Patent Application
20110008427
Not applicable.
The present invention relates to microcapsules and methods for the production of microcapsules. More specifically, the invention relates to microcapsules and methods for the production of same using sterically stabilized colloidal particles.
Active molecules such as drugs or pesticides are expensive to develop and manufacture. In addition, the application of such molecules often involves an indiscriminate single dosing that can lead to unwanted side-effects or the pollution of otherwise healthy tissue, organs or cells alongside the intended mode of operation at the targeted site of action. Likewise, the nature of the applications of cosmetics, personal care products and agrochemicals is such that the delivery of the often costly actives leads to the waste of the actives and/or environmental damage.
Consequently, routes that can provide the controlled delivery of active molecules to the intended site of action are much sought after. In addition, there are benefits that may be accrued from an ability to control the actual dosing rate of active molecules at the site of action. One proposed approach is the use of microcapsules that contain the active components isolated within a delivery matrix of microcapsules.
As a result of the need for effective delivery systems, the production of microcapsules for use in a wide range of industries such as agrochemicals, personal care products, pharmaceuticals, foods, pet foods and cleaning products is a rapidly increasing field of interest. The main drivers for the use of microcapsules in these applications are:
In practice, the lack of suitable targeted delivery systems results in an over-dosing of the active molecules and therefore a large proportion of the active molecules employed are wasted. This is both costly and potentially harmful.
A further requirement of the delivery system of active molecules is that the microcapsules act to protect the active molecules from a hostile environment on the journey to the site of action, for example, the delivery of pharmaceutically active molecules through the gut to the point of release.
Despite the obvious interest in microcapsules, one commercial manufacture of microcapsules relies on an interfacial polymerization methodology whereby, the microcapsule wall is prepared in-situ by the reaction of two or more chemical monomers at an oil-water interface to form a polymer shell. This approach has been shown to be successful for the production of a limited number of microcapsules such as those where the coating is a melamine formaldehyde material. There are however drawbacks with this technique for example:
Other commercial techniques for the manufacture of microcapsules include: coacervation and suspension polymerization. These techniques however also have the inherent problems of complex reaction conditions, including the use of heating (suspension polymerization), and the presence of contaminants.
An alternative process which has recently been proposed involves the use of particle stabilizers as the building blocks for a new range of capsules, which are frequently referred to as ‘colloidosomes’, as described in U.S. Patent Application Publication No. 2004/0096515.
In the system described therein, particulates are used to stabilize the oil-in-water or water-in-oil system of interest (the active molecule is usually in the dispersed phase) known as Pickering emulsions.
These particle stabilized emulsions have a shell composed of particulates. The term ‘particulates’ is usually deemed to refer to colloidal solids, which are usually polymer latex, however, the term can also be used to describe inorganic oxides, ceramics, and metals.
The shells are rendered ‘permanent’ by one of the following:
Such approaches have been demonstrated to be capable of producing robust capsule shells where some control over the porosity of the shell is possible. Whilst these methods are of interest, some limitations are also apparent for example:
In procedures 1, 2 and 3 above, the degree of porosity of the shell of the capsules is very large and therefore it is doubtful that these systems would have the potential for the encapsulation of molecular materials such as active molecules. Each of the methods highlighted are carried out using complicated manufacturing protocols and the capsules can only be produced at very low droplet concentrations.
It is therefore the aim of the present invention to provide an encapsulation system that is more robust and less complicated than existing procedures and which can therefore provide colloidosome-inspired microcapsules in large quantities and higher concentration for industrial application.
It is a further aim of the present invention to provide a method of encapsulation that can also provide a means of adjusting the pore size of the microcapsule shell.
It is yet a further aim of the present invention to provide an encapsulation system that enables the structure and size of the colloidosome-inspired microcapsules to be controlled in order to meet the specific requirements of targeted release profiles.
According to a first aspect of the present invention there is therefore provided a microcapsule comprising:
The colloidal particles (also known as a nanoparticles) can be prepared from a wide range of available materials including but not limited to for example:
metals, such as for example gold, silver and tungsten; metal oxides, such as for example, alumina, silica and iron oxide; and organic lattices such as for example polystyrene and poly(methyl methacrylate).
However, according to the present invention, the colloidal particles prepared herein are preferably comprised of polymer latex particles.
