Tunable, photodegradable polymers for cargo delivery in cosmetics

Abstract

A synthesis and modification of cyclodextrin metal organic frameworks (CD-MOFs) is provided, wherein the modified CD-MOFs is loadable with pharmaceuticals or other active ingredients to form CD-MOF-active ingredient complexes. The active ingredients in the CD-MOF-active ingredient complexes can be delivered slowly due to the retention properties of the modified CD-MOFs and can be released by UV radiation according to a release profile, allowing external delivery of macromolecules to the skin cells through tropical application of CD-MOF-active ingredient formulation and related cosmetic products.

Description

[0001] TUNABLE, PHOTODEGRAD ABLE POLYMERS FOR CARGO DELIVERY IN COSMETICS

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 666,246 filed on July 1, 2024, the content of which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND OF THE INVENTION

[0005] Cyclodextrin metal organic frameworks may be comprised of alpha cyclodextrins, beta cyclodextrins, and / or gamma cyclodextrins. These metal organic frameworks may be porous and capable of small molecule storage, allowing them to perform polymer-based cargo release / delivery in therapeutic and cosmetic products to release active ingredients into the body.

[0006] FIELD OF THE INVENTION

[0007] Embodiments of the present invention relate to synthesis and modification of cyclodextrin metal organic frameworks (CD-MOFs). Further embodiments of the present invention relate to loading the modified CD-MOFs with pharmaceuticals or other active ingredients to form CD- MOF-active ingredient complexes. Additional embodiments include delivery of the active ingredient from the modified cyclodextrins. In some embodiments, the delivery of the active ingredient is prolonged due to retention by the modified CD-MOFs. In further embodiments, the modified CD-MOFs may be opened by UV radiation to allow release of the active ingredient according to a release profile. By way of example, some embodiments of the present invention relate to external delivery of macromolecules to the skin cells through tropical application of CD- MOF-active ingredient formulations and related cosmetic products.

[0008] BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Various aspects of the present invention are illustrated by way of example, and not by way of limitation, in the accompanying drawings, wherein: Fig. 1 depicts an illustration summarizing modification, loading, and release of active ingredients using the CD-MOF in accordance with the principles of the present invention;

[0010] Fig. 2 depicts an illustrated diagram of rapid y-Cyclodextrin-based CD MOF synthesis and characterization thereof in accordance with the principles of the present invention;

[0011] Fig. 3 depicts a drawing of the chemical structure of an example functionalizing agent for modification of the CD-MOF in accordance with the principles of the present invention;

[0012] Fig. 4 depicts a drawing of synthesis of an example functionalizing agent in accordance with the principles of the present invention;

[0013] Fig. 5A depicts a drawing of the binding of a functionalizing agent with the CD-MOF to form the functionalized CD-MOF in accordance with the principles of the present invention;

[0014] Fig. 5B depicts a drawing of the binding of the functionalizing agent of Fig. 3 as the functionalizing agent with the CD-MOF to form the functionalized CD-MOF in accordance with the principles of the present invention;

[0015] Fig. 6 depicts an illustration of the characterization of a functionalized CD-MOF by FTIR in accordance with the principles of the present invention;

[0016] Fig. 7 depicts an illustration of the characterization of gamma cyclodextrin and functionalizing agent by NMR in accordance with the principles of the present invention;

[0017] Fig. 8 depicts an illustration of the characterization of the functionalized CD MOF of Fig. 6 in accordance with the principles of the present invention;

[0018] Fig. 9 depicts a graph comparison of the PXRD of CD MOF and functionalized CD MOF in accordance with the principles of the present invention;

[0019] Fig. 10A depicts an illustration of the dimerization of the functionalizing agent of Fig. 3 in accordance with the principles of the present invention;

[0020] Fig. 10B depicts an illustration of the dimerization of Epoxy Coumarin (7- Glycidyloxy coumarin) in accordance with the principles of the present invention; Fig. 1 1 depicts illustration and graphs identifying the cross-linking of the functionalizing agent of Fig. 3 in accordance with the principles of the present invention;

[0021] Fig. 12 depicts illustration and graphs indicating the cross-linking of functionalized CD MOFs in accordance with the principles of the present invention;

[0022] Fig. 13 depicts graphs indicating the cross-linking of functionalized CD MOFs in accordance with the principles of the present invention.

[0023] Fig. 14 depicts an illustration of loading of active ingredient into the cross-linked CD MOFs and release under UV exposure and the active ingredient release profile in accordance with the principles of the present invention;

[0024] Fig. 15 depicts a retinol release profile from the cross-linked y-CD MOFs active ingredient complexes under UV exposure in accordance with the principles of the present invention;

[0025] Fig. 16 depicts the drug release profile of retinol from the cross-linked y-CD MOFs active ingredient complexes under 254nm and no light according to the procedure of Fig. 14 with 5.9% loading efficiency in accordance with the principles of the present invention; and

[0026] Fig. 17 depicts the drug release profile of salicylic acid from the cross-linked y-CD MOFs active ingredient complexes in direct sunlight and no light according to the procedure of Fig. 14 with 9.9% loading efficiency in accordance with the principles of the present invention.

