 3% (A) and 5% (B) after preparation.

I

*.***. * *

FIGURE 21. Shows a size distribution by intensity of oil (15%) emulsion stabilised by lecithin (3%) printed from 2-propanol (A), ethanol (B) and tetrahydrofuran (C). *I*.

S S...

:8'r FIGURE 22. Shows a size distribution by intensity of bean oil (15%) emulsion stabilised by lecithin (3%) printed from one printer (A) and two printers (B).

FIGURE 23. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed from printer model #1(A) and printer model #2 (B).

FIGURE 24. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into various shapes of container, shape #1 (A), shape #2 (B) and shape #3(C).

FIGURE 25. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed in water under various pump speeds, speed #1(A), speed #2 (B) and speed #3 (C) of the first closed loop.

FIGURE 26. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed in water under co-solvent removal continuously during preparation (A) and after preparation (B).

FIGURE 27. Shows a size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed in water using thermal inkjet printers (#1, A and #2, B) and piezo inkjet (C) printers.

FIGURE 28. Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed in water equipped with dye Sudan IV (A) and without dye (B).

FIGURE 29. Size distribution by intensity of water in oil emulsion stabilised by Triton X-100 printed in paraffin oil (A). * ** * * * * I. * S

S **.** * S... *...

S

55.55. * . 7.

DETAILED DESCRIPTION OF THE INVENTION

[00221 The present invention teaches a method for the formation of emulsions utilising inkjet technology and is not limited to a particular inkjet technology and incorporates all such known technologies such as thermal inkjet, piezoelectric inkjet and continuous inkjet technologies.

[0023] The invention is directed particularly to the preparation of emulsions that comprise bio-active substances such as pharmaceuticals, neutraceuticals, flavourants and fragrances.

The invention is not limited to the manufacture of bio-active emulsion.

[0024] The teachings of the present invention are not limited to the use of one inkjet cartridge that comprises a single inkjet printhead. A plurality of inkjet cartridges can be used and an inkjet cartridge can be used with a plurality of inkjet printheads.

[0025] Fig. I shows an inkjet cartridge 110 used to generate a droplet jet 130 of a disperse phase of a first immiscible substance 105 that is printed into a container 140 of a continuous phase of the second immiscible substance 115. The droplets from the droplet jet 130 emulsify to form the emulsion 125 in the container 140. The droplets can be an oil phase which, when injected into an aqueous phase in the container 140, create an oil-in-water emulsion in the container 140. The droplets can be the aqueous phase which when injected into oil in the container 140 create a water-in-oil emulsion in the container 140.

[0026] An emulsifier 135 can be present in the disperse phase of the first immiscible substance 105 in the inkjet cartridge 110 or in the continuous phase of the second immiscible *: s::, substance 115 in the container 140. In one aspect of the invention, bio-active substances are present in the first immiscible substance 115 of the disperse phases which are then S...

spontaneously emulsified into the continuous phase of the second immiscible substance 115.

* S.... * S

[0027] For viscous substances, such as heavy oils, that may be used as either the first immiscible substance of the disperse phase 105 or the second immiscible substance of the continuous phase 115 in the manufacture of emulsions 125, heating of either the first * immiscible substance of the disperse phase 105 and/or the second immiscible substance of the Continuous phase 115 may be necessary. Alternatively it may be necessary to add co-solvents to either the first immiscible substance 105 and/or the second immiscible substance 115. Such co-solvents reduce the viscosity of the first immiscible substance of the disperse phase 105 and/or the second immiscible substance of the continuous phase 115 and therefore provide a sufficient flow rate for the first immiscible substance 105 and/or the second immiscible substance 115 in fluid channels of the entire apparatus. The co-solvents (where used) can be present in either the disperse phase of the first immiscible substance 105 or in the continuous phase of the second immiscible substance 115. The fluid channels include all areas of the apparatus as shown in Figures 1 and 2 that are in contact with any phase of the first immiscible substance of the disperse phase 105 and/or the second immiscible substance of the io continuous phase 115 that are used in the manufacture of the emulsion 125.

[00281 For liquids to be used in the inkjet cartridges 110 based on the thermal or bubble principle, the addition of volatile co-solvents may be necessary to generate a sufficient volume of vapour bubbles.

[0029] For liquids to be used in the inkjet cartridges 110, where the liquids have too large interfacial energy to spontaneously immerse in the continuous phase, the addition of co-solvents may be necessary.

