WO2020044308A1

WO2020044308A1 - High yield stabilized colloidal particle assemblies

Info

Publication number: WO2020044308A1
Application number: PCT/IB2019/057346
Authority: WO
Inventors: Heli Wang; Ganesh Kannan; Nitin Chopra; Ihab Nizar Odeh; C. William Gundlach Iv; Jonathon SCHOLIN
Original assignee: Sabic Global Technologies B.V.
Priority date: 2018-08-30
Filing date: 2019-08-30
Publication date: 2020-03-05

Abstract

The invention is directed to a composition comprising a stabilized colloidal particle assembly having an absolute value of surface zeta potential of at least 20 mV and produced at a yield of at least 40%. The colloidal particle assembly comprises a plurality of colloidal particles and a salt component. The salt component is a carbonic acid salt, and is present in an amount sufficient to stabilize the colloidal particle assembly. Further, the colloidal particle assembly may have a core/shell structure containing a void space, and is particularly suitable to be used for the slow-release delivery of active agents commonly used in healthcare and cosmetic industries. The invention further describes a method for preparing such a colloidal particle assembly, especially at high yields of production.

Description

HIGH YIELD STABILIZED COLLOIDAL PARTICLE ASSEMBLIES

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application

No. 62/724,630 filed August 30, 2018, which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention is directed to the field of colloidal particle assemblies.

BACKGROUND

[0003] Colloidal particle assemblies are used extensively as drug delivery systems or carriers, for delivery and release of active agents in various health care and therapeutic applications. Colloidal particle assemblies are particularly useful when the active agent has poor efficacy due to low water solubility or when the active agent needs to be released at a slow rate over a specific receptor or a target. Colloidal particle assemblies are also useful in the perfume and cosmetic industries, where such particle assemblies are used for encapsulating active agents in order to prevent degradation and to improve the stability of the active agent. Further, colloidal particle assemblies can be customized for slow-release of the fragrance active agents to prolong the effect of the fragrance over a longer period of time and thereby improving the efficacy of such active agents considerably.

[0004] Unfortunately, preparing colloidal particle assemblies are fraught with several challenges, such as the challenge of ensuring the dispersion stability of a colloidal particle assembly once it is formed and obtaining adequate production yields. Colloidal stability of a colloidal particle assembly is a critical consideration for any industrial use, as colloidal particles have an inherent tendency to flocculate or agglomerate when the desired conditions for stability are not achieved or are altered. Such agglomeration may cause the colloidal particle assembly to lose its property of encapsulation and its function as an active agent carrier. Therefore, a suitably stable colloidal particle assembly ensures an excellent delivery/carrier efficiency of the active agent, thereby improving the commercial viability of using such an assembly for various industrial applications.

[0005] Colloidal particle assemblies may be particularly sensitive to high temperature exposure, sharp fluctuations of pH, variation in the concentration of constituting materials during production and polarity of any additives incorporated. Attempts to address the drawback of colloidal particle stability, has been discussed by Uchida, et al (Chem. Phar. Bull. 45(3) 513- 517 (1997)), where the use of specific amounts of sodium chloride has been proposed to improve the stability of the polylactic acid (PLA) microspheres. However, as shown under Example 3 and Example 4 in this disclosure, the stability and the yield of microsphere or colloidal particle assemblies using sodium chloride are limited and can be further improved. Another challenge for artisans skilled in the art, is the low production yield of the colloidal particle assemblies, resulting in an increased cost of production. The yield is particularly important to ensure the commercial viability of producing colloidal particle assemblies at an industrial scale. Further, to ensure excellent loading efficiency and improved functionality as a carrier, it is desirable to have colloidal particle assemblies having individual colloidal particles of uniform size and shape thereby providing improved encapsulation of the active agents. Colloidal particles generally have irregular shape or size and may lead to inefficient packing of the particles, thereby affecting loading efficiency of the active agents and causing the colloidal particle assembly to lose their release efficiency.

[0006] For the foregoing reason there remains a need to develop colloidal particle assemblies having one or more benefits of (i) excellent dispersion stability, (ii) high yield of production, and (iii) improved size and shape of colloidal particles, suitable to function as a carrier for active agents when incorporated in such colloidal particle assemblies.

BRIEF SUMMARY

[0007] The invention relates to a composition comprising, a colloidal particle assembly having a plurality of colloidal particles and a salt component comprising at least one carbonic acid salt, wherein each of the plurality of the colloidal particles has an average diameter ranging from about 0.05 microns to about 2.5 microns and the salt component is present at a concentration sufficient to stabilize the colloidal particle assembly. Further, the colloidal particle assembly has an absolute value of surface zeta potential of at least 20 mV. In some embodiments of the invention, the colloidal particle assembly has an absolute value of surface zeta potential ranging from about 25 mV to about 70 mV.

[0008] In some embodiments of the invention, the colloidal particles are selected from the group consisting of microgel particles, nanogel particles, polymer particles, polymer brushes, surfactant molecules, metal oxide particles, lipid particles, block copolymers, cross-linked polymers, biopolymers, biomolecules, micellular/dendrimer structures, yolk/shell structures, core/shell structures, pomegranate structures, hollow structures/nanomaterials, functionalized microstructures, nanostructures, and combinations thereof. In one aspect of the invention, the colloidal particles are at least one of microgel particles and nanogel particles. In another aspect of the invention, the colloidal particles comprise, a gel phase having at least one polymer network selected from hydrophilic polymer network, hydrophobic polymer network, amphiphilic polymer network, amphiphobic polymer network, lipophilic polymer network, lipophobic polymer network, and combination thereof.