[0027] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The detailed description set forth below in connection with the appended drawings is intended as a description of various embodiments of the invention and is not intended to represent the only embodiments in which the invention may be practiced. The detailed description includes specific details for the purpose of providing a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without these specific details. In some instances, well known structures and components are shown in block diagram form in order to avoid obscuring the concepts of the invention. Aspects of the present invention are described herein with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems) and structures according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented as one or more steps of a method. In some steps, the method may be performed by a computer, such as, when measuring Fourier-transform spectroscopy (FT-IR), Nuclear Magnetic Resonance spectroscopy (NMR), powder X-ray diffraction spectroscopy (PXRD), etc. These computer program instructions may be provided to a processor of a controller, a general purpose computer, a special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which executed via the processor of the controller or other programmable data processing apparatus, create means for implementing the functions / acts specified in the flowchart and / or block diagram block or blocks. The output may be displayed in a graph on a scale that would be interpretable by one having ordinary skill in the art.

[0029] The following description is provided to enable any person skilled in the art to practice the various embodiments described herein. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments. Thus, the claims are not intended to be limited to the embodiments shown herein, but are to be accorded the full scope consistent with each claim’s language, wherein reference to an element in the singular is not intended to mean “one and only one” unless specifically so stated, but rather “one or more.” Similarly, references to an element in the singular in the description mean “one or more” unless specifically stated otherwise. All structural and functional equivalents to the elements of the various embodiments described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims. No claim element is to be construed under the provisions of 35 U.S.C. §112, sixth paragraph, unless the element is expressly recited using the phrase “means for” or, in the case of a method claim, the element is recited using the phrase “step for.” The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. Aspects of the invention were chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.

[0030] With respect to the present application, “congener” means a chemical constituent of the same kind or category, having similar chemical properties, binding affinity, and functionality, and minimal structural changes, relative to the referenced chemical compound.

[0031] With respect to the present application, Rl, R2, and R3 are each independently-H, halogen, alkyl, -OH, alkenyl, -O-alkyl, a fused aryl or fused heteroaryl, which are each substituted or unsubstituted.

[0032] With respect to the present application, “about” or “approximately” means within plus or minus one at the last reported digit. For example, about 1.00 means 1.00 ± 0.01 unit.

[0033] With respect to the present application, “around” used in conjunction with a numeral measurement means within plus or minus one unit. For example, around 50% means 49% - 51%. For example, around 11.01 units means 10.01 - 12.01.

[0034] With respect to the present description “and” and “or” shall be construed as conjunctively or disjunctively, whichever provides the broadest disclosure in each instance of the use of “and” or “or.”

[0035] Embodiments of the invention relate to synthesis of cyclodextrin metal organic frameworks (CD MOFs), modification of the CD MOFs, preparation of formulations comprising CD MOF-active ingredient complexes, and delivery of active ingredients thereby. Modification of the CD MOFs may include functionalization of the CD MOFs and / or cross-linking of the CD MOFs. More particularly, embodiments of the invention relate to external delivery of macromolecules to skin cells through topical application and related cosmetic products through CD MOFs.

[0036] Further embodiments of the present invention were shown through a direct and fast synthesis of Cyclodextrin based metal organic framework (CD MOF) achieved using rapid precipitation method. Synthesized CD MOF was characterized by Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR) techniques. Functionalizing agents were synthesized. Under solvothermal conditions, functionalizing agent and CD MOF were reacted to form the functionalized CD MOF. The free hydroxyl groups of Cyclodextrin reacted with benzophenone-based photocrosslinkers, diazirine-based photocrosslinkers, maleimide-based photocrosslinkers, anthracene-based photocrosslinkers, etc. Functionalized CD MOFs were then characterized using PXRD, FTIR and NMR techniques. Different wavelengths of ultraviolet light were irradiated on functionalized CD MOF to dimerize the coumarin ends to form cross-links between the CD MOFs. The cross-linked CD MOFs were characterized by spectroscopy. Furthermore, retinol was loaded over an extended period into the cross-linked CDMOF as the active ingredient. The release profde under ultraviolet light was then obtained.

[0037] Each photocrosslinker (or crosslinkers for short) may offer different advantages in terms of activation wavelength, reactivity, and biocompatibility. The crosslinkers may have the following properties: 1) photoresponsiveness. The photocrosslinkers should be activatable by a specific wavelength of light and release the active ingredients at a predictable rate upon cleaving the cross linkers at a different specific wavelength of light. 2) Stable under storage conditions and in the absence of light to prevent premature crosslinking or degradation. 3) Adequate dispersibility in final formulation. 4) The photocrosslinker and the light activation process should not compromise the stability and activity of the encapsulated active ingredients.

[0038] Improving the management of polymer-based cargo release / delivery can reduce side effects and better utilize the dosing of expensive therapeutics or cosmetics. Embodiments of the present invention include an ultraviolet-light-activated CD-MOF (cyclodextrin-based metal organic framework) delivery system. This CD-MOF may rely on different photochemical reactions to modify the MOFs and also to release active ingredients contained therein. The design, synthesis, characterization, and release study are described herein. Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose units joined by glycosidic bonds. CDs were produced from starch by a combination of commonly used enzymes. CDs of 6, 7, and 8 a-d-glucose residues are called a-, P-, and y-CD, respectively. CDs possess a hydrophilic exterior and a hydrophobic interior. The latter affords the ability to form inclusion complexes with hydrophobic chemicals making CDs useful in the food, cosmetic, pharmaceutical, and plastic industries as emulsifiers, antioxidants, stabilizing agents, and traps for volatiles.

