Hybrid nanofibrous mat and method of making same

Abstract

There is provided a hybrid nanofibrous mat comprising electrospun nanofibers formed by electrospinning of a polymer mix and porous silica capsules dispersed throughout the electrospun nanofibers during the electrospinning, the porous silica capsules having a hydrophobic liquid core containing an active. There is also provided a method of producing a hybrid nanofibrous mat comprising providing porous silica capsules having a hydrophobic liquid core containing an active, forming an electrospinning solution comprising the porous silica capsules and an electrospinning polymer mix, homogenising the electrospinning solution to fully disperse the porous silica capsules, and electrospinning the electrospinning solution to form the hybrid nanofibrous mat.

Description

[0001] HYBRID NANOFIBROUS MAT AND METHOD OF MAKING SAME

[0002] FIELD OF INVENTION

[0003] The present invention relates to a hybrid nanofibrous mat and a method of making same. In particular, the invention relates to hybrid nanofibrous mats that include nanofibers with dispersed silica particles having a hydrophobic liquid core.

[0004] BACKGROUND ART

[0005] There is ever-increasing demand for “non-invasive” transdermal delivery-based treatments, both from user and clinician perspectives. The big advantage with such treatments is that they allow pain free self-administration by the patients. The market reflects this and is expanding quickly, currently representing US$7.7 billion in sales in 2022, with 66 commercial patches available and close to 100 in clinical trials. The key benefit is facilitated by direct delivery of the drug into the bloodstream from the skin. This avoids the Gl tract and the liver, evading drug-metabolism by Gl tract enzymes and in the liver, thereby enhancing bioavailability. The drug release is sustained over the period of application leading to steady levels of drug and continued efficacy.

[0006] However, there are some issues with the current transdermal systems, including:

[0007] 1 . Suboptimal permeation of hydrophobic drugs;

[0008] 2. Need for very high drug loading to get optimal therapeutic dose;

[0009] 3. Waste of unused drug at the time of disposal (range: 50-97%);

[0010] 4. Serious public health risks for controlled drugs.

[0011] For example, there may be public health risks due to high drug loading and drug remaining in the patch at disposal which may cause accidental overdose or drug abuse, e.g. with fentanyl patches. Nevertheless, the clinical need for these patches is undeniable. Hence, it is crucial to develop a transdermal drug delivery system that can achieve high efficiency of delivery at relatively low drug loading.

[0012] This can be addressed by improving the penetration of the drug through the barrier posed by the skin's outermost layer called stratum corneum (SC), which is 10 to 20 pm thick.

[0013] Several methods are employed for this and are mainly classified into physical and chemical penetration. Physical penetration involves use of microneedle patches, heat, laser or ionophoresis. Chemical penetration enhancement into the skin can be achieved through use of pyrrolidones, alcohols , glycols, esters, water, esters sulfoxides (such as dimethyl sulfoxide) and their derivatives, hydrocarbons, terpenes and derivatives, Azone and its analogs, amides (including urea and its derivatives), fatty acids, surfactants (non-ionic, cationic, and anionic), oleo-dendrimers, ionic liquids, and deep eutectic solvents.

[0014] The invention focuses on developing patient-centric, biodegradable, efficient and safe transdermal patches. Towards that goal, the invention aims to develop a biodegradable, polymer-based delivery system using electrospinning.

[0015] Electrospinning is a relatively novel process that is used to produce nonwoven mats under application of high electrical field to polymeric mixes. This leads to the deposition of the polymer mix in the form of fibres onto a conducting substrate. Two types of electrospinning are currently employed: needle-based and needle-free. While oil / liquids encased in a nanofibrous core shell has been achieved using coaxial needle-based systems, this is not possible using the surface free needle free system. The major hurdle with the use of needle-based electrospinning is the difficult logistics of industrial scale up, the productivity is very low and is industrially not feasible. Multiple spinnerets have been tried in needle-based electrospinning to improve productivity, but the issues of clogging and electrical interference still remain major issues. The needle free system, on the other hand, employs free surface electrospinning and thus avoids the issues of clogging and electrical interference, and is eminently scalable. Additionally, it is particularly suitable for water-based depositions which makes this a method of choice for transference to the pharmaceutical industry.

[0016] The subject matter claimed herein is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate exemplary technology areas where some embodiments described herein may be practiced.

[0017] Various aspects and embodiments of the invention will now be described.

[0018] SUMMARY OF INVENTION

[0019] As mentioned above, the present invention relates generally to a hybrid nanofibrous mat and a method of making same. In particular, the invention relates to hybrid nanofibrous mats that include nanofibers with dispersed silica particles having a hydrophobic liquid core.

[0020] According to one aspect of the invention there is provided a hybrid nanofibrous mat comprising: electrospun nanofibers formed by electrospinning of a polymer mix; and porous silica capsules dispersed throughout the electrospun nanofibers during electrospinning, the porous silica capsules having a hydrophobic liquid core containing an active.

[0021] In a preferred embodiment, the porous silica capsules have a breakage percentage during centrifugation (12000g) of less than 50% and percentage active leaching (24 hours) of greater than 15%. The porous silica capsules preferably have a breakage percentage during centrifugation (12000g) of 25% or less, 10% or less, or even more preferably have no breakage during centrifugation (12000g). In a preferred embodiment, the porous silica capsules also have a breakage percentage of less than 10% breakage during electrospinning, and preferably have no breakage during electrospinning.

[0022] In certain embodiments, the porous silica capsules have a percentage active leaching (24 hours) of 15-20%. Further, in certain embodiments, the porous silica capsules have a percentage active leaching (6 hours) of 10-16%.

[0023] In preferred embodiments, the porous silica capsules have a particle size of 50- 300nm, more preferably 50-200nm.

[0024] In order to achieve desirable loading, the porous silica capsules preferably have an encapsulation efficiency of greater than 50%, preferably 70%, more preferably from 70-90%, during production of the silica particles.

[0025] Loading of the porous silica capsules in the hybrid nanofibrous mat is preferably from 10-35 grams / square metre (GSM).

[0026] As will be described in more detail below, the porous silica capsules are preferably formed from a hydrophobic silicon alkoxide or alkoxysilane precursor. The hydrophobic silicon alkoxide or alkoxysilane precursor is preferably selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl di-ethoxy silane, phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS). Most preferably, the hydrophobic silicon alkoxide or alkoxysilane precursor is Tetra Ethyl Orthosilicate (TEOS).

[0027] The quantity of the hydrophobic silicon alkoxide or alkoxysilane precursor used in the production of the porous silica capsules is preferably from 0.22-0.29 moles although this may be dependent on the scale of operation.

