FIELD

The present disclosure generally relates to microcapsules, processes for preparing microcapsules, and applications for the microcapsules.

BACKGROUND

Retention of soluble and volatile chemicals within microcapsules has been a significant challenge for decades. Encapsulation of an active has two key roles: i) it protects the active ingredient (Al) from the external environment, and ii) it allows for a controlled release of the Al.

Conventionally, organic polymers have been the preferred material for microcapsule shells. However, the inherent porous nature of such polymer shells makes them generally unsuitable for retaining small molecules, which can diffuse through the polymer matrix and be lost to the environment. Improving core retention of polymer microcapsules by modifying the properties of the polymer shell has had limited success. More recently focus has been directed to developing novel core-shell microcapsules that provide retention of low molecular weight volatile molecules until sufficient force is applied to trigger release, for example by electroless deposition of a thin metal shell onto polymer microcapsules. However, whilst metal shells have shown to provide good retention properties, they are an expensive option compared to polymer shell microcapsules.

In order to make the microcapsules attractive and affordable: i) the shell should be suitably thin so that it can easily be broken when required, whilst still retaining its impermeable nature pre-breakage; and, ii) the material chosen for the shell should be cost-effective and compatible to allow for use in industrial products such as paints, pesticides, insect repellents, sunscreen, fragrances, laundry detergents, agrochemicals, nutraceuticals, and food products, particularly functional food products, such as targeted delivery of nutrients and/or bioactive molecules through encapsulation.

Consequently, there is a need to provide alternative or improved microcapsules and processes for preparing alternative or improved microcapsules. SUMMARY

The present inventors have prepared a microcapsule comprising an ionic shell. The ionic shell may be an inorganic calcium phosphate shell. The microcapsule may comprise an inorganic calcium phosphate shell encapsulating an inner fluid core. The fluid core may be a gel core. In one embodiment, the inner gel core may comprise metal ions to support encapsulation by the ionic shell. The microcapsules may be delivered in a targeted manner or in response to a specific trigger. The present inventors have also identified a process for preparing microcapsules comprising an ionic shell such as an inorganic calcium phosphate shell. The process can comprise providing an inner gel core comprising metal ions, and encapsulating the inner gel core with an ionic shell, for example an inorganic calcium phosphate shell.

The present inventors have surprisingly found that presence of metal ions in the gel core material can promote growth of an ionic shell, for example an inorganic calcium phosphate shell, on the surface of a microcapsule. One or more advantages of the present disclosure according to at least some embodiments or examples as described herein is that the metal ions can produce microcapsules that are substantially impermeable to low molecular weight volatile molecules encapsulated therein until release of the encapsulated molecules is desired.

In one aspect there is provided a microcapsule comprising an ionic shell encapsulating a fluid core, wherein the fluid core comprises metal ions.

In an embodiment, the ionic shell may be an inorganic calcium phosphate shell. The inorganic calcium phosphate shell may comprise one or more calcium phosphate compounds selected from monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, octacalcium phosphate, dicalcium diphosphate, calcium triphosphate, calcium hydroxide phosphate, or combinations thereof. In an embodiment, the ionic shell may be formed around the fluid core. The fluid core may be a gel core.

In an embodiment, metal ions may be selected from one or more of iron, platinum, palladium, iridium, copper, nickel, magnesium, aluminium, and ruthenium. In another embodiment, the ionic shell may have a thickness of between about 1 nm to about 1000 nm. In one example, the ionic shell is impermeable to molecules smaller than 500 g.mol' ¹ .

In another embodiment, the gel core may comprise or consist of a gel carrier comprising one or more active agents and metal ions according to any examples or embodiments as described herein.

The gel core may be a hydrogel selected from alginate or alginate derivatives, agarose, and synthetic block copolymers.

In an embodiment or example, the active agent may be a water soluble active agent or an oil soluble active.

In another embodiment, the gel core may comprise or further optionally consist of one or more additives selected from an oil carrier (e.g. medium or long chain triglycerides, soy bean oil, isopropyl myristate, hydrocarbons), an aqueous carrier (e.g. water, buffer solution), a water / oil emulsion, an oil / water emulsion, a solid (e.g. cocoa butter). The gel core may comprise between about 45% to about 99.9% by weight of the microcapsule.

In another embodiment, the gel core may comprise or further optionally consist of an inner coating encapsulating the gel core from the ionic shell, wherein the ionic shell encapsulates the inner coating. In another example, the inner coating is a polymeric shell. The polymeric shell may be selected from a synthetic polymer or a naturally-occurring polymer.

In an embodiment, the inner coating may have a thickness of between about 10 nm to about 5000 nm. In another embodiment, the ratio by weight of the gel core to inner coating is between about 6:1 to 1 : 1.

In an embodiment, the metal ions may be present in the gel core or inner coating for catalysing an electroless plating deposition of the outer ionic shell thereon.

In an embodiment, the diameter of the microcapsules may be between about 0.05 pm to about 10000 pm.

In another aspect, there is provided a composition comprising a plurality of microcapsules defined above or according to any embodiments or examples thereof as described herein. In another aspect, there is provided a process for preparing a microcapsule, the process comprising providing an inner gel core comprising metal ions, and encapsulating the gel core with an ionic shell, for example an inorganic calcium phosphate shell. The ionic shell may be provided or deposited as a densely packed layer of calcium phosphate compounds over the gel core by electroless plating catalysed by the metal ions present at the surface of the gel core. In an embodiment, the metal ions may be at least embedded within the gel core prior to deposition of the ionic shell. In another embodiment, the process may further comprise encapsulating the gel core by an inner polymeric coating using an emulsification process. In an example, the metal ions may be incorporated, at or near the surface of the inner coating to form a discontinuous layer during the emulsification process. In another example, the metal ions may be embedded in or on the surface of the inner coating to form a discontinuous layer during the emulsification process.

In another aspect, there is provided a use of the microcapsule defined above or according to any embodiments or examples thereof as described herein, or composition comprising a plurality of the microcapsules defined above or according to any embodiments or examples thereof as described herein, as a drug delivery vehicle or carrier in controlled release of the inner gel core comprising an active agent.

In an embodiment, the microcapsule according to at least some examples as described herein may be used as an implant within a subject for controlled release of the active agent to a subject.

In another embodiment, the controlled release may be a sustained release, for example capable of being used to provide systemically administered doses.

In another aspect, there is provided a use of the microcapsule defined above or according to any embodiments or examples thereof as described herein, or composition comprising or consisting a plurality of the microcapsules defined above or according to any embodiments or examples thereof as described herein, in personal care products.

In another aspect, there is provided a use of the microcapsule defined above or according to any embodiments or examples thereof as described herein, or composition comprising or consisting a plurality of the microcapsules defined above or according to any embodiments or examples thereof as described herein, in agricultural products. In another aspect, there is provided a use of the microcapsule defined above or according to any embodiments or examples thereof as described herein, or composition comprising or consisting a plurality of the microcapsules defined above or according to any embodiments or examples thereof as described herein, in food products.

In another embodiment of any of the above aspects, embodiments or examples, the release of the inner gel core comprising or consisting of the active agent may be activated by ultrasound, degradation, or mechanical fracture.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the present disclosure are described and illustrated herein, by way of example only, with reference to the accompanying Figures in which:

Figure 1 is a series of scanning electron microscopy (SEM) images of calcium phosphate shells deposited onto a gel core(s), ai) is a low magnification overview of a ionic shell coated gel core, no FeCh in electroless deposition bath; aii) is a high magnification of the ionic shell coated gel core showing calcium phosphate in the shell of ai); aiii) is an elemental analysis of the outer shell; and bi) is a low magnification overview of the ionic shell coated gel core, FeCh in electroless deposition bath; bii) is a high magnification of the ionic shell coated gel core showing calcium phosphate in the shell of bi); biii) is an elemental analysis of the outer shell Elemental analysis obtained using energy dispersive x-ray spectroscopy.

Figure 2 is a plot showing the release profile over time of hexadecane from within calcium phosphate coated alginate microcapsules into ethanol, at room temperature. Circles represents alginate microcapsules without a calcium phosphate shell, crosses represent calcium phosphate coated alginate microcapsules.

Figure 3 is a scanning electron micrograph showing a magnified area of a cross section of a calcium phosphate coated microcapsule.