[0039] A typical process for cyclodextrin production involves the initial breakdown of starch by a-amylase to generate shorter oligosaccharides, followed by the action of Cyclodextrin Glycosyltransferase to convert these oligosaccharides into cyclodextrins. The resulting mixture may contain a combination of a-cyclodextrin, P-cyclodextrin, and y-cyclodextrin, depending on the specific action of the Cyclodextrin Glycosyltransferase used and the conditions of the reaction.

[0040] Metal-organic frameworks (MOFs) are a class of porous polymers consisting of metal clusters. They were fabricated by linking inorganic and organic units by strong non-covalent bonds. Combination of different organic molecules and metal clusters dictate different structures of MOFs and hence properties of the MOFs. Over the last ten years, MOFs have gained significant attention due to their unique properties, such as extended surface area, environmentally friendly, enhanced pore volume, hierarchical arrangements, and adjustable properties. These characteristics have resulted in their applications in many directions including drug delivery, gas storage, catalysis, separation, food package, sensors, and electrical gels.

[0041] In the following description, active ingredients include pharmaceuticals, nutrients, vitamins, neutraceuticals, and derivatives and congeners thereof. Example topical cosmetic active ingredients can be an alpha or beta hydroxy acid, anti-wrinkle agent, anti-aging agent, skin-lightening agent, anti-dark circle agent, peptide, amino acid, plant extracts, vitamin, antioxidant, anti-inflammatory agent, humectant, keratolytic agent, antibacterial agent, antifungal agent, a sunscreen agent, of which may include but not limited to niacinamide and resveratrol, glycolic acid, lactic acid, salicylic acid, gluconolactone, lacftobionic acid, citric acid, hyaluronic acid, sodium hyaluronate, retinol, retinyl palmitate, panthenol, allantoin, ceramide, caffeine, ubiquinone, kojic acid, hydroquinone, ascorbic acid, ascorbyl glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, acetyl hexapeptide-8, acetyl hexapeptide-3, palmitoyl tripeptide-38, palmitoyl tripeptide-1, palmitoyl tripeptide-5, hydrolyzed rice protein, bakuchiol, camellia sinensis leaf extract, centella asiatica extract, citrus aurantium dulcis fruit extract, citrus limon fruit extract, ferulic acid, ginkgo biloba leaf extract, glyceryl linoleate, glyceryl linolenate, lyceum barbarum fruit extract, oat amino acids, tocopherol, tocopheryl acetate, vitis vinifera leaf extract, lipoic acid, folic acid, coffea arabica seed extract, and cucumis sativus fruit extract.

[0042] CD MOFs can also encapsulate fragrance ingredients for perfume and fragrance cosmetic applications. Instead of releasing ingredients into the skin below, the encapsulated ingredients inside CD MOFs may be volatile and released into the air above. CD MOFs may encapsulate essential oils, fragrance oils, and / or specific aroma compounds such as esters, linear terpenes, cyclic terpenes, and aromatic. Examples of esters include geranyl acetate (rose), methyl butyrate (apple), ethyl butyrate (orange), and benzyl acetate (strawberries). Examples of linear terpenes include nerol (neroli), citral (lemongrass), linalool (lavendar), and ocimene (mango). Examples of cyclic terpenes include limonene (orange), camphor (campor laurel), menthol jasmone (jasmine), and eucalyptol (eucalyptus). Examples of aromatic include eugenol (clove), benzaldehyde (almond), vanillin (vanilla), and thymol (thyme).

[0043] Fig. 1 depicts an illustration summarizing modification, including functionalization and cross-linking of CD MOFs 14, loading of an active ingredient 12 to form an active ingredient- CD MOF complex 20, and release of the active ingredient 12 using the CD-MOF 14 in accordance with the principles of the present invention. The crosslinked CD MOF 18 may be photodegradable for delivery of the active ingredient 12.

[0044] In the first frame of the process, a CD MOF 14 is illustrated in structured arrangement. In this illustration, y-CD is shown as preferred CD 2 and potassium is shown as preferred alkali metal cations 4. However, any alkali metal can be used. Alternatively, embodiments of the present invention include a-, 0-, and / or y-CD as CD 2. Embodiments of the present invention may also include modified CDs 2, as will be later described.

[0045] Each CD MOF 14 is comprised of cyclodextrin sugar molecules 2 bound together in rings of various sizes, called glucopyranosides 10. Glucopyranosides 10 are glucose molecules that exist in the pyranose (six-membered) ring configuration. Six, seven, or eight glucopyranosides 10 bind with each other to form a-, 0-, and y-cyclodextrin 2, respectively. CD-MOFs 14 are supramolecules, they are extended frameworks composed of multiple cyclodextrin molecules 2 and metal ions 4 connected through coordination bonds. For example, y-CD-MOF 14 may form a cubic packed y-cyclodextrin superstructure.

[0046] The resulting interaction between units results in arrangement of CD MOFs 14 such that pores and channels may be formed. A spherical pore 13 contained within the y-CD cubes (y-CD) may have a diameter of 1-2 nm and the unit diameter may be around 15-18 nm. In some embodiments, the spherical pore 13 may have a diameter of 1.7 nm. Smaller triangular pores with diameters of about 0.4 nm may be present along the plane. These pores sizes may allow active ingredients 12, such as retinol 38, to pass into and release quickly (e.g., over the course of a few hours when the active ingredient 12 is retinol 38). However, the cross-linked y-CD-MOF 18 may be slightly larger in unit diameter than the y-CD-MOF 14, such as 16-19 nm, and having a spherical pore size similar to the y-CD-MOF.