[0028] In certain embodiments, the hydrophobic liquid core containing an active comprises an oil alone, or an oil / active mix. For example, the oil may comprise hemp seed oil, or the oil / active mix may comprise hemp seed oil / cannabidiol (CBD). Penetration enhancers, such as polypropylene glycol (PPG) may also be used in combination with an active such as CBD. Preferably, the electrospinning polymer mix comprises a Polyvinyl Alcohol (PVA) / Polyethylene Oxide (PEO) mix.

[0029] In another aspect the invention provides a method of producing a hybrid nanofibrous mat comprising: providing porous silica capsules having a hydrophobic liquid core containing an active; forming an electrospinning solution comprising the porous silica capsules and an electrospinning polymer mix; homogenising said electrospinning solution to fully disperse said porous silica capsules; and electrospinning the electrospinning solution to form the hybrid nanofibrous mat.

[0030] Again, the porous silica capsules preferably have a breakage percentage during centrifugation (12000g) of less than 50% and percentage active leaching (24 hours) of greater than 15%. The porous silica capsules may preferably have a breakage percentage during centrifugation (12000g) of 25% or less, 10% or less, or have no breakage during centrifugation (12000g). The porous silica capsules may also have a breakage percentage of less than 10% breakage during electrospinning, or preferably no breakage during electrospinning.

[0031] The porous silica capsules may have a percentage active leaching (24 hours) of 15-20% and may have a percentage active leaching (6 hours) of 10-16%.

[0032] As discussed above, the porous silica capsules may have a particle size of 50- 300nm, preferably 50-200nm.

[0033] The porous silica capsules preferably have an encapsulation efficiency of greater than 50%, preferably 70%, more preferably from 70-90% during production of the silica particles.

[0034] Loading of the porous silica capsules in the hybrid nanofibrous mat is preferably from 10-35 grams / square metre (GSM). Once again, the porous silica capsules are preferably formed from a hydrophobic silicon alkoxide or alkoxysilane precursor. For example, the hydrophobic silicon alkoxide or alkoxysilane precursor may be selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl di-ethoxy silane, phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS). The hydrophobic silicon alkoxide or alkoxysilane precursor is preferably Tetra Ethyl Orthosilicate (TEOS).

[0035] The quantity of the hydrophobic silicon alkoxide or alkoxysilane precursor used in the production of the porous silica capsules may be from 0.22-0.29 moles, although this may be dependent on the scale of operation.

[0036] Again, the hydrophobic liquid core containing an active may comprise an oil alone, or an oil / active mix. For example, the oil may comprise hemp seed oil, or the oil / active mix may comprise hemp seed oil / cannabidiol (CBD).

[0037] The electrospinning polymer mix preferably comprises a Polyvinyl Alcohol (PVA) / Polyethylene Oxide (PEO) mix.

[0038] Forming the electrospinning solution preferably comprises: mixing the porous silica capsules into a PVA solution, preferably a 16% PVA solution in DI water; adding a PEO solution, preferably a 10% PEO solution in DI water, and mixing; adding acetic acid, preferably 1 M acetic acid, to increase acidity and conductivity; and homogenising and mixing to fully disperse the porous silica capsules.

[0039] Homogenising and mixing may be conducted by hand and subsequently using a rotor stator, for example at 6000rpm for 5 minutes. The speed and time may be varied depending on the circumstances of a particular application. According to a further aspect of the invention there is provided a method of producing porous silica capsules for use in the hybrid nanofibrous mat as described above, or the method as described above, comprising: preparing an oil phase by mixing an oil or oil / active with a hydrophobic silicon alkoxide or alkoxysilane precursor; preparing a first water phase by adding a surfactant to water with stirring until solubilised; shear mixing the first water phase into the oil phase to form an oil-in- water emulsion; preparing a second water phase by adding an aminosilane catalyst to water; adding the second water phase to the oil-in-water emulsion; aging a resulting mixture with stirring to form an aged mixture; heating the aged mixture to complete the aging process, thereby forming the porous silica capsules in suspension; centrifuging the suspension to form a capsule slurry; and harvesting the porous silica capsules from the capsule slurry.

[0040] The hydrophobic silicon alkoxide or alkoxysilane precursor is preferably selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl di-ethoxy silane, phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS). More preferably, the hydrophobic silicon alkoxide or alkoxysilane precursor is Tetra Ethyl Orthosilicate (TEOS).

[0041] The quantity of the hydrophobic silicon alkoxide or alkoxysilane precursor used in the production of the porous silica capsules is from 0.22-0.29 moles. As noted above this may be somewhat dependent on the scale of the operation.

[0042] The oil may comprise hemp seed oil, or the oil / active mix may comprise hemp seed oil / cannabidiol (CBD).

[0043] The surfactant in the first water phase preferably comprises a mixture of polysorbates. More preferably, the mixture of polysorbates comprises Tween 20 and Tween 80, preferably in a 50:50 ratio. The catalyst in the second water phase preferably comprises an aminosilane catalyst, more preferably 3-aminopropyl triethoxysilane (APTES). The APTES is preferably added in an amount of above 5%, preferably above 7.5%, for example from 5-10% based on the total amount of silanes added.

[0044] It is anticipated that the porous silica capsules could also be produced using a mixture of a hydrophobic active (in powder or liquid form) after mixing / dissolving in the liquid material to produce the capsules. One can also surmise that hydrophobic solvent used for the dissolution of poorly soluble APIs can also be added to the silicon precursor oil mixture.

[0045] According to yet another aspect of the invention there is provided a transdermal patch, transdermal thin film or oral thin film for the delivery of a liquid containing active to a user, the transdermal patch, transdermal thin film or oral thin film comprising a hybrid nanofibrous mat as described above.

[0046] The transdermal patch generally further comprises a backing layer covering the hybrid nanofibrous mat, an adhesive layer for adhering to the skin of the user, and a removable protective liner.

[0047] BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

[0048] To further clarify various aspects of some embodiments of the present invention, a more particular description of the invention will be rendered by references to specific embodiments thereof, which are illustrated in the appended drawings. It should be appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting on its scope. The invention will be described and explained with additional specificity and detail through the accompanying drawings in which:

[0049] FIG. 1 illustrates a synthetic scheme for capsule preparation. FIG. 2 illustrates TEM of CBD / Hemp seed capsules with different silica precursor content (a-e).

[0050] FIG. 3 illustrates a comparison of CBD leached in samples produced with different TEOS quantities over time.

[0051] FIG. 4 illustrates TEM images showing the effect of varying surfactant ratios on the capsule morphology.

[0052] FIG. 5 illustrates TEM showing the impact of surfactant quantity on the morphology of capsules produced using 0.29 moles of TEOS.

[0053] FIG. 6 illustrates TEM showing impact of APTES on morphology of 0.29 mol TEOS capsules.

[0054] FIG. 7 illustrates TEM showing the Capsule morphology of sample prepared containing Hemp Seed Oil only (left), compared with sample prepared with Hemp Seed Oil / CBD (right).

