WO2010112379A1

WO2010112379A1 - Method and apparatus for the manufacture of a colloidal dispersion using controlled micro-channel flow

Info

Publication number: WO2010112379A1
Application number: PCT/EP2010/053820
Authority: WO
Inventors: Christine Barkmann; Stephan FÖRSTER
Original assignee: Centrum Für Angewandte Nanotechnologie (Can) Gmbh
Priority date: 2009-04-02
Filing date: 2010-03-24
Publication date: 2010-10-07
Also published as: GB0905632D0; EP2414091A1; GB2469087A

Abstract

The present invention discloses a method and an apparatus for the manufacture of a colloidal dispersion (125). The apparatus comprises a solution of a first immiscible substance (105) in a first immiscible substance container (110). The solution of the first immiscible substance (105) is applied to a second immiscible substance (115) via a micro-channel orifice (120) of a micro-channel (150) connectable to the first immiscible substance container (110). The micro-channel orifice (120) is immersed in an agitated second immiscible substance (115). The solution of the first immiscible substance (105) is applied to the second immiscible substance (115) by the operation of the pump (145) to manufacture the colloidal dispersion (125).

Description

Title: Method and apparatus for the manufacture of a colloidal dispersion using controlled micro-channel flow

Cross relation to other applications

[0001] The present application claims benefit and priority of UK patent application No. GB0905632.6 filed on 2 April 2009.

Field of invention

[0002] The present invention discloses a method and an apparatus for the manufacture of a dispersion using a controlled micro-channel flow.

Prior art

[0003] Methods and apparatus' for the manufacture of a dispersion are known in the art.

[0004] An article titled "Development of a new process for the manufacture of polyiso- butylcyano aero late nanoparticles" by N. Fallouh et al has been published in the International Journal of Pharmaceutics, 38, (1986), ppl25-132. The Fallouh document discloses the manufacture of a dispersion of an alcoholic solution of isobutylcyanoacrylate and oil in water by interfacial polymerisation techniques. The dispersion of the Fallouh disclosure comprises particulate nano-capsules with an average diameter of about 200-300nm. The method of the Fallouh document teaches an injection of an alcoholic solution achieved by gravity, of oil and a monomer through a silicon tube that is fitted with a fine tip into an aqueous phase that is subjected to magnetic agitation. Such gravity-driven flow of a solution of the dispersed phase through a capillary into the bulk continuous phase means that a mixing process cannot be carried out continuously or over longer periods of time. In addition the flow rate cannot be accurately maintained because the flow rate of the solution of the dispersed phase depends on the hydrostatic pressure, which decreases with time. A difficulty in the control of the flow rate of the solution of the dispersed phase occurs which yields irreproducible, inhomogeneous particle or droplet size distribution of the disperse phase in the colloidal dispersion.

[0005] Japanese patent application publication No. JP 2004-250367 is titled "Method and apparatus for manufacturing particle containing lipophilic compound". The applicant is Sumito Chemical Co. Japan. The Japanese patent application publication No. JP 2004- 250367 discloses a method and an apparatus for manufacturing uniform-sized particles containing a lipophilic compound by covering the surface of a droplet of the lipophilic compound which is unstable against water, light, oxygen, or the like with a covering agent. The method is achieved by an emulsion dispersion which contains fat-soluble vitamins that are contained inside a dispenser. The emulsion dispersion is dropped from a hollow-bore needle at the tip of the dispenser onto the covering agent from a feeder. The method enables the surface of the droplet of the emulsion dispersion to be covered with the covering agent. The obtained particle is passed through a sieve to be separated from the excessive covering agent and then heated to dry the moisture therein. The obtained particle has a size that is substantially equal to the diameter of the hollow-bore needle.

[0006] International patent application publication No. WO 2009/090824 is titled "Emulsifying apparatus and method of emulsification". The Applicant of the international patent application publication No. WO 2009/09082 is Toshiharu Fukai. The abstract of the international patent application publication No. WO 2009/090824 discloses an emulsifying apparatus and method for manufacturing an emulsion that remains emulsified over a long period of time. The emulsifying apparatus comprises a vessel, a circulatory connecting pipe through which a liquid in the vessel is led outside and thereafter introduced again into the vessel, a pump disposed in the circulatory connecting pipe, and stone-holding vessels holding stones inside. A mixer for mixing two or more liquids is disposed at the downstream-side end of the circulatory connecting pipe so as to be located below the liquid surface level in the vessel. A liquid in the vessel is injected into the mixer and then via the stone-holding vessels with the pump. The liquids in the vessel are circulated through the stone-holding vessels, the mixer, and the inside of the vessel, whereby the liquids are emulsified and the droplets in the emulsion are reduced into finer droplets by the stones. The international patent application publication No. WO 2009/090824 relies on a compli- cated apparatus for the manufacture of an emulsion and also relies on an action of stones to produce the emulsions.

[0007] International patent application publication No. WO 2009/014147 is titled "Wa- ter emulsion production apparatus". The Applicant of international patent application publication No. WO 2009/014147 is Yamato Ecology Corporation. The abstract of the international patent application publication No. WO 2009/014147 discloses a water emulsion production apparatus comprising: a water emulsion container; a pump for applying a pressure to an oil-water mixed solution; an injection nozzle for injecting the oil-water mixed solu- tion supplied through the pump into the water emulsion container; and a collision plate which is arranged opposed to the injection nozzle in the water emulsion container, and against which the oil-water mixed solution injected through the injection nozzle is caused to collide.

[0008] US patent application publication No. US 2007/0149651 is titled "Method for manufacturing dispersion and ink using dispersion obtained thereby". The US patent application publication No. US 2007/0149651 is assigned to Canon Kabushiki Kaisha. The US patent application publication No. US 2007/0149651 discloses a method and system in which at least two types of liquids are ejected from independently provided respective noz- zles so that a travelling direction of the liquids ejected from he nozzles intersect with each other at an angle of 120 degrees or less. The intersection of the liquids ensures that thee liquids flow in an integrated manner to form the desired product.

[0009] Japanese patent application publication No. JP 2007-125535 is titled "Emulsifi- cation process and emulsification apparatus". An abstract of the Japanese patent application publication No. JP 2007-125535 discloses a method which involves initially producing a preliminary emulsion with the aid of an emulsifier. The preliminary emulsion is then re- emulsifying by passing it through a porous membrane under pressure.

[0010] European patent application publication No. EP1842584 is titled "Method and device for obtaining micro and nanometre size particles" and is owned by the Universidad de Sevilla, Spain. The EP 1842584 document discloses a system for particle production and -A- the manufacture of dispersions by means of a flow focussing system. The flow focussing system consists of a chamber pressurised by a continuous supply of a first fluid. Inside the chamber a second fluid is injected by the pressurise created by the first fluid out of the chamber through a feeding point placed in front of a hole on the wall of the chamber. The first fluid pressurising the chamber surrounds the second fluid to expel the second fluid outside the chamber through the hole by producing a thin micro-jet of the second fluid in a controlled way. Due to a capillary instability the micro-jet located inside the laminar flow breaks inside the liquid wherein the device is immersed in a further fluid, producing a homogenous dispersion with controlled size drops. The EP 1842584 document describes a system and method that are highly complicated and require a first fluid flow for pressurising the chamber which surrounds the second fluid to expel the second fluid outside the chamber through the hole of the chamber producing a thin micro-jet of particles that can be used for an emulsion. The particles manufactured according to the EP 1842584 document have relatively large sizes which are not useful for a number of emulsion applications.

[0011] International patent application publication No. WO2007US71901 is owned by the Massachusetts Inst Technology (MIT) and Bringham & Womens Hospital of Massachusetts, USA. The WO2007US71901 patent application is titled "Micro fluidic synthesis of organic nanoparticles" and discloses micro fluidic systems for producing polymeric drug delivery particles. In general the microfluidic system comprises at least two channels that converge into a mixing apparatus.

[0012] German patent application No. DE 19925184Al is owned by Schering AG, Berlin (Germany). The German patent application No. DE19925184A1 describes a method for the continuous preparation of uniform micro- and nanoparticles using a micro-mixing device. The micro-mixing consist of multi-lamellar channel systems leading into a mixing chamber with a common outlet channel. The German patent application No. DE 19925184Al describes the use of the micro-mixing device for the manufacture of polymer micro-particles and microcapsules.

[0013] None of the prior art discloses a method or an apparatus for the manufacture of dispersions according to the present invention. Background of invention

[0014] A colloidal dispersion is a mixture of two immiscible substances that comprises of a disperse phase and a continuous phase. The disperse phase can be a solid or a liquid.

[0015] The dispersed phase is usually in the form of small particles or droplets comprising of a material which is immiscible with the continuous phase. Such dispersions are referred to as suspensions where the particle size of the disperse phase is of about 1 to 100 μm, or referred to as dispersions where the particle size of the disperse phase is smaller than 1 μm. The disperse phase can be an organic and/or an inorganic substance. A colloidal dispersion is referred to as emulsion if the dispersed phase is a liquid. Throughout the disclosure of the present invention the term dispersion or colloidal dispersion encompasses both liquid and solid dispersed phases.

[0016] Colloidal dispersions are often unstable inhomogeneous mixtures that do not form spontaneously. Colloidal dispersions need to be manufactured by special methods to remain stable and homogenous. After manufacture, colloidal dispersions usually have to be stabilised with an emulsifier.