[0047] Further examples include a-CD MOF, the unit size is around 10-15 nm, the pore size may be 0.5-1.5 nm. The size of P-CD MOF is between a-CD MOF and y-CD MOF.

[0048] A direct and fast synthesis of Cyclodextrin based metal organic framework (CD MOF) 14 using rapid precipitation method was described. This metal-organic framework (MOF) is based upon cyclodextrin (CD) tori 2 that are coordinated to alkali metal cations 4 (e.g., K+ ions) on both their primary and secondary faces in an alternating manner to form a porous framework. This porous frameworks with extended structures displaying robust crystallinity, permanent porosity, and excellent biocompatibility. As a result of the ability of their extended porous frameworks to absorb active ingredients, CD-MOFs 14 have potential applications in the skin care industry. The system performs a programmed drug release and deep penetration of the active ingredients into skin.

[0049] Table 1. Parameters of CD-MOFs Different types of cyclodextrins 2 were utilized in this process, each offering unique properties and functionalities, including a-Cyclodextrin, P-Cyclodextrin, y-Cyclodextrin, and modified Cyclodextrins. a-CD consists of six glucose units arranged in a cone-shaped structure. Its relatively small cavity size makes it suitable for encapsulating small guest molecules. 0-CD contains seven glucose units and has a larger cavity size compared to a-CD. This increased cavity size allows -CD to encapsulate larger guest molecules or accommodate multiple smaller molecules simultaneously. y-CD consists of eight glucose units and has an even larger cavity size than P-CD. It is particularly suitable for encapsulating larger guest molecules or bulky organic compounds. Various modified cyclodextrins, such as methylated, hydroxypropylated, or sulfonated cyclodextrins, were also used, to tailor the properties of CD MOFs 14. For example, commercially available, Randomly Methylated P-Cyclodextrin (RAMEB): CAS Number: 51166- 71-3, Hydroxypropyl-y-Cyclodextrin (HP-y-CD): CAS Number: 128446-34-4, Sulfonated P- Cyclodextrin (S-P-CD): CAS Number: 182410-00-0, were used.

[0050] These modifications can alter the solubility, stability, release time, and host-guest interactions of cyclodextrins 2, leading to enhanced performance in specific applications. Examples of modified cyclodextrins 2 used include methylated P-cyclodextrin, 2,6-di-O-methyl- P-cyclodextrin, hydroxypropyl-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, sulfobutylether-P- cyclodextrin, carboxymethyl-y-cyclodextrin, aminoethylated cyclodextrin, etc. Synthesized CD MOF 14 was successfully characterized by Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR) techniques.

[0051] Example modifications include the following.

[0052] Methyl-B-cyclodextrin:

[0053] Methylation involves the addition of methyl groups (-CH3) to the hydroxyl groups on the cyclodextrin ring. The introduction of methyl groups may disrupt the hydrogen bonding network of native CDs, reducing crystallinity and increasing hydrophobicity. Methylated CDs, such as methyl-P-cyclodextrin (M-P-CD), exhibit significantly enhanced water stability compared to their native counterparts. The addition of methyl groups can shield the hydroxyl groups from oxidation and hydrolysis, enhancing chemical stability. Also methylated CDs typically release encapsulated guests more quickly in water, making them suitable for applications requiring rapid delivery. The methylated CD is suitable for oil-based formula.

[0054] Hydroxypropyl-B-cyclodextrin, hydroxypropyl-Y-cyclodextrin:

[0055] Hydroxypropylation involves attaching hydroxypropyl groups (-CH2CH(OH)CH3) to the CD ring. These groups increase the hydrophilicity of CDs by introducing more hydroxyl groups and disrupting crystalline structures. They also provide steric protection to the CD ring, reducing susceptibility to oxidation and hydrolysis. This kind of modified CD is suitable for water-based formula in application.

[0056] Sulfobutyl ether-B-cyclodextrin:

[0057] Sulfonation involves the addition of sulfonic acid groups (-S03H) or sulfoalkyl groups to the CD ring. Sulfonated CDs, such as sulfobutyl ether-P-cyclodextrin (SBE- -CD), exhibit very high solubility in water and can dissolve in a wide range of pH conditions. The strong hydrophilicity and ionic nature of sulfonic acid groups can control the release rate by influencing the interaction between the CD and the encapsulated guest. SBE-P-CDs often provide a more sustained release compared to methylated or hydroxypropylated CDs, especially in ionic or buffered environments.

[0058] By selecting the appropriate modification, cyclodextrins can be tailored to meet the specific needs of various industrial, pharmaceutical, and environmental applications.