[0030] The emulsifier 135 may be present in either the disperse phase of the first immiscible substance 105 or in the continuous phase of the second immiscible substance 115.

[0031) In one aspect of the invention, the invention is used to produce emulsions 125 in a batch system 100. In this aspect the inkjet cartridge 110 is filled with the disperse phase of the first immiscible substance 105. The disperse phase of the first immiscible substance 105 is then printed as a droplet jet 130, through the inkjet printhead 120, into a container 140 of the continuous phase of the second immiscible substance 115. As the disperse phase of the first S...

immiscible substance 105 is printed first immiscible substance 105 immerses spontaneously :: into the continuous phase of the second immiscible substance 115 to produce the emulsion 125 in the container 140 situated below the inkjet cartridge 110.

[0032] As the disperse phase of the first immiscible substance 105 immerses into the S.....

* continuous phase of the second immiscible substance 115 the mixture is agitated in the container 140 to promote formation of the emulsion 125.

[0033] In a further aspect of the invention shown in Fig. 2, the emulsion 125 can be made in a continuous preparation that facilitates the manufacture of large quantities of the emulsion 125.

The example of Fig. 2 also allows the manufacture of emulsions that would otherwise be S prohibitive due to the immiscible substances being of low volatility (i.e. highly viscous). This is made possible by the fact that such low volatility substances can be thinned with the use of co-solvents and br heating that will increase the volatility of the immiscible substances. The co-solvents can then be removed from the emulsion with a dialysis apparatus. The example of Fig. 2 incorporates a collection reservoir 220 for collecting the emulsion 125 as the emulsion 125 is continuously manufactured. The collection reservoir 220 incorporates openings 280 and 281 for the extraction of the prepared emulsion 125. Valves 250 within the apparatus 200 allow the invention to be used for the continuous manufacture of the emulsions only, or for the continuous manufacture of the emulsions 125 that require co-solvents which are later removed. This example is described below in greater detail.

[0034] In this aspect of the invention where the invention is used to produce emulsions 125 in a continuous system 200. In this aspect the inkjet cartridge 110 is filled with the disperse phase of the first immiscible substance 105. The disperse phase of the first immiscible substance 105 is then printed as a droplet jet 130 through the inkjet printhead 120, into a container 140 of the continuous phase of the second immiscible substance 115. As the disperse phase of the first immiscible substance 105 is printed the first immiscible substance of the disperse phase immerses spontaneously into the continuous phase of the second immiscible substance 115 to produce the emulsion 125 in the container 140 below.

[0035JAs the disperse phase of the first immiscible substance 105 immerses into the * : :* continuous phase of the second immiscible substance 115 the mixture is agitated in the *. container 140 to promote formation of the emulsion 125. I.e.

*:: [0036] As the emulsion 125 is manufactured, the emulsion 125 is pumped from the container 140 via tubes 210 which cormect the container 140 to a collection reservoir 220 using a geared pump 230. The geared pump 230 is operable at a number of different speeds.

* [0037] In a further aspect of the invention where the invention is used for the Continuous manufacture of emulsions 125, a co-solvent can be used to lower the viscosity of the immiscible substances 105 and/or 115 used in the manufacture of emulsions 125. In continuous preparations of the emulsion 125 the disperse phase of the first immiscible substance 105 together with the possible co-solvents are filled into the inkjet cartridge 110.

The disperse phase of the first immiscible substance 105 is then printed as a droplet jet 130 through the inkjet printhead 120, into a container 140 of the Continuous phase of the second immiscible substance 115. As the disperse phase of the first immiscible substance 105 is printed the disperse phase immerses spontaneously into the continuous phase of the second immiscible substance 115 to produce the emulsion 125 in the container 140 below.

Jo [0038] The use of co-solvents in this aspect are not limited to their addition in the disperse phase of the first immiscible substance 105 and the co-solvents can also be added to the continuous phase of the second immiscible substances 115.

[0039] Where a co-solvent is used, the co-solvent needs to be removed from the manufactured emulsion 125. This is achieved by having the valves 250 in an open position and allowing the manufactured emulsion 125 to pass through a dialysis apparatus 290. The dialysis apparatus 290 is collectively shown in Fig. 2 to comprise of tubes 210, geared pumps 230 and a dialysis cartridge 240 which is equipped with a fresh water closed loop at the water reservoir 260. The water reservoir 260, is connected to a water system by pipes 270 and 271.

