Compositions comprising a dendrimer-retinoid complex and methods for making and using the same

Abstract

Compositions and pharmaceutical compositions including a dendrimer-retinoid complex, and methods for making and using the compositions are described herein. Methods of treating cancer, cardiovascular disease, cardiac failure, diabetes, Alzheimer's disease, Parkinson's disease and other brain diseases, fatty liver disease, obesity, cataracts, osteoporosis, muscle wasting, sleep disorders, acoustic trauma, inflammatory disease, psoriasis, arthritis, colitis, aging, viral disease, reproductive disease, and skin conditions or disorders including administering a therapeutically effective amount of the compositions to a subject in need are also provided. The compositions may be topically applied to skin or mucous membranes.

Description

Attorney Docket No. 892593-0003-WO01COMPOSITIONS COMPRISING A DENDRIMER-RETINOID COMPLEX AND METHODS FOR MAKING AND USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Patent Application No. 63 / 748,870, filed January 23, 2025, which is incorporated herein by reference in its entirety.FIELD

[0002] This disclosure relates to compositions and pharmaceutical compositions including a dendrimer-retinoid complex, and methods for making and using the compositions are described herein. The compositions may be topically applied to skin or mucous membranes.BACKGROUND

[0003] Retinoids generally have very low solubility in water. Retinol is a fat soluble molecule, and is practically insoluble in water (about 17 ng / mL). Pure retinol is sensitive to oxidization and is prepared and transported at low temperatures and oxygen free atmospheres. In spite of its great pharmacological potential, it remains a challenge to formulate retinol as a pharmacological agent due to its insolubility in water, poor stability, and poor pharmacokinetic properties.

[0004] Accordingly, there is a need for effective methods of formulating a retinoid to improve the aqueous solubility and stability of these hydrophobic compounds.SUMMARY

[0001] In an aspect, the disclosure relates to a composition comprising a dendrimer-retinoid complex.

[0002] In a further aspect, the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of the composition described herein and a pharmaceutically acceptable carrier.

[0003] Another aspect of the disclosure provides a method of treating a skin condition or disorder. The method may comprise topically administering a therapeutically effective amountAttorney Docket No. 892593-0003-WO01of the pharmaceutical composition described herein to a skin or mucous membrane of a subject in need thereof.

[0004] Another aspect of the disclosure provides a method of providing personal and / or cosmetic care. The method may comprise topically administering a composition described herein or a pharmaceutical composition described herein to a skin or mucous membrane of a subject in need thereof.

[0005] Another aspect of the disclosure provides a method of preparing a composition comprising a dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex. The method may comprise: mixing retinoid, optionally resveratrol, dendrimer, and a solvent to form a mixture comprising the dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex; and filtering the mixture.

[0006] The disclosure provides for other aspects and embodiments that will be apparent in light of the following detailed description and accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 is an illustration of the structure of a dendrimer.

[0008] FIGS. 2A-B show a HPLC chromatograph and a UV spectra of vitamin A (i.e., retinol). FIG. 2A is a HPLC chromatograph of retinol at 7.438 min. FIG. 2B is a UV spectra graph of retinol with a λmax at 324.8 nm.

[0009] FIG. 3 is a graph showing storage stability of dendrimer-retinol complexes over 365 days when stored at room temperature.

[0010] FIG. 4 is a graph showing retinol solubility with individual dendrimers.

[0011] FIG. 5 is a graph showing retinol solubility with two dendrimers.

[0012] FIG. 6 is a graph showing retinol solubility with three dendrimers.

[0013] FIG. 7 is a graph showing percentage DPPH inhibition of retinol.

[0014] FIG. 8 is a graph showing percentage of retinol permeability.Attorney Docket No. 892593-0003-WO01

[0015] FIGS. 9A-B show the percentage of retinol dissolved at simulated gastric fluid and intestinal environments. FIG. 9A is a graph showing percentage retinol dissolved at simulated gastric fluid (pH 1.2). FIG. 9B is a graph showing percentage of retinol dissolved intestinal environments (pH 6.8).

[0016] FIGS. 10A-B show a HPLC chromatograph and UV spectra of resveratrol and vitamin A (i.e., retinol). FIG. 10A is a HPLC chromatograph of resveratrol and vitamin A at 3.042 min and 7.332 min, respectively. FIG. 10B is a UV spectrum of resveratrol and vitamin A with their λmax at 304.6 nm and 324.8 nm, respectively.