[0059] In the second depiction in Fig. 1, y-CD MOF 14 may be modified by binding with a functionalizing agent 6, such as Epoxy Coumarin 9 to form a functionalized MOF 16. The bound Epoxy Coumarin groups 9 may then be dimerized with Epoxy Coumarin groups 9 of neighboring y-CD MOFs 14 by UV radiation until dimerization occurs. Dimerization may shorten the distance between neighboring y-CDs 2 such that the pore size of the cross-linked MOFs 18 may be slightly decreased. Furthermore, the photocrosslinkers (or crosslinkers for short) 8 may obstruct movement of active ingredient 12 into and out of the CD-MOF pores 13. For example, the pore size of the cross-linked CD MOFs 18 may be similar to those corresponding to table 1. For instance, this size and obstruction by crosslinkers 8 only allows active ingredient 12, such as retinol 38, to penetrate into the pore 13 very slowly. By way of example, adequate loading may require three days. Due to the pore size, the retinol 38 or other active ingredientl2 may navigate out of the pores 13 of the cross-linked CD MOFs 18 not necessarily release the active ingredient 12. After activation by decoupling the crosslinkers 8, active ingredient 12 may be released slowly, such as from 3 hours to 7 days. For example, the loaded, cross-linked CD MOF 20 may be caused to release active ingredient 12 due to exposure to UV light. For example, UV light at 254 nm may be notable in the gradual release of cross-linking between functionalized CD MOFs 16 and therefore release of the active ingredient 12.

[0060] After CD MOF 14 was synthesized, hydroxy groups on the surface of CD MOF 14 were then reacted with a functionalizing agent 6. The functionalizing agent 6 in the delivery system is of essential importance because it impacts the chemical property, stability, and the release of the active ingredients 12. On one end of the functionalizing agent 12, the crosslinker 8 should be able to react with hydroxy groups on the surface of CD MOF 14 and on the other end an alkene can be used for photo chemical reaction process. The process makes the whole delivery stable in water and release active ingredients 12 under certain UV condition. The light-triggered crosslinker 8 may be notable due to its spatiotemporal controllability and attractive prospects of improving the overall pharmacokinetics of the delivery system. Different kinds of photocrosslinkers that contain photoactive groups capable of forming covalent bonds upon exposure to light were synthesized, including benzophenone-based photocrosslinkers, diazirine- based photocrosslinkers, maleimide-based photocrosslinkers, anthracene-based photocrosslinkers.

[0061] Table 2. Classes of photocrosslinkers The synthesis of one of the examples of the functionalizing agents 6 was illustrated. 7- Glycidyloxycoumarin (Epoxy Coumarin) 9 was synthesized using previously reported condition. The epoxide functional group was able to react with free hydroxyl groups of CD MOF 14. The successful conjugation enables CD MOF 14 to store and release active ingredients 12 through the UV controlled and reversible dimerization of chemical bond between two coumarin groups 6. The dimerization of Epoxy Coumarin 9 is illustrated with respect to Fig. 10B.

[0062] The functionalized CD MOF 16 was characterized using PXRD, FTIR and NMR techniques.

[0063] Lastly, the 370 nm ultraviolet light was irradiated on functionalized CD MOF 16 to dimerize the coumarin ends 8 (cross-linking) and characterized the cross-linked CD MOF 18 with spectroscopy. Active ingredient 12 such as retinol 38 was loaded to the cross-linked CDMOF 18 as the active ingredient and studied the release profile under 254 nm ultraviolet light. In accordance with principles of the present invention, the experimental evidence described herein shows that coumarin dimerized CD MOF 18 is a highly promising system for realizing photochemical control of active ingredients release.

[0064] Fig. 2 depicts an illustrated diagram of rapid 'y-Cyclodextrin-based CD MOF 14 synthesis and characterization thereof in accordance with the principles of the present invention.

[0065] Direct and fast synthesis of y-Cyclodextrin-based metal organic framework (CD MOF) 14 was achieved using a rapid precipitation method 22. A solution was prepared of 6.50 g (5 mmol) y-Cyclodextrin 2 with 2.25 g (40 mmol) KOH 3 in 100 ml DI water 5 at room temperature. 75 ml methanol 7 was added dropwise. Colorless crystals were formed by precipitation and filtered using a filter paper and vacuum filtration 3 hours after addition of methanol for full crystallization as illustrated in 24. The resulting solid was washed four times by 30 ml methanol 7 each time. The material was then dried by super critical CO2 as illustrated in 26 and characterized by Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR) techniques, as shown in Fig. 2. The process described herein has the benefits of small particle size, fast synthesis, scalability and low solvent usage. Fig. 3 depicts the chemical structure of an example functionalizing agent for modification of the CD-MOF in accordance with the principles of the present invention. The functionalizing agent may be bound to the CD MOF 14 to form a functionalized CD MOF 16.

[0066] The synthesis of benzophenone-based photocrosslinkers generally involves several key steps, including the preparation of the benzophenone core, introduction of functional groups, and subsequent modification to create the crosslinking moieties. Friedel-Crafts acylation reaction was used to synthesize benzophenone-based photocrosslinkers. This involves the acylation of benzene with benzoyl chloride in the presence of a Lewis acid catalyst, such as aluminum chloride (A1C13). Benzophenone was then further functionalized by reacting with hydroxyl groups to allow for subsequent derivatization.

[0067] The synthesis of diazirine-based photocrosslinkers involves several steps, including the preparation of the diazirine core and subsequent functionalization to introduce photocrosslinking groups. Firstly, react phthalimide with an amine under basic conditions to form the corresponding phthalimide imine. Then, phthalimide imine was reacted with diazo compounds (such as diazomethane or diazomethane derivatives) leads to the formation of diazirines via elimination of nitrogen gas. Once the diazirine core is obtained, it can be functionalized with groups that facilitate photocrosslinking upon UV irradiation.