[0009] In an embodiment of the invention, each of the plurality of colloidal particles, has an average diameter ranging from about 0.05 microns to about 0.9 microns. In some embodiments of the invention, the colloidal particle assembly further comprises at least one void space enclosed by at least three colloidal particles. In some embodiments of the invention, the colloidal particle assembly has a core comprising a void space and the plurality of polymeric colloidal particles form a shell around the core. In one aspect of the invention, the void space comprises at least one active agent. In one embodiment of the invention, the active agent is selected from the group consisting of chemical agent, biological agent, oil, ionic liquid, a suspension, polymer, and combinations thereof.

[0010] In one aspect of the invention, the colloidal particles comprise a polymeric material selected from the group consisting of polylactic acids, polylactic-coglycolic acid copolymers, poly(N-isopropylacrylamides),N-isopropylacrylamide-(N,N'- methylenebisacrylamide) copolymers, N-isopropylacrylamide-(N,N'- methylenebisacrylamide)-allyl amine copolymers, polyethylene glycols, poly(vinyl alcohol), hydroxylated poly(meth)acrylates, ethylene-vinyl acetate copolymers, 2-hydroxyethyl methacrylates, polymaleic acid ethers, octyl vinyl ethers, polyurethanes, poly(acrylic acids), poly(stearyl acrylates), poly(acrylamides), polyolefins, alginates, chitosans, polyesters, polyethylene terephthalates, polybutylene terephthalates, poly (butyl succinates), polyester copolymers, glycerol copolymers, polycarbonates, polyetherimides, polyphenyloxides, polystyrenes, poly(methyl methacrylates), and combinations thereof.

[0011] In another aspect of the invention, the carbonic acid salt is selected from the group consisting of NaHCCb, Na₂CC>3, K2CO3, KHCO3, MgCCb, CaCCb, NH4HCO3, (NH^COs, bis(tetramethylammonium)carbonates, and combinations thereof. In some embodiments of the invention, the salt component is present at a concentration ranging from about 0.01 mM to about 500 mM. In some embodiments of the invention, the salt component is present at a concentration ranging from about 0.1 mM to about 5 mM.

[0012] In another aspect of the invention, a method is disclosed for preparing a colloidal particle assembly, wherein the method comprises (a) forming an aqueous salt solution comprising a carbonic acid salt, (b) forming a surfactant-salt solution comprising a surfactant and the aqueous salt solution; and (c) adding a colloidal particle dispersion comprising a plurality of colloidal particles and a dispersing solvent, to the surfactant-salt solution, and forming the colloidal particle assembly, wherein the adding step is optionally performed by stirring the colloidal particle dispersion into the surfactant-salt solution. In one aspect of the invention, the colloidal particle assembly is produced at a yield ranging from about 40% to about 80%.

[0013] In some embodiments of the invention, the surfactant is selected from the group consisting of surface active agents, (poly)alkylene oxides, (poly)alkylene glycols, emulsifiers, sodium dodecyl sulfates, tocopheryl polyethylene glycol succinates and combinations thereof. In some embodiments of the invention, the dispersing solvent is at least one of ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, methyl acetate, methylene chloride, isopropyl acetate, isobutyl acetate, chloroform, dichloroethane and any combinations thereof. In some embodiments of the invention, the plurality of colloidal particles is present at a concentration ranging from more than 0 mg/ml to less than about 100 mg/ml, in the colloidal particle dispersion.

[0014] Another aspect of the invention includes a composition comprising, a colloidal particle assembly having: (a) a plurality of colloidal particles comprising a polymeric material selected from the group consisting of poly lactic acids, polylactic-coglycolic acid copolymers, poly(N-isopropylacrylamides), N-isopropylacrylamide-(N,N'-methylenebisacrylamide) copolymers, N-isopropylacrylamide-(N,N'-methylenebisacrylamide)-allyl amine copolymers, polyethylene glycols, polyvinyl alcohol, hydroxylated poly(meth)acrylates, ethylene-vinyl acetate copolymers, 2-hydroxyethyl methacrylates, polymaleic acid ethers, octyl vinyl ethers, polyurethanes, poly(acrylic acids), poly(stearyl acrylates), poly(acrylamides), polyolefins, alginates, chitosans, polyesters, polyethylene terephthalates, polybutylene terephthalates, poly (butyl succinates), polyester copolymers, glycerol copolymers, polycarbonates, polyetherimides, polyphenyloxides, polystyrenes, poly(methyl methacrylates), and combinations thereof; (b) a salt component comprising at least one carbonic acid salt component is selected from the group consisting of NaHCCb, Na2CCb, K2CO3, KHCO3, MgCCb, CaCCb, NH4HCO3, (NFE^CCh, bis(tetramethylammonium) carbonates, and combinations thereof, wherein the salt component is present at a concentration ranging from about 0.01 mM to about 500 mM; and (c) at least one active agent selected from the group consisting of chemical agent, biological agent, oils, ionic liquid, suspension, polymer, and combinations thereof. Each of the plurality of colloidal particles, has an average diameter ranging from about 0.05 microns to about 0.9 microns and the colloidal particle assembly has an absolute value of surface zeta potential of at least 20 mV. Further, the colloidal particle assembly comprises at least one void space enclosed by at least three colloidal particles. [0015] Other objects, features and advantages of the present invention will become apparent from the following figures, detailed description, and examples. It should be understood, however, that the figures, detailed description, and examples, while indicating specific embodiments of the invention, are given by way of illustration only and are not meant to be limiting. Additionally, it is contemplated that changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. In further embodiments, features from specific embodiments may be combined with features from other embodiments. For example, features from one embodiment may be combined with features from any of the other embodiments. In further embodiments, additional features may be added to the specific embodiments described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] For a more complete understanding, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