[0017] FIG. 11 is a graph showing the combined stability profile of dendrimer-retinol and resveratrol, Vitamin C, Vitamin E-TPGS complexes over 60 days when stored at room temperature.DETAILED DESCRIPTION

[0018] The present disclosure relates to compositions comprising a retinoid and a dendrimer, or a dendrimer-retinoid complex. The retinoid may be encapsulated in and / or associated with a dendrimer. The compositions may further comprise optional additional components. The compositions may be in the form of a liquid (for example, a solution, such as an aqueous formulation), a semi-solid or a solid. The compositions may be prepared by mixing a retinoid and a dendrimer in an appropriate solvent to promote the encapsulation or association of the retinoid in or with the dendrimer to form a complex. The resulting compositions may increase the aqueous solubility and / or metabolic stability of the dendrimer-retinoid complex, resulting in improved pharmacokinetic properties of the retinoid, such as half-life and oral bioavailability. The dendrimer-retinoid complex may also have improved transdermal permeability.

[0019] The composition may also be used as a drug delivery system to deliver retinoid to subjects in need in an efficient manner. The composition may be used to treat a variety of conditions and / or disorders, particularly skin conditions and disorders.1. Definitions

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those describedAttorney Docket No. 892593-0003-WO01herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0021] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0022] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0023] It is specifically understood that any numerical value recited herein (e.g., ranges) includes all values from the lower value to the upper value, i.e., all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended. With respect to amounts of components, all percentages are by weight, unless explicitly indicated otherwise.

[0024] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry andAttorney Docket No. 892593-0003-WO01Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; March, Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0025] “Amine” refers to a group having the general structure NR1R2R3, wherein N, R1and R2are an amino group attached to R3, which is an independent substituent.

[0026] “Ci-C4alcohol” refers to C1-C4 alkyl groups having one or more hydroxyl substituents. “C1-C4 alcohol” may be exemplified by methanol, ethanol, propanol, and butanol.

[0027] “Glycol” refers to a compound having vicinal hydroxyl groups (two hydroxyl groups on adjacent carbon atoms).

[0028] “Hydroxy” or “hydroxyl” refers to -OH. Alcohol contains hydroxy groups. Hydroxy groups may be free or protected.

[0029] “Solvent” refers to a substance that dissolves a solute (e.g., a chemically different liquid, solid or gas), resulting in a solution.

[0030] “Organic solvent” refers to a carbon-containing solvent. Examples of organic solvents include C1-C4 solvents, wherein the solvent has between 1 and 4 carbons. Examples of organic C1-C4 solvents include, but are not limited to, butanol, propanol, ethanol, methanol, dichloromethane, dichloroethane, diethyl ether, glycerine, ethylene glycol, and tetrahydrofuran.

[0031] “Compositions essentially free of organic solvent” refers to compositions comprising no organic solvent or a negligible amount of organic solvent. For example, a negligible amount of organic solvent may be less than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or about 0.05%, or about 0.01% of organic solvent by weight of the composition.

[0032] “Compositions essentially free of free resveratrol” refers to compositions comprising no free resveratrol or a negligible amount of free resveratrol. For example, a negligible amountAttorney Docket No. 892593-0003-WO01of organic free resveratrol may be less than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, or about 0.05%, or about 0.01% of free resveratrol by weight of the composition.

[0033] “Compositions essentially free of free retinoid” refers to compositions comprising no retinoid or comprising a negligible amount of free retinoid. For example, a negligible amount of free retinoid may be less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.01% of retinoid by weight of the composition.

[0034] “Dendrimer-retinoid complex” or “retinoid-dendrimer complex” as used herein refers to a retinoid being associated with a dendrimer and / or a retinoid encapsulated or entrapped by a dendrimer. The dendrimer-retinoid complex may include one or more molecules of a retinoid entrapped in the molecular framework of the dendrimers. The retinoid may be associated with the dendrimer via hydrophobic interactions, hydrophilic interactions, electrostatic interactions, ionic interactions, hydrogen bonds, covalent bonding, ora combination thereof.

[0035] “Hybrid dendrimer” as used herein refers to a combination of dendrimers or dendrimers with other components. Hybrid dendrimers were prepared by in situ mixing of two different types of dendrimers such as by methods disclosed in Singh et al., Nanomedicine: Nanotechnology, Biology and Medicine. 2019; 21: 102043 and Singh et al., European Journal of Pharmaceutical Sciences. 2017; 96: 84-92; each of which is incorporated herein by reference in its entirety. The objective is to harness unique features of individual dendrimers and create a nano-assembly. Examples of hybrid dendrimers are described in International Patent Application Publication No. 2007 / 149500 A9 and Chauhan and Kaul, J Nanopart Res. 2018; 20: 226, each of which is incorporated herein by reference in its entirety.

[0036] “Administering” refers to administration of the compositions as needed to achieve the desired effect.