Figure 4 is a plot showing the release profile over time of a fluorescent dye, l,r-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (Dil), into ethanol at 40 °C. Circles represent alginate microcapsules without a calcium phosphate shell, crosses represent calcium phosphate coated alginate microcapsules prepared under standard conditions (with succinic acid and sodium fluoride) (condition A), triangles represent calcium phosphate coated alginate microcapsules prepared with succinic acid, sodium fluoride and additionally iron (III) chloride (condition B), pluses represent calcium phosphate coated alginate microcapsules prepared without succinic acid (condition C), diamonds represent calcium phosphate coated alginate microcapsules prepared without sodium fluoride (condition D), squares represent calcium phosphate coated alginate microcapsules prepared without succinic acid but with iron (III) chloride (Condition E).

Figure 5 is a plot showing the release profile over time of cannabidiol (CBD) into methanol at 40°C. Circles represent alginate microcapsules without a calcium phosphate shell, and crosses represent calcium phosphate coated alginate microcapsules.

DETAILED DECSRIPTION

The present disclosure describes the following various non-limiting examples, which relate to investigations undertaken to identify alternative and improved microcapsules and processes for preparing the microcapsules. The present inventors have prepared a microcapsule comprising an ionic shell. The microcapsule can comprise an ionic shell encapsulating a fluid core comprising metal ions. The fluid core may be a gel core. The ionic shell can be an inorganic calcium phosphate shell. The gel core can comprise metal ions. In another example, the microcapsules comprise an inner coating encapsulating a gel core, and an ionic shell encapsulating the inner coating. The present inventors have also identified a process for preparing the microcapsules wherein an inner core composition comprises metal ions.

At least according to some embodiments or examples as described herein, the present disclosure provides an alternative or improved microcapsule that has been prepared by depositing an outer ionic shell using metal ions as a catalyst, under fast, mild conditions, which delivers improved impermeable characteristics to the microcapsules, in a more cost-effective manner.

General Terms

Throughout this disclosure, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions or matter, groups of steps or groups of composition of matter. Thus, as used herein, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly indicates otherwise. For example, reference to “a” includes a single as well as two or more; reference to “an” includes a single as well as two or more; reference to “the” includes a single as well as two or more and so forth.

Those skilled in the art will appreciate that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

Each example of the present disclosure described herein is to be applied mutatis mutandis to each and every other example unless specifically stated otherwise. The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the disclosure as described herein.

The term "and/or", e.g., "X and/or Y" shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

The term "consists of', or variations such as "consisting of', refers to the inclusion of any stated element, integer or step, or group of elements, integers or steps, that are recited in context with this term, and excludes any other element, integer or step, or group of elements, integers or steps, that are not recited in context with this term.

Unless otherwise indicated, the terms "first," "second," etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and/or a higher-numbered item (e.g., a “third” item).

As used herein, the phrase “at least one of’, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed. The item may be a particular object, thing, or category. In other words, “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.

Reference herein to “example,” “one example,” “another example,” or similar language means that one or more feature, structure, element, component or characteristic described in connection with the example is included in at least one embodiment or implementation. Thus, the phrases “in one example,” “as one example,” and similar language throughout the present disclosure may, but do not necessarily, refer to the same example. Further, the subject matter characterizing any one example may, but does not necessarily, include the subject matter characterizing any other example.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Microcapsule composition and structure

The present disclosure provides a microcapsule comprising an ionic shell encapsulating a fluid core. The fluid core may be a gel core. The ionic shell may comprise or consist of an ionic compound, for example calcium phosphate. In an example, the ionic shell is an inorganic calcium phosphate shell. The gel core may comprise metal ions according to any examples thereof as described herein. The metal ions may be embedded within the inner gel core prior to deposition of the ionic shell. The microcapsules may further comprise an inner coating. The inner coating may comprise metal ions according to any examples thereof as described herein. The gel core and the inner coating may comprise metal ions according to any examples thereof as described herein. The metal ions may be incorporated or embedded in the inner coating and/or gel core. A microcapsule of the present disclosure can be designed to be substantially impermeable to low molecular weight volatile molecules, for example restricting or preventing release of the volatile molecules encapsulated within the inner core until the release is intentionally activated. It will be appreciated that direct addition of active ingredients in functional foods may be compromised by their degradation and the loss of their bioactivity during, for example, food processing and/or in the digestive tract once consumed. For example, the active ingredients may react with components present in, for example, a food matrix, which may change the taste or colour of the food product. The microcapsules of the present disclosure may (1) reduce gel core reactivity with environmental factors, such as temperature, humidity, interaction of other substances or UV radiation, (2) reduce evaporation or decrease the transfer rate of gel core material from the microcapsule to the surrounding environment, (3) mask certain properties of active substances, (4) promote easy handling of volatile compounds such as flavours; (5) dilute gel core material when it should only be used in very small amounts, for example vitamins, (6) control the release of the encapsulated active ingredient to ensure optimal timely and targeted dosage. It will be appreciated that, in addition to food ingredients such as vitamins and flavours, microencapsulation may also be extended to pharmaceuticals or living cells that become important for a wide variety of applications and technologies, ranging from nutraceuticals to drug delivery and biomedical applications.

The gel core may be referred to as an inner gel core. In one example, the ionic shell may be an outer ionic shell. In another example, there is provided a microcapsule comprising or consisting of an ionic shell encapsulating a gel core, the gel core comprising metal ions and optionally an inner coating. In another example, there is provided a microcapsule comprising or consisting of an inner polymeric coating encapsulating a gel core, wherein the inner polymeric coating and/or gel core comprises metal ions, and wherein an ionic shell encapsulates the inner polymeric coating and gel core.

It will be appreciated that encapsulation of low molecular weight volatile active molecules (e.g. < 500 g.moT ¹ ) for controlled release in microcapsules can be of value for a broad range of applications. It will be appreciated that a controlled release may include sustained release. For example, polymer microcapsules are often used for encapsulation, however polymer microcapsules are typically unable to retain low molecular weight volatile molecules for long periods of time (typically no longer than a few hours to a few days). Precious metals have been previously used to grow more impermeable shells around microcapsules, which can provide controlled release of the microcapsule contents by an external trigger. However, these precious metals are expensive and do not lend themselves to a large range of applications due to the significant barrier of cost of goods in manufacturing. The challenge is to grow impermeable shells around microcapsules which can provide controlled release of the microcapsule contents by an external trigger, without introducing toxic elements to the composition of the microcapsule, such that the microcapsules may be suitable in the food industry, in particular for encapsulation of functional foods.

At least according to some embodiments or examples as described herein, the microcapsules of the present disclosure can provide a more cost effective and controllable production of microcapsules that are substantially impermeable to low molecular weight volatile active molecules for sustained and / or controlled release.

It will be appreciated that the size of the microcapsules can be controlled by altering factors such as the needle diameter used when forming microbeads to provide a gel core, electrostatic potential, gel carrier material solution flow rate, metal ion concentration, and gel carrier concentration and viscosity, as well as gel carrier composition, used during a microencapsulation process.

In some embodiments or examples, the diameter of each microcapsule may be between about 0.05 pm to about 10000 pm. The diameter of the microcapsule may be in a range from about 0.06 pm to about 8000 pm, about 0.07 pm to about 6000 pm, about 0.08 pm to about 4000 pm, or about 0.1 pm to about 1000 pm. The diameter of the microcapsule may be at least 0.05 pm, at least 0.07 pm, at least 0.09 pm, at least 0.1 pm, at least 0.2 pm, at least 0.4 pm, at least 0.6 pm, at least 0.8 pm, at least 1.0 pm, at least 2.0 pm, at least 4.0 pm, at least 8.0 pm, at least 12.0 pm, at least 15.0 pm, at least 20.0 pm, at least 40.0 pm, at least 80.0 pm, at least 100 pm, at least 500 pm, at least 1000 pm, at least 2000 pm, at least 4000 pm, at least 6000 pm, at least 8000 pm, or at least 10000 pm. The diameter of the microcapsule may be less than 10000 pm , less than 8000 pm, less than 6000 pm, less than 4000 pm, less than 2000 pm, less than 1000 pm, less than 800 pm, less than 600 pm, less than 500 pm, less than 400 pm, less than 300 pm, less than 200 pm, or less than 100 pm. The diameter of the microcapsule may be in a range provided by any two lower and/or upper values as previously described.

The microcapsules may provide one or more further advantages such as they can be delivered in a targeted manner or in response to a specific trigger. According to at least some embodiments or examples as described herein, the microcapsules can provide a capsule that is substantially impermeable and can be suitable for use in various applications. The microcapsule can be impermeable to low molecular weight volatile molecules encapsulated within it thereby preventing release. For example, the microcapsule may be impermeable to molecules smaller than 500 g.mol' ¹ .

