Capsules of ferulic acid

Abstract

The present disclosure relates to a core-shell capsule comprising a hydrophobic core comprising ferulic acid, encapsulated within a hydrophilic shell formed of a poly(ethylene glycol)- containing amphiphilic polymer crosslinked by a polyacid having at least one carboxylic acid group, wherein the poly(ethylene glycol)-containing amphiphilic polymer is Poloxamer 407; and wherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule. The present disclosure also relates to a method of producing the core-shell capsule of the present disclosure.

Description

CAPSULES OF FERULIC ACIDCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of Singapore application no.10202403584T filed on 15 November 2024, the contents of it being hereby incorporated by reference in its entirety for all purposes.TECHNICAL FIELD

[0002] The present disclosure generally relates to a core-shell capsule comprising ferulic acid, and a method of producing the core-shell capsule.BACKGROUND

[0003] Organic bioactives are widely used as skincare ingredients, many of which are oilsoluble in nature. Techniques for modifying the lipophilic properties of such ingredients into hydrophilic properties are popular and often indispensable when the ingredients are to be incorporated into water-based formulations.

[0004] Ferulic acid is a hydroxycinnamic acid known for its broad antioxidant activity. Such antioxidant activity is beneficial for neutralizing free radicals and reducing visible signs of aging, among other effects. However, ferulic acid is sparingly soluble in water, with an aqueous solubility of only about 0.78 mg / mL. Ferulic acid readily precipitates and forms crystals in aqueous media, which prevents effective topical delivery into skin. Furthermore, incorporation of ferulic acid into aqueous formulations is problematic due to its instability; ferulic acid undergoes discoloration upon storage in water, thereby limiting its practical use.

[0005] As a naturally occurring antioxidant compound in plant cells, ferulic acid is generally regarded as safe and is already present in certain skincare products, where it has been reported to help reduce signs of aging and inflammation. Nonetheless, its limited aqueous solubility andpoor stability in water-based formulations remain significant obstacles to its broader application in cosmetic and dermatological products.

[0006] It is therefore desirable to provide a core-shell capsule and a method of producing the same that address at least one of the problems described hereinabove, or at least provide an alternative solution.SUMMARY

[0007] In accordance with a first aspect of the present disclosure, a core-shell capsule is provided. The core-shell capsule comprises a hydrophobic core comprising ferulic acid, encapsulated within a hydrophilic shell formed of a poly( ethylene glycol) -containing amphiphilic polymer crosslinked by a polyacid comprising at least one carboxylic acid group, wherein the poly( ethylene glycol)-containing amphiphilic polymer is Poloxamer 407; and wherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

[0008] In some embodiments, the core-shell capsule is capable of preventing discoloration of the ferulic acid in an aqueous emulsion. In certain embodiments, the core-shell capsule is capable of preventing discoloration of the ferulic acid in an aqueous medium when the coreshell capsule is redispersed in the aqueous medium.

[0009] In accordance with a second aspect of the present disclosure, a method of producing a core-shell capsule comprising ferulic acid is provided. The method comprises blending ferulic acid and a poly( ethylene glycol)-containing amphiphilic polymer at ambient temperature to form a mixture; and crosslinking the poly( ethylene glycol)-containing amphiphilic polymer with a polyacid comprising at least one carboxylic acid group to form a core-shell capsule comprising a hydrophobic core comprising ferulic acid, encapsulated within a crosslinked hydrophilic shell formed of the poly(ethylene glycol)-containing amphiphilic polymer, wherein the poly( ethylene glycol)-containing amphiphilic polymer is Poloxamer 407, and wherein theloading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

[0010] In some embodiments, the core-shell capsule is in the form of an aqueous emulsion having a particle size ranges from 1 nm to 1000 nm.