The term steric stabilization used herein refers to the extra stabilizing power given to the colloidal particles by the presence of a soluble polymer block projecting out from the surface of the particles. This provides a ‘protective sheath’ around each colloidal particle thereby preventing any other colloidal particles from approaching too closely that might lead to instability of the particle dispersion and aggregation of the colloidal particles.
According to the present invention, one form of steric stabilization of the colloidal particles is by a steric stabilizer, preferably a physisorbed stabiliser (located on the shell of the colloidal particle) and comprises a polymer, for example but not limited to a homopolymer or a copolymer. Examples of suitable homopolymers include for example but are not limited to: poly(2-di-alkyl ethylaminomethacrylate) [alkyl substituents include methyl, ethyl, propyl, phenyl]; polyethylene oxide; polyethylene glycol; poly(acrylic acid); polyacrylamide; polyethylene imine; polyvinyl alcohol; carboxymethyl cellulose; chitosan; guar gum; gelatin; amylose; amylopectin; and sodium alginate.
Alternatively the stabiliser is comprised of an end-grafted stabilizer. End-grafted stabilizers are preferably prepared by either the ‘grafting from’ or ‘grafting to’ approaches.
In the case of ‘grafting from’ end attached stabilisers, it is necessary to functionalise the surface of the particles by covering them with initiator groups from which a polymer chain can be grown. A range of polymerisation methodologies have been employed for this type of reaction including: anionic, cationic, RAFT, ATRP, and controlled ring-opening schemes. In all cases, the choice of an appropriate initiator group that can be attached to the particle surface is often critical.
In the case of ‘grating to’ end attached stabilisers it is necessary to produce end-functionalised polymers wherein the functional group specifically reacts with surface active sites on the particles.
Suitable functional groups for producing the end-functionalised polymers depend on the surface functional groups of the colloid particles. Examples include: thiol terminated polymers for reaction with gold particles or carboxy-terminal polymers for reaction with surface hydroxyl groups on particles such as silica or alumina.
In both cases, whether grafting-from or grafting-to, the result is a chemically attached end-grafted polymer layer that sterically stabilises the particles.
More preferably however, the polymer comprises a copolymer, more specifically a block copolymer, and most preferably an AB block copolymer.
When the physisorbed steric stabilizer comprises, for example, a block copolymer, one of the blocks in the block copolymer has a high affinity for the surface of the colloidal particles whilst the other block has no affinity for the surface of the colloidal particles. Consequently, in the colloidal particles of the present invention, one block of the block copolymer is firmly attached to the shell surface whilst the other block projects away from the shell surface into the bulk of the solution. This technique is commonly referred to in the art as a physisorption method of adding steric stabilizers to colloidal particles.
In an alternative approach to producing sterically stabilized colloidal particles, the steric stabilizer may be present during the manufacture of colloidal latex particles using emulsion polymerisation wherein, one block may be incorporated into the outer shell of the particle (especially relevant to organic latex particles) whilst the other block extends away from the shell surface of the particle. The key feature of this approach is that one block must have a high affinity for the solvent whilst the other block has a high affinity for the reactive monomer oil droplets in the precursor emulsion.
One block of the stabiliser is soluble in the monomer oil such that as polymerization takes place forming the latex, the stabiliser essentially becomes ‘locked into’ the colloidal particle. Consequently the process is not so much a surface adsorption but rather the polymer is instead incorporated into the outer parts of the colloidal particle formed. This ultimately produces a stabilizer that is very strongly attached to the colloidal particles. As a result of this process there is a region of the colloidal particles (or micro-particles) at the outer layer that comprises different composite material properties to that of the bulk of the micro-particles. Whilst not wishing to be bound by any particular theory it is thought that this region is one which comprises a lower Tg value and thereby allows the surface of the micro-particles to experience so called ‘melting’ at a different temperature to the bulk of the colloidal particles. By ‘melting’ in this context is meant a temperature above the glass-transition where chains can inter-diffuse and ultimately neighbouring particles can fuse together.
It is thought that this variation in Tg of the micro-particles through the steric sheath thus allows fusion of the microcapsule shell at reduced temperatures.