The temperature of the water reservoir 260 can be pre-set to conduct emulsification at different temperatures to further reduce the volatility of the immiscible substances. The dialysis apparatus 290 is connected to the container 140 and the collection reservoir 220 by a series of tubes 210. The emulsion forming materials are carried through the tubes 210 by a number of geared pumps 230 through the dialysis apparatus 290 where the co-solvent is removed by dialysis against a membrane (not shown). The manufactured emulsion 125 is then *:*:: substantially free of co-solvents and is transported to the collection reservoir 220 from the ** dialysis apparatus 290 via a series of tubes 210 and geared pumps 230.

:: [0040] The co-solvents used are usually miscible with either the disperse phase or the continuous phase and are used to reduce the volatility of such substances. The co-solvents do not react with any of the substances used, such as the emulsifiers 135 or the first 105 or *. S. second immiscible substances 115, or the formed emulsion 125.

*..S.S

S

[0041] The aspects of the invention are described in more detail with reference to Fig. 3. Fig 3 shows a schematic representation for the procedure of emulsion manufacture using inkjet technology.

[0042) Start 300 is followed by a step 310 of providing a first immiscible substance 105 which is filled into the inkjet cartridge 110. A next step 315 is to provide the second immiscible substance 115 in the container 140. This is followed by a step 320 whereby the emulsifier 135 is added to either the first immiscible substance of the disperse phase 105 or the second immiscible substance of the continuous phase 115. I0

[0043] In a method for the batch manufacture of emulsions 125, the emulsions 125 are then printed 330 in the container 140 which contains the second immiscible substance 115 which provides 340 the emulsion 125 ready for collection.

[0044] Fig. 3 also shows a method for the continuous manufacture of emulsions using inkjet technology according to the schematic in Fig 3. The start 300 is followed by the step 310 of providing of a first immiscible substance of the disperse phase 115 which is filled into the inkjet cartridge 110. The next step 315 is to provide the second immiscible substance of the continuous phase 115 in the container 140. This is followed by the step 320 whereby an emulsifier 135 is added to either the first immiscible substance of the disperse phase 105 or the second immiscible substance of the continuous phase 115.

[0045] The step 350 for the continuous manufacture differs from the batch manufacture process in that, the step 350 is for the addition of the co-solvent to either the first immiscible substance of the disperse phase 105 or the second immiscible substance of the continuous *:*::* phase 115. The first immiscible substance 105 is then printed in step 345 in the container 140 **** where the emulsion 125 is manufactured. The emulsion 125 is then withdrawn and subjected S...

to dialysis as in step 360 whereby the co-solvents are removed via the dialysis apparatus 270 from the emulsion 125 to lead to the step of collecting the manufactured emulsion 370. The steps 300 to 370 are then if necessary repeated for the continuous manufacture of the emulsion. It should be noted that this repetition can be used for the manufacture of emulsions * 125 without the use of co-solvents for the production of emulsions that contain non volatile *e*..* * first 105 or second 115 immiscible substances. K).

Examples

[0046] The examples demonstrate the various aspects of the invention but are not intended to limit the invention.

The graphs (Figs. 4 -Fig. 24) show a size distribution (for the examples 1 -17) by intensity (scattered light) of the sample, analysed using a Zetasizer Nano series Nano-ZS red label manufactured by Malvem Instruments.

[0047] Example I -Preparation of soy bean oil emulsions.

[0048] Soy bean oil (4.5 g) from Bio Planéte and egg lecithin (0.9 g) from Sigma (P5394) were mixed in 24.6 g 2-propanol and stirred until the lecithin is dissolved and a clear yellowish solution was obtained.

[0049] The solution was filled into the inkjet cartridge 110 and printed as a droplet jet 130 into the container 140 (which in this example a small beaker filled with water). The water is continuously pumped through a system as in Fig 2. The 2-propanol (co-solvent) was constantly removed from the solution in the reservoir 220 utilising cross flow dialysis 290.

The whole system is operated as shown in Fig. 2.

[0050] After the solution was printed into water the 2-Propanol (co-solvent) was removed by dialysis an to yield an opaque slightly yellowish emulsion.

[0051] A sample of the emulsion was filtered through a syringe filter (Schleicher & Schüll FP 30/5.0 CN) with a pore size of S.tm into a single use cuvette (Plastibrand, PS; semi micro *, from Brand) and analysed by dynamic light scattering using a Zetasizer Nano series Nano- ZS S...

red label by Malvern Instruments.