[0017] During the manufacture of the colloidal dispersion high shear forces are required to homogenise the disperse phase with the continuous phase. The high shear forces correspond to the provision of a large amount of energy to homogenise the disperse phase with the continuous phase. The large amount of energy usually results in a considerable amount of damage to either of the immiscible phases that are used to manufacture the colloidal dispersion. The damage can be mechanical damage which leads to denaturisation of bio- molecules, cleavage damage of chemical substances or the damage can be due to a result of an increase in temperature within the immiscible substances that is due to the energy uptake in the colloidal dispersion manufacturing process.

[0018] The emulsifier (also known as surfactant or tenside) is a substance which stabilises the colloidal dispersion to remain homogenous. An example of food emulsifier is egg yolk (where the main emulsifying chemical is lecithin), honey or mustard seed. Protein and low-molecular weight emulsifiers are also known. In some cases, particles can stabilise colloidal dispersions through a mechanism called Pickering stabilisation. A wide variety of emulsifiers are used in the pharmaceutical industry to prepare colloidal dispersions such as creams. Emulsifiers are often referred to as detergents when used for the stabilisation of immiscible phases of water and oil.

[0019] Colloidal dispersions are conventionally manufactured by mechanical methods. The mechanical methods involve a macroscopic two -phase system of the solid or liquid phase that is dispersed in the continuous phase. The mechanical methods include crushing, milling or shear- induced break-up of macroscopic particles or droplets of the disperse phase in the continuous phase. The shear-induced break-up of macroscopic particles or droplets is provided by mechanical methods such as shaking, stirring, homogenising or ultrasound. The mechanical methods require a large intake of energy into the colloidal dispersion, resulting in the dissipation of heat by the colloidal dispersion. The mechanical, shear or heat energy resulting from mechanical methods for the manufacture of the colloidal dispersion is unfavourable. This is because they can harm sensitive chemical compounds that are present in the colloidal dispersion. A further disadvantage of mechanical methods for the manufacture of colloidal dispersions is that it is difficult to predict and control size and size distribution of the disperse phase particles in the colloidal dispersion Such mechanical methods for the manufacture of colloidal dispersions are prohibitive, especially if the dispersion comprises sensitive or bio-active substances such as pharmaceuticals, neutraceuticals, nanoparticles, flavourants, or fragrances.

[0020] A further method for the manufacture of dispersions is by a phase-separation method, starting from a macroscopic one-phase system. In the phase-separation method a solution of the disperse phase in a solvent that is miscible with the continuous phase is mixed with the continuous phase that is a non-solvent for the disperse phase. After mixing, the disperse phase separates from the continuous phase. The phase separation can be carried out such that a stable colloidal dispersion, with particles or droplets in the size range of 1 nm to 1 mm can be manufactured. The phase-separation method, for the manufacture of the colloidal dispersion does not require chemical reactions or mechanical or shear forces. [0021] The phase-separation method for the manufacture of the colloidal dispersion involves the joining of a volume of a solution of the disperse phase with a volume of the continuous phase. The method of joining the two volumes has an important influence on the final particle or droplet size and the distribution of the particle in the colloidal disper- sion. Mixing of the two volumes on a macroscopic scale using conventional mixing devices such as mechanical stirrers, usually leads to an inhomogeneous mixing and a macroscopic phase separation of the disperse phase and the continuous phase. Subsequent breakup of the disperse phase into the colloidal dispersion requires mechanical or shear forces which has the disadvantages as described above.

[0022] A method for the direct manufacture of the colloidal dispersions by the phase- separation is possible if the two volumes of the solution of the disperse phase, with a volume of the continuous phase are mixed on a microscopic scale. This can be achieved by microfluidic devices by utilising microfluidic channel systems such as those described in international patent application No. WO2007US7190. In this method one channel containing the solution of the disperse phase is joined with a channel containing the continuous phase and leads into a common channel where the dispersion is formed. The use of microfluidic channel systems is intrinsically small-scale, elaborate and costly, but can produce stable dispersions of particles in the sub-micron size range. Higher throughput is possible by using multi-lamellar channel micro-mixers as described in German patent application No. DE 19925184Al. The German patent application No. DE 19925184Al describes the mixing of a solution of the dispersed phase and the continuous phase through multilamellar micro-channel systems into a mixing chamber. The mixing chamber joins the liquid streams into an outlet channel. The patent describes the preparation of particle disper- sions with sizes above and below 1 micron.

[0023] Surprisingly, a direct manufacture of stable colloidal dispersions by phase- separation methods by mixing on a microscopic scale can also be achieved, if the solution of the disperse phase is delivered through a micro-channel that is submerged into a bulk volume of the continuous phase. Such a method avoids the use of an additional micro- channel system for the continuous phase and avoids the need for a common outlet micro- channel system. [0024] Such a method and apparatus is described by the present invention. This method and apparatus for the manufacture of the colloidal dispersion is simple and less costly in comparison to the micro fluidic channel systems as described in the international patent application No. WO2007US7190 and the German patent application No. DE 19925184Al.

[0025] The method and apparatus of the present invention allows easy up-scaling for the manufacture of the large volumes of the colloidal dispersion. The method and apparatus of the present invention is adapted for the manufacture of pharmaceutical colloidal dispersions which is controllable, can be continuously carried out and avoids the use of harsh mechanical methods that are known in the art.

[0026] The present invention provides a method and an apparatus for the manufacture of the colloidal dispersion that contains sensitive compounds in an environment whereby the sensitive compounds are not damaged by conventional mechanical manufacturing methods or apparatus. The manufacture of colloidal dispersions according to the present invention produces dispersions with a highly uniform disperse phase particle or droplet size and avoids damage to the colloidal dispersion that is often observed by conventional manufacturing means.

[0027] A possible implementation of the method outlined in paragraph [0025] would be a gravity-driven flow of a solution of the dispersed phase through a capillary into the bulk continuous phase. Such a gravity-driven flow of a solution of the dispersed phase through a capillary into the bulk continuous phase is described in the article titled "Development of a new process for the manufacture of polyisobutylcyanoacrolate nanoparticles" by N. Fallouh et al in the International Journal of Pharmaceutics, 38, (1986), ppl25-132. However, in this case a mixing process cannot be carried out continuously or over longer periods of time. In addition the flow rate cannot be accurately maintained because the flow rate of the solution of the dispersed phase depends on the hydrostatic pressure, which decreases with time, the diameter of the syringe needle, and the viscosity of the solution, which de- pends on the concentration and molecular weight of the disperse phase, and itself can depend on the flow rate. Similar difficulties in the control of the flow rate of the solution of the dispersed phase occur if the flow is manually driven. Such methods yield irreproduci- ble, inhomogeneous particle or droplet size distribution of the disperse phase in the colloidal dispersion.

[0028] There is a need to increase the reproducibility of the size of the particles or droplets in the disperse phase of the colloidal dispersion and to overcome the aforementioned problems.

Summary of invention

[0029] The present invention discloses a method and an apparatus for the manufacture of a colloidal dispersion by utilising a controlled flow through a micro-channel.

[0030] The present invention provides a controllable, stable, and continuous flow of the disperse phase a dispersed phase into a bulk volume of a continuous phase. A solvent used to dissolve the dispersed phase can be continuously and simultaneously removed from the manufactured colloidal dispersion during manufacture, by solvent removal techniques such as dialysis.

[0031] The solution of the disperse phase can be delivered at a controlled rate using pumps. The manufacture of colloidal dispersions using the method of controlled micro- channel flow into the continuous phase produces dispersions or emulsions with highly uniform disperse particle or droplet sizes and avoids damage to the colloidal dispersion that is often observed in conventional manufacture methods.

[0032] In an aspect of the present invention the colloidal dispersion comprises a disperse phase of bioactive substances but is not limited to the manufacture of the colloidal dispersion containing bio-active substances.

[0033] The method comprises applying a first solution of a first immiscible substance with a second immiscible substance in a container. The solution of the first immiscible substance is applied through a micro-channel into the container where the solution of the first immiscible substance spontaneously mixes with the second immiscible substance. A micro-channel orifice of the micro channel is immersed in the second immiscible substance such that the mixing of the solution of the first immiscible substance as it leaves the micro- channel orifice with the second immiscible substance is spontaneous.

[0034] In an aspect of the present invention the method and apparatus provides for the manufacture of the colloidal dispersion in a continuous flow. The continuous flow allows for the manufacture of the colloidal dispersion in large quantities.

[0035] In a further aspect of the present invention the apparatus comprises a means to heat or cool the mixture of the first immiscible substance and the second immiscible substance during the manufacture of the colloidal dispersion.

[0036] The elution rate of the first immiscible substance through the micro-channel is controllable so that the elution rate of the solution of the first immiscible substance from the micro-channel orifice can be controlled during the addition of the solution of the first immiscible substance to the second immiscible substance. The ability to control the elution rate of the first immiscible substance is determinative of the size and the size distribution of particles and droplets of the disperse phase in the colloidal dispersion.

[0037] In an aspect of the present invention, one or a plurality of micro-channels with circular or lamellar cross-section with diameters of the micro-channel orifice between 1 and 1000 μm can be used. The diameter of the micro-channel orifice combined with the rate of elution of the solution of the first immiscible substance from the micro-channel orifice into the second immiscible substance enables control of the size of the particles or droplets of the dispersed phase in the continuous phase of the manufactured colloidal dispersion.