It will be appreciated that the present disclosure may provide a composition comprising a plurality of the microcapsules. The composition may include from 0.001% to 99%, by weight of the composition of the microcapsules. In another embodiment, the composition may include from 0.01% to 90% by weight of the composition of the microcapsules. In another embodiment, the composition may include from 0.1% to 75% by weight of the composition of the microcapsules. In another embodiment, the composition may include from 0.1% to 25% by weight of the composition of the microcapsules. In another embodiment, the composition may include from 1% to 15% by weight of the composition of the microcapsules. The composition may include a mixture of different microcapsules of the present disclosure. For example, the composition may comprise a mixture of microcapsules wherein a first microcapsule comprises a first gel core material and a second microcapsule comprises a second gel core material. It will be appreciated that the size distribution of the microcapsules can be determined using dynamic light scattering and transmission electron microscopy.

In some embodiments or examples, at least 75% by weight of the microcapsules in the composition have a particle size of between about 1 pm to about 100 pm. In an example, at least 75%, at least 85%, or at least 90% by weight of the microcapsules in the composition have a particle size of between about 1 pm to about 100 pm. In another example, at least 75%, at least 85%, or at least 90% by weight of the microcapsules in the composition have a particle size of between about 1 pm to about 50 pm. In another example, at least 75%, at least 85%, or at least 90% by weight of the microcapsules in the composition have a particle size of between about 10 pm to about 50 pm. In another example, at least 75%, at least 85%, or at least 90% by weight of the microcapsules in the composition have a particle size of between about 1 pm to about 30 pm. In another example, at least 75%, at least 85%, or at least 90% by weight of the microcapsules in the composition have a particle size of between about 1 pm to about 5 pm.

In some examples, the compositions are incorporated into various products, including but not limited to pharmaceutical products (i.e. drug delivery), pesticide/insecticide products, nutraceutical products, functional food products, agrochemicals, and personal products. The composition may also be included in an article, non-limiting examples of which include a dispenser/container. The compositions/articles disclosed herein may be made by combining the microcapsules disclosed herein with the desired adjunct material to form the product. The microcapsules may be combined with the adjuncts material when the microcapsules are in one or more forms, including a slurry form, neat particle form, or spray dried particle form. The microcapsules may be combined with the adjuncts material by methods that include mixing and/or spraying.

Ionic Shell

The present disclosure provides a microcapsule comprising or consisting of an ionic shell encapsulating an inner gel core. It will be appreciated that the ionic shell comprises, or is formed from, one or more ionic compounds. For example, the ionic shell may comprise or consist of one or more inorganic calcium phosphate compounds. The microcapsule may comprise or further consist of an inner coating encapsulating the gel core, wherein the ionic shell encapsulates the inner coating and gel core. The gel core and/or inner coating can comprise metal ions, which can facilitate deposition of the ionic shell on the gel core or the inner coating of the gel core.

The present inventors have unexpectedly found that a continuous substantially impermeable outer ionic shell can be deposited onto the microcapsule by electroless deposition under fast and mild reaction conditions using metal ions to catalyse the deposition.

It will be appreciated that the ionic shell comprises, is formed from, or consists of, one or more ionic compounds. It will also be appreciated that ionic compounds are neutral overall, but consist of positively charged “cations” and negatively charged “anions” that can pack together to form a three-dimensional network or crystalline lattice. The ionic compounds may comprise one or more alkaline earth metal. The alkaline earth metal can provide a cation in the ionic compound of the ionic shell. In one embodiment, the alkaline earth metal may be selected from beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), or combinations thereof. In other embodiments, the ionic shell comprises or consists of one or more ionic compounds selected from phosphates, sulphates, nitrates, silicates, carbonates, or combinations thereof. The ionic compound may be prepared in situ, for example grown or deposited around a gel core or inner coating of a gel core. In one embodiment, the ionic compound may comprise or consist of an alkaline earth metal in combination with one or more phosphates, sulphates, nitrates, silicates, carbonates, or combinations thereof. In other words, the cation of the ionic compound may be provided by one or more alkaline earth metals and the anion of the ionic compound may be provided by one or more of phosphates, sulphates, nitrates, silicates, and carbonates.

In other embodiments, the ionic compound may be selected from beryllium phosphate, beryllium sulphate, beryllium nitrate, beryllium silicate, beryllium carbonate, magnesium phosphate, magnesium sulphate, magnesium nitrate, magnesium silicate, magnesium carbonate, calcium phosphate, calcium sulphate, calcium nitrate, calcium silicate, calcium carbonate, strontium phosphate, strontium sulphate, strontium nitrate, strontium silicate, strontium carbonate, barium phosphate, barium sulphate, barium nitrate, barium silicate, barium carbonate, or combinations thereof. In another example, the ionic shell may comprise or consist of an inorganic calcium phosphate shell. The ionic shell, or ionic compound thereof, may comprise or consist of a calcium phosphate compound. In one embodiment, the inorganic calcium phosphate shell, or calcium phosphate compound thereof, may be selected from monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, octacalcium phosphate, dicalcium diphosphate, calcium triphosphate, calcium hydroxide phosphate, or combinations thereof.

In other embodiments, the ionic shell may have a thickness of between about 1 nm to about 1000 nm. The thickness of the ionic shell may in a range from about 2 nm to about 900 nm, about 4 nm to about 900 nm, about 6 nm to about 700 nm, about 8 nm to about 600 nm, about 10 nm to about 500 nm, about 12 nm to about 400 nm, about 14 nm to about 300 nm, about 16 nm to about 200 nm, or about 20 nm to about 150 nm. The thickness of the ionic shell may be at least 1 nm, at least 2 nm, at least 4 nm, at least 6 nm, at least 8 nm, at least 10 nm, at least 12 nm, at least 15 nm, at least 20 nm, at least 25 nm, at least 30 nm, at least 35 nm, at least 40 nm, at least 45 nm, or at least 50 nm. The thickness of the ionic shell may be less than 1000 nm, less than 800 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 200, less than 100 nm, or less than 50 nm. The thickness of the ionic shell may be in a range provided by any lower and/or upper limit as previously described.

It will be appreciated that the elemental composition analysis and elemental mapping of the ionic shell may be determined using transmission electron microscopy with energy dispersive X-ray, and the morphology of the ionic shell may be analysed using scanning electron microscopy.

It will be appreciated that the thickness of the ionic shell may have homogeneity of variance. The variance in the thickness of the ionic shell may be in the range of from 4 nm to 150 nm, about 6 nm to about 120 nm, about 8 nm to about 100 nm, or about 10 to about 50 nm. The variance in the thickness of the ionic shell may be at least 0.1 nm, at least 0.5 nm, at least 1.0 nm, at least 5.0 nm, at least 10 nm, at least 15 nm, at least 20 nm, at least 50 nm, at least 100 nm, at least 150 nm, or at least 200 nm. The variance in the thickness of the ionic shell may be less than 300 nm, less than 200 nm, less than 100 nm, less than 80 nm, less than 60 nm, or less than 40 nm. The variance in the thickness of the ionic shell may be in a range provided by any lower and/or upper limit as previously described. One or more further advantages of the present disclosure may be provided such as less variance in the thickness of the ionic shell thickness having been shown with a thicker ionic shell.

The characteristics of the ionic shell may be controlled by adjusting the calcium cation to phosphate anion ratio. In some embodiments, the calcium to phosphate ratio may be in the range of about 1 :3 to 3 : 1 or 1 :2 to 2: 1. For example, the calcium to phosphate ratio may be about 1 : 1. The addition of sodium fluoride during the formation of the ionic shell may further facilitate a close-packing of spherical calcium phosphate particles and / or crystals in the form of a single or multiple layers on the surface of the microcapsule. It will be appreciated that when sodium fluoride is added, calcium fluoride is a by-product of the reaction, and particles of the calcium fluoride can become incorporated within the ionic shell.