S..... * *

[0052] The emulsion droplets showed a diameter of 264 nm and a relative standard deviation (PDI) of 0.25 as shown in Fig 4 (Size distribution by intensity of soy bean oil emulsion). The **.

* emulsion aggregates in the range of days and showed creaming. The droplets were re-SS*.S.

* dispersible by simple shaking and showed the same diameter (258 nm) and size distribution (PDI: 0.24) as shown in Fig 5 (Size distribution by intensity of soy bean oil emulsion after 3 weeks) [00531 Example 2 -Preparation of soy bean oil emulsions in various concentrations.

[0054] The influence of the oil concentration was studied in preparations similar to Example [0055]Soy bean oil from Bio Planéte and egg lecithin (3% by weight) from Sigma (P5394) were mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0056] In every case an opaque and slightly yellowish emulsion was obtained after the preparation. Analysis by dynamic light scattering showed similar results to example 1. The diameter ranges from 193 nm to 261 nm (PDI 0,24 to 0.29), as shown in Fig 6 Size distribution by intensity of soy bean oil emulsions with various concentrations (15% -A, 3% -B, I %-C) of soy bean oil in the cartridge.. Other soy bean oil concentrations other than those shown in Fig. 6 show a mean sizes and relative standard deviations in the same range.

[0057] Example 3 -Soy bean oil and SDS in various concentrations.

[0058] The use of sodium dodecyl sulphate (SDS) and influence of the oil concentration was studied in preparations similar to Example 1.

[0059] Soy bean oil (5-15% by weight) from Bio Planéte was mixed in 2-propanol and stirred until a clear yellowish solution was obtained. SDS (3% by weight) from Roth was dissolved *.. in water and the printing process described in Example I was started using the SDS in water * ** . solution instead of pure water.

[0060] In every case an opaque and slightly yellowish emulsion was obtained after the preparation. Analysis by dynamic light scattering show a monomodal size distribution with a mean size of 270 and 288 nm (PDI: 0.24 and 0.25) as shown in Fig 7 (Size distribution by S...

intensity of soy bean oil (15%) emulsion stabilised by SDS after preparation (A) and after 5 weeks (B). Fig 8 shows a size distribution with a mean size of 213 and 257 nm (PDI: 0.18 and 0.21 (Size distribution by intensity of soy bean oil (5%) emulsion stabilised by SDS after preparation (A) and after S weeks (B).).

[0061] Example 4 -Soy bean oil and other surfactants.

[0062] The influence of the emulsifier was studied in preparations similar to Example 3.

[0063] Soy bean oil (15% by weight) from Bio Planëte was mixed in 2-propanol and stirred until the lecithin extract was dissolved and a clear yellowish solution was obtained. A surfactant (SDS, sodium laureth sulfate (SLES), sodium dodecylbenzene sulfonate (SDBS), egg lecithin (PC), cosmetic emulsifier "LV41", Disodiumcocoylglutamate, cetyltrimethylammonium bromide (CTAB), sodium cocoamphoacetate, polyethylene glycol sorbitan monooleate (Tween 80), polyethylene glycol octyiphenol ether (Triton X-100) and poly ethoxylated fatty alcohol (Dehydol LT7), 3% by weight) is dissolved in water and the printing process as described in Example 3 was started.

[0064] In every case an opaque and slightly yellowish emulsion was obtained after the preparation. Analyses by dynamic light scattering showed a monomodal size distribution with a mean size of 270, 256 and 265 nm (PDI: 0.24, 0.25 and 0.24) as shown in Fig 9 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised with various surfactants, sodium dodecyl sulfate (A), egg lecithine (B) and cetyltrimethylammonium bromide (C) (each 3%) -after preparation) and a mean size of 270, 250 and 240 nm (PDI: 0.24, 0.19 and 0.21) as shown in Fig 10 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by sodium dodecyl sulfate (A), sodium laureth sulfate (B) and sodium dodecyl herizene sulfonate (C) (each 3%) after preparation). Analyses of the emulsions stabilised by * : :* the other surfactants as described above [0064] show mean sizes and relative standard ****** deviations in the same range. Analyses after 3-5 weeks showed a mean size of 288, 280 and 251 nm(PDI: 0.25, 0.23 and 0.19) as shown in Fig 11 (Size distribution by intensity of soy :: bean oil (15%) emulsion stabilised with various surfactants, sodium dodecyl sulfate (A), sodium laureth sulfate (B) and sodium dodecyl benzene sulfonate (C) (each 3%) -after 3-5 : weeks.).