[0017] FIG. 1A is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention possessing void spaces defined by the colloidal particles;

[0018] FIG. IB is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention having a core comprising a void and the shell formed from the colloidal particles;

[0019] FIG. 2A is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention having a“pomegranate” type colloidal particle assembly having more than one core/shell structural arrangement;

[0020] FIG. 2B is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention having a“string-of-pearls” type colloidal particle assembly having two core/shell structural arrangement;

[0021] FIG. 2C is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention having an irregular shape and arrangement;

[0022] FIG. 3 is an illustration of a colloidal particle assembly prepared in accordance with an embodiment of the invention having an active agent encapsulated in the core;

[0023] FIG. 4 is a schematic representation of the preparation of the colloidal particle assembly in accordance with an embodiment of the invention;

[0024] FIG. 5 is graphical representation of the absolute value of surface zeta potential and yield of colloidal particle assembly obtained from the practice of the inventive Example 1 and Example 2 and the comparative Examples 3-5; [0025] FIG. 6A is a scanning electron microscope (SEM) image of a colloidal particle assembly prepared from the practice of inventive example (Example 1); and

[0026] FIG. 6B is a scanning electron microscope (SEM) image of a colloidal particle assembly prepared under the practice of comparative example (Example 3).

[0027] FIG. 6C is a scanning electron microscope (SEM) image of a colloidal particle assembly prepared as described in example 1.

[0028] FIG. 7 is normalized peak absorbance in 220 - 240 nm wavelength range with time, for first (with Na2CCh) and second (without Na2CCh) experiment of example 6.

DFTATEFD DESCRIPTION OF TTTF INVENTION

[0029] The invention, is based, in part, on the discovery, that a composition containing a colloidal particle assembly with specific features can exhibit one or more benefits of (i) excellent dispersion stability, (ii) high yield of production, and (iii) improved size and shape suitable to function as a carrier for active agents. Advantageously, the composition is designed to have unique features that impart dispersion stability to the colloidal particle assembly while retaining high yield of production. In particular, the size and shape of the individual colloidal particles constituting the colloidal particle assembly has an excellent uniformity in shape and size, features that enables a skilled artisan to use the colloidal particle assembly as a suitable carrier for active agents with excellent release efficiency.

[0030] The following includes definitions of various terms and phrases used throughout this specification.

[0031] The terms“wt.%”,“vol.%” or“mol %” refers to a weight, volume, or molar percentage of a component, respectively, based on the total weight, the total volume, or the total moles of the material that includes the component. In a non-limiting example, 10 moles of a component in 100 moles of the material means 10 mol % of the component. The term“M” refers to a molar concentration of a component, based on the moles per 1L volume. The term “mM” means one thousandth of a“M”.

[0032] Any numerical range used through this disclosure shall include all values and ranges there between unless specified otherwise. For example, a boiling point range of 50 ^°C to 100 ^°C includes all temperatures and ranges between 50 ^°C and 100 ^°C including the temperature of 50 ^°C and 100 ^°C.

[0033] The use of the words“a” or“an” when used in conjunction with the term “comprising,”“including,”“containing,” or“having” in the claims or the specification may mean“one,” but it is also consistent with the meaning of“one or more,”“at least one,” and “one or more than one.” [0034] The words“comprising” (and any form of comprising, such as“comprise” and “comprises”),“having” (and any form of having, such as“have” and“has”),“including” (and any form of including, such as“includes” and“include”) or“containing” (and any form of containing, such as“contains” and“contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0035] The process of the present invention can“comprise,”“consist essentially of,” or “consist of’ particular ingredients, components, compositions, etc., disclosed throughout the specification.

[0036] The term“active agent” as used throughout this disclosure means a chemical or biological agent having a specific functionality such as emanating fragrance, providing therapeutic effect, having specific biological or pharmacological function, having a function of an emollient or any other function that a chemical compound can be designed to have.

[0037] The term“loading efficiency” as used throughout this disclosure means the amount of active agent that can be encapsulated or carried by the colloidal particle assembly.

[0038] The term“colloidal particle assembly” as used throughout this disclosure means a network of individual colloidal particles connected together by way of electrostatic or other attractive forces.

[0039] The term“void space” as used throughout this disclosure means empty space or cavity located between the individual polymeric colloidal particles including any interstitial spaces located between the colloidal particles.

[0040] The details of the invention including the various embodiments of the invention is discussed in detail hereunder to enable a skilled artisan to appreciate the workings of the invention better.

[0041] Referring to FIG. 1A, in a version of the invention, a composition containing a colloidal particle assembly (100) comprises a plurality of colloidal particles (101) with a salt component (102) present on the surface of the colloidal particles (101). In one aspect of the invention, each of the plurality of colloidal particles (101) has an average diameter ranging from about 0.05 microns to about 2.5 microns, alternatively from about 0.1 microns to about 0.9 microns, alternatively from about 0.2 microns to about 0.5 microns. The diameter of the colloidal particles (101) may be determined using a scanning electron microscope. In one embodiment of the invention, the size distribution of the colloidal particles (101) is unimodal. In another embodiment of the invention, the size distribution of the colloidal particles (101) is bimodal. In yet another embodiment of the invention, the size distribution of the colloidal particles (101) is multimodal. [0042] In one aspect of the invention, the colloidal particles (101) are selected from the group consisting of microgel particles, nanogel particles, polymer particles, polymer brushes, surfactant molecules, metal oxide particles, lipid particles, block copolymers, cross-linked polymers, biopolymers, biomolecules, micellular/dendrimer structures, yolk/shell structures, core/shell structures, pomegranate structures, hollow structures/nanomaterials, functionalized microstructures, functionalized nanostructures, and combinations thereof. In one embodiment of the invention, the colloidal particles (101) are at least one of microgel particles and nanogel particles.