It will be appreciated to one skilled in the art that since AB Block copolymers are polymers that consist of two linked polymers (so linked at a single junction), one consisting of monomer A and the other consisting of monomer B, that variation in the properties of the copolymer can be obtained by variations in the monomers utilized. That is, depending on the nature of the monomers selected, the copolymers will have different chemical properties, the molecular weights of the copolymer (at a fixed ratio of the two component block sizes) will also vary, as will the ratio of the molecular weights of the constituent blocks (at a fixed overall molecular weight for the copolymer). Therefore, the selection of different molecular weight monomers for use in the block copolymers allows for a form of ‘tuning’ with regard to how close the colloidal particles can approach one another as a result of the size of the monomer block protruding from the surface of the particle shell. Consequently, the spacing between the particles and hence the pore spacing within the microcapsule shells that are the subject of the present invention can be controlled.
Preferably, the portion of the block copolymer that protrudes from the particle surface, referred to herein as the steric stabiliser block of the copolymer comprises a reversible hydrophilic/hydrophobic character that can be varied by altering the physical conditions. This allows a transition between a fully extended polymer (providing maximum stabilization power) through to a fully collapsed polymer chain (providing no stabilization power). Importantly, changes in the relative solubility between these limits can allow the ‘tuning’ of how much the polymer collapses and hence how close the particles may approach.
It is however preferred that all polymer types used according to the present invention whether grafted or physisorbed and whether copolymer or homopolymer are stimulu responsive.
In accordance with the present invention the steric stabilizer preferably comprises extensions of between 5 nm and 500 nm.
It will be also appreciated by one skilled in the art that the component monomers within the copolymer may be dispersed randomly, alternately or in blocks. Preferably however, the copolymer is a block copolymer. The block copolymer may further be selected from for example but not limited to: AB blocks, ABA blocks, ABC blocks, comb, random, ladder, and star copolymers. Most preferably however, the block copolymers comprise AB block copolymers or random copolymers for example an “A block” (that is a copolymer comprising monomer A and another monomer C) and the steric stabilising B block.
It is also preferred that the block copolymers include blocks that are capable of being adsorbed at the target surface. For example is it possible to utilize reactive monomers to allow chemisorption through a chemical reaction such as condensation. This mechanism is also relevant for end-functionalised polymers for use in the ‘grafting to’ process described previously. Suitable functional monomer groups will be dependent also on the surface of the particle. For example, thiol groups (SH) react excellently with gold giving a gold sulfur link that is chemically very stable. For silica surfaces, the use of reactive SiH [silane] groups is preferred.
It is also preferred that the block copolymers are sensitive to a stimulus. Preferably, the stimulus includes one or more of for example changes in pH, changes in temperature, humidity, changes in the wavelength of light, or the absence thereof, ionic strength and electrical and magnetic fields.
It is preferred that for the AB block copolymers comprising the steric stabilizers for use in the microcapsule(s) of the present invention that it is the steric block that is responsive to a stimulus. The attachment block of the copolymer does not however need to be responsive to a stimulus.
The AB block copolymers used in the present invention typically respond to stimuli such as: humidity, pH, ionic strength, temperature, light, electrical and magnetic fields.
Furthermore, the AB block copolymers utilized in the present invention may respond to a single stimulus system or alternatively, may respond to more than one stimuli.
Preferred stimuli according to the present invention comprise pH and/or temperature.
Examples of available monomers that can be utilised in the AB block copolymers of the present invention but not limited thereto include for example;
Most preferably the temperature sensitive monomers selected for use as copolymers in the colloidal particles according to the present invention comprise methylcellulose or poly(NIPAM).
The photosensitive molecule can be triggered by a change in the wavelength of light from substantially visible to substantially ultraviolet. Polymers responsive to a change in wavelength are selected from the group comprising: poly dimethylacrylamide/N-4-phenylazophenyl-acrylamide (DMAAm); poly dimethylacrylamide/4-phenylazophenylacryate (DMAA) and analagous polymers.
Preferred stimulus responsive monomers/polymers for use in the copolymers of the present invention comprise: poly(2-dimethylaminoethyl methacrylate)-b-poly(2-diethylaminoethyl methacrylate) [PDMA-b-PDEA], or poly(2-dimethylaminoethyl methacrylate)-b-poly(methylmethacrylate) [PDMA-b-PMMA], or poly(2-dimethylaminoethyl methacrylate)-b-poly(methacrylic acid) [PDMA-b-PMAA].