*0*Sss * . [0065] Example 5 -Soy bean oil and lecithin at various temperatures.

[0066] The influence of the temperature in respect to emulsion formation was studied in preparations similar to Example 1.

[00671 Soy bean oil (15% by weight) from Bio Planéte and egg lecithin (3% by weight) from Sigma (P5394) were mixed in 2-propanol and stirred until the lecithin is dissolved and a clear yellowish solution was obtained.

[0068] During the preparation process, the temperature of the water in the closed loop is set to various temperatures ranging from 6 °C to 45 °C.

[006911n every case an opaque and slightly yellowish emulsion was obtained afler the preparation of the emulsion. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of2lI, 306 and 250 nm (PDI: 0.27, 0.18 and 0.26) as shown in Fig 12 (Size distribution by intensity of soy bean oil (15%) emulsion at various temperatures, stabilised by lecithin (3%) at 6 °C (A), 15 °C (B) and 35 °C (C) -after preparation and a mean size of 304, 251 and 183/702 tim (PD!: 0.27, 0.26 and 0.39) as shown in Fig 13 (Size distribution by intensity of soy bean oil (15%) emulsion at various temperatures stabilised by lecithin (3%) at 6 °C (A), 15 °C (B) and 35 °C (C) -3-5 weeks after preparation. Other preparation temperatures than those as depicted from the experiment above(Fig. 12 and Fig 13) shown a mean sizes and relative standard deviations in the similar range.

[0070] Example 6 -Various oils and lecithin.

*:::* [0071] The influence of the type of oil was studied in preparations similar to those described

*. inExamplel. *.I.

:: [0072] An oil (soy bean, castor, coco, linseed, sunflower, walnut, maize seed, sweet almond, jojoba, fish, 15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) was mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

II

[0073] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 262, 258 and 270 nm (PDI: 0.25, 0.26 and 0.27) as shown in Fig 14 (Size distribution by intensity of various oil emulsions, of linseed oil (A), sweet almond oil (B) and fish oil (C) each 15% -stabilised by lecithin (3%) after preparation).

The other oils than those depicted in the results of Fig 14 shown mean sizes and relative standard deviations in a similar range.

[0074] Example 7-Fragrances in oil emulsions.

[0075] The printing of fragrant oils was studied in preparations similar to those described in

Example 1.

[0076] Soy bean oil (15% by weight) from Bio Planéte, a fragrance oil/ingredient (orange, ylang-ylang, carnation, coriander, bergamotte, menthol, 1% by weight) and egg lecithin (3% by weight) from Sigma (P5394) was mixed in 2-propanol and stirred until the lecithin is dissolved and a clear yellowish solution was obtained.

[0077] After the printing, in every case an opaque and slightly yellowish emulsion with a characteristic scent was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 300, 256 and 326 nm (PD!: 0.26, 0.24 and 0.24) as shown in Fig 15 (Size Size distribution by intensity of various oils -(15%) stabilised by lecithin (3%) and equipped with coriander oil (A), orange oil (B) and menthol (C) (1%) after preparation. Preparations with other fragrant oils than those depicted in the results of Fig 15 shown mean sizes and relative standard deviations in a similar range range. * ** * * . * S.

** [0078] Example 8 -Flavours in oil emulsions. S...

* [0079] The printing of flavoured emulsions was studied in preparations similar to Example 7.

: [0080J Soy bean oil (15% by weight) from Bio Planéte, a flavour oil/ingredient (orange, carnation, coriander, bergamotte, menthol, cayenne pepper extract, peppermint 1% by weight) arid egg lecithin (3% by weight) from Sigma (P5394) was mixed in 2-propanol and stirred until the lecithin is dissolved and a clear yellowish solution was obtained.

[0081] After the printing of the emulsion in every case an opaque and slightly yellowish emulsion with a characteristic scent and taste was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 300, 260 and 277 nm (PD!: 0.26, 0.26 and 0.42) as shown in Fig 16 (Size distribution by intensity of fragrant emulsions of soy bean oil (15%) stabilised by lecithin (3%) and equipped with coriander oil (A), carnation oil (B) and cayenne pepper extract (C) (1%) after preparation. Preparations using the other flavoured oils than those depicted by the results in Fig 16 shown mean sizes and relative standard deviations in the same range.