[0068] For maleimide-based photocrosslinkers, maleic anhydride underwent a Diels-Alder reaction with an appropriate diene to form a maleimide derivative. After obtaining the maleimide core, it can be functionalized with groups that facilitate photocrosslinking upon exposure to UV light.

[0069] Anthracene-based photocrosslinkers, as the anthracene-based functionalizing agent depicted in Fig. 3, may be used in materials science and polymer chemistry due to anthracene's ability to undergo photochemical reactions, particularly [2+2] cycloaddition reactions upon UV irradiation. One of the synthetic methods of anthracene-based photocrosslinkers is described as with respect to Fig. 4. Epoxy group of functionalizing agent will react with CD MOF 14 to give a functionalized CD MOF 16, which will be then used for crosslinking. Rl, R2, and R3 are each independently-H, halogen, alkyl, -OH, alkenyl, -O-alkyl, a fused aryl or fused heteroaryl, which are each substituted or un substituted.

[0070] Further commericially available examples of photocrosslinkers include: Benzophenone-Based Photocrosslinkers: Benzophenone Methacrylate (BPM) and 4- Benzoylbenzoic Acid; Diazirine-Based Photocrosslinkers: Sulfo-SANPAH (N-sulfosuccinimidyl 6-(4'-azido-2'-nitrophenylamino) hexanoate) and Diazirine-PEG-NHS; Maleimide-Based Photocrosslinkers: Maleimide-PEG-Biotin, and 4-Maleimidobenzophenone.

[0071] Fig. 4 depicts the synthesis of an example functionalizing agent 6 in accordance with the principles of the present invention. Synthesis of the functionalizing agent, 7- Glycidyloxycoumarin 9, was performed as follows. A solution of 18.0 g umbelliferone 28 in 260 ml ethanol 30 was prepared. 6.85 g KOH 3 was added to the solution. The mixture was stirred at 79 °C for 20 minutes. Then, 87.2 ml epichlorohydrin 32 was added to the solution dropwise. The reaction mixture was then stirred at reflux condition for 2.5 hours. The reaction mixture was then cooled to room temperature and concentrated by rotary evaporator to dryness. 250 ml dichloromethane was then added, followed by washing using 200 ml water 3 times. The organic layer was dried over anhydrous MgSO4. The solid was filtered and the solution contained product was concentrated and recrystallized in warm ethanol 30. The product was then filtered and dried under vacuum. The product was characterized by 1H NMR.

[0072] Fig. 5A depicts a drawing of the binding of a functionalizing agent 6 with the CD-MOF 14 to form the functionalized CD-MOF 16 in accordance with the principles of the present invention.

[0073] Fig. 5B depicts a drawing of the binding of the functionalizing agent 6 of Fig. 3 as the functionalizing agent 6 with the CD-MOF 14 to form the functionalized CD-MOF 16 in accordance with the principles of the present invention. For example, the 7- Glycidyloxycoumarin 9 of Fig. 4 may be bound to the CD-MOF 14 as the functionalizing agent 6.

[0074] Fig. 6 depicts an illustration of the characterization of a functionalized CD-MOF 16 by FTIR in accordance with the principles of the present invention.

[0075] Synthesis of the functionalized CD MOF 16 was performed as follows. A solution of 16.2 g (74 mmol) 7-glycidyloxycoumarin 9 in 300 ml ethanol 30 was prepared. 10.0 g CD MOF 14 was added to the solution. The reaction mixture was stirred at 79 °C for 3 days while stirring. The reaction mixture was then cooled to room temperature, followed by washing and drying. The mixture was filtered first, the afforded solid was washed by 100 ml ethanol 30 3 times. Then the solid was dried in the vacuum oven at 50 °C for 3 days. The resulting orange solid was characterized by PXRD, IR, and NMR. The new peaks at 1706 cm-1 and 1610 cm-1 indicated successful functionalization of CD MOF 14.

[0076] Fig. 7 depicts an illustration of the characterization of y-cyclodextrin 2 and functionalizing agent 6 by NMR in accordance with the principles of the present invention. NMR results of y-cyclodextrin 2 are provided on the left and the functionalizing agent 6 of Fig. 3 is provided on the right. The ratio between the integrations of anomeric hydrogen of y-cyclodextrin (at 4.9 ppm) (8 protons per cyclodextrin unit) and P-hydrogen of coumarin (at 8.1 ppm) can be used to quantify the functionalization.

[0077] Fig. 8 depicts an illustration of the characterization of the functionalized CD MOF 16 of Fig. 6 in accordance with the principles of the present invention. According to the result of NMR of functionalized CD-MOF 16, nearly 1.24 functionalizing units was coupled to each y- Cyclodextrin molecule 2.

[0078] Fig. 9 depicts a graph comparison of the PXRD of CD MOF 14 and functionalized CD MOF 16 in accordance with the principles of the present invention. The PXRD of CD MOF 14 is depicted as 34 and PXRD of the functionalized CD MOF 16 is depicted 36. Disappearance of major peak around 5.9° 20 after functionalization was observed. Disappearance of this peak indicates binding of the functionalization group 6 to the CD MOF 14. The disappearance of a peak in PXRD indicates binding or coordination of the functional group 6 to the CD MOF 14 because it reflects the chemical changes and interactions that occur during the functionalization process.