The inventors have surprisingly found that depositing an ionic shell on a microcapsule, for example depositing an inorganic calcium phosphate shell on a microcapsule, can provide a substantially impermeable microcapsule suitable for a number of applications, in particular, functional foods. In one embodiment, the ionic shell may be substantially impermeable to low molecular weight or volatile “active agent” molecules, for example molecules having a molecular weight of less than about 1000 g.mol' ¹ , 900 g.mol' ¹ , 800 g.mol' ¹ , 700 g.mol' ¹ , 600 g.mol' ¹ , 500 g.mol' ¹ , 400 g.mol' ¹ , 300 g.mol' ¹ , or 200 g.mol' ¹ . In other embodiments, the ionic shell microcapsules can retain low molecular weight active agents present in the gel core of the microcapsules for up to about 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, or 2 months. The impermeability or retention of active agent in the gel core may be measured by placing the prepared microcapsules into a solution (e.g. ethanol) for predetermined time, such as 1 week, and measuring the amount of active agent released into the solution. The retention of active agent within the microcapsule as a weight % of active agent may be at least about 80, 85, 90, 95, 98, 99, 99.5, 99.8, or 99.9.

In some embodiments, the ionic shell may be a densely packed, continuous layer of inorganic material (e.g. calcium phosphate) deposited onto the surface of the microcapsule. The inventors have unexpectedly found that metal ions incorporated or embedded in, on or near the surface of the inner gel core and/or inner coating can provide an effective catalyst and seed for the deposition of calcium phosphate onto the surface of the microcapsule. In other words, metal ions present at the surface of the gel core and/or inner coating can facilitate formation of the ionic shell. It will be appreciated that if the gel core comprises an inner coating encapsulating the gel core, the metal ions may be incorporated or embedded in, on or near the outer surface of the inner coating.

It will also be appreciated that the metal ions may act as an anchoring point for the ionic shell, i.e. the metal ions may provide a site of nucleation for the calcium phosphate material to be deposited as an ionic shell on the surface of the microcapsule. The inventors have unexpectedly found that one or more further advantages may be provides by the ionic shell, such as an inorganic calcium phosphate shell, which can auto-catalyse further deposition of the ionic shell over time to form a more continuous or thicker shell around the microcapsule to provide further improved impermeability characteristics. Core

The present inventors have surprisingly found that the microcapsules provide improved impermeability properties and are better able to retain the contents of the inner fluid core (e.g. gel core) without leakage over time.

The microcapsules may comprise an outer ionic shell encapsulating a fluid core. The fluid core may be referred to herein as an “inner fluid core”. The term “fluid core” or “inner fluid core” as used herein refers to a core material formed of one or more components that are fluid at standard ambient temperature and pressure. For example, the fluid core may comprise suspensions, such as a fluid carrier with suspended actives. The term “standard ambient temperature and pressure” refers to a temperature of 25°C and an absolute pressure of 100 kPa.

The microcapsules may comprise an outer ionic shell encapsulating a fluid core, wherein the fluid core may be a gel core. The fluid core may be a gel core. The gel core may be referred to herein as an “inner gel core”. The term “gel core” or “inner gel core” as used herein refers to a core material formed of one or more components that are gel at standard ambient temperature and pressure. For example, the gel core may comprise suspensions, such as a gel carrier with suspended actives. The term “standard ambient temperature and pressure” refers to a temperature of 25°C and an absolute pressure of 100 kPa.

In some embodiments, the gel core may comprise between 1% to about 99.9% by weight of the microcapsule. The gel core (by weight of the microcapsule ) may be in the range of from about 5% to about 99.9%, about 10% to about 99.9%, about 20% to about 99.9%, or about 45% to about 99.9%. The inner gel core (by weight of the microcapsule) may be at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 45%, at least 65%, at least 75%, at least 85%, at least 95%, at least 99%, at least 99.5%, or at least 99.9%. The inner gel core (by weight of the microcapsule) may be less than about 99.99%, 99.9%, 99.5%, 99%, 98%, 95%, 90%, 85%, 75%, 65%, 45%, 30%, or 20%. The gel core may be in a range provided by any lower and/or upper limit as previously described.

In some embodiments, the gel core may comprise one or more active agents. The microcapsules described herein are useful with a wide variety of active agents. In some embodiments or examples, the gel core may further comprise one or more additives selected from an oil carrier, an aqueous carrier, a solid, a water / oil emulsion, and oil / water emulsion.

In some embodiments, the active agent of the gel core may be selected from pharmaceuticals, nutraceuticals, functional foods, pesticides, insecticides, fertilizers, herbicides, perfumes, brighteners, insect repellents, silicones, waxes, flavours, vitamins, fabric softening agents, depilatories, skin care agents, enzymes, probiotics, dye polymer conjugate, perfume delivery system, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, flavourants, sweeteners, waxes, UV blockers/absorbers, or combinations thereof. In one embodiment, the active agent may be a water soluble active agent or an oil soluble active. In other embodiments, the active agent may be a hydrophilic active agent or a hydrophobic active agent. For example, the active agent may have a hydrophilic-lipophilic balance value at any value between 0 and 30.

In some embodiments, the gel core consists of one or more components which are liquid or gel at standard ambient temperature and pressure. In some examples, the gel core material comprises one or more components which are volatile. Unless otherwise specified, the term “volatile” as used herein refers to those materials that are liquid or gel under ambient conditions and which have a measurable vapour pressure at 25°C. These materials typically have a vapour pressure of greater than about 0.0000001 mm Hg, e.g. from about 0.02 mm Hg to about 20 mm Hg, and an average boiling point typically less than about 250°C.

The gel core may comprise of a single material or it may be formed of a mixture of different materials. In some embodiments, the gel core may comprise one or more active agents. The microcapsules described herein are useful with a wide variety of active agents. In some embodiments or examples, the inner gel core may further comprise one or more additives selected from an oil carrier, an aqueous carrier, a solid, a water / oil emulsion, and oil / water emulsion.

In some embodiments, the fluid core may be a gel core. The gel core may comprise a gel carrier. In an embodiment, the gel core may comprise a gel carrier, one or more active agents, and metal ions. In an embodiment, the gel carrier may be a crosslinkable polymer. The crosslinkable polymer may be an anionic polymer or a cationic polymer. In an embodiment, the anionic polymer may be selected from an alginate, agarose, pectin, carboxy methyl cellulose, hyaluronates, and combinations thereof. In other embodiments, the cationic polymer may be selected from chitosan, cationic guar, cationic starch, and combinations thereof.

In one embodiment, the gel carrier in the gel core may be a hydrogel. It will be appreciated that one or more crosslinkable polymers may form a hydrogel. The hydrogel may comprise alginate or alginate derivatives, agarose, and synthetic block copolymers. For example, alginate may form a hydrogel in the presence of polyvalent cations. The polyvalent cation may be divalent or trivalent and may be selected from divalent or trivalent metals including, but not limited to, calcium, barium, zinc, palladium, platinum, iron, iridium, and ruthenium. For example, the hydrogel may be barium alginate, calcium alginate, iron alginate, palladium alginate, platinum alginate, or ruthenium alginate. In one example, the hydrogel may be iron alginate.

The molecular weight of the gel carrier may be in a range between 32,000 and 400,000 g/mol. For example, the molecular weight may be at least about 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 200,000, 300,000 or 400,000. The molecular weight may be in a range of about 30,000 to 400,000, 40,000 to 300,000, 40,000 to 200,000, or 50,000 to 100,000. The molecular weight may be less than about 400,000, 350,000, 300,000, 250,000, 200,000, 100,000, 80,000, 60,000, or 40,000. The number average molecular weight may be in a range provided by any lower and/or upper limit as previously described. It will be appreciated that increasing the molecular weight of the gel carrier may improve the physical properties of the gel core. For example, manipulation of the molecular weight and its distribution can independently control the pre-gel solution viscosity and post-gelling stiffness. The elastic modulus of gels can be increased significantly, while the viscosity of the solution minimally raises, by using a combination of high and low molecular weight gel carriers. The rate of diffusion of components contained in the gel core can be controlled by adjusting the thickness and/or porosity of the gel core. For example, if alginate is used to form the gel core, then the porosity of the gel core (i.e., crosslinking density) can be controlled by adjusting the ratio of mannuronic units to guluronic units (M:G) to form the alginate polymer. For example, to obtain a fluid-like consistency, the mannuronic:guluronic ratio may be greater than 1 : 1, and the ratio may range from about 1.5 to 3: 1. In contrast, to obtain a gel-like consistency, the mannuronic:guluronic ratio may be less than 1 :1, and the ratio may range from about 0.4: 1 to 0.6: 1.

In some embodiments or examples, the viscosity of the gel carrier may be in a range between about 200 to 20,000 cps. For example, the viscosity may be at least about (cps) 200, 500, 1000, 5,000, or 20,000. The viscosity may be less than about (cps) 20,000, 10,000, 8,000, 6,000, 4,000, 2,000 1,000, 500 or 200. The viscosity may be in a range provided by any lower and/or upper limit as previously described.