[0011] In some embodiments, the method further comprises freeze-drying the aqueous emulsion to form the core-shell capsule in powder form.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Various embodiments of the present disclosure are described hereinbelow in the detailed description with reference to the following drawings:FIG. 1 shows a Nuclear Magnetic Resonance (NMR) spectrum of (a) a sample comprising ferulic acid encapsulated within Poloxamer 407 (also known as Pluronic F-127) without crosslinking, and (b) the same sample after adding a crosslinker.FIG. 2A shows a photograph of an aqueous solution containing 5% ferulic acid encapsulated within Pluronic F-127 (or F127) in a weight ratio of 1:20 after storage at room temperature for four months.FIG. 2B shows a photograph of an aqueous solution containing 5% ferulic acid encapsulated within polysorbate 20 (commercially available under the trade name Tween 20) in a weight ratio of 1 :20 after storage at room temperature for four months.FIG. 2C shows a photograph of an aqueous solution containing 5% ferulic acid encapsulated within polysorbate 80 (commercially available under the trade name Tween 80) in a weight ratio of 1:20 after storage at room temperature for four months.FIG. 2D shows a photograph of an aqueous solution containing 5% ferulic acid encapsulated in a weight ratio of 1:20 in Tween 20 (left), Tween 80 (middle) and F127 (right) after storage at 40 °C for 4 weeks.FIG. 2E shows a photograph of an aqueous solution containing 5% ferulic acid encapsulated in a weight ratio of 1:20 in Tween 20 (left), Tween 80 (middle) and F127 (right) after storage at 50 °C for 2 weeks.FIG. 3A shows a Scanning Electron Microscopy (SEM) image of a coating comprising dried particles prepared from an aqueous emulsion comprising ferulic acid and Tween 20 in a weight ratio of 1:20.FIG.3B shows an SEM image of a coating comprising dried particles prepared from an aqueous emulsion comprising ferulic acid and Tween 80 in a weight ratio of 1:20.FIG. 4A shows an SEM image of a coating comprising dried particles of sample El 6.FIG. 4B shows an SEM image of a coating comprising dried particles of sample El 7.FIG. 4C shows an SEM image of a coating comprising scattered powder of sample El 6. FIG. 4D shows an SEM image of a coating comprising scattered powder of sample El 7. FIG. 5 shows an SEM image of long elliptical particles.FIG. 6A illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Tween 20 in a weight ratio of 1:20, as determined by DLS.FIG. 6B illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Tween 80 in a weight ratio of 1:20, as determined by DLS.FIG. 6C illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with polysorbate 65 (commercially available under the trade name Tween 65) in a weight ratio of 1 :20, as determined by DLS.FIG. 6D illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with F127 in a weight ratio of 1:20, as determined by DLS.FIG. 7A illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Tween 20 in a weight ratio of 1 : 10, as determined by DLS.FIG. 7B illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Tween 80 in a weight ratio of 1:10, as determined by DLS.FIG. 7C illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Tween 65 in a weight ratio of 1:10, as determined by DLS.FIG. 7D illustrates the particle size distribution of an aqueous emulsion of ferulic acid encapsulated with Fl 27 in a weight ratio of 1:10, as determined by DLS.FIG. 8 A illustrates the particle size distribution of redispersed sample El 6, which comprises ferulic acid and F127 in a weight ratio of 1:8, without crosslinking.FIG. 8B illustrates the particle size distribution of redispersed sample El 7, which comprises ferulic acid and F127 in a weight ratio of 1:8, with crosslinking.DESCRIPTION

[0013] The following description sets forth exemplary methods, parameters, and the like. The embodiments are described in sufficient detail to enable those skilled in the art to practise the invention. Other embodiments may be utilized, and structural and logical changes may be made without departing from the scope of the invention. The various embodiments are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0014] Features that are described in the context of an embodiment may correspondingly be applicable to the same or similar features in the other embodiments. Features that are described in the context of an embodiment may correspondingly be applicable to the other embodiments, even if not explicitly described in these other embodiments. Furthermore, additions and / or combinations and / or alternatives as described for a feature in the context of an embodiment may correspondingly be applicable to the same or similar feature in the other embodiments.

[0015] In the context of various embodiments, the articles “a”, “an” and “the” as used with regard to a feature or element include a reference to one or more of the features or elements.

[0016] In the context of various embodiments, the term “about” or “approximately” as applied to a numeric value encompasses the exact value and a reasonable variance, e.g. within 10% of the specified value.

[0017] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0018] By “comprising” it is meant including, but not limited to, whatever follows the word “comprising”. Thus, use of the term “comprising” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present.

[0019] By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of’. Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present.

[0020] As used herein, the term “Polysorbate 20” refers to polyoxyethylene (20) sorbitan monolaurate, commercially available as Tween 20. In the present disclosure, the terms “Polysorbate 20” and “Tween 20” are used interchangeably, irrespective of supplier or grade, unless otherwise specified.

[0021] As used herein, the term “Polysorbate 80” refers to polyoxyethylene (20) sorbitan monooleate, commercially available as Tween 80. In the present disclosure, the terms “Polysorbate 80” and “Tween 80” are used interchangeably, irrespective of supplier or grade, unless otherwise specified.

[0022] As used herein, the term “Polysorbate 65” refers to polyoxyethylene (20) sorbitan tristearate, commercially available as Tween 65. In the present disclosure, the terms “Polysorbate 65” and “Tween 65” are used interchangeably, irrespective of supplier or grade, unless otherwise specified.

[0023] The present disclosure relates to capsules comprising ferulic acid having the following structure (I):

[0024] The capsules of ferulic acid of the present disclosure are pH-responsive and are triggered to release ferulic acid at relatively high pH, for example at pH 7 or above. The capsules are in an encapsulated form with high loading content. By being in the encapsulated form, the capsules prevent discolouration of ferulic acid in aqueous media, are readily dispersed in water, and maintain the activity of the ferulic acid, resulting in improved formulation stability and efficacy.