[0037] A molecule “encapsulated” in a dendrimer means that the molecule is embedded or stabilized in a matrix of the dendrimer or forms a complex with the dendrimer. Encapsulated includes molecules partially or fully encapsulated. Encapsulated may be used interchangeably with “entrapped” herein.Attorney Docket No. 892593-0003-WO01

[0038] “Excipient” includes physiologically compatible additives useful in preparation of a pharmaceutical composition. Examples of pharmaceutically or cosmetically acceptable carriers and excipients can for example be found in Remington Pharmaceutical Science, 16th Ed.

[0039] “Pharmaceutically acceptable carrier” means a carrier that is useful for the preparation of a pharmaceutical composition that is at least one of: generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable. “Pharmaceutically acceptable carrier” refers to any inert substance or composition that facilitates the administration of an active pharmaceutical ingredient (API) without adversely affecting its therapeutic efficacy or safety. Such carriers are non-toxic, non- reactive, and suitable for human or veterinary use, and should not introduce undesirable biological effects. Carriers can serve as solvents, diluents, stabilizers, or delivery vehicles, and they are selected based on compatibility with the API and the intended route of administration (oral, parenteral, topical, ophthalmic, etc.). A “pharmaceutically acceptable carrier” includes both one and more than one carrier. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal intramuscular, sublingual, nasal, and oral administration. “Pharmaceutically or cosmetically acceptable carrier” also includes agents for preparation of aqueous dispersions and sterile powders for injection or dispersions. Examples of “pharmaceutically acceptable carriers” include, but are not limited to, water and saline solutions, liposomes, polymeric micelles, microspheres, dendrimers such as those described herein, solid carriers for tablets (e.g., lactose, microcrystalline cellulose, starch), suspending agents and binders (e.g., hydroxypropyl methylcellulose (HPMC), povidone), lubricants and disintegrants (e.g., magnesium stearate, croscarmellose sodium), and ophthalmic carriers (e.g., artificial tear solutions, isotonic buffers for eye drops).

[0040] “Retinoid” refers to any natural or synthetic retinoid compounds known in the art. Examples of retinoids include, but are not be limited to, retinol, retinal, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), alitretinoin (9-cis-retinoic acid), etretinate, acitretin, adapalene, bexarotene, and tazarotene. Retinol, or (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-ol, has a structure shown below.OHRetinolAttorney Docket No. 892593-0003-WO01

[0041] " Semi-solid" denotes a physical state that is neither solid nor liquid. Semi-solids (or quasi-solids) are similar to a solid in some respects, e.g., a semi-solid can support its own weight and hold its shape but also shares some properties of liquids, such as shape conformity to something applying pressure to it, or the ability to flow under pressure. Semi-solids are characterized by a three-dimensional structure that is sufficient to impart solid-like character to the undisturbed system but that is easily broken down and realigned under an applied force. Semi-solids have a rigidity and viscosity intermediate between a solid and a liquid.

[0042] “Therapeutically effective amount” refers to a dosage of a sufficient amount of the compositions of the disclosure to bring about a desired in vivo effect and treat disorders or conditions, at a reasonable benefit / risk ratio applicable to any medical treatment.2. Compositions

[0043] In one aspect, the present disclosure provides a composition comprising a dendrimer-retinoid complex. The compositions may comprise one or more additional components.Compositions comprising a dendrimer-retinoid complex may have improved properties relative to compositions comprising retinoid not in a complex with a dendrimer. The compositions may effectively improve one or more of the following properties of a retinoid: aqueous solubility, metabolic stability, photostability, chemical stability, transdermal permeability, and oral bioavailability. The composition may be in the form of a liquid, a solution, an aqueous solution, a dispersion, a suspension, a nanosuspension, a solid, a semi-solid, ora combination thereof. The dispersions may be colloidal or coarse. Colloidal and coarse dispersion include emulsions, suspensions, and nanosuspensions. The semi-solid composition may be a cream, ointment, paste or gel for topical application to skin or mucous membranes.a. Dendrimer-Retinoid Complex

[0044] Encapsulating / entrapping a retinoid in the dendrimer may form a dendrimer-retinoid complex. In the dendrimer-retinoid complex, the retinoid may be associated with the dendrimer. The dendrimer-retinoid complex may include one or more molecules of the retinoid entrapped in the molecular framework of the dendrimers. The retinoid may be associated with the dendrimer via hydrophobic interactions, hydrophilic interactions, electrostatic interactions, ionic interactions, hydrogen bonds, covalent bond, or a combination thereof.Attorney Docket No. 892593-0003-WO01

[0045] The dendrimer and the retinoid may be coated on solid particles. The solid particles may be pharmaceutically acceptable excipients, including fillers, binders, humectants, cryoprotectants selected from trehalose, sucrose, mannitol, lactose, or combinations thereof, disintegrants, solution-retarding agents, absorption enhancers, wetting agents, absorbents, lubricants, and combinations thereof. In further embodiments, where the dosage form comprises capsules, tablets, or pills, one or more buffering agents may also be included. The retinoid may be conjugated to the dendrimer with a labile linker. The labile linker may be configured to be cleavable under predetermined conditions, including acidic pH, enzymatic action, hydrolytic conditions, or reducing intracellular environments, thereby enabling controlled release of retinol from the dendrimer conjugate. The labile linker may be cleaved before use of the composition.i. Dendrimer

[0046] Dendrimers are repetitively branched molecules. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology (FIG. 1).Dendrimers are monodisperse and can be highly symmetric, spherical compounds.