[0055] FIG. 8 illustrates FTIR spectra of native Hempseed oil and encapsulated hemp seed oil (after extraction).

[0056] FIG. 9 illustrates thermal analysis of dried hemp seed oil capsule sample. Heating rate = 10°C / min in air.

[0057] FIG. 10 illustrates TEM of PPG / CBD encapsulated in silica capsules.

[0058] FIG. 1 1 illustrates TEM of capsules produced at Low and high TEOS levels.

[0059] FIG. 12 illustrates TEM imaging of capsules following shear mix preparation for electrospinning. FIG. 13 illustrates SEM of Electro-spun mats produced using low and high TEOS capsules.

[0060] FIG. 14 illustrates FTIR of Hemp seed oil leached from the capsules (yellow) and from the mats with hempseed oil capsules (red) in comparison with pure Hemp seed oil (purple).

[0061] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] Hereinafter, this specification will describe the present invention according to the preferred embodiments. It is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned without departing from the scope of the appended claims.

[0063] As described above, it is considered that introducing oils or hydrophobic liquids in a protective polymeric core into the electrospinning mix will facilitate efficient incorporation of liquids such as penetration enhancers and small drug molecules into a final mat produced using needle free electrospinning technology.

[0064] Amorphous silica is chosen to create the core shell structure as it is 1 ) biologically and chemically inert, 2) mechanically strong to withstand post processing, 3) biodegradable and biocompatible, and 4) recognized as a GRAS ingredient by the FDA and is approved as an excipient for topical and oral formulations (>200 approved products). Silica is considered non-toxic by oral and external routes of exposure.

[0065] As described below, a porous silica shell with encapsulated liquid will be produced that will allow downstream mechanical processes, such as highspeed centrifugation and mixing procedures for electrospinning. The production of nano composite mats composed of oil containing capsules with a porous silica shell incorporated inside biodegradable hydrophilic polymeric fibres using needle-free electrospinning will be described in more detail.

[0066] Upon contact with moist skin, the nanofibers of the mat will dissolve liberating the nano-capsules which will then release their payload by diffusion through their porous silica shell. This payload can be a hydrophobic liquid e.g., oils or penetration enhancers or a combination of a hydrophobic drug, dissolved either in the liquids and / or incorporated in the nanofibers. As an example of an application, it is anticipated that presence of penetration enhancer together with a hydrophobic active will enhance its penetration through the SC significantly.

[0067] Specifically, the more detailed discussion below will:

[0068] 1 . Describe how to synthesise mechanically resistant and porous silica capsules that can survive the electrospinning process;

[0069] 2. Detail parameters that can be used to control the morphology of the capsules;

[0070] 3. Provide evidence of the release from encapsulated API from both the capsules and the capsules incorporated in the nanofibrous mat; and

[0071] 4. Show how the release can be controlled by controlling the microstructure of the silica shell.

[0072] As mentioned above, the encapsulation of oil compound inside hydrophilic biodegradable nano fibres can be achieved by using a needle-based electrospinning technique to produce co-axial core sheath geometry nanofibers. However, the industrial scale-up of these co-axial systems remains very challenging and incompatible with wire-based free-surface electrospinning systems (Needle free), which are currently the best developed for large pharmaceutical scale production and transference. When an oil is introduced in the water-based electrospinning mix directly, it leads to significant widening of the fibre diameter as well as to patchy, irregular and non-homogeneous depositions, resulting in fusing or melting of the fibrous network in various locations. The mat is generally non-homogeneous with a high fibre diameter (>1 micron). Such higher diameter fibres and fusion of the nanofibrous network leads to significant loss in surface area of the fibres and results in slower or inadequate dissolution and uncontrolled release of the oil payload. In contrast, when the oil is encapsulated in silica capsules, the open 3D nanofibrous structure is preserved with lower diameter (< 600 nm) as in the original mat, indicating a similar dissolution behaviour.

[0073] There is therefore a potential for silica encapsulation to render hydrophobic liquids compatible with the electrospinning process without any significant reformulation of the polymeric solution.

[0074] Synthetic conditions to achieve mechanical resistant capsules

[0075] Several authors have described processes for preparing a silica core-shell capsule containing a hydrophobic core and a silica shell. For most of those applications i.e., encapsulation of sunscreen, fragrance, catalyst (BPO) the goal is to avoid release altogether (sunscreen) or to have release triggered by mechanical rupture of the shell (fragrance) or depressurization (BPO catalyst).

[0076] In the present case, the aim is to:

[0077] 1 . Release the content of the capsule gradually by passive diffusion through the porous silica shell; and

[0078] 2. Generate a capsule that survives the high centrifugal forces during synthesis and subsequent incorporation into the electro-spun fibres.

[0079] Referring to Figure 1 , the process to make the capsules is an interfacial polymerisation and is based on a combination of oil-in-water emulsion and solgel chemistry. An Oil Phase is prepared by mixing an Oil / Active with a precursor material for the silica shell to be produced. The Oil may constitute the Active alone, or an additional Active material may be included in the Oil Phase. A Water Phase 1 is prepared by adding a Surfactant to Water with stirring until solubilised. The Water Phase 1 is then shear mixed into the Oil Phase to form an oil-in-water Emulsion.

[0080] A Water Phase 2 is prepared by adding an aminosilane Catalyst to Water, and the Water Phase 2 is added to the oil-in-water emulsion. The resulting mixture is Aged with stirring for an extended period, for example a 24 hour period. The mixture is then put through a Heating stage to complete the aging process, forming a Capsules Suspension. The suspension is subjected to Centrifugation to form a Capsules Slurry from which the capsules may be harvested.

[0081] EXAMPLES

[0082] More Detailed Procedure

[0083] 1 . The Active (liquid Hemp oil) and TECS are mixed in 1 :10 ratio (50 mL) by stirring for 10 minutes in a Schott bottle - Solution A.

[0084] 2. Polysorbates (Tween 20 and / or Tween 80) are mixed at 2.5% of each into 200 mL water with stirring until solubilised (~15 minutes) - Solution B.

[0085] 3. The TEOS / Active solution (A) are then shear mixed into the polysorbate aqueous solution (B), resulting in TECS concentration between 7-12.5% in the 500 mL mix.

[0086] 4. The whole mixture is then shear mixed into 200 mL of an acidic water phase 2 (0.001 M HCI in distilled water) for 5 minutes.

[0087] 5. After 5 minutes, an aminosilane catalyst (3-Aminopropyl) triethoxysilane (APTES), in a range of 0.8%-1.5% (3.78 mL - 7.38 mL) is added, and the mixture is left stirring for 24 hours (Note: a vortex needs to form).

[0088] 6. This is followed by heating for 3 hours at 45°C to complete the aging of the sample.