[0079] Fig. 10A depicts an illustration of the dimerization of the functionalizing agent 6 of Fig. 3 in accordance with the principles of the present invention. The dimerization depicted may occur while bound according to the depiction of Fig. 5B such that neighboring units become crosslinked as depicted in Fig. 1.

[0080] Fig. 10B depicts an illustration of the dimerization of Epoxy Coumarin (7- Glycidyloxycoumarin) 9 in accordance with the principles of the present invention. The dimerization depicted may occur while bound according to the depiction of Fig. 5B such that neighboring units become cross-linked as depicted in Fig. 1. Fig. 1 1 depicts illustration and graphs identifying the cross-linking of the functionalizing agent 6 of Fig. 3 in accordance with the principles of the present invention. Crosslinking of functionalizing agent 6 and characterization are evidenced by FTIR. The intensity of C=C bond of the coumarin 6 gradually decreases, whereas the intensity of C-C single bond is increasing. Intensity of C=C bond of the coumarin should decrease during the dimerization. As can be seen, the peaks for C=C bonds decreased at 12 hours, 40 hours, and 60 hours.

[0081] Fig. 12 depicts illustration and graphs indicating the cross-linking of functionalized CD MOFs 16 in accordance with the principles of the present invention.

[0082] The functionalized CD MOF 16 was evenly spread on a baking tray and radiated by 370 nm UV active LED for 3 days. The material was flipped every 24 hours. The product was collected after three days and characterized by FTIR, NMR, and PXRD. Intensity of C=C bond (1612 cm-1) of the coumarin 6 decreased indication successful dimerization.

[0083] Fig. 13 depicts graphs indicating the cross-linking of functionalized CD MOFs 16 in accordance with the principles of the present invention. NMR showed integration of the peak at 8.1 ppm decreased, indicating successful dimerization. PXRD does not show any difference after cross-linking.

[0084] Fig. 14 depicts an illustration of loading of active ingredient 12 into the cross-linked CD MOFs 18 and release under UV exposure and the active ingredient 12 release profile in accordance with the principles of the present invention.

[0085] The cross-linked CD MOFs 18 were added to a solution of Img / ml retinol 38 in ethanol 30 at 4 degrees Celsius for 36 hours. After this time, the retinol 38 was substantially loaded into the cross-linked CD MOFs 18 such that a resulting active ingredient-CD MOF 20 was formed. UV light 40 at 254 nm and 37 degrees Celsius was used to illustrate the release profile of retinol 38 from the retinol-CD MOFs 20 as the UV light 40 at 254 nm broke the bonds between crosslinkers 8. Aliquots were removed intermittently at various time points for testing the release of retinol 38. As 254 nm is a major component of outdoor sun exposure, a similar profile occurs when the solution is exposed to sun. Therefore, the retinol-CD MOF 20 was added to a sunscreen base for extended release of retinol 38 during sun exposure of the skin. Fig. 15 depicts a retinol 38 release profile from the cross-linked y-CD MOFs active ingredient complexes 20 under UV exposure in accordance with the principles of the present invention.

[0086] Retinol 38, a derivative of vitamin A, has been discovered to treat acne, reduce wrinkles and protect against conditions like psoriasis and ichthyosis. While retinol 38 is used as the primary active ingredient in many skin care formulations, its efficacy is often limited by a sensitivity to degrade and toxicity at high concentrations. The developed cross-linked CD MOF 18 is an appealing method to help overcome these issues.

[0087] Cross-linked CD MOF 18 was incubated in 1 mg / ml retinol 38 in ethanol solution 30 at 4°C. After 36 hours the reaction mixture was filtered, washed, and dried. The affording solid was then incubated at PBS pH 5 solution at 24 °C. The solution was radiated by 254 nm UV lamp. The aliquots of the solution were collected at various time points. Around 50% of retinol 38 was released within one hour and all the encapsulated retinol 38 was released after 4 hours.

[0088] Fig. 16 depicts the drug release profile of retinol 38 under 254 nm and no light according to the procedure of Fig. 14 with 5.9% loading efficiency in accordance with the principles of the present invention.

[0089] Fig. 17 depicts the drug release profile of salicylic acid 42 in direct sunlight and no light according to the procedure of Fig. 14 with 9.9% loading efficiency in accordance with the principles of the present invention.

[0090] 200 mg crosslinked CD MOF 18 was added to a solution of 200 ml / mg salicylic acid (SA) 42 in ethanol 30. The mixture was stirred at 25 °C for 36 hours. The mixture was then filtered and washed by 50 ml ethanol 30 2 times. The afforded solid was then dried under vacuum overnight at 50 °C.

[0091] 100 mg SA 42 loaded crosslinked CD MOF 18 was added to 10 ml PBS buffer in a round-bottom flask. The solution was first placed in dark for 24 hours and collected the sample for UV. No SA 42 release was observed. SA 42 loading efficiency was 9.9%.