[0047] The properties of dendrimers are dominated by the functional groups on the molecular surface, however, there are examples of dendrimers with internal functionality.Dendritic entrapment of functional molecules allows for the isolation of the active site, a structure that mimics that of active sites in biomaterials. Dendrimers may be water soluble by functionalizing their outer shell with charged species or other hydrophilic groups. Other controllable properties of dendrimers include toxicity, crystallinity, tecto-dendrimer formation, and chirality.

[0048] Dendrimers are also classified by their synthesis. For example, if a dendrimer is made by convergent synthesis, and the branching reactions are performed onto the core molecule three times, the resulting dendrimer is considered a third-generation dendrimer. Each successive generation results in a dendrimer roughly twice the molecular weight of the previous generation. Higher generation dendrimers also have more exposed functional groups on the surface, which can later be used to customize the dendrimer for a given application.

[0049] The dendrimer of the composition may be a generation 0 to generation 10 dendrimer. The dendrimer may be a generation 0, generation 1, generation 2, generation 3, generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, or generation 10 dendrimer.Attorney Docket No. 892593-0003-WO01

[0050] Dendrimers have three major portions: a core, an inner shell, and an outer shell. A dendrimer can be synthesized to have different functionality in each of these portions to control properties such as solubility, thermal stability, and attachment of compounds for particular applications. Synthetic processes can also precisely control the size and number of branches on the dendrimer. There are two defined methods of dendrimer synthesis: divergent synthesis and convergent synthesis. However, because the actual reactions include many steps needed to protect the active site, it is difficult to synthesize dendrimers using either method. This makes dendrimers hard to make and very expensive to purchase.

[0051] Dendrimers provide an alternative route to create very well-defined nanostructures suitable for drug solubilization applications. The properties of dendrimer may be tailored to address therapeutic needs, which makes them useful carriers for small molecule drugs and biomolecules. The three main properties of dendrimers are (i) nanoscale container properties (i.e., entrapment of a drug), (ii) nano-scaffolding properties (i.e., surface adsorption or attachment of a drug), and (iii) biocompatibility. The composition comprising the dendrimer-resveratrol complex may be used in several routes of administration, including intravenous, oral, transdermal, and ocular. The use of dendrimers as drug carriers by entrapment of hydrophobic drugs is a potential method for delivering highly active pharmaceutical compounds that may not be in clinical use due to their limited water solubility and resulting suboptimal pharmacokinetics.

[0052] The compositions of the present disclosure may have a concentration of the dendrimer of about 1120 μM or less. The composition may have a concentration of about 1100 μM or less, about 1000 μM or less, about 900 μM or less, about 800 μM or less, about 700 μM or less, about 600 μM or less, about 500 μM or less, about 400 μM or less, about 300 μM or less, about 200 μM or less, about 100 μM or less, about 75 μM or less, about 50 μM or less, about 25 μM or less, about 10 μM or less, or about 5 μM or less of the dendrimer. The composition may have a concentration of about 4.5 μM or greater, about 5 μM or greater, about 10 μM or greater, about 25 μM or greater, about 50 μM or greater, about 75 μM or greater, about 100 μM or greater, about 200 μM or greater, about 300 μM or greater, about 400 μM or greater, about 500 μM or greater, about 600 μM or greater, about 700 μM or greater, about 800 μM or greater, about 900 μM or greater, about 1000 μM or greater, or about 1100 μM or greater of the dendrimer.

[0053] Examples of dendrimers include, but are not necessarily limited to, poly(amidoamine) (PAMAM; such as those commercially available from Dendritech, Inc., Sigma-Aldrich / Merck,Attorney Docket No. 892593-0003-WO01and CD Bioparticles), poly(propyleneimine) (PPI; such as those available from DSM), poly(lysine), poly(glycerol), a hyperbranched structure, carbosilane dendrimers (such as those available from Creative Biolabs), phosphorus dendrimers (such as those available from Creative Biolabs), polyester / DMPA-based dendrimers (such as those available from CD Bioparticles), or DAB (diaminobutane) dendrimers (such as those available from CD Bioparticles). The hyperbranched structure may be a dendrigraft, a polyester, a polyamide, or a polyalcohol.