[0038] The micro-channel can be replaced with a micro-channel that has a different diameter of the micro-channel orifice. The micro-channel can be replaced with a micro- channel whereby the micro-channel orifice has various geometries, e.g. slots, sieves etc, this is useful for up-scaling the manufacture of the colloidal dispersion from a laboratory scale to a larger production scale. [0039] In an aspect of the present invention an emulsifier is present in either the first immiscible substance and/or the second immiscible substance to stabilise the manufactured colloidal dispersion.

[0040] In an aspect of the present invention the first immiscible substance or the second immiscible substance is combined with a co-solvent. The co-solvent increases the solubility of the first immiscible substance or the second immiscible substance and increases the efficiency of the manufacture of the colloidal dispersion. The co-solvent is removed from the manufactured colloidal dispersion via solvent extraction; using a dialysis apparatus.

[0041] The method and the apparatus of the present invention allows for the manufacture of a wide range of colloidal dispersions that either would not be possible, or would be difficult to manufacture according to the prior art.

[0042] The invention allows the manufacture of the colloidal dispersion without affecting the properties of either the first immiscible substance or the second immiscible substance or the manufactured colloidal dispersion. The method and apparatus allows for the manufacture of colloidal dispersions that comprise bio-active substances without affecting the properties of the bio-active substances.

[0043] In a further aspect of the present invention a continuous manufacture of the colloidal dispersions allows large quantities of colloidal dispersion to be manufactured with or without co-solvents.

[0044] The immersion of the micro-channel orifice into the second immiscible substance enables the manufacture of the colloidal dispersion which would not be possible in the instance where the first immiscible substance would be unstable if it came into contact with air.

[0045] The immersion of the micro-channel orifice in the second immiscible substance enables the manufacture of colloidal dispersions spontaneously and overcomes problems associated with agglomeration in a mixing chamber or at the micro-channel orifice. The second immiscible substance is continuously agitated during the addition of the first immiscible substance to the second immiscible substance.

Description of drawings

Figure 1. Shows an apparatus for the batch manufacture of a colloidal dispersion according to an aspect of the invention.

Figure 2. Shows an apparatus for the batch manufacture of a colloidal dispersion according to an aspect of the invention.

Figure 3. Shows an apparatus for the continuous or batch manufacture of a colloidal dispersion according to an aspect of the invention.

Figure 4. Shows an apparatus for the continuous or batch manufacture of a colloidal dispersion according to an aspect of the invention.

Figure 5. Shows an apparatus for the continuous manufacture of a colloidal dispersion according to an aspect of the invention including dialysis removal of a co-solvent from the colloidal dispersion.

Figure 6 - 11. Shows various geometries and designs of a micro-channel orifice of a micro-channel in various aspects of the invention.

Figure 12. Depicts a flow diagram for a method for the manufacture of a colloidal dispersion.

Figure 13. Shows a size distribution by intensity of poly-DL-lactide (A) colloidal dispersion.

Figure 14. Shows a size distribution by intensity of poly-DL-lactide colloidal dispersion with various solution concentrations (0.5% - A; 1% - B). Figure 15. Shows a size distribution by intensity of poly-DL-lactide colloidal dispersion with different emulsifϊers (SDS - A; Tween 80 - B).

Figure 16. Shows a size distribution by intensity of colloidal dispersion of different biode- gradable polymers (poly-ε-caprolacton - A; poly-DL-lactide-co-caprolactone - B; poly-DL- lactide-co- glycolide - C).

Figure 17. Shows a size distribution by intensity of poly-DL-lactide colloidal dispersion with various solvents in the used polymer solution (acetone - A; acetonitrile - B).

Figure 18. Shows a size distribution by intensity of poly-DL-lactide colloidal dispersion with a trace amount of the hydrophobic dye Sudan IV (A).

Figure 19. Shows a size distribution by intensity of poly-DL-lactide colloidal dispersion comprising an amount of a pharmaceutically active ingredient (Clotrimazol - A).

Figure 20. Shows a size distribution by intensity of poly-butylcyanacrylate (A) colloidal dispersion.

Figure 21. Shows a size distribution by intensity of poly-butylcyanacrylate colloidal dispersion stabilised with an emulsifier present in water (A).

Figure 22. Shows a size distribution by intensity of poly-butylcyanacrylate (A) colloidal dispersion stabilised with an emulsifier present in a monomer solution.

Figure 23. Shows a size distribution by intensity of poly-butylcyanacrylate (A) colloidal dispersion stabilised with an ultrahydrophobic excipient (olive oil).

Figure 24. Shows a size distribution by intensity of poly-butylcyanacrylate (A) colloidal dispersion stabilised with an ultrahydrophobic excipient (olive oil) and an emulsifier. Figure 25. Shows a size distribution by intensity of poly-butylcyanacrylate (A) colloidal dispersion containing a hydrophobic dye (Sudan IV) stabilised with an emulsifϊer.

Figure 26. Shows a size distribution by intensity of poly-butylcyanacrylate colloidal dis- persion containing a pharmaceutically active ingredient (Clotrimazol) stabilised with an ultrahydrophobic excipient (olive oil) in water (A) and emulsifϊer (T ween 80) solution (B).}

Figure 27. Shows a size distribution by intensity of SU-8 colloidal dispersion (A) prepared in the presence of a cycloaliphatic amine (diaminodicyclohexylamine - DDM) and an ultrahydrophobic excipient (olive oil) stabilised by SDS (2%) and tempered for 2 hours at 60 ⁰C after manufacture.

Figure 28. Shows a size distribution by intensity of SU-8 colloidal dispersion (A) manufac- tured in the presence of an aromatic amine (xylylenediamine - XDA) and an ultrahydrophobic excipient (olive oil), stabilised by SDS (2%) and tempered for 2 hours at 60 ⁰C after manufacture.

Figure 29. Shows a size distribution by intensity of PNIPAM colloidal dispersion (A) manufactured at 50 ⁰C.

Figure 30. Shows a size distribution by intensity of poly-n-isopropylacrylamide (PNIPAM) colloidal dispersion (A) stabilised with butylcyanoacrylate (BCA) manufactured at 50 ⁰C.

Figure 31. Shows a size distribution by intensity of polyisoprene-block-polyethyleneoxide (PI-PEO) colloidal dispersion (A) manufactured at 20 ⁰C.

Figure 32. Shows a size distribution by intensity of polybutadiene-block-polyethyleneoxide (PB-PEO) colloidal dispersion (A) manufactured at 40 ⁰C and polylactide-block- polyethyleneoxide (PLA-PEO) colloidal dispersion (B) manufactured at 80 ⁰C. Figure 33. Shows a size distribution by intensity of an oil-in-water colloidal dispersion manufactured from sunflower oil in a 2% SDS-solution.

Figure 34. Shows a size distribution by intensity of an oil-in-water colloidal dispersion manufactured from olive oil (A) and rape seed oil (B) in a 2% SDS-solution.

Figure 35. Shows a size distribution by intensity of an oil-in-water colloidal dispersion manufactured from sunflower oil in 2% SDS-solution and containing a trace amount of a hydrophobic dye (Sudan IV).

Figure 36. Shows a size distribution by intensity of an oil-in-water colloidal dispersion manufactured from sunflower oil in a 2% SDS-solution and containing a trace amount of a flavouring agent (bergamot oil).

Figure 37. Shows a size distribution by intensity of an oil-in-water colloidal dispersion manufactured from sunflower oil in a 2% SDS-solution and containing a trace amount of a pharmaceutically active agent (clotrimazol).

Figure 38. Shows a size distribution by intensity of a PLA colloidal dispersion manufac- tured in a continuous process using a lamellar micro-channel orifice.

Figure 39. Shows size-dependent reproducibility of a colloidal dispersion, of motorised elution (above) and of manual elution (below).

Figure 40. Shows dispersity-dependent reproducibility of motorised elution (above) and of manual elution (below) for the manufacture of a colloidal dispersion.

Detailed description of invention

[0046] For a complete understanding of the present invention and the advantages thereof, reference is made to the following detailed description taken in conjunction with the accompanying Figures. [0047] It should be appreciated that the various aspects and embodiments of the present invention disclosed herein are merely illustrative of specific ways to make and use the invention and do not therefore limit the scope of invention when taken into consideration with the appended claims and the following detailed description and the accompanying Figures.

[0048] It should be realised that features from one aspect and embodiment of the invention will be apparent to those skilled in the art from a consideration of the specification or practice of the invention disclosed herein and these features can be combined with features from other aspects and embodiments of the invention.

[0049] The present invention teaches a method and an apparatus for the manufacture of a colloidal dispersion 125. The colloidal dispersion 125 includes a dispersion with a dispersed particle size in the range of 10^"9 m to 10^"6 m. The colloidal dispersion 125 is manu- factured from a first solution of a first immiscible substance 105 and a second immiscible substance 115. The first immiscible substance 105 is a disperse phase or a continuous phase. The second immiscible substance 115 is a disperse phase or a continuous phase. The first immiscible substance 105 and the second immiscible substance 115 must be at least one of a disperse phase and a continuous phase, but cannot be the same phase.

[0050] The present invention is directed particularly to the manufacture of the colloidal dispersion 125 comprising a bio-active substance such as a pharmaceutical, a neutraceuti- cal, a flavourant or a fragrance. The invention is not limited to the manufacture of a colloidal dispersion 125 that comprises these bio-active substances.