However, the most preferred stimulus responsive monomers/polymers for use in the copolymers forming the steric stabilizers in the colloidal particles of the present invention comprise PDMA-b-PMMA; and the preferred mode of stimulus is via pH.
It is a further object of the present invention to produce microcapsules comprising sterically stabilized colloidal particulates that are size controlled. It is to be understood that in the present invention the size control is a pre-requisite for many of the envisaged applications of the invention. For example in drug delivery, the passage across biological membranes or cell walls is only possible for certain sized materials. Furthermore, the strength of shell wall depends not only on the thickness but also on the overall capsule size such that at a given wall thickness, larger capsules will fracture more easily.
Therefore, it will be appreciated that good size control is vital to maximizing the potential applications for the present invention.
It is yet a further object of the present invention to produce size-controlled microcapsules on batch scales, in quantities of greater than 1 litre. In the present invention, the mean size of the microcapsules is 1 to 100 μm. More preferably the mean size of the microcapsules is 1 to 20 μm.
The mean size of the microcapsules is achieved through the use of a controlled emulsification procedure such as: cross-membrane or rotating membrane emulsification, micro-channel emulsification or capillary extrusion techniques.
For larger droplet sizes that is, greater than 20 microns, rotating membrane emulsification is preferred. For smaller sizes cross membrane emulsification is preferred.
Both approaches work by forcing the disperse phase liquid out through pores of a controlled size into a continuous phase including a stabiliser (in this case the particles that comprise the microcapsule shell wall). The shear field (caused by liquid being forced to flow over the static membrane surface in cross-flow or by the moving membrane rotating in a static fluid in the rotating membrane system) assists in the detachment of the drops from the membrane. The membrane preferably comprises a regular array of pores all of which are the same size allowing the production of regular sized droplets.
Stabilisation of the droplets requires that the particles are surface active. The contact angle of the particles at the water-oil interface determines whether an oil-in-water or water-in-oil system is preferred. If the contact angle at an oil-water interface is less than 90° then an oil-in-water system is preferred. This is the preferred case for the present invention.
To date, there are no reports of microcapsules with mean sizes of less than 10 μm. Furthermore, good size control is reported only in a highly specialized micro-channel flow emulsifier capable of producing only a few ml of product. (Xu et al. Colloids and Surfaces A: Physicochem. Eng. Aspects 262 (2005) 94-100).
As discussed above, the microcapsules of the present invention represent a ‘smart capsule system’, that is a system of microcapsules that are able to respond to an external stimulus to release their contents. In the present invention, this has been achieved by the use of sterically stabilized particle emulsifiers where the steric stabilisers can be subsequently chemically cross-linked. The choice of cross-linking agent is dependent on the specific chemistry of the homopolymers or copolymers being used as steric stabilizers. Examples include but are not limited to: sodium hydroxide (NaOH) or divinylsulfone (DVS) as cross-linking agents for ethyl(hydroxyethyl) cellulose (EHEC); boric acid to cross-link guar gum; and glutaraldehyde for polyvinyl alcohol (PVA).
The steric stabilizers ideally possess specific stimuli-responsive functionality such that the microcapsules, when formed by the cross-linking process, are able to expand and collapse as a function of external stimuli such as: pH; ionic strength or temperature.
If this expansion/collapse response is reversible, for example by repeated pH cycling causing charge/discharge of a polymer chain and hence expansion/contraction cycles, then the capsule can be made to ‘breathe’ through repeated cycles of expansion and contraction that will expand and contract the capsule wall. If one thinks of the microcapsule system as a string bag, that can expand and collapse, then the colloidal particles are ‘dotted’ all over the string bag and provide mechanical strength (
Another feature of the microcapsule system of the present invention is that by controlling the size of the steric stabilizers, the inter-particle spacing can be controlled.
Larger spacings will allow larger pores and hence faster release rates.
In addition, by varying the size of the particles (as a ratio to the size of the steric stabilizers) this provides a means of producing a high degree of control over the porosity of the microcapsule.
Finally, by using a wide range of potential colloidal particle and steric stabilizer chemistries, it is possible to obtain a high degree of control on the microcapsule shell properties.