[0089] 7. The capsules are formed at this stage and the solution is spun down at 12000g for 20 minutes.

[0090] 8. Capsule containing slurry is harvested for further characterisation and use. Optimisation of Capsule synthesis for compatibilization with Electrospinning process

[0091] The synthesis method was optimised such that the silica shell has the following characteristics:

[0092] • Strong enough to provide protection of the liquid core, minimising breakage during synthesis and post processing involved in the subsequent electrospinning process;

[0093] • Porous to allow diffusion of the active through the silica shell; and

[0094] • Porosity can be controlled to deliver different rates of release.

[0095] In the following examples, Capsules were either formed using Hemp seed oil or alternatively, using a hydrophobic active ingredient, Cannabidiol (originally in powder form) mixed with Hemp Seed Oil to generate “CBD / Hemp-seed oil” capsules.

[0096] Impact of the amount of the silica precursor on the capsule structure and properties:

[0097] The goal here was to develop silica capsules with porous silica shells encapsulating the liquid active. Hence, a range of quantities of the silica precursor, TEOS were explored (0.16 - 0.29 mol) to identify the effect on capsule morphology and loading. Accordingly, TEOS was used at 35 mL, 45 mL, 50 mL, 55 mL, and 65 mL in a 500 mL scale preparation. There was no change to the remaining components (Polysorbate 20 & 80, Water phases, Hemp seed oil) except for APTES, a 90:10 molar ratio (TEOS to APTES) was maintained in the final mix (Tables 1 and 2).

[0098] Table 1 : Components of the synthesis mixture with increasing TEOS content (%)

[0099] Table 2: Molar ratio of silane precursors with increasing TEOS content

[0100] Morphology: The morphology of the capsules was determined by TEM (Figure 2). Capsule structure was evident clearly when precursor content was low, however at higher content (e), the capsule morphology was less obvious, and the presence of dense particles were noted. This suggests that the process is moving from an interfacial polymerisation to a bulk emulsion polymerisation when the amount of TEOS is >0.25 moles. Breakage during separation by high-speed centrifugation: The silica shell though porous, needs to be strong enough to withstand the high-speed centrifugal forces needed in the final step of the synthesis to separate the capsules from the supernatant. Hence, the impact of the silica content on the breakage of the capsules at centrifugation was assessed. This was evidenced by the presence of light green Hempseed oil in the supernatant and floating broken capsules after centrifugation. The breakage reduced with increasing TEOS content with minimal breakage in 0.22 moles TEOS capsules and no breakage in syntheses using 0.25 moles of TEOS or more (Table 3 below).

[0101] Loading of CBD (as % of the silica content) and Encapsulation Efficiency (EE, % of CBD added during synthesis): When CBD mixed with hemp seed oil (1 :1 ratio) was used, only CBD loading was used to assess the loading in the capsules, it was an indirect assessment of loading efficiency of these capsules. CBD loading was assessed in different formulations by HPLC and encapsulation efficiency was calculated (as percentage of the CBD loaded into the synthesis mix) (Table 3). CBD concentration was measured from the capsule slurry from the synthesis by leaching overnight in leaching solvent (80:20 v / v Ethanol: DI water mixed with 0.1% TFA). For example, 70 mg of slurry was leached in 1 .8 mL of the leaching solvent, which was subsequently diluted 2x for HPLC. The CBD content of the samples was estimated using an Agilent 1260 Infinity II LC system and an Agilent Zorbax Bonus - RP 5-micron 4.6 x 250mm column at 30°C. The mobile phase (0.1 %TFA in DI water (25%) mixed with acetonitrile (75%) was run at 0.75 mL / min.

[0102] Table 3: Characterisation of CBD / Hemp seed oil capsules produced at different Silica precursor content

[0103] With increasing amounts of precursor, the loading % increased, reaching highest value of -19% at 0.22 moles, and then a decrease was evident when 0.25 moles (~16%) and 0.29 moles (~12%) of TEOS were used. However, the encapsulation efficiency was the best in capsules produced using higher proportion of TEOS, i.e., 0.25 moles and 0.29 moles with -74% in capsules produced using 0.22 moles of TEOS.

[0104] Effect of silica content on capsule porosity: This was investigated by measuring the quantity of CBD leached in samples produced using 0.16, 0.22 and 0.29 moles of TEOS over 24 hours. The slurry samples were leached in 80:20 v / v Ethanol: DI water mixed with 0.1 % TFA, with gentle shaking. Samples were taken at 6 and 24 hours and were centrifuged at 500 rpm for 20 minutes. The clear supernatant was collected and diluted 2x for HPLC. CBD in the samples was estimated using an Agilent 1260 Infinity II LC system and an Agilent Zorbax Bonus - RP 5-micron 4.6 x 250mm column at 30°C. The mobile phase (0.1 %TFA in DI water (25%) mixed with acetonitrile (75%) was run at 0.75 mL / min.

[0105] Table 4: Leaching of CBD in Hemp oil from capsules synthesised with increasing silica precursor amounts Figure 3 illustrates a comparison of CBD leached in samples produced with different TEOS quantities over time. The graph shows % CBD leached in Ethanol (as % of the total CBD encapsulated) at 6 and 24 hors in samples produced using 0.16, 0.22 and 0.29 moles of TEOS.

[0106] With increasing amount of precursor, the rate at which CBD is leached from the sample decreases (Table 4 and Figure 5). At 0.16 moles, the highest quantity of CBD has leached with no change at 24 hours. In comparison, the CBD leached from the 0.22 and 0.29 mol samples after 6 hours is much lower, with increase at 24 hours, suggesting a slower rate of leaching and hence, lower porosity.

[0107] Overall, the formulations of interest were produced using 0.22, 0.25 and 0.29 moles of TEOS showing the best morphology and / or CBD loading and / or encapsulation efficiency and minimal breakage. However, the high encapsulation efficiency at high TEOS (0.29 moles) and the products compatibility to high-speed centrifugation was deemed significant, even though the capsules contained high silica (-50%) and were leaning towards matrix type morphology. It was expected that a capsule like morphology attained at high silica concentration will yield capsules with high encapsulation efficiency and greater strength to withstand high speed centrifugation and other downstream processes such as electrospinning. Hence, further optimisation was carried out to achieve capsule like morphology at high silica precursor concentration. using highest

[0108] As mentioned earlier, the goal was to obtain capsules with strong silica shell at 100nm-300nm size range. Therefore, in these experiments, firstly the impact of the surfactant quantity and ratios, on high TEOS capsule morphology, strength and loading efficiencies was assessed. It was expected that varying the ratios of the surfactant or the quantity will have an impact on the size of the emulsion droplet and hence, will impact on the size and morphology of the capsules. Further, variations in the quantity of the catalyst, APTES, were tested. It was anticipated that varying the impact of the catalyst will affect the rate of condensation and hence, will impact on the final morphology and properties of the capsules.