[0025] In a first aspect, a core-shell capsule is provided. The core-shell capsule comprises a hydrophobic core comprising ferulic acid, encapsulated within a hydrophilic shell formed of a poly(ethylene glycol)-containing amphiphilic polymer crosslinked by a polyacid having at least one carboxylic acid group, wherein the poly( ethylene glycol)-containing amphiphilic polymer is Poloxamer 407; and wherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

[0026] As used herein, the term “poly( ethylene glycol)-containing amphiphilic polymer” refers to any polymer that comprises poly( ethylene glycol) (PEG) or poly( ethylene oxide) (PEO) segments in its structure. Such polymers may include, but are not limited to, PEG homopolymers of various molecular weights; block copolymers comprising PEG segments, such as poloxamers (e.g., PEO-PPO-PEO triblock copolymers), PEG-poly(lactic acid) copolymers, PEG-polycaprolactone copolymers, and PEG-poly(lactic-co-glycolic acid) copolymers; graft or random copolymers having PEG side chains; PEG derivatives such as PEG diacrylate, PEG dimethacrylate, and PEG urethane crosslinked polymers; and PEGylated lipids or other PEGylated polymers.

[0027] In some embodiments, the poly(ethylene glycol)-containing amphiphilic polymer is a triblock copolymer. In certain embodiments, the poly( ethylene glycol)-containing amphiphilic polymer is Poloxamer 407 (also known under the trade name Pluronic F-127), a triblock copolymer of polyethylene oxide)-poly(propylene oxide)-poly( ethylene oxide) (PEO-PPO-PEO). The Poloxamer 407 acts as a surfactant and its hydrophobic PPO blockinteracts with the hydrophobic ferulic acid, while its hydrophilic PEO blocks extend into water, forming a stable oil-in-water emulsion comprising a polyethylene (PEG)-containing shell, where ferulic acid droplets are encapsulated within the PEG-containing shell to form capsules of ferulic acid.

[0028] In the present disclosure, the terms “Poloxamer 407” and “Pluronic F-127” (or F127) are used interchangeably, irrespective of supplier or grade, unless otherwise specified.

[0029] In various embodiments, the ferulic acid and the poly(ethylene glycol)-containing amphiphilic polymer are present in a weight ratio ranging from 1:20 to 1:3.3. In some embodiments, the weight ratio is about 1:20, 1:10, 1:8. 1:5 or 1:3.3.

[0030] In various embodiments, the polyacid with the at least one carboxylic acid group comprises a poly acrylate backbone. The polyacrylate has a molecular weight ranging from 500 Dalton to 10,000,000 Dalton.

[0031] In various embodiments, the polyacid is selected from the group consisting of polyacrylic acid, copolymers of acrylic acid, poly(methacrylic acid) and copolymers of methacrylic acid. In some embodiments, the polyacid is polyacrylic acid or copolymers of acrylic acid. In other embodiments, the polyacid is poly(methacrylic acid) or copolymers of methacrylic acid.

[0032] The polyacid crosslinks with the PEG-containing shell of the core-shell capsule. The carboxyl (carboxylic acid) group(s) of the polyacid form hydrogen bonds or covalent linkages with the hydroxyl group(s) of the PEG segment(s) in the poly( ethylene glycol)-containing amphiphilic polymer, thereby stabilizing the core-shell capsule and providing a crosslinked PEG-containing outer shell. Such crosslinking enhances structural integrity and confers pH-responsive release properties of the core-shell capsule.

[0033] The PEO blocks of the poly(ethylene glycol)-containing amphiphilic polymer or Poloxamer 407 are hydrophilic and they contain a plurality of ethylene glycol units. In variousembodiments, the molar ratio of the carboxylic acid group of the polyacid to the ethylene glycol unit of the poly(ethylene glycol)-containing amphiphilic polymer ranges from 2:1 to 0.01:1.

[0034] In various embodiments, the poly( ethylene glycol)-containing amphiphilic polymer has a degree of crosslinking of about 8%, the degree of crosslinking being calculated based on the molar ratio of polyacid to poly(ethylene glycol)-containing amphiphilic polymer.

[0035] In various embodiments, the core-shell capsule is provided in the form of an aqueous emulsion having a particle size ranging from 1 nm to 1000 nm, preferably from 10 nm to 500 nm, and more preferably from 100 nm to 300 nm.

[0036] In some embodiments, the core-shell capsule is provided in powder form and has a particle size ranging from 1 nm to 1000 nm after redispersion, preferably from 10 nm to 500 nm, more preferably from 100 nm to 300 nm.

[0037] In various embodiments, the encapsulated form of the core-shell capsule prevents discoloration of the ferulic acid in the aqueous emulsion. In some embodiments, the encapsulated form prevents discoloration of the ferulic acid in an aqueous medium when the core-shell capsule is redispersed in the aqueous medium.

[0038] In various embodiments, the core-shell capsule has a relatively high hydrophilic-lipophilic balance (HLB) value, for example about 22. A high HLB value is associated with increased water solubility, which in turn facilitates improved dispersibility of the core-shell capsule in aqueous systems and enables higher loading of the ferulic acid.

[0039] The core-shell capsule of the present disclosure exhibit a relatively high loading of 8 to 11%, preferably about 10%, which is higher than that achieved by certain commercial products, and a high encapsulation efficiency (EE%) in the range of 89 to 95% or 93 to 95%. These results demonstrate that the method of the present disclosure is suitable for preparing core-shell capsule of ferulic acid using Poloxamer 407 as a surfactant, while maintaining high encapsulation efficiency.