[0051] The bioactive substance can either be present in the first immiscible substance 105 or the second immiscible substance 115.

[0052] An embodiment of the apparatus according to the present invention is shown in Figure 1 and the apparatus comprises: a first immiscible substance container 110 for holding the first immiscible substance 105, a pump 145 to apply the first immiscible substance 105 from the first immiscible substance container 110, - a micro-channel 150 attached to the first immiscible substance container 110, a micro-channel orifice 120 of the micro-channel 150 immersed in a second immiscible substance 115. The second immiscible substance 105 is in a container 140 into which the colloidal dispersion 125 is manufactured.

[0053] The micro-channel 150 is in the form of a tube and is connectable to the first immiscible substance container 110.

[0054] The pump 145 maintains and controls a rate of elution of the first immiscible substance 105 from the first immiscible substance container 110, via the micro-channel orifice 120, into the second immiscible substance 115. When the first immiscible substance 105 and the second immiscible substance 115 come into contact, the dispersion 125 is manufactured.

[0055] The pump 145 is not limited to a particular type of pump 145. In the embodi- ment of the invention shown in Figure 1, the first immiscible substance container 110 is a syringe. In the embodiment of the invention shown in Figure 1, the pump 145 is a motor driven syringe pump. In the embodiment of the invention shown in Figure 1, the micro - channel 150 is in the form of a syringe needle. In a further aspect of the present invention the micro-channel 150, can be replaced with a micro-channel 150 that has a different di- ameter of the micro-channel orifice 120 in the range of about 0.1 to 1.2 mm.

[0056] The pump 145 is used to apply the first immiscible substance 105 through the micro-channel orifice 120 with a controllable elution rate. A flow rate of the pump 145 can be set within a typical elution rate of between 0.1 to 99.9 ml/hour. The elution rate is not limited to between 0.1 to 99.9 ml/hour. [0057] The teachings of the present invention are not limited to the use of one pump 145. A plurality of pumps 145 can be used in further aspects of the present invention.

[0058] Figure 2 shows a further embodiment of the present invention. In Figure 2 the pump 145 is connected to the first immiscible substance container 110 to control the elu- tion of the first immiscible substance 105, via the micro-channel orifice 120, into the second immiscible substance 115. When the first immiscible substance 105 and the second immiscible substance 115 come into contact, the colloidal dispersion 125 is manufactured. The pump 145 is this embodiment could be for example a geared pump. In the embodiment of the invention shown in Figure 2, the first immiscible substance container 110 is connected directly to the pump 145. In the embodiment of the invention shown in Figure 2, the micro-channel 150 is in the form of tube.

[0059] In a further aspect of the present invention the micro-channel 150, can be re- placed with a micro-channel 150 that has a different diameter of the micro-channel orifice 120 in the range of about 0.1 to 1.2 mm. In the embodiment of Figure 2 a heating and or agitating device 155 is provided to heat and or agitate the colloidal emulsion 125 during its manufacture. The heating facilitates the manufacture of dispersions 125 where either the first immiscible substance 105 or the second immiscible substance 115 is a viscous sub- stance. An emulsifϊer 135 may be present in either of the first immiscible substance 105, the second immiscible substance 115 or may be added to the manufactured colloidal dispersion 125 as a stabiliser.

[0060] As the first immiscible substance 105 is eluted from the micro-channel orifice 120 the first immiscible substance 105 comes into immediate contact with the second immiscible substance 115. The immediate contact arises because the micro-channel orifice 120 is always immersed in the second immiscible substance 115. Simultaneously the dispersion 125 is manufactured when the first immiscible substance 105 comes into contact with the second immiscible substance 115.

[0061] In the embodiments of the present invention as shown in Figure 1 and 2, the colloidal dispersion 125 is manufactured in a batch manufacturing apparatus. In the em- bodiments shown in Figure 1 and 2, the first immiscible substance container 110 is filled with the first immiscible substance 105. The first immiscible substance 105 is then applied by the pump 145 through the micro-channel orifice 120 via the micro-channel 150 into the container 140, which holds the second immiscible substance 115. As the first immiscible substance 105 is applied through the micro-channel orifice 120, into the second immiscible substance 115, the dispersion 125 is spontaneously manufactured in the container 140. During the manufacture of the dispersion 125, the second immiscible substance 115 is constantly stirred as the colloidal dispersion 125 is manufactured. The constant stirring of the second immiscible substance 115, avoids agglomeration of the manufactured dispersion 125 at the micro-channel orifice 120 and promotes the manufacture of the dispersion 125 having a relatively consistent particle sizes within the dispersion 125.

[0062] In a further embodiment of the present invention as shown in Figure 3 and Figure 4, the colloidal dispersion 125 can be manufactured in a continuous manufacturing apparatus. The continuous manufacturing apparatus allows for the manufacture of large quantities of the colloidal dispersion 125. The embodiments of Figure 3 and Figure 4 comprise a collection reservoir 220 for collecting the manufactured colloidal dispersion 125 as the colloidal dispersion 125 manufactured.

[0063] As the first immiscible substance 105 is eluted from the micro-channel orifice 120 the first immiscible substance 105 comes into immediate contact with the second immiscible substance 115. The immediate contact arises because the micro-channel orifice 120 is always immersed in the second immiscible substance 115. Simultaneously the dispersion 125 is manufactured when the first immiscible substance 105 comes into contact with the second immiscible substance 115. During the manufacture of the dispersion 125, the second immiscible substance 115 is constantly stirred as the colloidal dispersion 125 is manufactured. The constant stirring of the second immiscible substance 115, avoids agglomeration of the manufactured dispersion 125 at the micro-channel orifice 120 and promotes the manufacture of the dispersion 125 having a relatively consistent particle sizes within the dispersion 125. [0064] As the colloidal dispersion 125 is manufactured in the container 140, the colloidal dispersion 125 is pumped by a geared pump 230 from the container 140 via a series of tubes 210 into the collection reservoir 220. As the manufactured colloidal dispersion 125 is collected from the collection reservoir 220 the first immiscible substance 105 and the sec- ond immiscible substance 115 are replenished in the first immiscible substance container 110 and the container 140 respectively.

[0065] In the embodiment of Figure 4 a heating and or agitating device 155 is provided to heat and or agitate the colloidal emulsion 125 during its manufacture. The heating facili- tates the manufacture of dispersions 125 where either the first immiscible substance 105 or the second immiscible substance 115 is a viscous substance.

[0066] The emulsifϊer 135 may be present in the first immiscible substance 105, the second immiscible substance 115, or may be added to the manufactured colloidal emulsion 125 in either the container 140 or the collection reservoir 220. The emulsifϊer 135 is used to stabilise the colloidal dispersion 125.

[0067] In the embodiment of the invention as shown in Figure 5, the apparatus is used to manufacture the dispersion 125 in a continuous manufacturing apparatus using a co- solvent. The co-solvent is removed from the manufactured colloidal emulsion 125 by a dialysis apparatus 290. The embodiment of the invention as shown in Figure 5 can also be used for the manufacture of the colloidal dispersion 125, in a continuous manufacturing apparatus without using a co-solvent.

[0068] In an aspect where no co-solvent is used, the first immiscible substance container 110 (not shown) is filled with the first immiscible substance 105. The first immiscible substance 105 is then applied with the pump 145 (not shown) via the micro-channel 150 through the micro-channel orifice 120, into the container 140. The container 140 contains the second immiscible substance 115. As the first immiscible substance 105 is ap- plied, the first immiscible substance 105 spontaneously immerses into the second immiscible substance 115 because the micro-channel orifice 120 is immersed in the second im- miscible substance to lead to the manufacture of the colloidal dispersion 125 in the container 140.

[0069] As the first immiscible substance 105 immerses into the second immiscible sub- stance 115, the second immiscible substance 115 is constantly stirred. The constant stirring of the second immiscible substance 115, avoids agglomeration of the manufactured dispersion 125 at the micro-channel orifice 120 and promotes the manufacture of the dispersion 125 having relatively consistent particle size within the colloidal dispersion 125. In the embodiment of Figure 5 a heating and or agitating device 155 is provided to heat and or agitate the colloidal emulsion 125 during its manufacture. The heating facilitates the manufacture of dispersions 125 where either the first immiscible substance 105 or the second immiscible substance 115 comprises a viscous substance.

[0070] As the colloidal dispersion 125 is manufactured in the container 140, the colloi- dal dispersion is pumped by the geared pump 230 from the container 140 via a series of tubes 210 into the collection reservoir 220. As the manufactured colloidal dispersion 125 is collected from the collection reservoir 220 the first immiscible substance 105 and the second immiscible substance 115 are replenished in the first immiscible substance container 110 and the container 140 respectively.

[0071] In an aspect where no co-solvent is used, valves 250 are used to isolate the continuous manufacturing apparatus from the dialysis apparatus 290.