[0054] The core of PAMAM is a diamine. PAMAM is synthesized by reacting the diamine with methyl acrylate, and then another diamine to make the generation-0 (G-0) PAMAM.Successive reactions create higher generations, which tend to have different properties. Lower generations can be thought of as flexible molecules with no appreciable inner regions, while medium sized (G-3 or G-4) do have internal space that is essentially separated from the outer shell of the dendrimer. Very large (G-7 and greater) dendrimers can be thought of more like solid particles with very dense surfaces due to the structure of their outer shell.

[0055] The surface groups of the dendrimer of the composition may be amine, hydroxyl, carboxylate, pyrrolidinone, cysteamine, or PEG moieties. In some embodiments, the surface groups of the dendrimer may be amine or pyrrolidinone surface groups. In some embodiments, the dendrimer comprises amine surface groups. In some embodiments, the dendrimer comprises pyrrolidinone surface groups.

[0056] The core of the dendrimer of the composition may be ethylenediamine, diaminobutane, 1,12-diaminododecane, or cysteamine.

[0057] In an embodiment, the dendrimer may be a generation 4 (G4) PAMAM dendrimer comprising a diaminobutane core and pyrrolidinone (PYR) surface groups. This dendrimer may also be referred to herein as a PAMAM G4-PYR dendrimer or biodendrimer.

[0058] In an embodiment, the dendrimer may comprise more than one dendrimer, such as a hybrid dendrimer. For example, a hybrid dendrimer may be made in situ by mixing PAMAM G4-NH2 and PAMAM G4–COONa; or PAMAM G4-NH2 and PAMAM G4–PYR; or PAMAM G4-NH2 and PAMAM G4–OH; or PAMAM G4-NH2 and PAMAM G4–PEG; or other possible combinations using other dendrimers to create a nano-assembly. Examples of hybrid dendrimers are described in International Patent Application Publication No. 2007 / 149500 A9 and Chauhan and Kaul, J Nanopart Res. 2018; 20: 226, each of which is incorporated herein by reference in its entirety.Attorney Docket No. 892593-0003-WO01ii. Retinoids

[0059] The retinoid may be selected from retinol, retinal, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), alitretinoin (9-cis-retinoic acid), etretinate, acitretin, adapalene, bexarotene, tazarotene, and a combination thereof. In some embodiments, the retinoid comprises retinol. An example of a retinoid is retinol. Retinol, a common form of Vitamin A, is an important nutrient for the development and health of vision, bone, tooth, reproduction, skin and mucous membranes. As an antioxidant, retinol also protects the body from risk of certain cancers. Known methods for improving retinol intake include dietary modification toward retinol- rich food sources, food fortification through addition of synthetic retinol, and high-dose retinol supplements.

[0060] At least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, by weight, of the retinoid may be encapsulated in the dendrimer. The composition may be essentially free of free retinoid. In some embodiments, the composition has no free retinoid.

[0061] The concentration of the retinoid encapsulated in the dendrimer may be from about 1.5 µM to about 2500 µM, as measured according to the total volume of the composition at pH 7. The concentration of the retinoid encapsulated in the dendrimer may be at least about 1.5 µM, at least about 5 µM, at least about 10 µM, at least about 25 µM, at least about 50 µM, at least about 75 µM, at least about 100 µM, at least about 200 µM, at least about 300 µM, at least about 400 µM, at least about 500 µM, at least about 600 µM, at least about 700 µM, at least about 800 µM, at least about 900 µM, at least about 1000 µM, at least about 1100 µM, at least about 1200 µM, at least about 1300 µM, at least about 1400 µM, at least about 1500 µM, at least about 1600 µM, at least about 1700 µM, at least about 1800 µM, at least about 1900 µM, at least about 2000 µM, at least about 2100 µM, at least about 2200 µM, at least about 2300 µM, or at least about 2400 µM, as measured according to the total volume of the composition at pH 7. The concentration of the retinoid encapsulated in the dendrimer may improve an aqueous solubility over neat retinoid at pH 7.Attorney Docket No. 892593-0003-WO01

[0062] The concentration of the retinoid encapsulated in the dendrimer may be from about 1.5 µM to about 2500 µM, as measured according to the total volume of the composition at pH 2.5. The concentration of the retinoid encapsulated in the dendrimer may be at least about 1.5 µM, at least about 5 µM, at least about 10 µM, at least about 25 µM, at least about 50 µM, at least about 75 µM, at least about 100 µM, at least about 200 µM, at least about 300 µM, at least about 400 µM, at least about 500 µM, at least about 600 µM, at least about 700 µM, at least about 800 µM, at least about 900 µM, at least about 1000 µM, at least about 1100 µM, at least about 1200 µM, at least about 1300 µM, at least about 1400 µM, at least about 1500 µM, at least about 1600 µM, at least about 1700 µM, at least about 1800 µM, at least about 1900 µM, at least about 2000 µM, at least about 2100 µM, at least about 2200 µM, at least about 2300 µM, or at least about 2400 µM, as measured according to the total volume of the composition at pH 2.5. The concentration of the retinoid encapsulated in the dendrimer may improve aqueous solubility over neat retinoid at pH 2.5.