[0109] Effect of surfactant / s on the morphology of capsules a) Ratio of Surfactant

[0110] In these optimisations, the 0.29 mole TEOS trials were conducted using varying ratios of the two polysorbates, Tween 20 and Tween 80 to identify any impact of varying ratios on the morphology.

[0111] • 100% Tween 20

[0112] • 75%: 25% Tween 20:80

[0113] • 50%:50% Tween 20:80

[0114] • 25%: 75% Tween 20:80

[0115] • 100% Tween 80

[0116] As expected, the surfactant ratio has a clear impact on the morphology of the particles (Figure 4), capsule morphology is more obvious with increasing proportion of Tween 80. However, the fragility of the capsules also increased in that proportion, as seen from the clear breakage in the silica shell in capsules produced using Tween 80 at 75 and 100% by TEM. The size of the capsules decreased at high Tween 20 proportion. Overall, the best and the most uniform morphology was noticed at 50:50 ratio of the two surfactants. b) Quantity of surfactant

[0117] Next, increased quantity of surfactant (Tween 20 and Tween 80 at 1 :1 ratio) was tested in 0.29 moles TEOS preparation to assess if the size of the produced capsules can be changed without loss of strength, loading and encapsulation efficiencies.

[0118] Referring to Figure 7, the CBD loading, encapsulation efficiency and the capsule ability to withstand centrifugation were assessed (Table 5).

[0119] Table 5: Characterisation of Capsules produced at different Surfactant quantity

[0120] When the surfactant quantity was increased by 50%, it had no impact on the size of the capsules, while encapsulation efficiency was significantly reduced (Table 5 and Figure 5). The breakage was also more prominent in these capsules. Hence, we decided to focus on the standard method using the polysorbates at 1 :1 ratio for further optimisation. Impact of the Catalyst quantities on capsule morphology at highest silica precursor concentration

[0121] In these experiments, the molar ratio of the catalyst (APTES) was varied, and it was tested at 1%, 5%, 7.5% and 10% molar ratio) using 0.29 moles of TECS (Table 6). The sample was aged for 24 hours and harvested at 12,000g by centrifugation. The slurry was characterised for morphology and CBD loading as described above.

[0122] Table 6: Synthesis mixture composition (as % components of total weight of the synthesis mix) at varying mol% ratio of APTES.

[0123] Figure 6 shows the morphology (TEM) of capsules produced using 0.29 moles of TEOS at different molar % of APTES. It is clear that at 5% and 7.5%, the capsule-like discrete morphology was obtained with size ranging between about 100-200 nm, which is also optimal for incorporation in nanofibers. Use of the 7.5% APTES molar ratio allowed the capsules to withstand the centrifugation and washing stage with minimal breakage.

[0124] Assessment of encapsulation efficiencies and CBD loading clearly showed that at 7.5% APTES, the loading was the highest at 19.7 % with high EE at 77.5% (Table 7). The breakage was not seen at 10% APTES. Table 7: CBD loading and encapsulation efficiency at different proportion of APTES (%) vs. total amount of silanes added. and characterisation Hemp seed oil was encapsulated on its own using 0.22 moles of TEOS, and 0.026 moles of APTES (10% molar ratio) (Table 8).

[0125] Steps:

[0126] 1 . The Hemp seed oil (liquid) and TEOS were mixed in 1 :10 ratio (50 mL) by stirring for 10 minutes in a Schott bottle - Solution A

[0127] 2. Polysorbates (Tween 20 and / or Tween 80) are mixed at 2.5% of each into 200 mL water with stirring until solubilised (~15 minutes) - Solution B

[0128] 3. The TEOS / Oil solution (A) is then shear mixed into the polysorbate aqueous solution (B), resulting in TEOS concentration between 9.74% in the 500 mL mix.

[0129] 4. The whole mix is then shear mixed into 200 mL of an acidic water phase 2 (0.001 M HCI in distilled water) for 5 minutes.

[0130] 5. After 5 minutes, an Aminosilane catalyst, e.g. (3-Aminopropyl) triethoxysilane (APTES), in a range of 1.18% (5.68 mL) is added, and the mixture is left stirring for 24 hours (Note: a vortex needs to form).

[0131] 6. This is followed by heating for 3 hours at 45°C to complete the aging of the sample.

[0132] 7. The capsules are formed at this stage and the solution is spun down at 12000g for 20 minutes.

[0133] 8. Capsule containing slurry is harvested for further characterisation and use.

[0134] Table 8: Composition of the synthesis mixture for Hemp seed oil encapsulation using low TEOS method (%)

[0135] Morphology: TEM imaging of capsules prepared using hemp seed oil without solubilised CBD show the same size and structure to those samples produced with active included (figure 7).

[0136] Characterisation of encapsulated Hemp seed oil:

[0137] FTIR: The capsules were leached as described above and comparison of the leached capsules show several peaks (2800-3000 cm-1, 1700cm-1and 1 100- 1200 cm-1) which match with the peaks present when Hemp seed oil alone is read (Figure 8). This suggested that there is minimal loss of integrity of the hempseed oil during encapsulation.

[0138] Thermal Gravimetric assessment (TGA): Thermal analysis of a capsule produced with 0.22 mol TEOS and containing Hemp seed oil was carried out using a NETZSCH Jupiter 3 STA analyser. Sample analysis was carried out under air conditions, and with ramping of 10°C / min. The thermal analysis data of the dried solid is shown in Figure 9.

[0139] The TGA trace reflects 3 broad regions:

[0140] • A first weight loss from 40°C to 150°C which corresponds to the evaporation of water and possibly some residual ethanol from the hydrolysis of TEOS;

[0141] • A second weight loss, composed of several stages which are reflected as exothermic reactions in the DSC trace and which correspond to the pyrolysis of the organic constituents (Surfactant and Hemp oil) in air; A weight loss plateau with an associated small exothermic peak in the DSC from 700 to 900C which corresponds to a sintering of the silica shells.

[0142] Therefore, from the analysis of Figure 9, the composition of the capsules was calculated to be -4.5% water, 20% silica and the remaining 75% as hemp seed oil and surfactant (Tween 20 and Tween 80).

[0143] Due to the overlap of the boiling points and flash point temperatures of Tween 20, Tween 80 and Hemp seed oil, which all occur over a range of 100 - 400°C, it is impossible to differentiate the decomposition of hempseed oil from the surfactant without further analysis, using combined TGA-Mass spectroscopic analysis.

[0144] Based on the mass balance of materials used in the capsule preparation the maximum expected amount of surfactant in the final product is 13wt % of the dry mixture by weight. Therefore, we can assume that the capsule contains at least 62 wt% of Hemp seed oil. In other words, the hemp seed oil loading in the capsule is 62% which is much higher than the CBD loading reported for CBD / Hempseed oil capsules in Table 3.