The gel carrier may be characterised by a compressive modulus. In some embodiments or examples, the gel core may have a compressive modulus in a range of about 50 to 250 kPa. The compressive modulus may be less than about (kPa) 250, 200, 150, 100, 90, 80, 70, 60, or 50. The compressive modulus may be at least (kPa) 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, or 240. The compressive modulus may be in a range provided by any lower and/or upper limit as previously described.

The gel core may comprise of a single material or it may be formed of a mixture of different materials. In some embodiments, the gel core may comprise a gel carrier. In some embodiments, the gel core may comprise a gel carrier and one or more active agents. The microcapsules described herein are useful with a wide variety of active agents. In some embodiments or examples, the inner gel core may further comprise one or more additives selected from an oil carrier, an aqueous carrier, solids, a water / oil emulsion, and an oil / water emulsion. In an embodiment, the oil carrier may be selected from oils including, but not limited to, one or more of triglyceride oils, mineral oil, petroleum oil, isopropyl myristate, soy bean oil, and silicon oil. It will be appreciated that the oil carrier can be selected from any oil carrier that can dissolve the active ingredient. In an embodiment, the aqueous carrier can be water, buffer solution, or a combination thereof. In an embodiment, the solid may be selected from, but not limited to, cocoa butter.

Metal Ions

The inventors have unexpectedly found that the presence of metal ions within a gel core composition can enable the deposition of a densely packed and/or continuous substantially impermeable ionic shell around a gel core to form a microcapsule. The deposition may be an electroless deposition under relatively fast and mild reaction conditions. It has been found that the metal ions present in the gel core can effectively catalyse the deposition of an ionic shell to encapsulate the gel core. It is believed that the metal ions act as a catalyst by increasing the rate of reaction and act as a seed to localise the deposition of the ionic compound, for example calcium phosphate, as an outer ionic or inorganic shell of the microcapsule.

In one embodiment the metal ions may be selected from one or more of iron, platinum, palladium, iridium, copper, nickel, magnesium, aluminium, and ruthenium. The metal ions may be selected from one or more of iron, platinum, palladium, iridium, and ruthenium. It will be appreciated that the metals may have different oxidation states. The typical oxidation states for the metal ions may be +2 and/or +3. It will be appreciated that various combinations and groups of the above mentioned metal ions may be used in the gel core of the present disclosure.

In one embodiment, the source of metal ions may be from an ionic compound. For example, the source of metal ions may be from an aqueous soluble ionic compound. It will be appreciated that reference to metal ions in the gel core refers to a metal in the form of an ionic compound comprising both anions and cations. For example a chloride anion may be the counter ion for an iron metal cation. Some example counter ions that may be used are NCh’, Cl", SC ² ', PC ² ', C2H3CF ² . For example, the ionic compound may be iron (II) chloride, iron (III) chloride, copper (II) chloride, nickel (II) chloride, magnesium (II) chloride, aluminium (II) chloride, iron (III) nitrate, iron (II) sulphate, iron (III) acetate, iron (III) phosphate, platinum (II) chloride, platinum (II) nitrate, platinum (II) sulphate, platinum (II) acetate, palladium

(II) chloride, palladium (II) nitrate, palladium (II) sulphate, palladium (II) phosphate, palladium (II) acetate, iridium (III) chloride, iridium (III) acetate, iridium (III) sulphide, iridium (III) phosphate, ruthenium (III) chloride, ruthenium (III) phosphate, ruthenium

(III) acetate, ruthenium (III) sulfate, barium (II) chloride, or combinations thereof. The source of metal ions may be, for example, selected from ionic compounds selected from the group comprising iron (II) chloride, iron (III) chloride, copper (II) chloride, nickel (II) chloride, magnesium (II) chloride, aluminium (II) chloride, platinum (II) chloride, palladium (II) chloride. The source of metal ions may be iron (II) chloride, iron (III) chloride, platinum (II) chloride or palladium (II) chloride. For example, the metal ion may be sourced from iron (II) chloride, iron (III) chloride, iron (II) sulphate, iron (III) phosphate, (e.g. the metal ion may be iron (II) or iron (III) cation).

In one embodiment, the amount of metal ions in the gel core may be in a range between about 0.2 weight % to about 2 weight % by weight of the total gel core. The amount of metal ions in the gel core may be in the range of about 0.2 weight % to 2 weight %, about 0.25 weight % to 1.8 weight %, or about 0.3 weight % to 1.6 weight %. The amount of metal ions in the gel core may be at least 0.2 weight %, at least 0.4 weight %, at least 0.8 weight %, at least 1 weight %, at least 1.4 weight %, at least 1.6 weight %, at least 1.8 weight %, or at least 2 weight %. The amount of metal ions in the gel core may be less than 2 weight %, less than 1.8 weight %, less than 1.5 weight %, less than 1 weight %, less than 0.5 weight %, or less than 0.3 weight %. The amount of metal ions in the gel core may be in a range provided by any lower and/or upper limit as previously described.

In another embodiment, the ratio by weight of the metal ions to gel core may be between about 10: 1 to about 0.05: 1. The ratio by weight of the metal ions to gel core may be in the range of from about 9: 1 to about 0.1 : 1, about 8:1 to about 0.25: 1, about 7: 1 to about 0.5: 1, or about 6: 1 to about 1 : 1. The ratio by weight of the metal ions to gel core may be at least 0.05: 1, at least 0.1 : 1, at least 0.25: 1, at least 0.5: 1, at least 1 : 1, at least 2: 1, or at least 4: 1. The ratio by weight of the metal ions to gel core may be less than 8: 1, less than 6: 1, less than 4: 1, less than 2: 1, less than 1 : 1, less than 0.5:1, less than 0.2: 1, or less than 0.1 : 1. The ratio by weight of the metal ions to gel core may be in a range provided by any lower and/or upper limit as previously described.

Optional Inner Coating

In some embodiments or examples, the inner gel core may further comprise an inner coating that encapsulates the gel core from the ionic shell. The inner coating may be a polymeric shell. In an embodiment, the polymeric shell may comprise or consist of a polymeric material. In an example, the polymeric shell may comprise or consist of a synthetic polymer or a naturally-occurring polymer. In some embodiments or examples, the synthetic polymer may be selected from nylon, polyethylenes, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyureas, polyurethanes, polyolefins, polysaccharides, epoxy resins, vinyl polymers, polyacrylates, or combinations thereof. The polymeric shell may comprise or consist of one or more thermoplastic polymers.

In another embodiment, the naturally-occurring polymer may be selected from silk, wool, gelatin, cellulose, alginate, proteins, chitosan or combinations thereof.

In some embodiments or examples, the polymeric shell may comprise or consist of a homopolymer or a copolymer. In an example, the polymeric shell may comprise or consist of a biodegradable polymer.

Process for preparing microcapsules

The microcapsules defined by the present disclosure may be prepared by forming microbeads of the inner fluid core materials followed by encapsulating the inner fluid core with an ionic shell. In some embodiments, the fluid core may be a gel core. In some embodiments, the ionic shell may be deposited as a densely packed and/or continuous layer over the gel core. For example, the ionic shell may be deposited as a densely packed and/or continuous layer over the inner gel core by electroless plating catalysed by metal ions present at the inner gel core interface.

In some embodiments, the process comprises incorporating or embedding the metal ions within the inner gel core prior to deposition of the outer inorganic shell.

In other embodiments, the process may further comprise forming an inner coating around the microbeads, prior to formation of the ionic shell around the inner coating. In an embodiment, the process may comprise encapsulating the gel core by an inner coating using an emulsification process prior to deposition of the ionic shell on to the inner coating. For example, the metal ions present in the gel core composition are incorporated or embedded within the inner coating to form a discontinuous layer metal ions on the surface of the inner coating during the emulsification process. The ionic shell may then be deposited on to the inner coating to further encapsulate the gel core and form a microcapsule according to at least some embodiments or examples as described herein. Gel core synthesis

In an embodiment or example, the microcapsules may be formed by forming a gel core. It will be appreciate that the gel core may be a hydrogel. For example the hydrogel may comprise alginates or alginate derivatives, agarose, and synthetic block copolymers. Hydrogels are three-dimensionally cross-linked networks composed of hydrophilic polymers with high water content.