[0063] The composition may include the retinoid-dendrimer complex in an amount, by weight, of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. The composition may include the retinoid- dendrimer complex in an amount, by weight, of less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, less than about 90%, less than about 91%, less than about 92%, less than about 93%, less than about 94%, less than about 95%, less than about 96%, less than about 97%, less than about 98%, or less than about 99%. The composition may comprise the retinoid-dendrimer complex in an amount, by weight, of about 1 % to about 50%, about 1 % to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1%Attorney Docket No. 892593-0003-WO01to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 60%, about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 96% to about 99%, about 97% to about 99%, or about 98% to about 99%.

[0064] In certain embodiments, the retinoid may be chemically conjugated to surface-functionalized dendrimers through one or more linker moieties, also referred to as a labile linker herein, to form dendrimer–retinol and dendrimer–surfactant retinol conjugates. The linker moiety may be selected from ester, carbonate, carbamate, amide, hydrazone, imine (Schiff base), acetal, ketal, disulfide, thioether, peptide, phosphoester, phosphoramidate, sulfonamide, urea, thiocarbamate, oxime, azo, boronate, self-immolative spacer groups, ether, or combinations thereof. The dendrimers may include, but are not limited to, NH2terminated, COOH-terminated, OH-functionalized, and PYR-functionalized dendrimers. The hydroxyl functionality of retinoid may be derivatized and coupled to reactive groups on the dendrimer surface through ester, carbonate, carbamate, amide, hydrazone, disulfide, peptide, or other suitable linker chemistries. In certain embodiments, the linker may be cleavable under predetermined physiological, enzymatic, pH-responsive, or redox conditions to enable controlled release of the retinoid from the dendrimer scaffold. The resulting conjugates may be designed to enhance solubility, stability, bioavailability, and targeted delivery of retinoid. In further embodiments, the cleavable linker solution may be provided separately and combined with the dendrimer-retinol or dendrimer-surfactant retinol conjugates prior to administration or use.b. Other Componentsi. Resveratrol

[0065] In some embodiments, the composition further comprises resveratrol. The composition may optionally include resveratrol associated with dendrimer in a dendrimer-resveratrol complex as described in U. S. Patent No. 9,855,223, U. S. Patent No. 10,406,119,Attorney Docket No. 892593-0003-WO01U. S. Patent No. 11,110,068, and U. S. Patent No. 11,931,321; the entire contents of each of which are incorporated herein by reference. In some embodiments, the composition further comprises resveratrol, which forms a dendrimer-resveratrol complex with the dendrimer.

[0066] When resveratrol is present in the composition, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, by weight, of the resveratrol in the composition may be associated with the dendrimer. The composition may be essentially free of free resveratrol. The composition may have no free resveratrol.

[0067] The concentration of resveratrol associated with the dendrimer may be from about 10 µM to about 1000 µM, as measured according to the total volume of the composition at pH 7. The concentration of resveratrol associated with the dendrimer may be at least about 10 µM, at least about 20 µM, at least about 30 µM, at least about 40 µM, at least about 50 µM, at least about 60 µM, at least about 70 µM, at least about 80 µM, at least about 90 µM, at least about 100 µM, at least about 150 µM, at least about 200 µM, at least about 250 µM, at least about 300 µM, at least about 350 µM, at least about 400 µM, at least about 450 µM, at least about 500 µM, at least about 550 µM, at least about 600 µM, at least about 650 µM, at least about 700 µM, at least about 750 µM, at least about 800 µM, at least about 850 µM, or at least about 900 µM, as measured according to the total volume of the composition at pH 7. The concentration of the resveratrol associated with the dendrimer may improve an aqueous solubility over neat resveratrol.