[0040] In a second aspect of the present disclosure, a method of producing a core-shell capsule comprising ferulic acid is provided. The method comprises blending ferulic acid and a poly(ethylene glycol)-containing amphiphilic polymer at ambient temperature to form a mixture; and crosslinking the poly( ethylene glycol)-containing amphiphilic polymer with a polyacid comprising at least one carboxylic acid group to form a core-shell capsule comprising a hydrophobic core comprising ferulic acid, encapsulated within a crosslinked hydrophilic shell formed of the ploy(ethylene glycol)-containing amphiphilic polymer, wherein the poly(ethylene glycol)-containing amphiphilic polymer is Poloxamer 407, and wherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

[0041] In various embodiments, the step of blending comprises introducing an aqueous carrier into the mixture and subjecting the mixture with the aqueous carrier to homogenization under high-shear conditions. In some embodiments, the homogenization may be performed using a high-shear mixer to obtain a fine and homogenous aqueous emulsion. Any suitable types of high-shear mixer can be employed, including but not limited to, rotor-stator high-shear mixer, inline high-shear mixers and ultra-high shear inline mixers.

[0042] In various embodiments, the aqueous solution may include, but not limited to, waterbased carriers such as water, including deionized water, distilled water and purified water.

[0043] In some embodiments, the ferulic acid and the poly(ethylene glycolj-containing amphiphilic polymer are blended in a weight ratio ranging from 1:20 to 1:3.3. In some embodiments, the weight ratio is about 1:20, 1:10, 1:8. 1:5 or 1:3.3.

[0044] In some embodiments, step of crosslinking comprises subjecting the mixture comprising the polyacid to further homogenization under high-shear conditions. The conditions under which the further homogenization takes place may be the same or different from the homogenization of the ferulic acid with the poly(ethylene glycolj-containing amphiphilicpolymer. In various embodiments, homogenization is performed at a speed of 3,000 to 25,000 rpm.

[0045] In various embodiments, the polyacid with the at least one carboxylic acid group comprises a polyacrylate backbone. The polyacrylate has a molecular weight ranging from 500 Dalton to 10,000,000 Dalton.

[0046] In various embodiments, the polyacid is selected from the group consisting of polyacrylic acid, copolymers of acrylic acid, poly(methacrylic acid) and copolymers of methacrylic acid. In some embodiments, the polyacid is polyacrylic acid or copolymers of acrylic acid.

[0047] In some embodiments, the core-shell capsule is provided in the form of an aqueous emulsion. In these embodiments, the core-shell capsule has a particle size ranging from 1 nm to 1000 nm, preferably from 10 nm to 500 nm, and more preferably from 100 nm to 300 nm.

[0048] In some embodiments, the method may optionally include freeze-drying the aqueous emulsion to form core-shell capsule in powder form, with a particle size ranging from 1 nm to 1000 nm after redispersion, preferably from 10 nm to 500 nm, more preferably from 100 nm to 300 nm. Any conventional method of freeze-drying may be employed without departing from the scope of the present disclosure. The choice of freeze-drying parameters, including freezing rate, shelf temperature, chamber pressure, and cycle duration, may be varied as needed, so long as the dried capsules retain their structural integrity.

[0049] In various embodiments, the core-shell capsule is capable of preventing discoloration of the ferulic acid in the aqueous emulsion. In some embodiments, the core-shell capsule is capable of preventing discoloration of the ferulic acid in an aqueous medium when the coreshell capsule is redispersed in the aqueous medium.

[0050] In some embodiments, the core-shell capsule of the present disclosure may be employed as an encapsulated medium for preventing discoloration of ferulic acid in a cosmetic product.

[0051] The method of the present disclosure provides for a relatively high loading of ferulic acid (8 to 11%) within the core-shell capsule without the need for organic solvents or heating. The method offers a cost-effective and environmentally friendly process, and more importantly, the method advantageously prevents discoloration of the aqueous emulsion, which may otherwise occur due to premature release of ferulic acid from the core material of the core-shell capsule.

[0052] The core-shell capsule of the present disclosure is pH-responsive, enabling triggered release of ferulic acid at elevated pH values, such as pH 7 or above. In certain embodiments, the use of high-HLB surfactants, for example Poloxamer 407 with an HLB value of about 22, facilitates higher loading of ferulic acid and contributes to stability in aqueous formulations. The encapsulated form of the core-shell capsule confers improved water dispersibility and preserves the activity of ferulic acid, thereby overcoming limitations associated with the poor aqueous solubility and instability of free ferulic acid.