It will be appreciated that chemical and/or physical cross-linking of hydrophilic polymers are typical approaches to forming hydrogels, and their physicochemical properties are highly dependent on the cross-linking type and crosslinking density, in addition to the molecular weight and chemical composition of the polymers. In one embodiment, the gel core may be prepared from an aqueous alginate solution combined with a solution comprising a ionic cross-linking agent, e.g. metal ions such as polyvalent cations including, but not limited to, iron, platinum, palladium, iridium, and ruthenium. It will be appreciated that the metal ions may bind solely to the guluronate residues of the alginate chains, as the structure of the guluronate residues may allow a high degree of coordination of the ions. The guluronate residues of one polymer may then form junctions with the guluronate residues of adjacent polymer chains resulting in a gel structure, i.e. forming a gel core. The source of metal ions may be, for example, selected from ionic compounds selected from the group comprising iron (II) chloride, iron (III) chloride, copper (II) chloride, nickel (II) chloride, magnesium (II) chloride, aluminium (II) chloride, iron (III) nitrate, iron (II) sulphate, iron (III) acetate, iron (III) phosphate, platinum (II) chloride, platinum (II) nitrate, platinum (II) sulphate, platinum (II) acetate, palladium (II) chloride, palladium (II) nitrate, palladium (II) sulphate, palladium (II) phosphate, palladium (II) acetate, iridium (III) chloride, iridium (III) acetate, iridium (III) sulphide, iridium (III) phosphate, ruthenium (III) chloride, ruthenium (III) phosphate, ruthenium (III) acetate, ruthenium (III) sulfate, barium (II) chloride, or combinations thereof. The source of metal ions may be, for example, selected from ionic compounds selected from the group comprising iron (II) chloride, iron (III) chloride, copper (II) chloride, nickel (II) chloride, magnesium (II) chloride, aluminium (II) chloride, platinum (II) chloride, palladium (II) chloride. The source of metal ions may be iron (II) chloride, iron (III) chloride, platinum (II) chloride or palladium (II) chloride. For example, an iron (III) cation (e.g. iron (III) chloride) may cross-link different polymer chains of an alginate polymer material to provide the gel core.

In one embodiment, the gel core may be formed by ionic gelation of the gel carrier into microbeads. The ionic gelation may be external ionic gelation. In alternate embodiments, the gel core may be formed by ionic gelation of the inner gel carrier into microbeads and forming an inner coating around the microbeads to provide an inner gel core comprising an inner coating. It will be appreciated that microencapsulation of the inner gel core may be provided using a variety of methods known in the art, including, for example, coacervation methods, in situ polymerisation methods or interfacial polymerisation methods.

In one embodiment, the gel core may be prepared by: (i) providing an aqueous phase comprising a gel carrier and one or more active agents to form a gel carrier material; (ii) providing an aqueous phase comprising a metal ion; and (iii) adding droplets of the gel carrier material to the aqueous phase comprising a metal ion to provide microbeads, thereby encapsulating the gel core material.

In other embodiments, the inner coating may be a polymeric shell. The polymeric shell can be formed by an interfacial polymerisation process. In an embodiment, the polymeric shell may be prepared by an interfacial polymerisation process which involves the use of a non-aqueous phase comprising the inner gel core and one or more oil-soluble monomers; and an aqueous phase comprising one or more water-soluble monomers and an emulsifier.

In an alternate embodiment, the polymeric shell may be provided by interfacial polymerisation of a pre-polymer. Such processes may be used to prepare a range of different polymeric shell materials. For example, a polymeric shell comprising a copolymer of polylactic acid and polyglycolic acid may be prepared by such a process.

Ionic shell deposition

In some embodiments or examples, the ionic shell is deposited by an electroless plating procedure catalysed by the metal ions described herein. In another example, metal ions catalyse an electroless plating process. Further advantages can be provided when metal ions are embedded or incorporated within the gel core or inner coating, which can provide an effective catalyst and seed for the deposition of an ionic compound such as calcium phosphate onto the surface of the microcapsule. The ionic shell may be prepared, for example, in-situ and formed from, or consists of, one or more ionic compounds (e.g. calcium phosphate). The ionic compound may be prepared in situ, for example grown or deposited around the gel core or inner coating of a gel core.

In some embodiments, following the incorporation of the metal ions on the surface of the gel core or the surface of the inner coating encapsulating the gel core, a film of the ionic shell may be formed on the discontinuous layer of metal ions, thereby coating the surface of the gel core or the surface of the inner coating encapsulating the gel core with a densely packed and/or continuous inorganic coating that surrounds the microcapsule. In an embodiment, the ionic shell may be calcium phosphate that has been prepared in-situ.

It will be appreciated that the composition or properties of the ionic shell, such as thickness of the ionic shell, may be provided by any one or more of the embodiments or examples as previously described herein for the ionic shell.

The ionic shell may be formed by an electroless plating process in which the deposition of an ionic compound (e.g. calcium phosphate) may be catalysed by the metal ions within the gel core. In an embodiment, the electroless deposition process may comprise contacting the microcapsules in which the metal ions are bound with a solution of calcium ions in the presence of a reducing agent (phosphate ions), in the absence of an electric current. In an embodiment, the reducing agent may be the phosphate source and the electroless plating may be performed under acidic or alkaline conditions. In an embodiment, the electroless plating may be performed under acidic conditions. In an example, the acid may be selected from succinic acid. In another embodiment, the electroless plating may be performed using thiourea. In another embodiment, the electroless plating may be performed under alkaline conditions. It will be understood that an acid or base may be used to control the pH range. In some embodiments, the pH range may be in the range from about 4.5 to about 10. The pH may be in the range of from about 4.7 to about 9.8, about 4.9 to about 9.5, about 5.1 to about 9.3, or about 5.3 to about 9.2. The pH may be at least 4.5, at least 4.6, at least 4.7, at least 4.8, at least 4.9, at least 5.0, at least 5.0, at least 5.2, at least 5.3, at least 5.4, or at least 5.5. The pH may be less than 10, less than 9.9, less than 9.8, less than 9.7, less than 9.6, less than 9.5, less than 9.4, less than 9.3, less than 9.2, less than 9.1, less than 9.0, less than 8.9, or less than 8.8. The pH may be in a range provided by any lower and/or upper limit as previously described.

Once the electroplating reaction commences, the deposition of the ionic compound (i.e. ionic shell) may become auto-catalytic. In an embodiment, the thickness of the ionic shell may be controlled by limiting the concentration of the ions of the in solution and/or the duration of the electroless deposition procedure. In some embodiments or examples, further advantages are provided by the ionic shell being an inorganic calcium phosphate shell, which can provide further effective auto-catalysis.

In some embodiments or examples, the ratio of calcium ions to phosphate ions may be between about 20: 1 to about 0.1 : 1. The ratio of calcium ions to phosphate ions may be in the range of from about 15: 1 to about 0.2: 1, about 10: 1 to about 0.4: 1, about 5: 1 to about 0.5: 1, or about 2: 1 to about 1 :1. The ratio of calcium ions to phosphate ions may be at least 0.1 : 1, at least 0.2: 1, at least 0.4: 1, at least 0.5: 1, at least 1 : 1, at least 2: 1, or at least 4: 1. The ratio of calcium ions to phosphate ions may be less than 15: 1, less than 10: 1, less than 4: 1, less than 2: 1, less than 1 : 1, less than 0.5: 1, or less than 0.2: 1. The ratio of calcium ions to phosphate ions may be in a range provided by any lower and/or upper limit as previously described.

Suitable techniques for conducting the electroless plating procedure are described, for example, in the following documents: Basarir et al., ACS Applied Materials & Interfaces, 2012, 4(3), 1324-1329; Blake et al., Langmuir, 2010, 26(3), 1533-1538; Chen et al., Journal of Physical Chemistry C, 2008, 112(24), 8870-8874; Fujiwara et al., Journal of the Electrochemical Society, 2010, 157(4), pp. D211-D216; Guo et al., Journal of Applied Polymer Science, 2013, 127(5), 4186-4193; Haag et al., Surface and Coatings Technology, 2006, 201(6), 2166-2173; Horiuchi et al., Surface & Coatings Technology, 2010, 204(23), 3811-3817; Ko et al., Journal of the Electrochemical Society, 2010, 157(1), pp. D46-D49; Lin et al., International Journal of Hydrogen Energy, 2010, 35(14), 7555-7562; Liu et al., Langmuir, 2005, 21(5), 1683- 1686; Ma et al., Applied Surface Science, 2012, 258(19), 7774-7780; Miyoshi et al., Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2008, 321(1-3), 238-243; Moon et al., 2008, Ultramicroscopy, 108(10), 1307-1310; Wu et al., Journal of Colloid and Interface Science, 2009, 330(2), 359-366; Ye et al., Materials Letters, 2008, 62(4-5), 666-669; and Zhu et al., Surface and Coatings Technology, 2011, 205(8- 9), 2985-2988.