[0145] This is an example of encapsulation of the penetration enhancer, Polypropylene Glycol, to produce viable capsules using this method. Here, given the high solubility of CBD in Polypropylene glycol, CBD dissolved in PPG was encapsulated.

[0146] In this reaction, 5 g CBD powder was solubilised in 12 g PPG and visually complete dissolution was noted. Powder was able to be nearly fully dissolved in this quantity of liquid.

[0147] Steps: 1 . The Active (liquid) and TEOS were mixed in 1 :3 ratio (35 mL) by stirring for 10 minutes in a Schott bottle - Solution A

[0148] 2. Polysorbates (Tween 20 and / or Tween 80) are mixed at 2.5% of each into 200 mL water with stirring until solubilised (-15 minutes) - Solution B

[0149] 3. The TEOS / Active solution (A) is then shear mixed into the polysorbate aqueous solution (B), resulting in TEOS concentration of 7% in the 500 mL mix.

[0150] 4. The whole mix is then shear mixed into 200 mL of an acidic water phase 2 (0.001 M HCI in distilled water) for 5 minutes.

[0151] 5. After 5 minutes, a 1 :1 mixture of pre-hydrolysed APTES (8 mL) is added, and the mixture is left stirring for 24 hours (Note: a vortex needs to form).

[0152] 6. This is followed by heating for 3 hours at 45°C to complete the aging of the sample.

[0153] 7. The capsules are formed at this stage and the solution is spun down at 12000g for 20 minutes.

[0154] 8. Capsule containing slurry is harvested for further characterisation and use.

[0155] Characterisation:

[0156] The TEM of these capsules showed a denser morphology, however, a uniform population of ~200nm capsules were produced (Figure 10).

[0157] The CBD was encapsulated at 1 1 .4% loading efficiency and encapsulation efficiency was -70% (Table 9). Some breakage was evident (-25%) potentially leading to marginally lower encapsulation efficiency estimations. This example demonstrates the feasibility of our approach to encapsulate different types of liquids which are sturdy enough for downstream electrospinning.

[0158] Table 9: Characterisation of PPG / CBD capsules

[0159] After finalising two primary methods of capsule synthesis, CBD-Hempseed capsules were produced using either 0.22 moles TEOS / 10% APTES (Low TEOS) or 0.29 moles of TEOS / 7.5% APTES (High TEOS). These were subsequently used for further development for the preparation of hybrid nanofibrous mat using needle free electrospinning.

[0160] • 5 g Cannabidiol isolate powder (PharmaHemp), 6 g Hemp Seed Oil (The Cannabis Company) + 46.65g TEOS were stirred using a magnetic stirrer in a 100 mL Schott bottle.

[0161] • In parallel, equal proportions of Polysorbate 20 (5 g) and Polysorbate 80 (5 g) were made up to 200 g with DI water in a 500 mL Schott bottle and stirred until solubilised.

[0162] • Added CBD / Oil / TEOS solution to the Polysorbate solution and shearmixed for 5 minutes at 20,000 rpm in an ice bath to reduce heating of mixture.

[0163] • Shear mixed solution was then added to acidified water (0.001 M HCI) in a 1 L Schott bottle with stirring for 5 minutes.

[0164] • After 5 minutes, a 1 :1 mixture of pre-hydrolysed APTES: DI water mixture (15.6 mL) was added to the solution above.

[0165] • This solution was left stirring for 24 hours, and then stirred at 45°C for further 3 hours.

[0166] • Solution was spun down at 8.8k rpm (12,000 RCF) for 20 minutes.

[0167] • Final weight of slurry sample = 84.873 g.

[0168] High TEOS CBD / Hemp seed oil capsules • 5 g Cannabidiol isolate powder (PharmaHemp), 6 g Hemp Seed Oil (The Cannabis Company) + 60.65 g TEOS were stirred using a magnetic stirrer in a 100 mL Schott bottle.

[0169] • In parallel, equal proportions of Polysorbate 20 (5g) and Polysorbate 80 (5 g) were made up to 200g with DI water in a 500 mL Schott bottle and stirred until solubilised.

[0170] • Added CBD / Oil / TEOS solution to the Polysorbate solution and shearmixed for 5 minutes at 20,000 rpm in an ice bath to reduce heating of mixture.

[0171] • Shear mixed solution was then added to acidified water (0.001 M HCI) in a 1 L Schott bottle with stirring for 5 minutes.

[0172] • After 5 minutes, a 1 :1 mixture of pre-hydrolysed APTES: DI water mixture (11 .2 mL) was added to the solution above.

[0173] • Solution was left stirring for 24 hours, before heating to 45°C and stirring for a further 3 hours.

[0174] • Solution was spun down at 8.8 k rpm (12,000 RCF) for 20 minutes.

[0175] • Final weight of slurry sample = 1 17.244 g.

[0176] Characterisation of the Capsules

[0177] The capsules were characterised for solid content (after drying), morphology (TEM), CBD loading (HPLC) and Breakage during centrifugation as described below:

[0178] Solids content determination

[0179] The slurry was dried at 40°C and weighed until no loss of weight was observed.

[0180] The solid content was then calculated as % of the total wet slurry produced.

[0181] • Low TEOS: 22.79%

[0182] • High TEOS: 16.79%

[0183] Morphology The morphology of both types of particles showed silica shell with opaque cargo in the middle suggesting presence of the liquid cargo (Figure 1 1 ). The particles ranged from 50-300nm.

[0184] Low and high TEOS capsules

[0185] CBD loading and Encapsulation Efficiency

[0186] The CBD loading was determined as described above, with three different samples produced, and the data was averaged. Samples consistently demonstrated >19% CBD loading with >75% of encapsulation efficiency (Table 10).

[0187] The samples showed consistent high loadings at the same levels and EE >75% and demonstrated very good recovery (~80%-90%) after centrifugation with minimal breakage as clearly shown by (1 -10%) of the detectable active (CBD) in the supernatants collected after centrifugation (Table 10).

[0188] Incorporation of Liquid Capsules into the Electrospinning Mix

[0189] The electrospinning solution was prepared by mixing the following components:

[0190] 1 . Hemp seed oil capsules a. CBD encapsulated (loading based on capsule dry weight) i. 19.70% - Low TEOS sample ii. 20% - High TEOS sample

[0191] 2. 16% concentration Polyvinyl Alcohol (PVA) solution in DI water

[0192] 3. 10% concentration Polyethylene Oxide (PEO) solution in DI water 4. 1 M Acetic Acid in DI water

[0193] The composition of the two electrospinning mixes using low or high TEOS capsules is detailed in Table 11 and Table 12. • Capsules were hand mixed into the 16% PVA solution until homogenous.