[0053] To facilitate a better understanding of the present disclosure, the following examples of specific embodiments are given. In no way should the following examples be read to limit or define the entire scope of the disclosure. One skilled in the art will recognize that the examples set out below are not an exhaustive list of the embodiments of this disclosure.EXAMPLESSurfactants Used in the Examples

[0054] The surfactants employed in the following Examples include polyoxyethylene sorbitan esters (Tween 20, Tween 80, Tween 65) and poloxamers (e.g. Poloxamer 407 (also known as Pluronic F-127)). For clarity, the chemical structures of these surfactants are provided as follows:Phsronic Fl 27Tween 65Example 1

[0055] Examples 1 to 4: Encapsulation of ferulic acid using Tween 20

[0056] A sample El was prepared by blending ferulic acid with Tween 20 at ambient temperature in a weight ratio of 1:20. 20 mL of deionized water was added to the mixture, and the mixture were homogenized using a high-shear mixer (Ultra Turrax T18 / T25 basic homogenizer) until a fine and homogeneous aqueous emulsion was obtained.Example 2

[0057] A sample E2 was prepared in the same manner as described in Example 1, except that the weight ratio of ferulic acid to Tween 20 was adjusted to 1:10.Example 3

[0058] A sample E3 was prepared in the same manner as described in Example 1, except that the weight ratio of ferulic acid to Tween 20 was adjusted to 1:5.Example 4

[0059] A sample E4 was prepared in the same manner as described in Example 1, except that the weight ratio of ferulic acid to Tween 20 was adjusted to 1:3.3.Example 5

[0060] Examples 5 to 8: Encapsulation of ferulic acid using Tween 80

[0061] A sample E5 was prepared by blending ferulic acid with Tween 80 at ambient temperature in a weight ratio of 1:20. 20 mL of deionized water was added to the mixture, and the mixture were homogenized using a high-shear mixer (Ultra Turrax T18 / T25 basic homogenizer) until a fine and homogeneous aqueous emulsion was obtained.Example 6

[0062] A sample E6 was prepared in the same manner as described in Example 5, except that the weight ratio of ferulic acid to Tween 80 was adjusted to 1:10.Example 7

[0063] A sample E7 was prepared in the same manner as described in Example 5, except that the weight ratio of ferulic acid to Tween 80 was adjusted to 1:5.Example 8

[0064] A sample E8 was prepared in the same manner as described in Example 5, except that the weight ratio of ferulic acid to Tween 80 was adjusted to 1:3.3.Example 9

[0065] Examples 9 to 12: Encapsulation of ferulic acid using Tween 65

[0066] A sample E9 was prepared by blending ferulic acid with Tween 65 at ambient temperature in a weight ratio of 1:20. 20 mL of deionized water was added to the mixture, and the mixture were homogenized using a high-shear mixer (Ultra Turrax T18 / T25 basic homogenizer) until a fine and homogeneous aqueous emulsion was obtained.Example 10

[0067] A sample E10 was prepared in the same manner as described in Example 9, except that the weight ratio of ferulic acid to Tween 65 was adjusted to 1:10.Example 11

[0068] A sample Ell was prepared in the same manner as described in Example 9, except that the weight ratio of ferulic acid to Tween 65 was adjusted to 1:5.Example 12

[0069] A sample E12 was prepared in the same manner as described in Example 9, except that the weight ratio of ferulic acid to Tween 65 was adjusted to 1:3.3.Example 13

[0070] Examples 13 to 19: Encapsulation of ferulic acid using Pluronic F-127

[0071] A sample E13 was prepared by blending ferulic acid with Pluronic F-127 at ambient temperature in a weight ratio of 1:20. 20 mL of deionized water was added to the mixture, and the mixture were homogenized using a high-shear mixer (Ultra Turrax T18 / T25 basic homogenizer) until a fine and homogeneous aqueous emulsion was obtained.Example 14

[0072] A sample E14 was prepared in the same manner as described in Example 13, except that the weight ratio of ferulic acid to Pluronic F-127 was adjusted to 1:10.Example 15

[0073] A sample E15 was prepared by blending ferulic acid with Pluronic F-127 at ambient temperature in a weight ratio of 1:10. 20 mL of deionized water was added to the mixture, and the mixture were homogenized using a high-shear mixer (Ultra Turrax T18 / T25 basic homogenizer) until a fine and homogeneous aqueous emulsion, comprising polyethylene (PEG) shell capsules, was obtained.

[0074] Polyacrylic acid (PAA) (mw=5,000, 50% solution, PolyScience) was added to the aqueous emulsion, and further homogenized for about 3 minutes to crosslink the PEG shells of the capsules. In this example, 0.15 g of PAA was added to the aqueous emulsion containing 2 g of Pluronic F-127, which converted a degree of about 8% crosslinking, calculated using molar ratio.Example 16

[0075] A sample E16 was prepared in the same manner as described in Example 13, except that the weight ratio of ferulic acid to Pluronic F-127 was adjusted to 1:8.Example 17

[0076] A sample E17 was prepared in the same manner as described in Example 15, except that the weight ratio of ferulic acid to Pluronic F-127 was adjusted to 1:8. The same result of 8% crosslinking was obtained.Example 18

[0077] A sample El 8 was prepared in the same manner as described in Example 13, except that the weight ratio of ferulic acid to Pluronic F-127 was adjusted to 1:5.Example 19

[0078] A sample E19 was prepared in the same manner as described in Example 13, except that the weight ratio of ferulic acid to Pluronic F-127 was adjusted to 1:3.3.Results of the Examples

[0079] The results obtained from Examples 1 to 19 are summarized below.