[0082] Example 9 -Active ingredients in oil emulsions.

[0083] The ability to print emulsions containing active ingredients was studied in preparations similar to Example 7.

[0084] Soy bean oil (15% by weight) from Bio Planéte, an active ingredient tocopherol (Vitamin E), cod liver oil, clotrimazol (Antifungal medicament), piroxicam (on steroidal anti inflammatory drug), 1% by weight and egg lecithin (3% by weight) from Sigma (P5394) were mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0085] After the printing of the emulsion, in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 218, 307 and 289 nm (PD!: 0.24, 0.24 and 0.24) as shown in Fig 17 (Size distribution by intensity of emulsions containing various active ingredients with *.. soy bean oil (15%) stabilised by lecithin (3%) equipped with tocopherol (A), clotrimazol (B) *.... and piroxicam (C) -(1%) after preparation). The preparation equipped with cod liver oil S...

showed a mean size of 231 nm and a relative standard deviation (PD!: 0.20) in a similar *.....

* . range.

* : [0086] Example 10 -Paraffin oil emulsions. *

S.....

* [0087] The influence of the oil concentration was studied in preparations similar to Example 3.

[00881 Paraffin oil (2-15% by weight) from Caelo was mixed in tetrahydrofuran (TI-IF) and a clear solution was obtained. SDS (3% by weight) from Roth is dissolved in water and the printing process described in Example 1 is started using the SDS in water solution.

[0089] In every case a colourless (white) emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 310, 303 and 281 nm (PDI: 0.31, 0.25 and 0.36) as shown in Fig 18 (Size distribution by intensity of emulsions with concentrations of 15% (A), 5% (B) and 2% (C) of paraffin oil in the cartridge stabilised by SDS (3%) after preparation [0090] Example 11 -Paraffin oil emulsions.

[0091] The influence of the surfactant was studied in preparations similar to Example 10.

[0092] Paraffin oil (15% by weight) from Caelo was mixed in THF and a clear solution was obtained. A surfactant (SDS, SDBS, SLES, Plantaren APG 1200, 3% by weight) was dissolved in water and the printing process described in Example I is started using the surfactant in water solution.

[0093] In every case a colourless (white) emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 334, 356 and 325 nm (PD!: 0.37, 0.28 and 0.36) as shown in Fig 19 (Size distribution by intensity of paraffin oil (15%) emulsion stabilised by -SDS (A), SDBS (B) and SLES (C) (3%) after preparation * I* * * I * *.

*.. [0094] Example 12-Paraffin oil emulsions. S...

:: [0095] The influence of the surfactant concentration was studied in preparations similar to

Example 10. I... II*.

[0096] Paraffin oil (5% by weight) from Caelo was mixed in THF and a clear solution was obtained. A surfactant (SDS, SDBS, SLES) 3 and 5% by weight was dissolved in water and the printing process described in Example 1 was started using the surfactant in water solution.

[0097] In every case a colourless (white) emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 303 and 221 nm (PDI: 0.25 and 0.35) as shown in Fig 20 (Size distribution by intensity of paraffin oil (5%) emulsion stabilised by -SDS with concentrations of 3% (A) and 5% (B) after preparation.). Analyses of preparations using SDBS and SLES at concentrations of 3% and 5% shown a mean size and size distributions in a similar range.

[0098] Example 13 -Castor oil -lecithin in various solvents.

[0099] The influence of the type of the solvent was studied in preparations similar to Example 1.

[01001 Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in various solvents (2-propanol, ethanol and tetrahydrofüran and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0101] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 204, 198 and 320 nm (PDI: 0.29, 0.23 and 0.28) as shown in Fig 21 (Size distribution by intensity of oil (15%) emulsion stabilised by lecithin (3%) printed from 2-propanol (A), ethanol (B) and tetrahydrofliran (C).

[0102] Example 14-Influence of number of printers.

.. [0103] The influence of the number of the printers was studied in preparations similar to * *.

*. Example 1. * SI.

:: [0104] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish *... solution was obtained. I...

S

S.....

* [0105] During the preparation one or two printers were used.

[0106] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 256 and 266 nm (PDI: 0.25 and 0.26) as shown in Fig 22. (Size distribution by intensity of bean oil (15%) emulsion stabilised by lecithin (3%) printed from an HP 2000C printer.

[0107] Example 15-Influence of type of printer cartridge.

[0108] The influence of the model of the printer was studied in preparations similar to

Example 1.