[0043] In another aspect of the invention, the colloidal particles (101) comprise, a gel phase having at least one polymer network selected from hydrophilic polymer network, hydrophobic polymer network, amphiphilic polymer network, amphiphobic polymer network, lipophilic polymer network, lipophobic polymer network, and combination thereof.

[0044] In one embodiment of the invention, the colloidal particles (101) comprise a polymeric material selected from the group consisting of polylactic acid, polylactic-coglycolic acid copolymers, poly(N-isopropylacrylamides), N-isopropylacrylamide-(N,N'- methylenebisacrylamide) copolymers, N-isopropylacrylamide-(N,N'- methylenebisacrylamide)-allyl amine copolymers, polyethylene glycols, polyvinyl alcohol, hydroxylated poly(meth)acrylates, ethylene-vinyl acetate copolymers, 2-hydroxyethyl methacrylates, polymaleic acid ethers, octyl vinyl ethers, polyurethanes, poly(acrylic acids), poly(stearyl acrylates), poly(acrylamides), polyolefins, alginates, chitosans, polyesters, polyethylene terephthalates, polybutylene terephthalates, poly (butyl succinates), polyester copolymers, glycerol copolymers, polycarbonates, polyetherimides, polyphenyloxides, polystyrenes, poly(methyl methacrylates), and combinations thereof. In a preferred embodiment, the polymeric material is polylactic acid. For drug delivery application, it is particularly preferred to use biopolymers or polymers which are compatible with biological systems. Further, it is preferable that the polymeric material contains a polar functional group which can impart hydrophilicity to the otherwise hydrophobic polymer backbone and thereby assisting in preparing the colloidal particle assembly (100) through an emulsification process. In another aspect of the invention, the polymeric material has a molecular weight ranging from about 30,000 amu to about 250,000 amu, alternatively from about 40,000 to about 60,000 amu. Without wishing to be bound by any specific theory, it is believed that the polymeric material used, has sufficient molecular weight, to allow the formation of colloidal assemblies with ease while maintaining the desired chemical stability in a dispersion medium. [0045] In embodiments of the invention, the salt component (102) is a carbonic acid salt. In one aspect of the invention, the carbonic acid salt is selected from the group consisting of NaHCCb, NaiCCb, K2CO3, KHCO3, MgCCb, CaCCb, NH4HCO₃, (NH₄)₂CC>3, bis(tetramethylammonium) carbonates, and combinations thereof. In an aspect of the invention, the salt component (102) is present at a concentration sufficient to stabilize the colloidal particle assembly (100). In one embodiment of the invention, the salt component (102) is present at a concentration ranging from about 0.01 mM to about 500 mM, alternatively from about 0.01 mM to about 5 mM, alternatively from about 0.8 mM to about 2 mM. Without being bound by any specific theory, the salt component (102) imparts ionic charge on the surface of colloidal particles (101), which in turn influences the surface zeta potential of the colloidal particles (101) and stabilizes the colloidal particle assembly by way of electrostatic stabilization.

[0046] In another aspect of the invention, the colloidal particle assembly has an absolute value of surface zeta potential of at least 20 mV. As discussed in several published literature such as the publication by Sharma et al (“ Interfacial and Colloidal properties of emulsified systems", Colloid and Interface Science in Pharmaceutical Research and Development 2014 , pp 149-172 ), it may be appreciated by a skilled artisan, that higher the absolute value of the surface zeta potential of a colloidal assembly, greater is the colloidal stability. In another embodiment of the invention, the colloidal particle assembly (100) has an absolute value of surface zeta potential of at least 30 mV. In one embodiment of the invention, the colloidal particle assembly (100) has an absolute value of surface zeta potential ranging from about 25 mV to about 70 mV, alternatively from about 35 mV to about 60 mV. Without being bound by any theory, it is believed that at a relatively high surface zeta potential, the electrostatic forces are sufficiently strong between the colloidal particles (101) to prevent aggregation or flocculation. The surface zeta potential may be measured using any of the techniques known in the literature such as an electro-kinetic measurement using zeta potential analyzers.

[0047] Referring to FIG. 1 A, in one aspect of the invention, the colloidal particle assembly (100) further comprises at least one void space (103) enclosed by at least three colloidal particles. In one embodiment of the invention, the void space (103) is an interstitial cavity positioned between at least three polymeric colloidal particles. Referring to FIG. 1B, in another aspect of the invention, the colloidal particle assembly (100) has a core (104) comprising a void space and the plurality of colloidal particles form a shell (105) around the core (104). In embodiments of the invention, referring to any of the figures, FIG. 1B or FIG. 2A or FIG. 2B, the colloidal particle assembly (100) has a uniform shape and size comprising at least one core (104) and at least one shell (105) formed by the plurality of colloidal particles (101). In another embodiment of the invention, referring to FIG. 2C the colloidal particle assembly (100) has an irregular size and shape with only one core (104). Referring to FIG. 1B, the core (104) is particularly useful in encapsulating and limiting the exposure of therapeutic active agents or fragrance emanating agents to external reactive conditions.