Previous teachings have involved a permanent locking of the particles on the capsule wall and no inherent reversibility of the porosity through a so-called ‘breathing’ mechanism as described above. The chemical cross-linking method of the present invention allows the production of single layered stimulus responsive soft shells, which have potential for use in the triggered release of a wide range of active encapsulants including larger encapsulants such as cells. Use of a disperse phase soluble cross-linking agent allows the production of capsules at relatively high droplet concentrations, typically up to 60% by volume compared with less than 0.1% in earlier work. Consequently, by linking from the inside it is possible to operate at very high droplet concentrations many orders of magnitude higher than those already described making a commercial manufacture process viable.
It is also a key point of the present invention that the use of a steric stabiliser provides a polymer that can have a low Tg and hence fuse at temperatures well below those of the core colloidal particles. This is important because heating usually damages active molecules. Preferred Tg values are typically in the range of from 5 to 90° C., more preferably 30 to 50° C.
Whilst latex particles could be made with low Tg for use as surface-active particles in colloidosome-inspired capsule manufacture, this is not feasible for inorganic or metal particles. Therefore, the surface steric ‘film’ may provide an alternative route to fusion of the shell in these cases. This is also the case for high Tg polymer lattices such as polystyrene. By only fusing the outer steric shell it is possible to retain the mechanical properties of the main particles giving good strength (and controllable properties) to the microcapsule shell wall.
Finally, the present invention provides a system that can fix the particles on a disperse droplet by heat treatment at a temperature lower than 100° C. The procedure can therefore be conducted in both a simple aqueous oil/water system and water/oil system. Whilst permanent binding of the particles via heat treating and melting of the particles has been proposed, the materials chosen typically had a Tg value higher than 100° C. Higher Tg (>60° C.) values are preferred for mechanical strength at room temperature but require a high-melting temperature to generate fusion. This can be detrimental to many actives of interest. By using a sterically stabilized particle system, it has been found that multiple phase transition temperature are achievable so that it is possible to fuse the colloidal particles at considerably lower temperatures whilst still retaining the core high Tg materials for mechanical strength.
In the present invention three Tg values were observed for a sterically stabilised latex particle: these values arise from the nature of;
A key feature of the present invention is that (a) and (b) are lower than (c).
Also observed in the present invention is a reduction in the Tg from 105° C. (for PS particles) to about 75° C. for the steric polymer sheath. An intermediate Tg at approximately 85° C. was also seen for the PMMA/PS region at the outer part of the particle.
In the case of latex stabilised in this way by an embedded block of a block copolymer stabiliser, it is possible to tune the degree of fusion by adjusting the temperature and the time over which it is applied. This allows some control over the system porosity and eventual mechanical properties.
Therefore, the presence of the steric stabilizer results in a reduction in the temperature needed for fusion of the particles as a result of the composite nature of the particles.
According to a second aspect of the present invention there is provided a method of producing microcapsules using sterically stabilized colloidal particulates as the primary building blocks comprising the steps of:
preparing an emulsion through the addition of a first liquid to a second liquid such that the first liquid forms droplets dispersed within the second liquid;
coating the dispersed droplets with sterically stabilized particles whereby the colloidal particulates act as a stabiliser of the liquid-liquid interface; and
securing the sterically stabilized particles on the surface of the droplets to form a system of microcapsules.
The sterically stabilized particles are secured in place on the surface (or shell) of the droplets by either heat treatment or chemical cross-linking of the steric stabilizer polymers.
When heat treatment is the preferred method, the preferred temperature range is between 70° C. and 80° C. The preferred stabilizer comprises PDMA-b-PMMA on the polystyrene (PS) latex system.
The preferred droplet concentration is less than 5% by volume, in order to prevent aggregation between multiple particle stabilised oil droplets.
When chemical cross-linking is the preferred method, an internal cross-linking method is employed which fixes the nanoparticles in place as a single layer on the shell or surface. A preferred cross-linking compound comprises 1,2-bis(2-iodoethyloxy)ethane, which is insoluble in water.
Before the emulsification step takes place, a known amount of the preferred cross-linker compound is dissolved in the oil phase. The advantages of employing the internal cross-linking method are that it is possible to carry out the method using high droplet concentrations. For example, droplet concentrations of 60% or higher by volume may be used.
It will be appreciated by one skilled in the art that the exact nature of the cross-linking compound will depend upon the type of steric stabiliser employed and also whether the system employed is a water-in-oil or oil-in-water emulsion.