[0109] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[01 10] During the preparation two different printers (HP 2000C and I-[P Business lnkjet 2200) using different printheads were used.

[0111] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering show a monomodal size distribution with a mean size of 257 and 218 nm (PDI: 0.25 and 0.25) as shown in Fig 23 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed by printer HP 2000C (A) and printer HP Business Inkjet 2200 (B).

[0112] Example 16-Influence of shape of container. e.

[0113] The influence of the shape of the container in the first closed loop was studied in * :.: preparations similar to Example 1.

[0114] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0115] During the preparation of the emuJsions containers of various shapes were used, in the first closed loop.

[0116] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 256, 325 and 259 nm (PDI: 0.24, 0.33 and 0.24) as shown in Fig 24 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into various shapes of container, shape #1(A), shape #2 (B) and shape #3(C).

Analyses of preparations using other shapes of container 140 showed a mean size and size distributions in the same range.

[01171 Example 17-influence of pumping speed.

[0118] The influence of the pumping speed was studied in preparations similar to Example 1.

[0119] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0120] During the preparation the speed of the geared pump in the first closed loop was altered to vary the pumping speed in a linear manner.

[0121] After the preparation in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size between of 244, 281 and 284 nm (PDI: 0.24, 0.28 and 0.25) as shown in Fig 25 :: (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into water under pump speed #1, speed #2 and speed #3 of the geared pump of the * : ..: first closed loop. Increasing pump speed increases the volume exchange rate in container 140.

Analyses of preparations using different pump speeds of in the first closed loop shown a mean size and size distributions in a similar range. as shown in Figure 24 (Size distribution by **** *..: intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed in water under various pump speeds, speed #1(A), speed #2 (B) and speed #3 (C) of the first closed loop).

[00122] Example 18 -influence of point of time of dialysis.

[0123] The influence of the point of time of the solvent dialysis was studied in preparations similar to Example 1.

[01241 Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish solution was obtained.

[0125] The dialysis was operated during the preparation of the emulsion and after the completion of the preparation.

[0126] After the preparation and dialysis step in every case an opaque and slightly yellowish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 256 and 281 nm (PDI: 0.29 and 0.30) as shown in Fig 26 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into water under co-solvent removal continuously during preparation and after preparation.

[0127] Example 19-influence of drop generation principle [0128] The influence of the drop generation principle was studied in preparations similar to

Example 1.

[0129] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) are mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish * solution was obtained. *. ** * S ***

* :: [0130] The preparation was operated using thermal inkjet printers (HP 2000C) and piezo inkjet printers (EPSON StylusColor 300). S...

: [0131] After the preparation and dialysis step in every case an opaque and slightly yellowish *:": emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 243, 244 and 217 nm (PD!: 0.33, 0.25 and 0.22) as shown in Fig 27 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into water using thermal inkjet printers and piezo inkjet printers).

[0132] Example 20 -influence of hydrophobic dye [0133] The influence of presence of a hydrophobic dye was studied in preparations similar to

Example 1.

[0134] Soy bean oil (15% by weight) and egg lecithin (3% by weight) from Sigma (P5394) were mixed in 2-propanol and stirred until the lecithin was dissolved and a clear yellowish * solution was obtained.

[0135] The soy bean oil was equipped with a trace of the dye Sudan IV in one case.

[0136] After the preparation and dialysis step in every case an opaque and slightly yellowish or reddish emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 260 and 277 nm (PDI: 0.34 and 0.27) as shown in Fig 28 (Size distribution by intensity of soy bean oil (15%) emulsion stabilised by lecithin (3%) printed into water equipped with dye Sudan IV and without dye).

[0137] Example 21 -preparation of a water in oil emulsion [0138] The possibility of preparation a water in oil emulsion using inkjets was studied in a preparation similar to Example 1. * 0.

" [0139] Water (15% by weight) and Triton X-l00 (3% by weight) were mixed in 2-propanol se..

and stirred until a clear colourless solution was obtained.

C ****.

* [0140] After the preparation an opaque and colourless emulsion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 1304 nm *..* *..: (PDI: 0.23) as shown in Fig 29 (Size distribution by intensity of water in oil emulsion stabilised by Triton X-lOO printed into water).