[0068] The concentration of resveratrol associated with the dendrimer may be from about 10 µM to about 1000 µM, as measured according to the total volume of the composition at pH 2.5. The concentration of resveratrol associated with the dendrimer may be at least about 10 µM, at least about 20 µM, at least about 30 µM, at least about 40 µM, at least about 50 µM, at least about 60 µM, at least about 70 µM, at least about 80 µM, at least about 90 µM, at least about 100 µM, at least about 150 µM, at least about 200 µM, at least about 250 µM, at least about 300 µM, at least about 350 µM, at least about 400 µM, at least about 450 µM, at least about 500 µM, at least about 550 µM, at least about 600 µM, at least about 650 µM, at least about 700 µM, at least about 750 µM, at least about 800 µM, at least about 850 µM, or at least about 900 µM, as measured according to the total volume of the composition at pH 2.5. The concentration of the resveratrol associated with the dendrimer may improve aqueous solubility over neat resveratrol.Attorney Docket No. 892593-0003-WO01

[0069] The composition may include dendrimer-resveratrol complex in an amount, by weight, of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. The composition may comprise dendrimer-resveratrol complex in an amount, by weight, of less than about 1 %, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, less than about 90%, less than about 91%, less than about 92%, less than about 93%, less than about 94%, less than about 95%, less than about 96%, less than about 97%, less than about 98%, or less than about 99%. The composition may comprise dendrimer-resveratrol complex in an amount, by weight, of about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 60%, about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 96% to about 99%, about 97% to about 99%, or about 98% to about 99%.

[0070] In some embodiments, the composition is essentially free of resveratrol. In some embodiments, the composition has no resveratrol.ii. SolventsAttorney Docket No. 892593-0003-WO01

[0071] The composition may further comprise a solvent. Suitable solvents will be capable of having dendrimer-retinoid complex dispersed or dissolved therein. Examples of solvents include, but are not limited to, water and other non-organic solvents, such as liquid ammonia and sulfur dioxide. In some embodiments, the composition comprises water. The composition may comprise solvent in an amount, by weight, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. The composition may comprise solvent in an amount, by weight, of less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, less than about 90%, less than about 91%, less than about 92%, less than about 93%, less than about 94%, less than about 95%, less than about 96%, less than about 97%, less than about 98%, or less than about 99%. The composition may comprise solvent in an amount, by weight, of about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 8%, about 1% to about 7%, about 1% to about 6%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 1% to about 99%, about 5% to about 95%, about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 60%, about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, about 70% to about 99%, about 75% to about 99%, about 80% to about 99%, about 85% to about 99%, about 90% to about 99%, about 91% to about 99%, about 92% to about 99%, about 93% to about 99%, about 94% to about 99%, about 95% to about 99%, about 96% to about 99%, about 97% to about 99%, or about 98% to about 99%. The balance of theAttorney Docket No. 892593-0003-WO01composition may be water or non-organic solvent. The composition may be essentially free of organic solvent. The composition may be essentially free of solvent.iii. Antioxidants

[0072] Compositions of the present disclosure may include at least one antioxidant. The inclusion of an antioxidant may improve the therapeutic benefits of the composition, and may protect the retinoid from oxidative damage.

[0073] Exemplary antioxidants include, but are not limited to, ascorbic acid (vitamin C) and salts and esters thereof (e.g., sodium ascorbate, ascorbyl phosphate and salts thereof such as magnesium ascorbyl phosphate, ascorbyl esters of fatty acids such as ascorbyl palmitate), epichlorocatechin, curcumin, tocopherol (vitamin E) and salts and esters thereof (e.g., tocopheryl acetate, tocopheryl phosphate), butylated hydroxy benzoic acids and their salts, butylated hydroxytoluene, butylated hydroxyanisole, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the trade name Trolox™), gallic acid and its alkyl esters (e.g., propyl gallate), uric acid and its salts and alkyl esters, sorbic acid and its salts, amines (e.g., N, N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), sodium metabisulfite, dihydroxy fumaric acid and its salts, ferulic acid, and cannabinoids.

[0074] An antioxidant or a mixture of antioxidants may be included in the composition at an amount, by weight, of up to about 0.01%, up to about 0.02%, up to about 0.03%, up to about 0.04%, up to about 0.05%, up to about 0.06%, up to about 0.07%, up to about 0.08%, up to about 0.09%, up to about 0.10%, up to about 0.11%, up to about 0.12%, up to about 0.13%, up to about 0.14%, up to about 0.15%, up to about 0.16%, up to about 0.17%, up to about 0.18%, up to about 0.19%, up to about 0.20%, up to about 0.25%, up to about 0.30%, up to about 0.35%, up to about 0.40%, up to about 0.45%, up to about 0.50%, up to about 0.55%, up to about 0.60%, at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.10%, at least about 0.11%, at least about 0.12%, at least about 0.13%, at least about 0.14%, at least about 0.15%, at least about 0.16%, at least about 0.17%, at least about 0.18%, at least about 0.19%, at least about 0.20%, at least about 0.25%, at least about 0.30%, at least about 0.35%, at least about 0.40%, at least about 0.45%, at least about 0.50%, at least about 0.55%, at least about 0.60%, about 0.01%, about 0.02%, aboutAttorney Docket No. 892593-0003-WO010.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, or about 0.60%.