Consequently, the use of the sterically stabilized particles applied to the surface of the oil droplets form a stable emulsion. This applies when the emulsion is an oil in water (o/w) or a water in oil (w/o) emulsion. Furthermore, the above method can be applied to oil-in-oil emulsions where the two oils are themselves immiscible.
In the present application the use of the term ‘stable’ is used herein to mean that the droplets do not break down or aggregate in a time scale of relevance. For example, in the present invention the emulsion may be required to be stable for 24 to 48 hours prior to the commencement of the cross-linking reaction. After the cross-linking or heat treatment stage has taken place, the system is indefinitely stable since the particles are no longer able to leave the interface.
In the present method according to a second aspect of the present invention, the affinity of the sterically stabilized particles for the surface of droplets is controlled by the relative wettability of the sterically stabilized particles within either phase. A contact angle of 60° to 90° is preferred for the formation of an oil-in-water emulsion.
In addition it is preferred that the particles are dispersed in the continuous phase prior to emulsification.
Consequently, by using the method according to the second aspect of the present invention it is possible to produce microcapsule emulsions. Therefore according to a second embodiment of the second aspect of the present invention there is provided a method of producing microcapsule emulsions comprising the steps of:
(i) preparing an emulsion comprising droplets;
(ii) stabilizing the droplet emulsion by means of colloidal particulates, followed by;
(iii) linking the particles together to form microcapsules.
The membrane emulsification stage of step (i) above has the effect that the size of the droplets can be controlled. Consequently, the size of the microcapsules can also be controlled as a result of steps (ii) and (iii) above.
In the method according to the second aspect of the present invention, if the process of chemical cross-linking achieves the linking of the particles, then the resultant micro-capsules are referred to as ‘soft-shell’ capsules. This term means that when solvent is removed from the microcapsules the microcapsules collapse as evidenced using SEM imaging.
Alternatively, if the method utilizes heat-treating in order to effect the linking of the particles, then the resultant microcapsules are referred to as ‘hard-shell’ microcapsules. The term ‘hard-shell’ refers to the fact that when the solvent is removed from the microcapsules the microcapsules do not collapse, as seen using SEM imaging.
Microcapsules prepared using the method according to the second aspect of the present invention comprise colloidal particles that:
Furthermore, the method allows the porosity of the microcapsule shell wall to be controlled by means of variation of particle concentration and the time and/or temperature of the fusion reaction.
Alternatively, the method according to the second aspect of the present invention can be used to prepare ‘soft shell’ microcapsules from emulsions produced using sterically stabilized colloids (nanoparticles) where the sterically stabilised colloid particles are chemically cross-linked by the reaction of the steric stabilizers.
‘Soft-shell’ microcapsules refers to microcapsules which collapse as evidenced using SEM imaging when the solvent is removed.
Consequently, in order to prepare ‘soft-shell’ microcapsules, the method according to the second aspect of the present invention further comprises the step of:
adding a chemical cross-linking agent to the emulsion.
Most preferably the chemical crosslinker comprises 1,2-bis(2-iodoethyloxy)ethane, which is insoluble in water.
Furthermore, it is preferred that the chemical cross-linker has no solubility in the continuous phase.
It is also most preferred that the reaction that cross-links the sterically stabilized particles occurs from within the droplets allowing the production of microcapsules at high volume fraction of emulsion droplets.
That is, by carrying out a reaction from the inside of the microcapsule, only reactive groups within each droplet are able to react together. If the reaction were performed from the outside, then it would be possible for chains on two neighbouring droplets to react together linking them to one another. Essentially the inside of each droplet is shielded from another droplet whilst the outside parts are interacting.
It will be further appreciated by one skilled in the art that the above method may be applied to oil-in-water, water-in-oil, or oil-in-oil emulsions as long as:
(a) the two phases are immiscible;
(b) the chemical cross-linker is soluble only in the dispersed phase; and
(c) the emulsion produced can be stabilized by an assembled layer of the sterically stablised particles.
Furthermore, in the method of producing ‘soft shell’ microcapsules described above the sterically stabilized particles are “stimulus-responsive”. As mentioned in the first aspect of the present invention, suitable stimuli include: temperature, pH, salt concentration, light, electricity and magnetic fields. A response to a stimulus will have the result that the shell of the microcapsules effectively contracts or expands leading to an increase or decrease in the porosity.