In some embodiments or examples, the ions of the ionic compound may be present in the solution at a concentration of from 0.05 to 2000 mM. The concentration may be in a range of about 0.1 to 1500 mM, 0.5 to 1000 mM, 1.0 to 800 mM, or 10 to 500 mM. The concentration may be at least 5 mM, at least 10 mM, at least 15 mM, at least 20 mM, at least 25 mM, at least 30 mM, at least 45 mM, at least 60 mM. The concentration may be less than 800 mM, less than 500 mM, less than 250 mM, 230 mM, less than 225 mM, less than 200 mM, less than 150 mM, less than 100 mM, or less than 50 mM. The concentration may be in a range provided by any lower and/or upper limit as previously described. In an example, calcium chloride may be provided in a concentration range of 10 to 500 mM, 45 to 225 mM, or 60 to 100 mM, and hypophosphate may be provided in a concentration range of 10 to 500 mM, 25 to 230 mM, or 30 to 100 mM.

In some embodiments or examples, the electroless plating process may be performed at temperature in a range from between 10°C to 100°C. The temperature may be in the range of from about 15°C to about 95°C, about 20°C to about 90°C, about 25°C to about 85°C, about 30°C to about 80°C, about 35°C to about 75°C, about 40°C to about 70°C, or about 45°C to about 65°C. The temperature may be at least 15°C, at least 20°C, at least 25°C, at least 30°C, at least 35°C, at least 40°C, at least 45°C, at least 50°C, at least 55°C, at least 60°C, or at least 65°C. The temperature may be less than 90°C, less than 85°C, less than 80°C, less than 75°C, less than 70°C, less than 75°C, less than 70°C, less than 65°C, less than 60°C, or less than 55°C. The temperature may be in a range provided by any lower and/or upper limit as previously described. Impermeability and leakage tests

The microcapsules are designed to release their gel core when the microcapsules are ruptured. The rupture can be caused by forces applied to the outer inorganic shell during mechanical interactions. The microcapsules may have a fracture strength of from about 0.01 MPa to about 25 MPa. In an embodiment, the microcapsules may have a fracture strength of at least 0.5 MPa. So that the microcapsules are readily friable, the fracture strength may be less than about 50 MPa, 25 MPa, 20 MPa, 15 MPa, 10 MPa, 5 MPa, 2 MPa, 1.0 MPa, 0.5 MPa, 0.2 MPa, or 0.1 MPa. The fracture strength may be at least about 0.01 MPa, 0.05 MPa, 0.1 MPa, 0.2 MPa, 0.5 MPa, 1.0 MPa, 2.0 MPa, 5.0 MPa, 10 MPa, 15 MPa, 20 MPa, 25 MPa, 30 MPa, 40 MPa, 50 MPa, or 100 MPa. The microcapsules may have a fracture strength of from in a range between about 0.01 to 100 MPa, 0.1 to 50 MPa, 0.2 to 25 MPa, or 0.5 to 10 MPa. The fracture strength may be in a range provided by any lower and/or upper limit as previously described.

The fracture strength of the microcapsules may be measured using the Fracture Strength Test Method where three different measurements can be made and two resulting graphs can be utilized. The three separate measurements may be: i) the volume-weighted particle size distribution (PSD) of the microcapsules; ii) the diameter of at least 10 individual microcapsules within each of 3 specified size ranges, and; iii) the rupture-force of those same 30 or more individual microcapsules. The two graphs created can be: a plot of the volume-weighted particle size distribution data collected at i) above; and a plot of the modelled distribution of the relationship between microcapsule diameter and fracture-strength, derived from the data collected at ii) and iii) above. The modelled relationship plot can enable the strength range of the microcapsules to be identified as a specific region under the volume-weighted PSD curve, and then calculated as a percentage of the total area under the curve.

The volume-weighted particle size distribution (PSD) of the microcapsules can be determined via single-particle optical sensing (SPOS), also called optical particle counting (OPC). A capsule slurry, and its density of particles can be adjusted with DI water as necessary via autodilution to result in particle counts of at least 9200 per ml. During a time period of 120 seconds the suspension can be analyzed. The resulting volume-weighted PSD data can be plotted and recorded, and the values of the mean, 5 ^th percentile, and 90 ^th percentile can be determined.

The diameter and the rupture-force value (also known as the bursting-force value) of individual microcapsules can be measured via Atomic Force Microscopy (AFM).

A drop of the microcapsule suspension can be placed onto a glass microscope slide, and dried under ambient conditions for several minutes to remove the water and achieve a sparse, single layer of solitary particles on the dry slide. Adjusting the concentration of microcapsules in the suspension as needed can achieve a suitable particle density on the slide.

The slide can then be placed on a sample-holding stage of the AFM instrument. Thirty or more microcapsules on the slide(s) can be selected for measurement, such that there can be at least ten microcapsules selected within each of three pre-determined size bands. Each size band can refer to the diameter of the microcapsules. The three size bands of particles can be: the Mean Diameter +/- 2 pm; the 5 ^th Percentile Diameter +/- 2 pm; and the 90 ^th Percentile Diameter +/- 2 pm. Microcapsules which appear deflated, leaking or damaged can be excluded from the selection process and are not measured.

For each of the 30 or more selected microcapsules, the diameter of the microcapsule can be measured from the image on the AFM and recorded. That same microcapsule can then be compressed between two surfaces, namely the AFM cantilever tip and the glass microscope slide, until the microcapsule is ruptured. During the compression step, the probe force required to break the capsule (rupture force) can be measured and recorded by the data acquisition system of the AFM instrument.

The cross-sectional area can be calculated for each of the microcapsules, using the diameter measured and assuming a spherical particle (7t% ² , where r is the radius of the particle before compression).

The Fracture Strength of each of the 30 or more microcapsules can be calculated by dividing the rupture force (in Newtons) by the calculated cross-sectional area of the respective microcapsule. On a plot of microcapsule diameter versus fracture-strength, a Power Regression trend line is fit against all 30 or more raw data points, to create a modelled distribution of the relationship between microcapsule diameter and fracture-strength.

The percentage of microcapsules which have a fracture strength value within a specific strength range can be determined by viewing the modelled relationship plot to locate where the curve intersects the relevant fracture-strength limits, then reading off the microcapsule size limits corresponding with those strength limits. These microcapsule size limits can then be located on the volume-weighted PSD plot and thus identify an area under the PSD curve which corresponds to the portion of microcapsules falling within the specified strength range. The identified area under the PSD curve can then be calculated as a percentage of the total area under the PSD curve. This percentage can indicate the percentage of microcapsules falling with the specified range of fracture strengths.

The microcapsules may be characterised in terms of their permeability. The permeability may be tested using the Ethanol Stability test where a known volume of microcapsules can be isolated and dispersed in an aqueous solution comprising a 1 :4 solution of water to absolute ethanol. The dispersion can be heated to 40°C. After 7 days at 40°C, the microcapsules can be isolated from the aqueous solution using centrifugation at 7000 rpm for 1 minute. Alternatively, the dispersion can be maintained at room temperature. After 7 days at room temperature, the microcapsules can be isolated from the aqueous solution using centrifugation at 7000 rpm for 1 minute. The aqueous solution can then be subjected to analysis using gas chromatography to determine the content of the gel core material that has leached from the microcapsules. To confirm the presence of the gel core material within the microcapsules, a known sample of microcapsules can be crushed with a spatula in a vial prior to addition of 2 ml ethanol. The microcapsules can be isolated from the aqueous solution using centrifugation at 7000 rpm for 1 minute. The aqueous solution can then be subjected to analysis using gas chromatography to determine the content of the gel core material that has leached from the microcapsules.