[0194] • Following this, 10% PEO solution was added to the solution and again mixed by hand.

[0195] • Added 1 M acetic acid was added to solution to make it more acidic and conductive.

[0196] • Following homogenisation by hand, mixture was mixed using a rotor stator at 6k rpm for 5 minutes, until capsules were fully dispersed into mixture.

[0197] Table 11 : Composition of the electrospinning (ES) mixture for Low TEOS capsules

[0198] Table 12: Composition of the electrospinning (ES) mixture for High TEOS capsules

[0199] To identify the structural integrity of the capsules following shear mixing, a sample of Electro-spun mat was dissolved, and a TEM was carried out on the resulting capsules. The sample imaged was produced using low TEOS capsules (50 mL).

[0200] Imaging of the sample does not show any broken capsules, with the structure of the capsules appearing whole, and similar to that of the initial sample (Figure 12).

[0201] Production of the Non-woven Mats by Electrospinning

[0202] Incorporation of capsules into nanofibrous mat

[0203] Electrospinning was carried out using a Nanospider NS Lab 2.0 needle free electrospinning machine. Two types of mats were produced:

[0204] • Hemp seed oil capsule mats

[0205] • CBD / hemp-seed oil capsule mats Typically, for electrospinning for all types of mats, the non-woven mat was deposited onto a waxed paper substrate, placed at 180 mm distance from the electrospinning wire. The electrospinning of the polymeric solutions containing the capsules (see Tables 1 1 and 12 for details) was performed at 65 kV voltage.

[0206] Characterisation of Electro-spun Mat

[0207] The electro-spun mats were characterised for morphology (SEM), GSM measurement (mat weight), CBD loading (HPLC) and for Hemp seed oil mats, FTIR and HPLC based characterisation was carried out as described below.

[0208] CBD concentration was measured from the mat samples by leaching overnight in leaching solvent (80:20 v / v Ethanol: DI water mixed with 0.1 % TFA). For example, a 1 .54 cm2mat sample was leached in 1 .8 mL of the leaching solvent for HPLC. CBD in the samples was assessed using an Agilent 1260 Infinity II LC system and an Agilent Zorbax Bonus - RP 5-micron 4.6 x 250mm column at 30°C. The mobile phase (0.1%TFA in DI water (25%) mixed with acetonitrile (75%) was run at 0.75 mL / min.

[0209] Uniform mats were produced at ~34 and 11 GSM (grams / square meter) with high homogeneity (<3% error, N=6) for low and high TEOS mats, respectively. The presence of CBD in the mats indicated successful incorporation of the capsules in the mats (also confirmed by TEM, Figure 12). Interestingly, even at high GSM, the CBD loading of Low TEOS mats was significantly low at ~2.5% vs. ~9% CBD loading in low GSM / High TEOS mats. It is not clear why this variation is observed.

[0210] Characterisation of active released from the and from the incorporated in the mats

[0211] It was clearly shown by the CBD loading and leaching data (Table 4, Figure 3) that the CBD loaded as CBD / HEMP seed oil mixture is releasable from the capsules and rate of release is dependent upon the porosity of silica shell. These studies were carried out to confirm the integrity of the hemp seed oil after incorporation in the capsules and after incorporation of the capsules in the polymeric mats. Typically, Hemp seed oil was extracted using Ethanol with overnight shaking from the capsules or using Ethanol / DI water mix (0.1%TFA) from pre-weighed mats. The extracts were analysed by either FTIR for qualitative assessments and compared with pure active in its original form.

[0212] Integrity of Hemp seed oil

[0213] The integrity of the hemp seed oil incorporated in the capsules as well as from the capsules incorporated in the mats was clearly proven by FTIR (Figure 14). Comparison of the pure hemp seed oil with hemp seed oil leached from the electrospun mat shows the presence of similar peaks, suggesting that the hemp seed oil is unchanged by the encapsulation and electrospinning process. Comparison of the leached capsules and Electrospun mats with hempseed oil capsules show several peaks (2800-3000 cm-1, 1700cm-1and 1 100-1200 cm-1) which match with the peaks present in the spectra of the Hemp seed oil alone.

[0214] Further, the integrity of CBD from CBD / Hempseed oil capsules or released from either the capsules or the capsule in electrospun mats was clearly shown by HPLC based loading determinations for both capsules and Electrsopun mats as described above for various optimisations. The peak profiles of the CBD released from both did not show any variation from the HPLC of the CBD standard, suggesting the intact integrity of CBD during encapsulation and during electrospinning.

[0215] This shows the feasibility of such an approach to incorporate hydrophobic actives in liquid form. Conclusions

[0216] • The inventors have developed an optimised process to encapsulate hydrophobic liquids (either alone or as a mixture with other miscible actives (liquid or solid) with a. High active loadings (-20%) b. High Encapsulation efficiencies (>75%) c. Customisable porosity to controlled release rates. d. Compatibility to high-speed centrifugation with minimal breakage (<50% preferably <10%) during high-speed centrifugation e. Compatibility to electrospinning process with compatible size range (50-300nm, preferably 50-200nm) and intact morphology in the final non-woven mats.

[0217] • The inventors have also successfully produced non-woven, polymeric nanofibrous mats incorporating hydrophilic polymers and liquid capsules to produce homogeneous mats with clear evidence of active loading (CBD / Hemp seed oil or Hempseed oil).

[0218] • The integrity of the liquid active (CBD+Hempseed oil or Hempseed oil) is retained during the whole process of encapsulation as well as during electro-spinning to produce nanofibrous mats with liquid capsules (FTIR or HPLC).

[0219] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of steps, elements or integers. Thus, in the context of this specification, the term “comprising” is used in an inclusive sense and thus should be understood as meaning “including principally, but not necessarily solely”. Unless the context requires otherwise or specifically stated to the contrary, integers, steps or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

[0220] It will be appreciated that the foregoing description has been given by way of illustrative example of the invention and that all such modifications and variations thereto as would be apparent to persons of skill in the art are deemed to fall within the broad scope and ambit of the invention as herein set forth.

Claims

CLAIMS1 . A hybrid nanofibrous mat comprising: electrospun nanofibers formed by electrospinning of a polymer mix; and porous silica capsules dispersed throughout said electrospun nanofibers during said electrospinning, said porous silica capsules having a hydrophobic liquid core containing an active.

2. A hybrid nanofibrous mat as claimed in claim 1 , wherein said porous silica capsules have a breakage percentage during centrifugation (12000g) of less than 50% and percentage active leaching (24 hours) of greater than 15%.

3. A hybrid nanofibrous mat as claimed in claim 2, wherein said porous silica capsules have a breakage percentage during centrifugation (12000g) of 25% or less, 10% or less, or have no breakage during centrifugation (12000g).

4. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules have a breakage percentage of less than 10% breakage during electrospinning, preferably no breakage during electrospinning.

5. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules have a percentage active leaching (24 hours) of 15-20%.

6. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules have a percentage active leaching (6 hours) of 10-16%.

7. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules have a particle size of 50-300nm, preferably 50-200nm.

8. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules have an encapsulation efficiency of greater than 50%, preferably greater than 70%, preferably from 70-90% during production of said silica particles.

9. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein loading of said porous silica capsules in said hybrid nanofibrous mat is from 10-35 grams / square metre (GSM).

10. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said porous silica capsules are formed from a hydrophobic silicon alkoxide or alkoxysilane precursor.1 1. A hybrid nanofibrous mat as claimed in claim 10, wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl diethoxy silane, phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS).

12. A hybrid nanofibrous mat as claimed in claim 11 , wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is Tetra Ethyl Orthosilicate (TEOS).

13. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said hydrophobic liquid core containing an active comprises an oil alone, or an oil / active mix.

14. A hybrid nanofibrous mat as claimed in claim 13, wherein said oil comprises hemp seed oil, or wherein said oil / active mix comprises hemp seed oil / cannabidiol (CBD).

15. A hybrid nanofibrous mat as claimed in any one of the preceding claims, wherein said electrospinning polymer mix comprises a Polyvinyl Alcohol (PVA) / Polyethylene Oxide (PEO) mix.

16. A method of producing a hybrid nanofibrous mat comprising: providing porous silica capsules having a hydrophobic liquid core containing an active; forming an electrospinning solution comprising said porous silica capsules and an electrospinning polymer mix; homogenising said electrospinning solution to fully disperse said porous silica capsules; and electrospinning said electrospinning solution to form said hybrid nanofibrous mat.

17. A method as claimed in claim 16, wherein said porous silica capsules have a breakage percentage during centrifugation (12000g) of less than 50% and percentage active leaching (24 hours) of greater than 15%.

18. A method as claimed in claim 17, wherein said porous silica capsules have a breakage percentage during centrifugation (12000g) of 25% or less, 10% or less, or have no breakage during centrifugation (12000g).

19. A method as claimed in any one of claims 16-18, wherein said porous silica capsules have a breakage percentage of less than 10% breakage during electrospinning, preferably no breakage during electrospinning.

20. A method as claimed in any one of claims 16-19, wherein said porous silica capsules have a percentage active leaching (24 hours) of 15-20%.

21. A method as claimed in any one of claims 16-20, wherein said porous silica capsules have a percentage active leaching (6 hours) of 10-16%.

22. A method as claimed in any one of claims 16-21 , wherein said porous silica capsules have a particle size of 50-300nm, preferably 50-200nm.

23. A method as claimed in any one of claims 16-22, wherein said porous silica capsules have an encapsulation efficiency of greater than 50%, preferably greater than 70%, preferably from 70-90% during production of said silica particles.

24. A method as claimed in any one of claims 16-23, wherein loading of said porous silica capsules in said hybrid nanofibrous mat is from 10-35 grams / square metre (GSM).

25. A method as claimed in any one of claims 16-24, wherein said porous silica capsules are formed from a hydrophobic silicon alkoxide or alkoxysilane precursor.

26. A method as claimed in claim 25, wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl di-ethoxy silane, phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS).

27. A method as claimed in claim 26, wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is Tetra Ethyl Orthosilicate (TEOS).

28. A method as claimed in any one of claims 16-27, wherein said hydrophobic liquid core containing an active comprises an oil alone, or an oil / active mix.

29. A method as claimed in claim 28, wherein said oil comprises hemp seed oil, or wherein said oil / active mix comprises hemp seed oil / cannabidiol (CBD).

30. A method as claimed in any one of claims 16-29, wherein said electrospinning polymer mix comprises a Polyvinyl Alcohol (PVA) / Polyethylene Oxide (PEO) mix.

31. A method as claimed in claim 30, wherein forming said electrospinning solution comprises:mixing said porous silica capsules into a PVA solution, preferably a 16% PVA solution in DI water; adding a PEO solution, preferably a 10% PEO solution in DI water, and mixing; adding acetic acid, preferably 1 M acetic acid, to increase acidity and conductivity; and homogenising and mixing to fully disperse the porous silica capsules.

32. A method as claimed in claim 31 , wherein homogenising and mixing is conducted by hand and subsequently using a rotor stator, for example at 6000rpm for 5 minutes.

33. A method of producing porous silica capsules for use in the hybrid nanofibrous mat as claimed in any one of claims 1 -15, or the method as claimed in any one of claims 16-32 comprising: preparing an oil phase by mixing an oil or oil / active with a hydrophobic silicon alkoxide or alkoxysilane precursor; preparing a first water phase by adding a surfactant to water with stirring until solubilised; shear mixing the first water phase into the oil phase to form an oil- in-water emulsion; preparing a second water phase by adding an aminosilane catalyst to water; adding the second water phase to the oil-in-water emulsion; aging a resulting mixture with stirring to form an aged mixture; heating the aged mixture to complete the aging process, thereby forming the porous silica capsules in suspension; centrifuging the suspension to form a capsule slurry; and harvesting the porous silica capsules from the capsule slurry.

34. A method as claimed in claim 33, wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is selected from Tetra Ethyl Orthosilicate (TEOS), methyl tri ethoxy silane, dimethyl di-ethoxy silane,phenyl tri methoxy silane, phenyl triethoxy silane and tetrapropoxy silane (TPOS).

35. A method as claimed in claim 34, wherein said hydrophobic silicon alkoxide or alkoxysilane precursor is Tetra Ethyl Orthosilicate (TEOS).

36. A method as claimed in any one of claims 33-36, wherein said oil comprises hemp seed oil, or wherein said oil / active mix comprises hemp seed oil / cannabidiol (CBD).

37. A method as claimed in any one of claims 33-36, wherein said surfactant in the first water phase comprises a mixture of polysorbates.

38. A method as claimed in claim 37, wherein said mixture of polysorbates comprises Tween 20 and Tween 80, preferably in a 50:50 ratio.

39. A method as claimed in any one of claims 33-38, wherein said catalyst in the second water phase comprises an aminosilane catalyst, preferably 3-aminopropyl triethoxysilane (APTES).

40. A method as claimed in claim 39, wherein APTES is added in an amount of above 5%, preferably above 7.5%, for example from 5-10% based on the total amount of silanes added.41 . A transdermal patch, transdermal thin film or oral thin film for the delivery of a liquid containing active to a user, said transdermal patch, transdermal thin film or oral thin film comprising a hybrid nanofibrous mat as claimed in any one of claims 1 -15.

42. A transdermal patch as claimed in claim 41 further comprising a backing layer covering said hybrid nanofibrous mat, an adhesive layer for adhering to the skin of the user, and a removable protective liner.

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