The method described above can be used to prepare microcapsules that are capable of encapsulating a wide variety of active materials. For example the active material may comprise an active material that is soluble in the dispersed phase of the emulsion; or the active material may itself comprise an oil that can also act as the disperse phase. Furthermore, the active material may comprise a particulate that can be dispersed in the disperse phase; or an active material that comprises a bio-molecule that is dispersible in the disperse phase; alternatively, the active material may comprise a natural oil that can act as the disperse phase; or the active material may comprise a cellular organism.
The microcapsules according to the present invention are suitable for use in a range of industrial applications for example but not limited: the cosmetics industry, personal care products, homecare and cleaning products, agrochemicals, paints and coatings, and pharmaceutical formulations. Consequently, the microcapsules may further comprise components such as for example: additives, biocides, perfumes, colourants etc as required by the particular field of application. It will however be appreciated by one skilled in the art that this list is by no means exhaustive.
It is envisaged that in any of the fields of interest listed above that in most cases the active will either be soluble in the disperse phase (usually oil but sometimes water) or will itself be an oil. Occasionally however, the microcapsules may be utilised in water-in-water or oil-in-oil systems.
The invention will now be further illustrated by way of the following examples in which all parts are by weight unless otherwise stated, and by way of
FIG. 1—illustrates the volume average and the number average size distribution data for mineral oil oil/water emulsions prepared using a fixed amount of sterically stabilized colloidal latex particles.
FIG. 2—illustrates a graph of the differential scanning calorimetric (DSC) analysis of nanoparticles.
FIG. 3—illustrates an optical micrograph of colloidosome-inspired microcapsules dispersed in water (oil/water emulsion heat treated at 86° C. for 5 minutes.
FIG. 4—illustrates a scanning electron micrograph (SEM) image of the colloidsome microcapsules of
FIG. 5—illustrates an optical micrograph of crosslinked colloidosome-inspired microcapsules dispersed in water.
FIG. 6—illustrates a scanning electron micrograph (SEM) image of a microcapsule of
FIG. 7—illustrates a scanning electron micrograph (SEM) image of the arrangement of nanoparticles on colloidosome-inspired microcapsules of
FIG. 8—illustrates a single pass crossflow membrane emulsification system for the preparation of colloid stabilised emulsions.
FIG. 9—illustrates an emulsion produced using XME with a ceramic membrane of 0.5 μm.
a and 12b illustrate optical microscope images recorded 5 minutes after homogenisation of oil-in-water emulsions prepared in the presence of 20 nm gold nanoparticles coated with p[DMAEMA]28 homopolymer. In both cases the aqueous phase is at pH 10 to facilitate the adsorption of particles at the oil-water interface. Particle concentration in the aqueous phase is 0.03 wt % (a) and 0.3 wt % (b), respectively.
a and 14b there is illustrated two images demonstrating variations in crosslinking.
a and 15b illustrate optical images of the same sample of emulsion droplets stabilised by responsive polymer-coated latex particles redispersed at different pHs.
In
In
Standard homogenisers (rotor-stator type and other derivatives) and mixers may be used for the production of emulsions. For high precision emulsions, the use of cross-membrane, rotating membrane, and microchannel emulsifiers can be employed.
In this present invention oil/water emulsions were used as the base substrates for the preparation of the particle stabilised emulsions. The oils used included a medium liquid white oil (Batch No. 320352), dodecane (available from Fluka, at greater than or equal to 98.0% purity), vegetable oil such as sunflower oil and perfume oil). It will be appreciated that in principle, any oil may be used, the choice of sterically stabilised particle will to some extent be dependent on the choice of oil/water system to be stabilised.
In all cases, the emulsions may be prepared across a wide range of droplet volume fractions from 0.1 to 60%. Typical operating conditions depend on the method chosen and can be specified for one or all of them.
Any suitable standard approach for the emulsification technique is applicable and is considered to be within the scope of this application. Examples include micro-homogenisers or high-shear mixing devices.
High precision cross-membrane and rotating membrane approaches have not previously been reported for applications as described herein.
Two methodologies for the locking of the particle shells are described:
The crossflow emulsification system (1) as shown in
The size control of the emulsion systems was investigated by varying the ratio of the amount of oil to latex particle used.