[0048] In an embodiment of the invention, the colloidal particle assembly comprises at least one active agent. In one aspect of the invention, referring to FIG. 3, the active agent (106) is encapsulated in the core (104). In some embodiments of the invention, the active agent (106) is located on the surface of the colloidal particles (101). In one aspect of the invention, the colloidal particles (101) are stimulus responsive, which promotes release of the active agent loaded or encapsulated in the colloidal assembly (100) upon responding to a stimulus. Without wishing to be bound to any theory, the term stimulus responsive as used herein, means a chemical or physical alteration of the colloidal particles (101) including deformation of the size and shape of the colloidal particles (101), which causes the release of the active agent (106) from the colloidal particle assembly (100). Non-limiting examples of stimulus required for releasing the active agent (106) include temperatures, pH, radiation, mechanical forces, humidity, ionic strength, electricity, magnetic, ultrasound, redox strength and combinations thereof. In a preferred embodiment of the invention, the stimulus is pH.

[0049] The active agent can be selected from the group consisting of chemical agent, biological agent, oil, ionic liquid, suspension, polymer, and combinations thereof. In one aspect, the active agent is preferably a chemical agent. Non-limiting examples of the chemical agent include any one of pharmaceutical drugs, cosmetic agents, flavoring agents, fragrance- producing chemicals, malodor agents, reactive agents, cross-linkers, reactive diluents, solvents, inorganic chemicals, organic chemicals, metallo-organic systems, petrochemicals, reducing agents, oxidizing agents, aqueous salts, proteins, peptides, nucleic acids, carbohydrates, lipids, and any combinations thereof.

[0050] In one aspect of the invention, referring to FIG. 4, a method for preparing the colloidal particle assembly (100) is provided, wherein the method comprises the steps of (a) forming an aqueous salt solution (405) comprising a carbonic acid salt (404); (b) forming a surfactant-salt solution (407) comprising a surfactant (406) and the aqueous salt solution (405); and (c) adding a colloidal particle dispersion (403), comprising a plurality of colloidal particles (401) and a dispersing solvent (402), to the surfactant-salt solution (407), and forming the colloidal particle assembly (100), the adding step is optionally performed by stirring the colloidal particle dispersion (403) into the surfactant- salt solution (407). In one embodiment of the invention, the colloidal particle assembly (100) is further dispersed in a solvent to form a dispersion containing the colloidal particle assembly (100). In another aspect of the invention, a solution containing an active agent is blended with the dispersion containing the colloidal particle assembly (100).

[0051] In some embodiments of the invention, the plurality of colloidal particles (401) is present at a concentration ranging from more than 0 mg/ml to less than about 100 mg/ml, alternatively from about 5 mg/ml to about 50 mg/ml, alternatively from about 15 mg/ml to about 30 mg/ml, in the colloidal particle dispersion (403). The concentration of the colloidal particles is desired to be at a suitable range to prevent agglomeration of the colloidal particles and thereby stabilize the colloidal particle assembly (100). In embodiments of the invention, the dispersing solvent is at least one of ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, methyl acetate, methylene chloride, isopropyl acetate, isobutyl acetate, chloroform, dichloroethane and any combinations thereof.

[0052] In one embodiment of the invention, the plurality of colloidal particles and the dispersing solvent are mixed together at a temperature ranging from about 85 ^°C to about 95 ^°C, alternatively from about 88 ^°C to about 92 ^°C. In one aspect of the invention, the colloidal particles comprise a polymeric material. In one embodiment of the invention, the colloidal particle dispersion formed, contains a plurality of polymer droplets comprising the polymeric material, dispersed in the dispersing solvent. It is preferred to have the polymer droplets to be of suitable diameter, so as to allow sufficient stabilization of the polymer droplets by the surfactant, on subsequent addition to the surfactant-salt solution.

[0053] In another aspect of the invention, the surfactant is selected from the group consisting of surface active agents, (poly)alkylene oxides, (poly)alkylene glycols, emulsifiers, sodium dodecyl sulfates, tocopheryl polyethylene glycol succinates and combinations thereof. In a preferred embodiment of the invention, the surfactant is tocopheryl polyethylene glycol succinates (TPGS).

[0054] In one aspect of the invention, the colloidal particle assembly (100) is produced at a yield ranging from about 40% to about 80%, alternatively from about 60% to about 75%, alternatively from about 65% to about 70%. The high yield of production of colloidal particle assembly (100) allows industrial scale production of the colloidal particle assembly at an acceptable cost. Without limiting to any specific factor, it is believed that the unique combination of (a) the concentration of the colloidal particles, and (b) the concentration and the type of salt component, helps in achieving previously unseen benefits of producing colloidal particle assemblies having high yield of production with sufficient colloidal stability suitable to be used as carriers of active agents in health care and perfume industries.

[0055] As part of the disclosure of the present invention, specific examples are included below. The examples are for illustrative purposes only and are not intended to limit the invention. Those of ordinary skill in the art will readily recognize parameters that can be changed or modified to yield essentially the same results.

EXAMPLES

Example 1

Stabilized colloidal particle assembly prepared in accordance with an embodiment of the invention using a suitable concentration of a carbonic acid salt

[0056] Purpose: Example 1 illustrates a stabilized colloidal particle assembly prepared in accordance with an embodiment of the invention.