[0092] Another mixture of the same solution was placed under 100-400 nm sunlight for 24 hours, samples were collected at different time point (30 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours). Release of salicylic acid 42 was observed. Incorporation Procedure for Activated Crosslinked CD MOF 20 in Topical Cream / Lotion / Oil / Serum Products

[0093] Incorporating the activated crosslinked CD MOF 20 into a topical product such as cream, lotion, oil, or serum using a homogenizer involves a systematic process to ensure homogeneity and stability. The procedure is as follows:

[0094] • Preparation: Measure and prepare the activated crosslinked CD MOF 20 at a concentration ranging from 0.001% to 15.0% of the final product.

[0095] • Initial Mixing: Slowly add the activated CD MOF 20 to the bulk cream, serum, or other topical base. Perform continuous stirring or mixing with a homogenizer set at 4000 to 15,000 RPM, maintaining a temperature range of 0 to 45°C. This step ensures the even distribution of the CD MOF 20 throughout the product.

[0096] • Homogenization: Continue homogenizing until uniformity is achieved, verifying that the CD MOF 20 is thoroughly incorporated into the product. This process may require periodic adjustments to mixing speed and duration to achieve optimal results.

[0097] • Cooling and Final Processing: If the product was heated during mixing, allow it to cool to room temperature. Transfer the homogenized product into clean, sterile containers.

[0098] • Packaging: Seal and label the containers appropriately, ensuring the product is ready for distribution or further testing.

[0099] By following these steps, the activated crosslinked CD MOF 20 can be effectively incorporated into a topical product, resulting in a stable and homogeneous formulation.

[0100] Unless otherwise specified herein, materials identified above have been purchased or are purchasable from Sigma Aldrich.

[0101] Although the invention has been discussed with reference to specific embodiments, it is apparent and should be understood that the concept can be otherwise embodied to achieve the advantages discussed. In this regard, the foregoing description of the systems and methods is presented for purposes of illustration and description.

[0102] Furthermore, the description is not intended to limit the invention to the form disclosed herein. Accordingly, variants and modifications consistent with the following teachings, skill, and knowledge of the relevant art, are within the scope of the present invention. The embodiments described herein are further intended to explain modes known for practicing the invention disclosed herewith and to enable others skilled in the art to utilize the invention in equivalent, or alternative embodiments and with various modifications considered necessary by the particular application(s) or use(s) of the present invention.

Claims

ClaimsWhat is claimed is:

1. An activated cross-linked cyclodextrin metal organic framework complex comprising: a plurality of cyclodextrin molecules; a functionalizing agent; a photocrosslinker; and an active ingredient.

2. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the plurality of cyclodextrin molecules is y-cyclodextrin.

3. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the plurality of cyclodextrin molecules is a-cyclodextrin.

4. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the plurality of cyclodextrin molecules is P-cyclodextrin.

5. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the functionalizing agent is epoxy coumarin.

6. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the photocrosslinker further comprises benzophenone-based photocrosslinkers, diazirine-based photocrosslinkers, maleimide-based photocrosslinkers, or anthracene-based photocrosslinkers.

7. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the active ingredient is retinol.

8. The activated cross-linked cyclodextrin metal organic framework complex of claim 1, wherein the active ingredient is salicylic acid.

9. A method of synthesizing an extended release activated cyclodextrin metal organic framework complex, comprising: synthesizing a cyclodextrin metal organic framework; modifying the cyclodextrin metal organic framework with a functionalizing agent to form a functionalized cyclodextrin metal organic framework; cross-linking the functionalized cycloedextrin metal organic framework with a first wavelength of UV light; and loading the cross-linked functionalized cyclodextrin metal organic framework with an active ingredient.

10. The method of claim 9, wherein the step of synthesizing a cyclodextrin metal organic framework further comprises synthesizing a gamma cyclodextrin metal organic framework using a rapid precipitation method.

11. The method of claim 9, wherein the step of modifying the cyclodextrin metal organic framework with a functionalizing agent to form a functionalized cyclodextrin metal organic framework further comprises binding the cyclodextrin metal organic framework with epoxy coumarin.

12. The method of claim 9, wherein the step of cross-linking the functionalized cycloedextrin metal organic framework with a first wavelength of UV light further comprises reacting the functionalized cyclodextrin metal organic framework with a photocrosslinker.

13. The method of claim 9, wherein the step of loading the cross-linked functionalized cyclodextrin metal organic framework with an active ingredient further comprises utilizing retinol or salicylic acid as the active ingredient.

14. The method of claim 9, further comprising: exposing the loaded cross-linked functionalized cyclodextrin metal organic framework to UV radiation to cause a release of the active ingredient.

15. An extended-release complex, comprising: a cyclodextrin metal organic framework that is bound to a functionalizing agent and cross-linked at the bound functionalizing agent to neighboring units of the cyclodextrin metal organic framework to form a cross-linked functionalized cyclodextrin metal organic framework; and an active ingredient within pores of the cross-linked functionalized cyclodextrin metal organic framework.

16. The extended-release complex of claim 15, wherein the cyclodextrin metal organic framework is gamma cyclodextrin.

17. The extended-release complex of claim 15, wherein the functionalizing agent is epoxy coumarin.

18. The extended-release complex of claim 15, the active ingredient is retinol or salicylic acid.

19. The extended release complex of claim 15, further comprising a photocrosslinker.

20. The extended release complex of claim 19, wherein the photocrosslinker comprises benzophenone-based photocrosslinkers, diazirine-based photocrosslinkers, maleimide-based photocrosslinkers, or anthracene-based photocrosslinkers.

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