[0080] In particular, the compositions of the samples prepared in Examples 1 to 19 are summarized in Table 1 below. As shown in Table 1, the weight ratios of ferulic acid to surfactant are selected at 1:20, 1:10, 1:8, 1:5 and 1:3.3, respectively. For samples E15 and E17, crosslinking was carried out, where 0.15 g of PAA was added to the system, which converted a degree of about 8% crosslinking, calculated using molar ratio.

[0081] Table 1: Summary of compositions in Examples 1 to 19 (El to E19). The compositions are expressed in units of gram. The ratio ranges from 1 :20, 1:10, 1:8, 1 :5, to 1:3.3. “PAA” denotes poly acrylic acid (mw=5000).Compositions El E2 E3 E4 E5 E6 E7 E8 E9 E10 Ell E12 E13 E14 E15 E16 E17 E18 E19 Tween 20 2 2 2 2Tween 80 2 2 2 2Tween 65 2 2 2 2Pluronic F127 2 2 2 2 2 2 2 Ferulic acid o.l 0.2 0.4 0.6 0.1 0.2 0.4 0.6 0.1 0.2 0.4 0.6 0.1 0.2 0.2 0.25 0.25 0.4 0.6 PAA 0.15 0.15Encapsulation Efficiency

[0082] Successful encapsulation of ferulic acid was achieved for samples El, E5, E9, El 3, when ratio of ferulic acid to surfactant was set at 1:20, which is the lowest among all the samples. At this ratio, the encapsulation efficiency is about 100% for all samples. When the ratio increases to 1:10, 1:5 and 1:3.3, precipitation of ferulic acid in the system was observed for samples E2, E3, E4, E6, E7, E8, E10, Ell, E12, E18, E19, except for E14. The observed precipitation clearly indicates the poor encapsulation efficiency.

[0083] As for sample E14 with a ratio of 1:10, ferulic acid was successfully encapsulated. Sample E16 was tested with a slightly higher weight ratio of 1:8, and results turned out to be favourable as well. Crosslinking of samples E14 and E16 yielded samples E15 and El 7, respectively, and the encapsulation efficiencies of these samples are believed to be not affected as the capsules were pre-formed before adding PAA as the crosslinker.Effect of surfactant hydrophilic lipophilic balance (HLB) on the encapsulation efficiency

[0084] At a relatively high feed ratio of ferulic acid to surfactant, different surfactants exhibited different encapsulation efficiencies. The hydrophilic lipophilic balance (HLB) values of the surfactants may be the contributor. Table 2 summarizes the HLB values of the surfactants and the corresponding loading results. A higher HLB value was generally associated with a higher loading of ferulic acid in the surfactant, which may be attributed to the increased water solubility of surfactants with higher HLB values.

[0085] Table 2: Summary of the HLB values for the surfactants and the corresponding loading results.NMR Analysis of Crosslinking

[0086] Crosslinking of PAA to PEG-containing shell was analysed using NMR spectroscopy. Freeze-dried white powder of Pluronic F-127 and the ferulic acid capsules (El 4) was redispersed in deuterium oxide (D2O). FIG. 1 shows the NMR spectrum of the ferulic acid encapsulated with the Pluronic F-127 (a) without crosslinking in D2O, and (b) with crosslinking after the addition of the PAA crosslinker. Small quantity of dimethyformamide (DMF) as reference chemical was added to the NMR tube, which helped to quantify the integration of proton signals ascribed to the PEG segment of the Pluronic F-127. When capsules were formed without the addition of PAA crosslinker (FIG. 1(a)), the PEG segments of the redispersed sample were freely moible and produced signals under NMR spectroscopy. The peaks at 3.6 ppm were attributed to protons of the PEG, with an intensity ratio of 5.14 relative to the signal from DMF (aldehyde proton). Upon addition of the crosslinker, the peaks at 3.6 ppm decreased sharply (FIG. 1(b)), indicating that the crosslinking restricted the mobility of the PEG shell. The signals from the PEG protons showed a decreased ratio of 2.61 relative to the signal from DMF (aldehyde proton). These results clearly indicate the successful crosslinking of the PEG shell with the crosslinker.HPLC Analysis of Ferulic Acid Loading

[0087] Samples El 4, E15, E16 and El 7 represent the highest loading and optimal encapsulation efficiency for ferulic acid. The ferulic acid loading in Pluronic F-127 samples was determined by high-performance liquid chromatograph (HPLC), and the results are summarized in Table 3.

[0088] Table 3 summarises the feed loading percentage, the HPLC-determined loading percentage, and the corresponding encapsulation efficiency for the four samples. The HPLC loading percentage was close to the feed loading percentage, reflecting the high encapsulation efficiency (ranging from 89% to 95%). These results indicate that Pluronic F-127 provides effective encapsulation of ferulic acid, achieving both high loading performance and high encapsulation efficiency. The difference in the measured loading between the non-crosslinkedand crosslinked capsules was minimal, indicating that crosslinking did not materially alter the loading of the active ingredient as mentioned hereinabove.