[0072] Where the co-solvent is used, the co-solvent may be added to either the first immiscible substance 105 and/or to the second immiscible substance 115. The co-solvent is used to alter the viscosity of the first immiscible substance 105 and/or the second immiscible substance 115. An example of a co-solvent is acetone. The co-solvent provides a sufficient flow rate of the first immiscible substance 105 and/or the second immiscible substance 115 in the apparatus shown in Figure 5. The co-solvent facilitates efficient manufac- ture of the colloidal dispersion 125. In the aspect of the invention where the co-solvent is used, the co-solvent is removed from the manufactured colloidal emulsion 125, by having the valves 250 open. [0073] The first immiscible substance 105 is applied through the micro-channel orifice 120 into the container 140 which contains the second immiscible substance 115. As the first immiscible substance 105 is applied, the first immiscible substance immerses spontaneously into the second immiscible substance 115. Since the micro-channel orifice 120 of the micro-channel is immersed in the second immiscible substance 115, spontaneous manufacture of the dispersion 125 occurs.

[0074] The co-solvent is removed from the colloidal dispersion 125 using the dialysis apparatus 290. The embodiment of Figure 5 incorporates a collection reservoir 220 for collecting the manufactured colloidal dispersion 125. The collection reservoir 220 comprises outlets 280 and 281 for the extraction of the manufactured dispersion 125.

[0075] Removal of the co-solvent is achieved by having valves 250 in an open position and allowing the manufactured dispersion 125 to pass through the dialysis apparatus 290. The dialysis apparatus 290 is collectively shown in Figure 5. The dialysis apparatus comprises tubes 210, geared pumps 230 and a dialysis cartridge 240. The dialysis cartridge 240 is attached to a fresh water closed loop at a water reservoir 260. The water reservoir 260 is connected to a water system (not shown) by pipes 270 and 271. The temperature of the water reservoir 260 can be pre-set to facilitate the removal of the co-solvents at different temperatures. The different temperatures also facilitate the reduction in volatility of the first immiscible substance 105 and/or the second immiscible substance 115.

[0076] The dialysis apparatus 290 is connected to the container 140 and the collection reservoir 220 by a series of the tubes 210. The dispersion forming materials (the first im- miscible substance 105, the second immiscible substance 115, and the co-solvent as well as the emulsifier 135) are carried through the tubes 210 by the geared pumps 230 through the dialysis apparatus 290. The co-solvent is removed by dialysis against a membrane (not shown). The manufactured dispersion 125 is then substantially free of the co-solvent and is transported to the collection reservoir 220 from the dialysis apparatus 290 via the tubes 210 and the geared pumps 230. The manufactured dispersion 125 is collected from the collection reservoir 220 via outlets 280 and 281. [0077] The co-solvent is miscible with either the fist immiscible substance 105 or the second immiscible substance 115. The co-solvent is miscible with water. The co-solvent is inert (i.e. are uncreative) towards the first immiscible substance 105, the second immiscible substance 115, the emulsifϊer 135 and the colloidal dispersion 125. An example of a co-solvent used in the present invention is acetone.

[0078] As the colloidal dispersion 125 is manufactured and collected from the collection reservoir 220, the first immiscible substance container 110 can be re-filled with more first immiscible solvent 105 and the container can be re-filled with more second immis- cible solvent 115 to enable the continuous manufacture of the colloidal dispersion 125.

[0079] In a further aspect of the present invention the micro-channel 150, has a micro- channel orifice 120 that may have different geometries and designs, which are shown in Figures 6-11. The different geometries and designs of the micro-channel orifice 120 are useful for up-scaling a manufacturing process of the colloidal dispersions 125 from laboratory scale to production scale. For example, the micro-channel orifice 120 can be shaped as a rectangular slot (Figure 6), which has a size in a transverse direction in the range of 50 to 1000 μm and in the longitudinal direction in the range of 0.1 to 10 cm. In a further aspect of the invention the micro-channel orifice 120 can be shaped as a zigzag slot or of as a me- andering shape (Figure 7). In a further aspect of the invention the micro-channel orifice 120 can be engineered as an assembly comprising of a plurality of concentrically telescopic tubes of increasing diameters, in which the clearance between the concentrically telescopic tubes is in the range of 50 to 1000 μm (Figure 8). The rims of the concentrically telescopic tubes or slots can be arranged in a single plane (Figure 8a) or in a staggered ar- rangement (Figure 8d), or in an alternating arrangement (Figure 8b and 8c). In a further aspect of the invention the micro-channel orifice 120 can have the form of a sieve (Figure 9). In a further aspect of the invention the orifice of the feed pipe can be intersected by lamellae (Figure 10). In a further aspect of the invention the micro-channel orifice 120 can be continuously adjusted during the manufacture of the colloidal dispersion 125. The con- tinuous adjustment of the micro-channel orifice 120 can be achieved by a mechanically or electro-mechanically adjustable micro-channel orifice 120 (Figure 11). The continuous adjustment of the micro-channel orifice 120 during the manufacture of the colloidal disper- sion is advantageous. It has been observed that not only the flow rate of the first immiscible substance 105 from the micro-channel orifice 120, but also the geometry of the micro channel orifice is influential in determining the size and distribution of particles during the manufacture of the colloidal dispersion 125.

[0080] The method for the manufacture of the colloidal dispersion 125 is described with reference to Figure 12. Figure 12 shows a schematic representation for the method for the manufacture of the colloidal dispersion 125 according to the present invention.

[0081] Start 300 is followed by a step 310 of providing the first immiscible substance 105 which is filled into the first immiscible substance container 110. A next step 315 is to provide the second immiscible substance 115 in the container 140. This is followed by the optional step 320 whereby the emulsifier 135 is added to either the solution of the first immiscible substance 105 or the second immiscible substance of the continuous phase 115.

[0082] In the method for the batch manufacture of dispersions 125, the solution of a first immiscible substance 105 is then applied into the container 140 via the micro-channel orifice 120 which is immersed into a constantly agitated second immiscible substance 115 which provides 340 the dispersion 125 ready for collection.

[0083] Figure 12 also shows a method for the continuous manufacture of dispersions according to the present invention. The start 300 is followed by the step 310 of providing of a first immiscible substance 115 which is filled into the first immiscible substance container 110. The next step 315 is to provide the second immiscible 115 to the container 140. This is followed by the optional step 320 whereby the emulsifier 135 is added to either the first immiscible substance 105 or the second immiscible substance 115.

[0084] The step 350 for the continuous manufacture of the dispersion allows for the addition of the co-solvent to either the first immiscible 105 or the second immiscible sub- stance 115. The solution of the first immiscible substance 105 is then applied in step 345 to the container 140 where the colloidal dispersion 125 is manufactured. The first immiscible substance 105 is applied via the micro-channel orifice 120 which is immersed in the sec- ond immiscible substance 115. The manufactured colloidal dispersion 125 is then withdrawn and subjected to dialysis in step 360 whereby the co-solvent is removed via the dialysis apparatus 290 from the colloidal dispersion 125 to leads to the step of collecting the manufactured colloidal dispersion 370. The steps 300 to 370 are then, if necessary, re- peated for the continuous manufacture of the dispersion 125. It should be noted that this repetition can be used for the manufacture of dispersions 125 without the use of co- solvents for the production of dispersions that contain non volatile first 105 or second 115 immiscible substances.

Examples

[0085] The examples demonstrate the various aspects of the invention but are not intended to limit the invention. Figures 13 - 38 show a size distribution of the particles of the colloidal dispersion by intensity (scattered light), dynamic light scattering measurements of the manufactured colloidal dispersions 125 was made using a Zetasizer Nano series Nano- ZS red label machine manufactured by Malvern Instruments.

[0086] Example 1 - Manufacture of po Iy-DL- lactide colloidal dispersion.

[0087] Poly-DL-lactide (0.5 g) prepared by anionic polymerisation was dissolved in acetone (9.5 g) and stirred until a clear solution of the first immiscible substance 105 was formed.

[0088] The clear solution of the first immiscible substance 105 was filled into the first immiscible substance container 110 and applied into the container 140 (which in this example is small beaker filled the second immiscible substance 115 - water). The water is continuously pumped through the system as depicted in Figure 5. The acetone (co-solvent) was constantly removed utilising cross flow dialysis provided by the dialysis apparatus 290. [0089] After the first immiscible substance 105 was applied to the second immiscible substance 115 the acetone (co-solvent) was removed by dialysis in the dialysis apparatus 290 to yield an opaque slightly white colloidal dispersion 125.

[0090] The manufactured dispersion 125 was filtered through a syringe filter (Schlei- cher & Schϋll FP 30/5.0 CN) with a pore size of 5 μm into a single use cuvette (Plasti- brand, PS; semi micro from Brand).

[0091] The particles of the colloidal dispersion show a diameter of 115 nm and a rela- tive standard deviation (PDI) of 0.08 as shown in Figure 13 (Size distribution by intensity of poly-DL-lactide dispersion). The dispersion shows good stability over a period of approximately six weeks.

[0092] Example 2 - Manufacture of poly-DL-lactide dispersions in various concentra- tions.

[0093] The influence of the polymer concentration was studied in manufactures similar to Example 1.

[0094] Poly-DL-lactide was dissolved in various concentrations of about 0.1 to 5% by weight in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[0095] In every case an opaque and slightly white dispersion was obtained after the manufacture method. Analysis by dynamic light scattering showed similar results to example 1. The diameter of the particles of the dispersion range from 60 nm to 180 nm (PDI 0.04 to 0.12) as shown in Figure 14, Size distribution by intensity of poly-DL-lactide dispersions with various concentrations poly-DL-lactide solution. Figure 14 shows a size distribution with a mean size of 74, 115 and 131 nm (PDI: 0.1, 0.08 and 0.08 (Size distribu- tion by intensity of poly-DL-lactide dispersion (0.1%) (A), size distribution by intensity of poly-DL-lactide dispersion (0.5%) (B) and size distribution by intensity of poly-DL-lactide dispersion (1.0%) (C). Other concentrations of po Iy-DL- lactide concentrations than those shown in Figure 14 show mean sizes and relative standard deviations in the same range.