[0141] The above examples illustrate various aspects of the invention for the preparation of emulsions using inkjet technology but do not intend to delimit the invention: The use of different inkjet devices (thermal, piezo, gel (piezo inkjet using a viscous ink)); the use of batch (100) and continuous devices (200); the preparation of oil-in-water and water-in-oil emulsions; the use of different surfactants at different concentrations (lecithin, SDS, SLES, SDBS, LV41, Disodiumcocoylglutamate, CTAB, sodium cocoamphoacetate, Tween 80, Triton X-l0O, Dehydol LT7) at 1-5% by weight; the use of different oils at different concentrations (soy bean, castor, coco, linseed, sweet almond, jojoba, fish, paraffin, sunflower, walnut, maize seed) at 1-15% by weight; the use of different co-solvents at different concentrations and their removal at different points in time (2-propanol, ethanol, THF); the emulsification at different temperatures (6 -45°C); the emulsification of different active ingredients (tocopherol, cod liver oil, clotrimazol, piroxicam); the emulsification of different flavours (orange, carnation, coriander, bergamotte, menthol, cayenne pepper extract, peppermint; the emulsification of different fragrances (orange, ylang-ylang, carnation, coriander, bergamotte, menthol); the use of different numbers and models of printers; the use of different shapes of the container, the operation at different pumping speeds of the pump of the first closed loop.

[01421 The invention has been described in terms of illustrative examples. The person skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the attached claims. At least, it should be noted that the invention is not limited to the detailed description of the invention and/or of the examples of the invention. * ** * . * * ** S... * S

S

S. ..S* * S S...

S S...

S *.S * S

Claims

Claims 1. A method for the manufacture of emulsions comprising: -providing (310) a first immiscible substance (105) in at least one inkjet cartridge (110); -providing (320) a second immiscible substance in a container (140); -printing (330) the first immiscible substance (105) through the inkjet printhead (120) to emerge as a droplet jet (130) from the inkjet printhead (120) into container (140) such that the first immiscible substance (105) forms the emulsion (125) with the second immiscible substance (115).
2. A method of claim I, being a batch method for the manufacture of emulsions.
3. A method of claim 1, being a continuous method for the manufacture of emulsions.
4. The method according to one of the above claims, wherein the first immiscible substance (105) comprises a dispersed phase of the emulsion.
5. The method according to the above claims, wherein the second immiscible substance (115) comprises a continuous phase of the emulsion. * ** * * * * ** *.*.
6. The method according to any one of the above claims, further providing an emulsifier : (320) (135) in the at least one inkjet cartridge (110) or the container (140).
7. The method according to any one of the above claims, further comprising agitating the prepared emulsion (125). *

****.* * *
8. The method according to any of the above claims wherein the first immiscible substance is selected from the group consisting of pharmaceuticals, nutraceuticals, foodstuffs, perfumes, flavorants.
9. The method of any one of the above claims, further providing a co-solvent (350) in the inkjet cartridge (110) or the container (140).
10. The method of claim 8, further comprising dialysis removal (360) of the co-solvent.
11. A method of any one of the above claims, selecting temperature during dialysis removal of co-solvent.
12. The method according to any one of the above claims wherein either the first immiscible substance (105) or the second immiscible substance (115) is an aqueous solution.
13. An apparatus (100) for the preparation of emulsions (125) comprising: at least one inkjet cartridge (110) containing at least a first immiscible substance (105) and having at least one inkjet printhead (120); a container (140) positioned underneath the inkjet printhead (120) and containing a second immiscible substance (1 15), such that the first immiscible substance (105) is printed through the inkjet printhead (120) to form the emulsion (125) in the container (140).
14. The apparatus (100) of claim 13, wherein the first immiscible substance (:05) is a bio-active substance.

15. The apparatus according to claim 13 or 14 further comprising: an agitator for agitating the emulsion to aid the formation of the emulsion.
15. The apparatus (200) for the continuous manufacture of emulsions according to one of *.... claims 12-14, further comprising: a dialysis apparatus (270) a plurality of geared pumps (230) S...

a plurality of valves (250) a collection reservoir (220)
16. The apparatus (200) according to any one of claims 12-15, wherein the container (140) is a continuous-flow reservoir wherein, in use, the first immiscible substance (105) and second immiscible substance (115) is replenishable as the emulsion is removed from the collection reservoir (220).
17. The apparatus (200) according to any one of claims 12-16, wherein the dialysis apparatus (270) is used to remove co-solvents used.
18. Use of the apparatus according to one of claims 13 to 18 in a continuous-flow process. * S. * S * * S. S... * S * S..

*S.S.S * .

S *SSS

S.....