[0057] Materials: The table below provides a summary of the materials used for preparing the colloidal particle assembly and the supplier from whom the materials were procured: Table: 1 Material description

[0058] Process/Procedure: The following method was practiced for preparing the colloidal particle assembly for the purpose of this Example. Referring to FIG. 4, the method comprised the steps of (a) forming an aqueous salt solution (405) containing a carbonic acid salt (404); (b) thereafter, forming a surfactant-salt solution (407) comprising a surfactant (406) and the aqueous salt solution (405); and (c) subsequently adding a colloidal particle dispersion (403), comprising a plurality of colloidal particles (401) and a dispersing solvent (402), to the surfactant-salt solution (407), and forming the colloidal particle assembly (100), the adding step optionally performed by stirring the colloidal particle dispersion (403) into the surfactant- salt solution (407). [0059] More particularly, an aqueous 1.5 mM sodium carbonate solution was prepared by dissolving the salt in 100 ml of deionized water. Separately, a surfactant solution was prepared by mixing 30 mg of tocopheryl polyethylene glycol succinate (TPGS) in 100 ml of deionized water. The surfactant solution was subsequently divided into 10 bottles of 10 ml each. Thereafter, 0.74 mL of ethyl acetate was added to each bottle and was stirred until a clear solution was obtained. A surfactant-salt solution comprising the sodium carbonate salt solution and the TPGS surfactant was prepared by adding 5 mL of the sodium carbonate salt solution to each bottle containing the surfactant solution. Separately a colloidal particle dispersion, having polymeric colloidal particles, was prepared by dispersing 0.5 g of polylactic acid (PLA) into 20 mL of ethyl acetate at reflux and was subsequently allowed to cool to room temperature and then subjected to filtration using 0.22 pm PTFE filter. Thereafter, 2 mL of the resultant filtrate was added to the surfactant-salt solution present in each 10 mL bottle, and stirred open to atmosphere over night at 1200 RPM to obtain the colloidal particle assembly.

[0060] Results: The colloidal particle assembly obtained from the procedure practiced under the present Example, was analyzed and the results are tabulated below:

Table 3: Colloidal particle assembly obtained from Example 1

[0061] The diameter of the colloidal particle, was measured using a combination of dynamic light scattering and scanning electron microscope (SEM), and the image obtained is illustrated under FIG. 6A. The surface zeta potential was measured using the Dynamic Light Scattering (DLS) system using Malvern Zetasizer NanoZS. FIG. 6C shows SEM image from the colloidal particle assembly. Arrows are added in the figure to show some of cores in the colloidal particle assembly. The cores contain void space and a plurality of colloidal particles form a shell around the cores.

[0062] Discussion: The results from Example 1 indicate the formation of a colloidal particle assembly having excellent colloidal stability while being produced at high yield. Further, as evidenced from the SEM image under FIG. 6A, the colloidal particle assembly has a uniform structure and shape which is particularly useful for functioning as a carrier for active agents. The results obtained is compared with that obtained from the practice of comparative examples (Example 3 to Example 5), and the results summarized under Table 8.

Example 2

Illustrates the Formation of a Colloidal particle assembly using a relatively higher concentration of carbonic acid salt

[0063] Purpose: Example 2 is an inventive example as an embodiment of the invention, to demonstrate the effects of using five times higher concentration of carbonic acid salt component, on the colloidal particle assembly stability and yield.

[0064] Materials: The materials used were the same as that described under Example 1.

[0065] Process/Procedure: The procedure followed was the same as described under

Example 1, except that 7.5 mM of sodium carbonate was used instead of 1.5 mM.

[0066] Results: The colloidal particle assembly obtained from the procedure practiced under Example 2 was analyzed and the results are tabulated below:

Table 4: Colloidal particle assembly obtained from the practice of Example 2

[0067] Discussion: The results obtained from the practice of Example 2 shows a lower yield for the colloidal particle assembly along with reduced surface zeta potential when compared to Example 1, indicating a lower stability. However, when compared with the results obtained from using non-carbonic acid salt components such as the results obtained from comparative examples (Example 3-5), Example 2 was able to demonstrate the unique combination of high yield of production of the colloidal particle assembly while maintaining sufficient colloidal stability to prevent agglomeration and flocculation.

COMPARATIVE EXAMPLES (Example 3, 4 and 5)

(Comparative) Example 3

Illustrates the formation of a colloidal particle assembly using a non-carbonic acid salt component for stabilization and yield

[0068] Purpose: Example 3 is a comparative example to demonstrate the effects of using sodium chloride salt on the colloidal particle assembly stability and yield. [0069] Materials: The materials used were the same as that described under Example 1 or under Example 2, except that sodium chloride procured from Sigma Aldrich was used instead of sodium carbonate.

[0070] Process/Procedure: The procedure followed was the same as described under Example 1, except that sodium chloride was used as the salt component to prepare the aqueous salt solution. The sodium chloride was used at a concentration of 3 mM.

[0071] Results: The colloidal particle assembly obtained from the procedure practiced under Example 3, was analyzed and the results are tabulated below:

Table 5: Colloidal particle assembly obtained from the practice of Example 3

[0072] Discussion: The results obtained from the practice of Example 3 shows a lower yield of colloidal particle assembly as compared to the yield obtained from the use of the carbonic acid salt described under Example 1 and Example 2. The yield obtained from the practice of Example 3 is almost 74% lower than that obtained from Example 1. In addition, the absolute value of surface zeta potential of the colloidal particle assembly is lower by almost 33% than that obtained from the practice of Example 1, thereby indicating a much lower stability of the colloidal particle assembly obtained through the practice of Example 1. Comparing the results obtained from Example 3 with that of Example 2, the yield obtained was 59% lower compared to Example 2 although the zeta potential was 23% higher, indicating better stability. The results obtained from Example 2 thereby indicate improved yield with acceptable level of lower stability when compared to Example 3.

(Comparative) Example 4

Illustrates the formation of a colloidal particle assembly using a non-carbonic acid salt component for stabilization and yield at high concentration

[0073] Purpose: Example 4 is a comparative example to demonstrate the effects of using five times higher concentration of sodium chloride salt on the stability and yield of colloidal particle assembly as compared to Example 3 and compare the results so obtained with the inventive Example 1 and inventive Example 2. [0074] Materials: The materials used were the same as that described under Example 1 and Example 2, except that sodium chloride procured from Sigma Aldrich was used instead of sodium carbonate.