[0089] Table 3: Shows the feed loading percentage, HPLC loading percentage and the encapsulation efficiency percentage (EE%) for Samples E14 to E17.Prevention of discoloration in water

[0090] After encapsulation, the ferulic acid embedded in the surfactant helps to prevent discoloration of the core-shell capsule of ferulic acid. Surprisingly, it was found that the protection from discoloration from Pluronic F-127 (Fl 27) is much better than Tween 20 and Tween 80. FIGs. 2A, 2B and 2C show the discoloration of the aqueous solutions comprising 5% ferulic acid encapsulated in F127 (2A), Tween 20 (2B) and Tween 80 (2C) after storage at room temperature for 4 months. Both 5% ferulic acid in Tween 20 (2B) and Tween 80 (2C) samples turned from colorless to yellow after 4 months of storage (the color change is not apparent in the black-and-white image of FIG. 2). In contrast, the 5% ferulic acid solution in F127 remained colorless.Prevention of discoloration at higher temperature

[0091] FIG. 2D shows the discoloration of aqueous solution containing 5% ferulic acid encapsulated in Tween 20 (left), Tween 80 (middle) and F127 (right) after storage at 40 °C for 4 weeks. Both 5% ferulic acid emulsions prepared with Tween 20 and Tween 80 exhibited a change in appearance from colorless to yellow after 4 weeks of storage. In contrast, the 5% ferulic acid emulsion prepared with F127 remained colorless.

[0092] FIG. 2E shows the discoloration of aqueous solution containing 5% ferulic acid encapsulated in Tween 20 (left), Tween 80 (middle) and F127 (right) after storage at 50 °C for 2 weeks. As can be seen, after 2 weeks of storage, the 5% ferulic acid emulsions prepared with Tween 20 and Tween 80 turned yellow, whereas the 5% ferulic acid emulsion prepared with Fl 27 showed only slight yellowing. The results indicate that the capsules of ferulic acid encapsulated in Fl 27 possess good stability against discoloration at high temperature.

[0093] Samples prepared with Tween 65 formed a waxy solid after homogenization and were therefore not included for comparison.

[0094] The results clearly indicate the superior effect from using Fl 27 as a surfactant that effectively prevents discoloration of ferulic acid in aqueous solution, a factor critical to the appearance and consumer acceptability of the final product. It is worth to mention that 4 months is the estimated time for consumers to finish one bottle of skincare product.Morphology and particle sizes

[0095] The morphologies of the samples were measured by scanning electron microscopy (SEM). SEM samples were prepared on a silicon wafer by dry-coating the aqueous emulsion or by scattering the core-shell capsules in powder form onto the silicon wafer. FIG. 3A shows an SEM image of dried particles obtained from an aqueous emulsion containing 5% ferulic acid and Tween 20, while FIG.3B shows an SEM image of dried particles obtained from an aqueous emulsion containing 5% ferulic acid and Tween 80, both prepared at a weight ratio of 1:20, respectively. Irregular particles were observed for both the samples, which were well below 1 pm. Agglomerates of particles were formed during the drying process. The images represent the morphological properties of the particles formed during the drying process.

[0096] For the samples with high ferulic acid loading, sample of ferulic acid in Fl 27 without crosslinker (El 6) and sample of ferulic acid in Fl 27 with crosslinker (El 7) were selected for comparison. FIG. 4A and FIG. 4B show the SEM images of the E16 and E17 samples, respectively. The samples were prepared by redispersing the E16 and El 7 powders in aqueousmedium, followed by dry coating onto a silicon wafer, respectively. For both the noncrosslinked and the crosslinked particles samples, irregular elliptical shapes were observed. During the coating process, the drying process stimulated the aggregation of particles. A representative elliptical morphology is shown in FIG. 5.

[0097] FIG. 4C and FIG. 4D are SEM images of El 6 and E17 samples, respectively, prepared by scattering the samples in powder form onto the silicon wafer. Both samples appeared as flakes after freeze-drying, and no obvious differences were observed between the samples before and after crosslinking. This confirms the hypothesis that particles are preformed before crosslinking. The flakes in FIG. 4A and FIG. 4B appear to be larger than the elliptical particles, which again can be attributed to aggregation effect.

[0098] The particle sizes of the samples in aqueous emulsion were measured with dynamic light scattering (DLS). DLS curves for samples prepared with a 1:20 feed ratio of ferulic acid to the various surfactants are shown in FIGs. 6A to 6D. After homogenization, the aqueous emulsions appeared to be multi-dispersed and the particle sizes were below 1000 nm. For the sample having a 1:20 feed ratio of ferulic acid to Pluronic F-127 (F127) (FIG. 6D), the particle size distribution exhibited a major peak at 7 nm.