Advantageously, the microcapsules can be delivered in a targeted manner or in response to a specific trigger. According to at least some embodiments or examples as described herein, the microcapsules can provide a capsule that is substantially impermeable and can be advantageously suitable for use in various applications. The microcapsule can be impermeable to low molecular weight volatile molecules encapsulated within it thereby preventing release. The inventors have surprisingly found that depositing an ionic shell on a microcapsule, for example depositing an inorganic calcium phosphate shell on a microcapsule, can provide a substantially impermeable microcapsule suitable for a number of applications, including but not limited to, drug delivery, personal care products, agricultural products and food products such as functional foods. In some embodiments or examples, the ionic shell may be substantially impermeable to low molecular weight or volatile “active agent” molecules, for example molecules having a molecular weight of less than about 1000 g.mol' ¹ , 900 g.mol' ¹ , 800 g.mol' ¹ , 700 g.mol' ¹ , 600 g.mol' ¹ , 500 g.mol' ¹ , 400 g.mol' ¹ , 300 g.mol' ¹ , or 200 g.mol' ¹ . In an example, the microcapsule may be impermeable to molecules smaller than 500 g.mol' ¹ . In another example, the microcapsules can retain low molecular weight active agents present in the gel core of the microcapsules for up to about 12 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, or 2 months. The impermeability or retention of active agent in the gel core may be measured by placing the prepared microcapsules into a solution (e.g. ethanol) for predetermined time, such as 1 week, and measuring the amount of active agent released into the solution. In an embodiment or example, the microcapsules may retain at least 50% by weight of the inner gel core. The retention of active agent within the microcapsule as a weight % of active agent may be at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, or 99.9%. The retention of the active agent within the microcapsule as a weight % of active agent may be less than, 99.99%, 99.9%, 99.8%, 99.5%, 99%, 98%, 95%, 90%, 85%, 75%, or 55%. The retention of the active agent within the microcapsule may be in a range provided by any lower and/or upper limit as previously described.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

EXAMPLES

The present disclosure is further described by the following examples. It is to be understood that the following description is for the purpose of describing particular examples only and is not intended to be limiting with respect to the above description.

Example la: Preparation of gel core comprising iron ions at the interphase of a hydrogel

To form a gel core, sodium alginate (1.51 g) was dissolved in ultrapure water to give a 100 mL solution. Iron (III) chloride hexahydrate (FeCh, 1.62 g) was dissolved in ultrapure water to give a 500 mL solution. The sodium alginate solution (3 mL, 70 mM) was added to 0.5 mL poly(vinyl pyrrolidine) (2wt%) and hexadecane (0.5 mL). This was vortexed for 3 minutes to form an emulsion. The emulsion was then dropped into stirring FeCh solution (10 mL) using a 21G needle. The alginate beads were left to stir overnight.

Example lb : Preparation of microcapsules comprising a calcium phosphate ionic shell:

For electroless deposition of CaP onto the microcapsules, the aqueous phase was removed and the alginate beads redispersed in 3 mL water. Approximately a third of the beads (1 mL) were added to a calcium phosphate plating solution, consisting of calcium chloride (1.0 mL, 192 mM, sodium fluoride (1.0 mL, 119 mM), sodium hypophosphite (1.0 mL, 47 mM), and succinic acid (1.0 mL, 59 mM) and optionally iron (iii) chloride (0.5 mL, 20 mM). In another example, platinum (ii) chloride (0.5 mL, 20 mM) can optionally be added. In yet another example, palladium (ii) chloride (0.5 mL, 20 mM) can optionally be added. This was stirred magnetically at 400 rpm for 15 min at 55°C then left to stand at room temperature overnight. This was then washed via centrifugation at 2000 rpm for 10 min at 10°C and redispersed in 3 mL ultrapure water to provide a plurality of microcapsules having an outer ionic shell of calcium phosphate encapsulating a gel core comprising iron ions. Example 2a: Preparation of gel core comprising iron ions at the interface of a hydrogel and an active ingredient

To form alginate microcapsules with an oil core containing the active ingredient, sodium alginate (250 cps) (7.2 g) was dissolved in ultrapure water to give a 500 mL solution. Separately, 10 mg l,l'-dioctadecyl-3,3,3'3'-tetramethylindo- carbocyanine perchlorate was dissolved in ethanol. 100 pL was then added to 49.9 mL sesame oil. In another preparation, 30 mL of the dye-oil solution was removed and diluted to 100 mL, then 200 mg cannabidiol was dissolved in the 100 mL sesame oildye solution. Separately, iron (III) chloride (6.49 g) was dissolved in 400 mL ultrapure water.

A Buchi Encapsulator 390 was used to prepare the core-shell alginate microcapsules. The alginate was pumped through a 400 pm outer nozzle and the oil containing dye, or dye with cannabidiol was pumped through the inner 200 pm nozzle, at 450 mbar pressure, 350 Hz frequency and 2000 V voltage. The capsules were collected in a stirring bath of iron chloride solution, and left to stir for at least 4 hours.

Example 2b: Preparation of microcapsules comprising a calcium phosphate shell. For electroless deposition of CaP onto the microcapsules prepared using the Buchi Encapsulator, the aqueous phase was removed and the alginate microcapsules were washed with water three times prior to exposure to the plating bath. An aliquot of 100 mg of alginate microcapsules with dye core (dry) was added to a calcium phosphate plating solution consisting of calcium chloride (1 mL 192 mM), sodium hypophosphate (1 mL 47 mM), and optionally sodium fluoride (1 mL, 119 mM), succinic acid (1 mL, 59 mM) and iron (III) chloride (1 mL, 20 mM). For each component omitted in a given reaction, 1 mL ultrapure water was added so the volume of the plating bath was constant. The samples were agitated in a shaking incubator at 55 °C for 1 hour, then left to stand at room temperature overnight. The aqueous phase was removed and replaced with ultrapure water. Example 3: Characterisation of microcapsules

The morphology of the CaP shell was analysed using a JEOL JSM-7100F field emission scanning electron microscope. Samples were dried and sputter coated with 15 nm carbon prior to imaging. CaP particles were observed to completely cover the gel surface. Elemental composition analysis using energy dispersive X-ray spectroscopy (EDX) (JEOL 129 eV resolution silicon drift detector) confirmed that CaP was present (see Figure 1). This was compared to an uncoated and bare iron-alginate bead in the absence of a CaP outer shell.

To determine the permeability of the protective calcium phosphate shell, 14 coated microcapsules (2.6 mm diameter) prepared in example lb were added to 2 mL absolute ethanol and agitated at room temperature. A known volume (200 pL) of the ethanol solvent was collected at specified time intervals up to 7 days for gas chromatography analysis to test for the presence of hexadecane, as shown in Figure 2.

This was compared to the release of hexadecane over time from 14 alginate microcapsules without a deposited calcium phosphate shell. Samples were run on a Shimadzu GC-2010 with FID detector using an Agilent Ultra-1 column of 50m in length, 0.2 mm internal diameter and 0.33 pm film thickness. The temperature program started at 75 °C and was ramped to 320 °C at 20 °C per minute, before holding at 320 °C for a further 3 minutes. The injector and detector ports were set at 300 °C and an injection volume of 4 pL was used. The concentration of hexadecane release was calculated from a calibration curve of peak area as a function of known hexadecane concentrations.

To determine the thickness of the calcium phosphate shell, coated alginate microcapsules were set in a resin, LR White, and observed using a Thermo Fisher Apreo - High Resolution FESEM with a VolumeScope Serial Block Face System, to slice cross sections of the microcapsules to obtain the thickness of the CaP shell, as shown in Figure 3.

To determine the permeability of the protective calcium phosphate shell against release of l,l'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate, 5 microcapsules prepared at each of the plating conditions described in example 2b were added to 500 pL absolute ethanol and agitated at 40 °C. This was compared to the release of l,l'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate over time from bare alginate microcapsules. A known volume (180 pL) was removed at specified time intervals over 7 days and the fluorescence intensity (excitation 540 nm, emission 570 nm) was measured in a black 96 well plate using a Tecan 2000 plate reader. The 180 pL was returned to the sample post-measurement. The results were compared to calibration samples of l,T-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate in ethanol at concentrations between 0.5 pg/mL and 10 pg/mL, as shown in Figure 4.

To determine the permeability of the protective calcium phosphate shell against release of cannabidiol, 40mg of microcapsules was added to 500 pL of methanol and agitated at 40 °C. This was compared to the release of cannabidiol from 40 mg bare alginate microcapsules. A known volume (3 pL) of methanol solvent was removed at set time intervals over 24 hours for the measurement of UV absorbance at 230 nm, using an Implen NanoPhotometer. The results were compared to calibration samples of cannabidiol in methanol at concentrations between 0.25 pg/mL and 10 pg/mL, as shown in Figure 5.