[0075] Process/Procedure: The procedure followed was the same as described under Example 1, except that 15 mM of sodium chloride was used as the salt component to prepare the aqueous salt solution.

[0076] Results: The colloidal particle assembly obtained from the procedure practiced under Example 4, was analyzed and the results are tabulated below:

[0077] Discussion: The results obtained from the practice of Example 4 show a 73% lower yield of colloidal particle assembly as compared to the yield obtained from the use of the carbonic acid salt described under Example 1. In addition, the absolute value of surface zeta potential of the colloidal particle assembly is lower by almost 84% than that obtained from the practice of Example 1, thereby indicating a much lower stability of the colloidal particle assembly obtained through the practice of Example 1. Comparing the results obtained from Example 4 with that of Example 2, the yield obtained from the practice of Example 4 was 58% lower compared to Example 2 while surface zeta potential was 70% lower indicating much lower colloidal stability for the colloidal particle assembly obtained from Example 4.

(Comparative) Example 5

Illustrates the formation of a colloidal particle assembly without the use of any salt

[0078] Purpose: Example 5 is a comparative example to demonstrate the effects of using salt on the colloidal particle assembly stability and yield.

[0079] Materials: The materials used were the same as that described under Example 1 or Example 2, except that no salt was used.

[0080] Process/Procedure: The procedure followed was the same as described under Example 1 or Example 2, except that no salt component was used to prepare the colloidal particle assembly. [0081] Results: The colloidal particle assembly obtained from the procedure practiced under Example 5, was analyzed and the results are tabulated below:

[0082] Discussion: The results obtained from the practice of Example 5 shows a 56% lower yield as compared to the yield obtained from the practice followed under the inventive Example 1. In addition, the absolute value of surface zeta potential of the colloidal particle assembly is lower by at least 20% than that obtained from the practice of Example 1, thereby indicating a much lower stability of the colloidal particle assembly obtained through the practice of Example 1. Comparing the results obtained from Example 5 with that of Example 2, the yield obtained from the practice of Example 5, was at least 26% lower than that from Example 2. Although the surface zeta potential of the colloidal particle assembly obtained from Example 5 was higher, indicating a higher colloidal stability, the higher yield obtained from the practice of Example 2 helps in providing the desired balance between the yield of colloidal particle assembly produced and the colloidal stability, as obtained from the practice of Example 2

[0083] Summary of Results from Examples 1-5: The results of the inventive Example 1 and 2, along with that of Comparative Examples 3, 4 and 5, are summarized below and may be appreciated further by way of FIG. 5, which illustrates graphically the relationship between yield of colloidal particle assembly formed and the colloidal stability of the colloidal particle assembly represented by way of the surface zeta potential. Table 8: Summary of results obtained from Examples 1-5

[0084] As can be concluded from the results summarized under Table 8, the colloidal particle assembly produced in accordance with an embodiment of the invention, enables artisans to design and prepare colloidal particle assemblies having high yield of production while retaining the desired level of stability, required for functioning as a delivery carrier for active agents. From FIG. 6A, the size and shape of the of the colloidal particle assembly produced from the inventive Example 1 is uniform and well defined as compared to that produced by the practice of Example 3, using sodium chloride salt as shown by FIG. 6B. Therefore, it is concluded that the uniformity in size and shape of the colloidal particle assembly produced from the inventive Example 1, makes the packing of the colloidal particle assembly effective for functioning as a carrier for active agents.

Example 6

Limonene containing colloidal particle assembly: colloidal particle assembly containing

Na₂C0₃ holds limonene longer than that without.

[0085] Process/Procedure: Two parallel experiments were performed. In a first experiment colloidal particle assembly containing limonene as active agent and NaiCCh were prepared from PLA microgel. In second experiment colloidal particle assembly containing limonene as active agent but without NaiCCh were prepared from PLA microgel. For each experiments, around 20 mg of colloidal particle assembly was inserted into Slide-A-LyzerTM Dialysis cassette (ThermoFisher) together with 1.5 ml ethanol. The locked cassette was then placed inside a bag containing 20ml ethanol. [0086] Discussion/Results: Ethanol helps to disrupt the colloidal particle assembly and limonene contained leaks out of cassette’s membrane. Leaked limonene was detected using UV-vis spectroscopy. The absorbance in the 220-240 nm increased with time, showing more limonene migrated from inside cassette to the bag. The absorbance peaked at about 223 nm in the beginning of the test, and shifted to about 239nm after about 2h. Normalized absorbance peak (FIG. 7) shows, colloidal particle assembly containing Na2CCb holds limonene, the active agent, longer compared to colloidal particle assembly without Na2CCb

Claims

1. A composition comprising, a colloidal particle assembly having;

(a) a plurality of colloidal particles; and

(b) a salt component comprising at least one carbonic acid salt;

wherein each of the plurality of the colloidal particles has an average diameter ranging from about 0.05 microns to about 2.5 microns;

wherein the salt component is present at a concentration sufficient to stabilize the colloidal particle assembly ; and

wherein the colloidal particle assembly has an absolute value of surface zeta potential of at least 20 mV.

2. The composition of claim 1, wherein the colloidal particles are selected from the group consisting of microgel particles, nanogel particles, polymer particles, polymer brushes, surfactant molecules, metal oxide particles, lipid particles, block copolymers, cross- linked polymers, biopolymers, biomolecules, micellular/dendrimer structures, yolk/shell structures, core/shell structures, pomegranate structures, hollow structures/nanomaterials, functionalized microstructures, or functionalized nanostructures, and combinations thereof.

3. The composition of claim 1, wherein the colloidal particles are at least one of microgel particles and nanogel particles.