[0099] DLS curves for the sample with a 1:10 feed ratio of ferulic acid to the various surfactants are shown in FIGs. 7A to 7D. Similarly, the samples appeared to be multi-dispersed, with particle sizes below 1000 nm. For the sample with a 1:10 feed ratio of ferulic acid to Pluronic F-127 (F127) (FIG. 7D), the particle size distribution again exhibited a major peak at 7 nm.

[0100] Redispersed samples El 6 and E17 show particles sizes in 20 nm range, as shown in FIGs. 8A and 8B. These results indicate that although agglomeration may occur during drying, the final particle size remains in the nanometer range upon redispersion. This property is advantageous for subsequent formulation of the powder into a final composition without risk of persistent agglomeration.

[0101] Although embodiments of the invention have been shown and described, the invention is not limited to the described embodiments. Instead, it would be appreciated by those skilled in the art that various modifications and variations can be made to the embodiments of the invention without departing from the scope of the invention, the scoop of which is set forth in the following claims.

Claims

Claims1. A core-shell capsule comprising:a hydrophobic core comprising ferulic acid, encapsulated within a hydrophilic shell formed of a poly(ethylene glycol)-containing amphiphilic polymer crosslinked by a polyacid having at least one carboxylic acid group,wherein the poly( ethylene glycol)-containing amphiphilic polymer is Poloxamer 407; andwherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

2. The core-shell capsule of claim 1 , wherein the ferulic acid and the poly( ethylene glycol) amphiphilic polymer are present in a weight ratio ranging from 1:20 to 1:3.3.

3. The core-shell capsule of claim 1, wherein the polyacid comprises a polyacrylate backbone and has a molecular weight ranging from 500 Dalton to 10,000,000 Dalton.

4. The core-shell capsule of claim 1, wherein the polyacid is selected from the group consisting of polyacrylic acid, copolymers of acrylic acid, poly(methacrylic acid) and copolymers of methacrylic acid.

5. The core-shell capsule of claim 4, wherein the polyacid is polyacrylic acid or copolymers of acrylic acid.

6. The core-shell capsule of claim 1, wherein the poly( ethylene glycol) -containing amphiphilic polymer comprises an ethylene glycol unit, and the molar ratio of the carboxylicacid group of the polyacid to the ethylene glycol unit of the poly(ethylene glycol)-containing amphiphilic polymer ranging from 2:1 to 0.01 : 1.

7. The core-shell capsule of claim 1, wherein the core-shell capsule is in the form of an aqueous emulsion having a particle size ranging from 1 nm to 1000 nm.

8. The core-shell capsule of claim 1, wherein the core-shell capsule is in powder form and has a particle size ranging from 1 nm to 1000 nm after redispersion.

9. The core-shell capsule of claim 7, wherein the core-shell capsule is capable of preventing discoloration of the ferulic acid in the aqueous emulsion.

10. A method of producing a core-shell capsule comprising ferulic acid, the method comprising:blending ferulic acid and a poly( ethylene glycol)-containing amphiphilic polymer at ambient temperature to form a mixture; andcrosslinking the poly( ethylene glycol) -containing amphiphilic polymer with a polyacid comprising at least one carboxylic acid group to form a core-shell capsule comprising a hydrophobic core comprising ferulic acid, encapsulated within a crosslinked hydrophilic shell formed of the poly(ethylene glycol)-containing amphiphilic polymer, wherein the poly(ethylene glycol)-containing amphiphilic polymer is Poloxamer 407, and wherein the loading of the ferulic acid in the core-shell capsule ranges from 8 to 11%, relative to the total weight of the core-shell capsule.

11. The method of claim 10, wherein the step of blending comprises introducing an aqueous carrier into the mixture and subjecting the mixture with the aqueous carrier to homogenization under high-shear conditions.

12. The method of claim 10, wherein the ferulic acid and the poly( ethylene glycol)-containing amphiphilic polymer are blended in a weight ratio ranging from 1:20 to 1:3.3.

13. The method of claim 10 or 11, wherein the step of crosslinking comprises subjecting the mixture comprising the polyacid to homogenization under high-shear conditions.

14. The method of claim 10, wherein the polyacid comprises a polyacrylate backbone and has a molecular weight ranging from 500 Dalton to 10,000,000 Dalton.

15. The method of claim 10, wherein the polyacid is selected from the group consisting of polyacrylic acid, copolymers of acrylic acid, poly(methacrylic acid) and copolymers of methacrylic acid.

16. The method of claim 15, wherein the polyacid is polyacrylic acid or copolymers of acrylic acid.

17. The method of claim 10, wherein the core-shell capsule is provided in the form of an aqueous emulsion having a particle size ranging from 1 nm to 1000 nm.

18. The method of claim 17, further comprising:freeze-drying the aqueous emulsion to form the core-shell capsule in powder form, the powder having a particle size ranging from 1 nm to 1000 nm after redispersion.

19. The method of claim 10, wherein the core-shell capsule is capable of preventing discoloration of the ferulic acid in the aqueous emulsion.

20. Use of a core-shell capsule as defined in any one of claims 1 to 9 as an encapsulated medium for preventing discoloration of ferulic acid in a cosmetic product.

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