[0096] Example 3 - poly-DL-lactide and Tween 80 emulsifier in various concentra- tions.

[0097] The use of Tween 80 emulsifier and influence of the polymer concentration was studied in a manufacture method similar to Example 1.

[0098] Poly-DL-lactide (0.5 % by weight) was dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained. Tween 80 (2% by weight) from Roth was dissolved in water and the method described in Example 1 was followed using the Tween 80 in water as the second immiscible substance 115 instead of pure water.

[0099] In every case an opaque and slightly white dispersion was obtained after the manufacture. Analysis by dynamic light scattering show a monomodal size distribution with a mean size of 112 nm (PDI: 0.08) as shown in Figure 15 (Size distribution by intensity of poly-DL-lactide (0.5%) stabilised by Tween 80 after manufacture (A). Other emul- sifier concentrations than those shown in Figure 15 show mean sizes and relative standard deviations in the same range.

[00100] Example 4 - Various polymers.

[00101] The usability of other per se known as bioactive polymers were studied in methods similar to those described in Example 1.

[00102] The biodegradable polymers (poly-ε-caprolactone, poly-DL-lactide-co- caprolactone or poly-DL-lactide-co-glycolide 1% by weight) were dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained. [00103] After the manufacture in every case an opaque and slightly white dispersion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution with a mean size of 137, 165 and 111 nm of the particles of the dispersion (PDI: 0.07, 0.08 and 0.04) as shown in Figure 16 (Size distribution by intensity of various dispersions, of poly- ε-caprolactone (A), poly-DL-lactide-co-caprolactone (B), poly-DL-lactide-co-glycolide (C) each 0.5%). Other polymer concentrations than those shown in Figure 16 show mean sizes and relative standard deviations in the same range.

[00104] Example 5 - Different solvents for polymer-solutions in dispersions.

[00105] The manufacture of polymeric dispersions using different solvents was studied in manufactures similar to those described in Example 1.

[00106] Poly-DL-lactide (0.5 % by weight) was dissolved in a solvent (acetone, or ace- tonitrile) and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00107] After the manufacture of the dispersion 125, in every case an opaque and slightly white dispersion was obtained. Analysis by dynamic light scattering showed a monomodal size distribution of the particles of the dispersion with a mean size of 90 and 138 nm (PDI: 0.08 and 0.04) as shown in Figurel7 (Size distribution by intensity of poly- DL-Lactide (0.5%) prepared from acetone (A) and acetonitrile (B) after manufacture. Manufacture of dispersions with other solvents than those depicted in the results of Figure 17 show mean sizes and relative standard deviations in a similar range. The particles of dispersions produced of solutions from other solvents than those shown in Figure 17 show mean sizes and relative standard deviations in the same range.

[00108] Example 6 - Influence of lipophilic soluble dyes on poly-DL-lactide dispersions.

[00109] Poly-DL-lactide (0.5 % by weight) was dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained. [00110] A trace of the lipophilic soluble dye Sudan IV was added to the obtained solution first immiscible substance 105.

[00111] The manufacture process described in Example 1 was started using Tween 80 in water solution (2%) as the second immiscible substance 115.

[00112] After the manufacture an opaque and slightly pink dispersion was obtained. The dispersed particles showed a diameter of 130 nm and a relative standard deviation (PDI) of 0.18 as shown in Figure 18 (Size distribution by intensity of poly-DL-lactide dispersion). The dispersion showed good stability over a period of approximately six weeks. Other dyes than those shown in Figure 18 show mean sizes and relative standard deviations in the same range.

[00113] Example 7 - Manufacture of poly-DL-lactide dispersions containing pharmaceu- tically active ingredients.

[00114] Poly-DL-lactide was dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00115] 10 mg of a pharmaceutically active ingredient (Clotrimazol) was added to 10 g of the obtained solution first immiscible substance 105.

[00116] The manufacture process described in Example 1 was started using Tween 80 in water solution (2%) as the second immiscible substance 115.

[00117] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles of the dispersion showed a diameter of 160 nm and a relative standard deviation (PDI) of 0.08 as shown in Figure 19 (Size distribution by intensity of poly- DL-lactide dispersion). The dispersion showed good stability over a period of approxi- mately six weeks. Other pharmaceutical active ingredients than those shown in Figure 19 show mean sizes and relative standard deviations in the same range. [00118] Example 8 - Manufacture of poly-butylcyanacrylate dispersions.

[00119] Poly-butylcyanacrylate (from Henkel Loctite) (1% by weight) was mixed with acetone and stirred until a clear solution of the first immiscible substance 105 was ob- tained.

[00120] The manufacture process and the dialysis process were performed as described in Example 1.

[00121] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles of the dispersion showed a diameter of 110 nm and a relative standard deviation (PDI) of 0.09 as shown in Figure 20 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. Other butylcyanacrylate concentrations than those shown in Figure 20 show mean sizes and relative standard deviations in the same range.

[00122] Example 9 - Manufacture of poly-butylcyanacrylate dispersion stabilised with emulsifier.

[00123] Butylcyanacrylate (from Henkel Loctite, 1% by weight) was mixed with acetone and stirred until a clear solution was obtained. The manufacture process described in Example 1 was started using the Tween 80 in water solution (2%) instead of pure water.

[00124] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 98.4 nm and a relative standard deviation (PDI) of 0.19 as shown in Figure 21 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. Other emulsifier concentrations than those shown in Figure 21 show mean sizes and relative standard deviations in the same range.

[00125] Example 10 - Manufacture of poly-butylcyanacrylate dispersions being stabilised with emulsifier. [00126] Butylcyanacrylate (from Henkel Loctite, 1% by weight) and Tween 80 (2% by weight) were mixed with acetone and stirred until a clear solution of the first immiscible substance 105 was obtained. The manufacture process described in Example 1 was started using of pure water as the second immiscible substance.

[00127] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 89.5 nm and a relative standard deviation (PDI) of 0.09 as shown in Figure 22 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. Other butylcyanacrylate or emulsifier concentrations than those shown in Figure 22 show mean sizes and relative standard deviations in the same range.

[00128] Example 11 - Manufacture of poly-butylcyanacrylate dispersions mixed with oil.

[00129] Butylcyanacrylate (from Henkel Loctite, 1% by weight) and sunflower oil (25% by weight related to the monomer butylcyanacrylate) were mixed with acetone and stirred until a clear solution was obtained of the first immiscible substance 105. The manufacture process described in Example 1 was started using pure water as the second immiscible sub- stance 115.

[00130] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 120 nm and a relative standard deviation (PDI) of 0.065 as shown in Figure 23 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. Other butylcyanacrylate or oil concentrations than those shown in Figure 23 show mean sizes and relative standard deviations in the same range.

[00131] Example 12 - Manufacture of Po Iy- Butylcyanacrylate dispersions containing oil and being stabilised with emulsifier. [00132] Butylcyanacrylate (from Henkel Loctite, 1% by weight) and sunflower oil (25% by weight related to the monomer butylcyanacrylate) were mixed with acetone and stirred until a clear solution of the first immiscible substance 105 was obtained. The manufacture process described in Example 1 was started using the Tween 80 in water solution (2%) as the second immiscible substance 115.

[00133] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 127 nm and a relative standard deviation (PDI) of 0.11 as shown in Figure 24 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. Other butylcyanacrylate or oil concentrations than those shown in Figure 24 show mean sizes and relative standard deviations in the same range.

[00134] Example 13 - Influence of hydrophobic dye on poly-butylcyanacrylate particles.

[00135] Butylcyanacrylate (from Henkel Loctite, 05 % by weight) and sunflower oil (25% by weight related to the monomer butylcyanacrylate) were mixed with acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00136] A trace of the hydrophobic dye Sudan IV was added to the first immiscible substance 105.

[00137] The manufacture process described in Example 1 was started using the SDS in water solution (2%) in one case and pure water in another case to give the second immis- cib Ie substance 115.

[00138] After the manufacture an opaque and slightly pink dispersion was obtained. The dispersed particles showed a diameter of 137 nm and 169 nm and a relative standard deviation (PDI) of 0.13 and 0.06 as shown in Figure 25 (Size distribution by intensity of poly- butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. (Figure 17: size distribution by intensity of poly-butylcyanacrylate particles containing Sudan IV in water (A) and in Tween 80 solution (B). Other butylcyanacrylate or dye concentrations than those shown in Figure 25 show mean sizes and relative standard deviations in the same range.

[00139] Example 14 - Manufacture of poly-butylcyanacrylate dispersion containing pharmaceutically active ingredients.

[00140] Butylcyanacrylate (from Henkel Loctite, 1% by weight) and sunflower oil (25% by weight related to the monomer butylcyanacrylate) were mixed with acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00141] 10 mg of a pharmaceutically active ingredient (Clotrimazol) was added to 10 g of the first immiscible substance 105.

[00142] The manufacture process described in Example 1 was started using pure water in one case and the Tween 80 in water solution (2%) in another case to form the second immiscible substance.