4. The composition of claim 1 or 3, wherein the colloidal particles comprise, a gel phase having at least one polymer network selected from hydrophilic polymer network, hydrophobic polymer network, amphiphilic polymer network, amphiphobic polymer network, lipophilic polymer network, lipophobic polymer network, and combination thereof.

5. The composition of Claim 1, wherein the colloidal particle assembly has an absolute value of surface zeta potential ranging from about 25 mV to about 70 mV.

6. The composition of Claim 1, wherein each of the plurality of colloidal particles, has an average diameter ranging from about 0.05 microns to about 0.9 microns.

7. The composition of Claim 1, wherein the colloidal particle assembly further comprises at least one void space enclosed by at least three colloidal particles.

8. The composition of Claim 1, wherein the colloidal particle assembly has a core comprising a void space and the plurality of colloidal particles form a shell around the core.

9. The composition of Claim 1, wherein the colloidal particles comprise a polymeric material selected from the group consisting of polylactic acids, polylactic-coglycolic acid copolymers, poly(N-isopropylacrylamides), N-isopropylacrylamide-(N,N'- methylenebisacrylamide) copolymers, N-isopropylacrylamide-(N,N'- methylenebisacrylamide)-allyl amine copolymers, polyethylene glycols, polyvinyl alcohol, hydroxylated poly(meth)acrylates, ethylene-vinyl acetate copolymers, 2- hydroxyethyl methacrylates, polymaleic acid ethers, octyl vinyl ethers, polyurethanes, poly(acrylic acids), poly(stearyl acrylates), poly(acrylamides), polyolefins, alginates, chitosans, polyesters, polyethylene terephthalates, polybutylene terephthalates, poly (butyl succinates), polyester copolymers, glycerol copolymers, polycarbonates, polyetherimides, polyphenyloxides, polystyrenes, poly(methyl methacrylates), and combinations thereof.

10. The composition of Claim 1, wherein the carbonic acid salt is selected from the group consisting of NaHCCb, Na₂CC>3, K2CO3, KHCO3, MgCCb, CaCCb, NH4HCO₃, (NH₄)₂C0₃, bis(tetramethylammonium) carbonates, and combinations thereof.

11. The composition of Claim 1, wherein the salt component is present at a concentration ranging from about 0.01 mM to about 500 mM.

12. The composition of Claim 1, wherein the salt component is present at a concentration ranging from about 0.1 mM to about 5 mM.

13. The composition of Claim 1, wherein the void space comprises at least one active agent.

14. The composition of Claim 13, wherein the active agent is selected from the group consisting of chemical agent, biological agent, oil, ionic liquid, suspension, polymer, and combinations thereof.

15. A method of preparing a colloidal particle assembly, wherein the method comprises:

(a) forming an aqueous salt solution comprising a carbonic acid salt component;

(b) orming a surfactant-salt solution comprising a surfactant and the aqueous salt solution; and

(c) adding a colloidal particle dispersion, comprising a plurality of colloidal particles and a dispersing solvent, to the surfactant- salt solution, and forming the colloidal particle assembly, the adding step optionally performed by stirring the colloidal particle dispersion into the surfactant-salt solution.

16. The method of Claim 15, wherein the colloidal particle assembly is produced at a yield ranging from about 40% to about 80%.

17. The method of Claim 15, wherein the surfactant is selected from the group consisting of surface active agents, (poly)alkylene oxides, (poly)alkylene glycols, emulsifiers, sodium dodecyl sulfates, tocopheryl polyethylene glycol succinates and combinations thereof.

18. The method of Claim 15, wherein the dispersing solvent is at least one of ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, methyl acetate, methylene chloride, isopropyl acetate, isobutyl acetate, chloroform, dichloroethane and any combinations thereof.

19. The method of Claim 15, wherein the plurality of colloidal particles is present at a concentration ranging from more than 0 to less than about 100 mg/ml, in the colloidal particle dispersion.

20. A composition comprising, a colloidal particle assembly having:

(a) a plurality of colloidal particles comprising a polymeric material selected from the group consisting of poly lactic acids, polylactic-coglycolic acid copolymers, poly(N-isopropylacrylamides), N-isopropylacrylamide-(N,N'- methylenebisacrylamide) copolymers, N-isopropylacrylamide-(N,N'- methylenebisacrylamide)-allyl amine copolymers, polyethylene glycols, polyvinyl alcohol, hydroxylated poly(meth)acrylates, ethylene-vinyl acetate copolymers, 2-hydroxyethyl methacrylates, polymaleic acid ethers, octyl vinyl ethers, polyurethanes, poly(acrylic acids), poly(stearyl acrylates), poly(acrylamides), polyolefins, alginates, chitosans, polyesters, polyethylene terephthalates, polybutylene terephthalates, poly (butyl succinates), polyester copolymers, glycerol copolymers, polycarbonates, polyetherimides, polyphenyloxides, polystyrenes, poly(methyl methacrylates), and combinations thereof;

(b) a salt component comprising at least one carbonic acid salt component is selected from the group consisting of NaHCCb, Na2CCb, K2CO3, KHCCb, MgCCb, CaCCb, NH4HCO3, (NTri^CCb, bis(tetramethylammonium) carbonates, and combinations thereof, wherein the salt component is present at a concentration ranging from about 0.01 mM to about 500 mM; and

(c) at least one active agent selected from the group consisting of chemical agent, biological agent, oils, ionic liquid, suspension, polymer, and combinations thereof;

wherein each of the plurality of colloidal particles, has an average diameter ranging from about 0.05 microns to about 0.9 microns;

wherein the colloidal particle assembly has an absolute value of surface zeta potential of at least 20 mV; and

wherein the colloidal particle assembly comprises at least one void space enclosed by at least three colloidal particles.