An emulsion prepared using 1.5 ml of mineral oil and 3 ml of latex suspension was divided into smaller aliquots and the samples were subsequently heat-treated at temperatures ranging from 75° C. to 92° C. Optical microscopy of the samples showed that when the temperature used was greater than 90° C., as shown in
Two further temperature values were selected for investigation of the nanoparticles, namely, 86° C. and 75° C. In both cases, colloidosome-like microcapsules were produced although initial investigations suggest that the shell formed at 86° C. is stronger than that produced at 75° C.
From
A closer examination of
Dodecane was used as the oil phase in the preparation of colloidosome-inspired microcapsules via a chemical cross-linking method. The cross-linking agent was dissolved in the oil phase before being emulsified into the aqueous latex containing phase. In this way, it was hoped that only the nanoparticles assembled onto the oil droplet surfaces could react with the cross-linker from the oil phase. This approach ensured that only one layer of nanoparticles was locked into the colloidosome-like structure after reaction. As a result of this reaction process, there was no need to separate free nanoparticles from the oil droplet, or to dilute the emulsion to avoid the aggregation of microcapsules during the cross-linking reaction. Hence, it was shown that it is possible to produce microcapsules at high concentrations.
In
In
In Table 2 there is detailed a list of the polymers grafted onto the surface of gold nanoparticles and their corresponding molecular weights as measured by NMR and GPC.
In the case where the polymer-coated nanoparticles are adsorbed on the surface of the microcapsules, the packing is controlled by the size of the particle/polymer unit and the distance between the solid (gold) cores of the nanoparticles will be approximately equal to the length of the polymer chain.
The pore size within the membrane of the microcapsules corresponds to the size of the interstices between the particles. The size of the interstices is determined by the size of the particles and the distance between them, which is controlled by the polymer size. Hence, it is possible to use the above particles (as measured in
The wettability of particles can be varied by changing the environmental conditions to which the polymer is responsive to.
(a) is controlled by the environmental stimuli the grafted polymer is responsive to
(b) controls the adsorption of the particles at an air-water or oil-water interface.
In addition, in
More importantly it is crucial to note that the emulsion droplets prepared in the same conditions, including same particle concentrations, using an aqueous phase at pH 4 were not stable and coalesced instantaneously, indicating very little or no particle adsorption at the oil-water interface in this case.
In
In
In
When dispersing the microcapsules into a highly basic environment, the polymers on the surface of the particles forming the membrane deprotonate and become highly hydrophobic. This subjects the microcapsule membrane to a high stress as a response to the changes in pH within the system. Under these conditions it is observed that some of the oil contained within the microcapsules being released. This demonstrates the ability of these microcapsules to control the release of encapsulated material upon changes in pH.
In
In
In
In
Furthermore,
The above images demonstrate the ability of the capsules to absorb active molecules in the cores.
Therefore, the manufacture of colloidosome-inspired microcapsules using a sterically stabilised colloidal latex is demonstrated. The production of the microcapsules was achieved either through fusion of the latex particles or by chemical cross-linking of the grafted polymer stabilisers. In the melting method, a temperature lower than 100° C. (lower than the glass transition point of particle stabilisation (PS) (˜105° C.)) was applied. The lower temperature (75-90° C.) affords not only a simplified reaction system and preparation process, but also potentially reduces issues surrounding the encapsulation of thermally sensitive ingredients. The permeability and strength of the microcapsules can be adjusted by varying the melting temperature, melting time and number of nanoparticle layers present on the emulsion droplets.
The cross-linking reaction has been carried out from the inside of the droplets by using a cross-linker that is soluble in the dispersed phase. This internal cross-linking approach formed single layered stimulus responsive shell, and allowed the reaction to be carried out at a high concentration.
The interstices between the nanoparticles and ‘breath-ability’ can be controlled by the cross-linking extent through the control of cross-linking agent concentration and/or the amount of PDMA-PMMA grafted on the PS nanoparticles.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0718300.7 | Sep 2007 | GB | national |
This application is a 35 U.S.C. §371 national stage application of PCT Application No. PCT/GB2008/003197, filed 22 Sep. 2008, and entitled Microcapsules and Methods, hereby incorporated herein by reference, which claims priority to UK Patent Application No. 0718300.7, filed 20 Sep. 2007, hereby incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2008/003197 | 9/22/2008 | WO | 00 | 8/27/2010 |