[00143] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 167 nm and 141 nm and a relative standard deviation (PDI) of 0.08 and 0.05 as shown in Figure 26 (Size distribution by intensity of poly-butylcyanacrylate dispersion). The dispersion showed good stability over a period of about six weeks. (Figure 18: size distribution by intensity of poly-butylcyanacrylate particles containing Clotrimazol in Tween 80-solution (A) and in water (B). Other pharmaceutically active ingredients than those shown in Figure 26 show mean sizes and relative stan- dard deviations in the same range.

[00144] Example 15 - Manufacture of SU 8 dispersions.

[00145] SU-82 (0.5 g), diamino dicyclohexyl methane (DDM) (0.2 g) and olive oil (0.035 g) were mixed with dioxane (13.3 g) and stirred until a clear solution of the first immiscible substance 105 was obtained. [00146] The manufacture process described in Example 1 was started using sodium do- decyl benzene sulfonate (SDBS) in water solution (2%) instead of pure water to give the second immiscible substance 115.

[00147] After the manufacture an opaque and slightly white dispersion was obtained. The dispersed particles showed a diameter of 127 nm and a relative standard deviation (PDI) of 0.07 as shown in Figure 27 (Size distribution by intensity of SU-82/DDM dispersion). The dispersion showed good stability over a period of about 4 weeks. Other concentrations than those shown in Figure 27 show mean sizes and relative standard deviations in the same range.

[00148] Example 16 - Manufacture of SU 8 dispersions with other amines.

[00149] SU-82 (0.5 g), xylylene diamine (XDA) (0.14 g) and olive oil (0.032 g) were mixed with dioxane (12.16 g) and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00150] The manufacture process described in Example 1 was started using sodium do- decyl benzene sulfonate (SDBS) in water solution (2%) instead of pure water as the second immiscible substance 115.

[00151] After the manufacture an opaque and slightly white dispersion was obtained. The solution was heated for two hours at a temperature of approximately 60 ⁰C.

[00152] After the heating the manufactured dispersion was prepared for the light scattering experiments by filtering as described in example 1. The dispersed particles showed a diameter of 139 nm and a relative standard deviation (PDI) of 0.09 as shown in Figure 28 (Size distribution by intensity of SU-82/XDA dispersion). The dispersion showed good stability over a period of about 4 weeks. Other concentrations than those shown in Figure 28 show mean sizes and relative standard deviations in the same range.

[00153] Example 17 - Manufacture of PNIPAM dispersions. [00154] Poly-n-isopropylacrylamide (PNIPAM, from Aldrich) (1%) was dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00155] The manufacture process described in Example 1 was started using pure water as the second immiscible substance 115 at a temperature of approximately 50 ⁰C.

[00156] After the manufacture an opaque and slightly white dispersion was obtained.

[00157] After the heating the manufactured dispersion was prepared for the light scattering experiments by filtering as described in example 1 The dispersed particles showed a diameter of 133 nm and a relative standard deviation (PDI) of 0.04 as shown in Figure 29 (Size distribution by intensity of PNIPAM dispersion). The dispersion showed good stability over a period of about 2 weeks when stored at 50 ⁰C. Other concentrations than those shown in Figure 29 show mean sizes and relative standard deviations in the same range.

[00158] Example 18 - Manufacture of PNIPAM dispersions stabilised with BCA.

[00159] Poly-n-isopropylacrylamide (PNIPAM, from Aldrich) (1%), n-butylcyanacrylate (25% related to PNIPAM) was dissolved in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00160] The manufacture process described in Example 1 was started using pure water as the second immiscible substance 115 at a temperature of about 50 ⁰C.

[00161] After the manufacture an opaque and slightly white dispersion was obtained.

[00162] After the heating the manufactured dispersion was prepared for the light scattering experiments by filtering as described in example 1. The dispersed particles showed a diameter of 133 nm and a relative standard deviation (PDI) of 0.04 as shown in Figure 30 (Size distribution by intensity of PNIPAM dispersion at 50 ⁰C (A) and at 20 ⁰C (B)). The dispersion showed good stability over a period of about 2 weeks when stored at 20 ⁰C. Other concentrations than those shown in Figure 30 show mean sizes and relative standard deviations in the same range.

[00163] Example 19 - Manufacture of vesicular dispersions.

[00164] Polyisoprene-block-polyethyleneoxide (PI-PEO) (1%) was dissolved in THF and stirred until a clear solution if the first immiscible substance 105 was obtained.

[00165] The manufacture process described in Example 1 was started using pure water as the second immiscible substance 115.

[00166] After the manufacture an opaque and slightly white dispersion was obtained.

[00167] After the heating the manufactured dispersion was prepared for the light scatter- ing experiments by filtering as described in example 1. The dispersed vesicles showed a diameter of 118 nm and a relative standard deviation (PDI) of 0.21 as shown in Figure 31 (Size distribution by intensity of PI-PEO vesicles (A)). The vesicles showed good stability over a period of about 4 weeks. Other concentrations than those shown in Figure 31 show mean sizes and relative standard deviations in the same range.

[00168] Example 20 - Manufacture of vesicles from different polymers at different temperatures.

[00169] A vesicle forming polymer (polybutadiene-block-polyethyleneoxide (PB-PEO), polyethyleneoxide-block-polylactide (PEO-PLA) (1%)), was dissolved in THF and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00170] The manufacture process described in Example 1 was started using pure water as the second immiscible substance 115, in the case of PB-PEO (A) at a temperature of about 40 ⁰C and in the case of PEO-PLA (B) at a temperature of about 80 ⁰C. After the manufacture process the samples were stored at room temperature. [00171] After the manufacture an opaque and slightly white solution was obtained.

[00172] After the heating the manufactured dispersion was prepared for the light scattering experiments by filtering as described in example 1. The dispersed vesicles showed a diameter of 212 nm (A) and 253 nm (B) a relative standard deviation (PDI) of 0.28 (A) and 0,4 (B) as shown in Figure 32 (Size distribution by intensity of PB-PEO vesicles (A) and PEO-PLA vesicles (B)). The vesicles showed good stability over a period of about 4 weeks. Other concentrations than those shown in Figure 32 show mean sizes and relative standard deviations in the same range.

[00173] Example 21 - Manufacture of oil-in-water dispersion.

[00174] Sunflower oil (1%) was dissolved in iso-propanol and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00175] The manufacture process described in Example 1 was started using 2% SDS in water as the second immiscible substance 115.

[00176] After the manufacture an opaque and slightly white dispersion was obtained.

[00177] The manufactured dispersion was prepared for the light scattering experiments by filtering as described in example 1. The dispersion particles showed a diameter of 118 nm and a relative standard deviation (PDI) of 0.21 as shown in Figure 33 (Size distribution by intensity of sunflower oil dispersion (A)). The dispersion showed good stability over a period of about 4 days. Other concentrations than those shown in Figure 33 show mean sizes and relative standard deviations in the same range.

[00178] Example 22 - Manufacture of oil-in-water dispersion using different oils.

[00179] Olive oil (A) or rape seed oil (B) (each 1 %), was dissolved in iso-propanol and stirred until a clear solution of the first immiscible substance 105 was obtained. [00180] The manufacture process described in Example 1 was started using 2% SDS in water as the second immiscible substance 115.

[00181] After the manufacture an opaque and slightly white dispersion was obtained.

[00182] The dispersion was prepared for the light scattering experiment as described in example 1. The dispersion droplets showed a diameter of 118 nm (A) and (B) and a relative standard deviation (PDI) of 0.21 (A) and (B) as shown in Figure 34 (Size distribution by intensity of olive oil dispersion (A) and rape seed oil (B)). The dispersion showed good stability over a period of about 4 days. Other concentrations than those shown in Figure 34 show mean sizes and relative standard deviations in the same range.

[00183] Example 23 - Manufacture of oil in water dispersions containing a hydrophobic dye.

[00184] Sunflower oil (1 %) and a trace amount of a hydrophobic dye (Sudan IV) were dissolved in iso-propanol and stirred until a clear red solution of the first immiscible substance 105 was obtained.

[00185] The manufacture process described in Example 1 was started using 2% SDS in water as the second immiscible substance.

[00186] After the manufacture an opaque and slightly pink dispersion was obtained.

[00187] The dispersion was prepared for the light scattering experiment as described in example 1. The dispersion droplets showed a diameter of 118 nm (A) and a relative standard deviation (PDI) of 0.21 (A) as shown in Figure 35 (Size distribution by intensity of sunflower oil dispersion (A) containing a hydrophobic dye). The dispersion showed good stability over a period of about 4 days. Other concentrations than those shown in Figure 35 show mean sizes and relative standard deviations in the same range. [00188] Example 23 - Manufacture of oil in water dispersions containing a flavouring agent.

[00189] Sunflower oil (1 %) and a trace amount of a flavouring agent (bergamot oil) were dissolved in iso-propanol and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00190] The manufacture process described in Example 1 was started using 2% SDS in water as the second immiscible substance 115.

[00191] After the manufacture an opaque and slightly white dispersion was obtained.

[00192] The dispersion was prepared for the light scattering experiment as described in example 1. The dispersion droplets showed a diameter of 118 nm (A) and a relative stan- dard deviation (PDI) of 0.21 (A) as shown in Figure 36 (Size distribution by intensity of sunflower oil dispersion (A) containing a flavouring agent). The dispersion showed good stability over a period of about 4 days. Other concentrations than those shown in Figure 36 show mean sizes and relative standard deviations in the same range.

[00193] Example 23 - Manufacture of oil in water dispersion containing a pharmaceutically active ingredient.

[00194] Sunflower oil (1 %) and a pharmaceutically active ingredient (clotrimazole) (0.1%) was dissolved in iso-propanol and stirred until a clear solution of the first immis- cible substance 105 was obtained.

[00195] The manufacture process described in Example 1 was started using 2% SDS in water as the second immiscible substance 115.

[00196] After the manufacture an opaque and slightly white dispersion was obtained. The dispersion was prepared for the light scattering experiment as described in example 1. The dispersion droplets showed a diameter of 118 nm (A) and a relative standard deviation (PDI) of 0.21 (A) as shown in Figure 37 (Size distribution by intensity of sunflower oil dispersion (A) containing a pharmaceutically active ingredient). The dispersion showed good stability over a period of about 4 days. Other concentrations than those shown in Figure 37 show mean sizes and relative standard deviations in the same range.

[00197] Example 24 - Manufacture of poly-DL-lactide dispersions in a continuous process using a lamellar shaped orifice.

[00198] Poly-DL-lactide was dissolved in a concentration of about 0.5% by weight in acetone and stirred until a clear solution of the first immiscible substance 105 was obtained.

[00199] The production process was started using an apparatus as shown in Figure 3. The dispersion was prepared for dynamic light scattering as described in Example 1. Analysis by dynamic light scattering showed a diameter of the particles in the range of about 120 nm (PDI 0.1) as shown in Figure 38 (Size distribution by intensity of poly-DL- lactide solution). Other concentrations of poly-DL-lactide than those shown in Figure 38 show mean sizes and relative standard deviations in the same range.

[00200] The pump 145 provides the advantage of constant, controllable elution of the first immiscible substance 105 from the micro-channel orifice 120 into the second immiscible substance 115 in a controllable, constant manner over long periods of time. The elution rate is typically in the range of 0.1 to 99.9 ml/h.

[00201] The ability to control the elution rate of the first immiscible substance 105 is relevant for the determination of the size and distribution of particles in the manufactured dispersion 125.

[00202] The elution rate where a pump 145 is not used, i.e. elution under gravity such as that known in the literature depends on the height from which the first immiscible substance is the added to the second immiscible substance and also depends upon the diameter of the capillary tube orifice and the viscosity of the substances (Hagen-Poiseulle law). The viscosity will depend on a number of parameters, e.g. molecular weight and concentration of the additive, but also on the elution rate itself. The prior art methods provide very little control on the elution rate and therefore very little control on the size and distribution of particles in the dispersion. Furthermore the rate of elution will also decrease over a period of time because the volume of the first immiscible substance will decrease.

[00203] The ability to control the elution rate is of the first immiscible substance 105 is therefore critical, since the size and size distribution of particles in the dispersion 125 depends on the elution rate.

[00204] The significant increase in reproducibility between manually controlled elution and motor driven elution is shown in Figure 39. Figure 39 shows size-dependent reproducibility of motorised elution (above) and of manual elution (below). Figure 39 demonstrates the size measurements of hydro dynamic radii and the polydispersities of particles of the dispersion are the highly reproductive for motorised elution in comparison to manual elution for the manufacture of the dispersion 125.

[00205] In addition, the polydispersities for the motorised elution are much smaller than for manual elution as shown in Figure 40. Figure 40 shows dispersity-dependent repro- ducibility of motorised elution (above) and of manual elution (below). Small polydispersities of the order of 0.1 or smaller are routinely achieved with motorised elution and are therefore highly beneficial in applications for the manufacture of bio-active dispersions. The reproducibility of manual elution is far worse, as is the polydispersity (up to 0.6).

[00206] The present physico-chemical insight into the particle formation kinetics of the colloidal dispersion 125 corroborates the results observed in the example experiments. A constant elution rate leads to constant, homogeneous, reproducible particle formation kinetics which in turn leads to narrow and reproducible size distributions of the particles in the colloidal dispersion 125.

[00207] Having thus described the present invention in detail, it is to be understood that the foregoing detailed description of the invention is not intended to limit the scope of the invention thereof. What is desired to be protected by letters patent is set forth in the following claims.

Reference Numerals

100 - Batch manufacturing apparatus

105 - First immiscible substance 110 - First immiscible substance container

115 - Second immiscible substance

125 - Colloidal dispersion

120 - Micro-channel orifice

135 - Emulsifϊer 140 - Container

145 - Pump

150 - Micro-channel

155 - Heating device

200 - Continuous manufacturing apparatus with dialysis 210 - Tubes

220 - Collection reservoir

230 - Geared pump

240 - Dialysis cartridge

250 - Valves 260 - Water reservoir

270, 271 - Pipes

280, 281 - Outlets

290 - Dialysis apparatus

Claims

1. A method for the manufacture of a colloidal dispersion (125) comprising: -providing (310) a first immiscible substance (105) in at least one first immiscible sub- stance container (110),

- providing (320) a second immiscible substance in a container (140); -agitating the second immiscible substance (115),

- applying (330) the at least one first immiscible substance (105) by at least one pump (145) through a micro-channel orifice (120) of a micro-channel (150) connectable to the least one first immiscible substance container (110), whereby the micro-channel orifice (120) is immersed in the second immiscible substance (115) to the manufacture of the colloidal dispersion (125).

2. The method according to claim 1, wherein an elution rate of the solution of the first immiscible substance (105), from the micro-channel orifice (120), determines the size and distribution of particles in the colloidal dispersion (125).

3. The method according to claim 2, wherein the elution rate is determined by settings on the pump (145).

4. The method according to any one of the above claims, wherein the micro-channel orifice (120) size determines the size and distribution of particles in the dispersion (125).

5. The method of any one of the above claims, being a batch method for the manufacture of the colloidal dispersion (125).

6. The method of any one of the above claims, being a continuous method for the manufacture of the colloidal dispersion (125).

7. The method according to any one of the above claims, wherein the first immiscible substance (105) comprises a dispersed phase.

8. The method according to the above claims, wherein the second immiscible substance (115) comprises a continuous phase.

9. The method according to any of the above claims, further comprising adding an emul- sifier (320) (135) to either the first immiscible substance (105) and/or the second immiscible substance (115).

10. The method according to any one of the above claims, further comprising heating or cooling either the first immiscible substance (105), or the second immiscible substance or heating both the first immiscible substance (105) and the second immiscible substance during the manufacture of the colloidal dispersion (125).

11. The method according to any of the above claims, wherein the dispersion (125) is heated/cooled and agitated simultaneously during manufacture of the colloidal dispersion (125).

12. The method according to any one of the above claims, wherein the micro-channel orifice (120) is continuously adjustable by a mechanical or an electro-mechanically adjustable micro-channel orifice (120) during the addition of the first immiscible substance (105) to the second immiscible substance.

13. The method according to any of the above claims wherein the first immiscible substance (105) or the second immiscible substance (115) comprises a pharmaceutical, a nutraceutical, a foodstuffs, a nanoparticles, a perfume, a flavourant or a biodegradable polymer.

14. The method of any one of the above claims, further providing a water miscible co- solvent (350) to the first immiscible substance (105) or the second immiscible substance (115).

15. The method of claim 14, further comprising dialysis removal (360) of the co-solvent.

16. The method according to claim 15, whereby dialysis removal of the co-solvent is conducted at a certain temperature.

17. A colloidal dispersion (125) obtainable by the method of any one of the above claims.

18. An apparatus for the manufacture of a colloidal dispersion (125) comprising:

- a first immiscible substance (105) in at least one first immiscible substance container (110),

- a second immiscible substance in a container (140), - an agitator to agitate the second immiscible substance (150), and

- at least one pump (145) to apply the first immiscible substance (105) through a micro- channel orifice (120) of a micro-channel (150) connectable to the least first immiscible substance container (110), wherein the micro-channel orifice (120) is immersed in the second immiscible substance (115).

19. The apparatus according to claim 18, wherein the micro-channel (150) can be replaced with a micro-channel (150) having a different micro-channel orifice (120) diameter.

20. The apparatus according to any one of claims 18 to 19, wherein the micro-channel ori- fice (120) has a form of a rectangular slot, a zigzag slot, a meandering shape, concentrically telescopic tubes of increasing diameters, a sieve or a lamellae.

21. The apparatus according to any one of claims 18 to 20, wherein the micro-channel orifice (120) is continuously adjustable by a mechanical or electro-mechanically adjustable micro-channel orifice (120).

22. The apparatus according to any one of claims 18 to 21, further comprising:

- a cross flow dialysis apparatus (290),

- a plurality of pumps (230), - a plurality of valves (250),

- a collection reservoir (220),

- a plurality of tubes (210), and - a heating device (155).

23. The apparatus according to any one of claims 18 to 22, wherein the container (140) is a continuous- flow reservoir wherein, in use, the first immiscible substance (105) and second immiscible substance (115) is replenished as the colloidal dispersion (125) is removed from the collection reservoir (220).

24. The apparatus according to any one of claims 22 to 23, wherein the cross flow dialysis apparatus (290) is used to remove a water miscible co-solvent from the colloidal disper- sion.

25. A use of the apparatus according to any one of claims 18 to 24 for the manufacture of a colloidal dispersion (125).