[0075] An antioxidant or a mixture of antioxidants may be included in the composition at from about 5 µM to about 5500 µM. An antioxidant or a mixture of antioxidants may be included in the composition at an amount of at least about 5 µM, at least about 10 µM, at least about 25 µM, at least about 50 µM, at least about 75 µM, at least about 100 µM, at least about 200 µM, at least about 300 µM, at least about 400 µM, at least about 500 µM, at least about 600 µM, at least about 700 µM, at least about 800 µM, at least about 900 µM, at least about 1000 µM, at least about 1100 µM, at least about 1200 µM, at least about 1300 µM, at least about 1400 µM, at least about 1500 µM, at least about 1600 µM, at least about 1700 µM, at least about 1800 µM, at least about 1900 µM, at least about 2000 µM, at least about 2100 µM, at least about 2200 µM, at least about 2300 µM, at least about 2400 µM, at least about 2500 µM, at least about 2600 µM, at least about 2700 µM, at least about 2800 µM, at least about 2900 µM, at least about 3000 µM, at least about 3100 µM, at least about 3200 µM, at least about 3300 µM, at least about 3400 µM, at least about 4500 µM, at least about 4600 µM, at least about 4700 µM, at least about 4800 µM, at least about 4900 µM, at least about 5000 µM, at least about 5100 µM, at least about 5200 µM, at least about 5300 µM, or at least about 5400 µM.iv. Additives

[0076] Compositions of the present disclosure may include at least one of the following, or any combination thereof: a glycol; a chelating agent; an emollient (such as coconut oil, cetyl esters, and certain silicones); a humectant (such as glycerin); an occlusive agent (such as petrolatum, mineral oil, and dimethicone); other moisturizers to provide moisturizing, skin softening, skin barrier maintenance, anti-irritation, or other skin health benefits; an emulsifier (such as glyceryl stearate and stearic acid), a preservative, which may have anti-microbial activity; a steroidal anti-inflammatory agent; a nonsteroidal anti-inflammatory agent; a retinoid; an opacifier (such as titanium dioxide); a penetration enhancer; a vitamin; a fragrance; a colorant; an exfoliant; an anti-acne agent; an anti-aging agent; a body lotion; a body treatment; a toner; a facial moisturizer; a facial treatment; makeup foundation; any skin care product; a cryoprotectant; bulking agents such as mannose, trehalose, and sucrose; surfactants such as TPGS (D-α-tocopheryl polyethylene glycol succinate) which is a water-soluble, syntheticAttorney Docket No. 892593-0003-WO01derivative of vitamin E, paraffin oil, Tween 80, and Span 80. These components may be added in an amount that is requisite with obtaining the desired effect in the composition.

[0077] A glycol or a mixture of glycols may be included in the composition at an amount, by weight, of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%, at least about 10%, up to about 0.1%, up to about 0.2%, up to about 0.3%, up to about 0.4%, up to about 0.5%, up to about 0.6%, up to about 0.7%, up to about 0.8%, up to about 0.9%, up to about 1.0%, up to about 1.5%, up to about 2.0%, up to about 2.5%, up to about 3.0%, up to about 3.5%, up to about 4.0%, up to about 4.5%, up to about 5.0%, up to about 5.5%, up to about 6.0%, up to about 6.5%, up to about 7.0%, up to about 7.5%, up to about 8.0%, up to about 8.5%, up to about 9.0%, up to about 9.5%, up to about 10%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10%.

[0078] A chelating agent or a mixture of chelating agents may be included in the composition at an amount, by weight, of up to about 0.01%, up to about 0.02%, up to about 0.03%, up to about 0.04%, up to about 0.05%, up to about 0.06%, up to about 0.07%, up to about 0.08%, up to about 0.09%, up to about 0.10%, up to about 0.15%, up to about 0.20%, up to about 0.25%, up to about 0.30%, up to about 0.35%, up to about 0.40%, up to about 0.45%, up to about 0.50%, up to about 0.55%, up to about 0.60%, up to about 0.70%, up to about 0.80%, up to about 0.90%, up to about 1.0%, at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.30%, at least about 0.35%, at least about 0.40%, at least about 0.45%, at least about 0.50%, at least about 0.55%, at least about 0.60%, at least about 0.70%, at least about 0.80%, at least about 0.90%, at least about 1.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, aboutAttorney Docket No. 892593-0003-WO010.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, or about 1.0%.

[0079] An emulsifier or mixture of emulsifiers may be included in the composition at an amount, by weight, of at least about 0.1 %, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%, at least about 10%, up to about 0.1%, up to about 0.2%, up to about 0.3%, up to about 0.4%, up to about 0.5%, up to about 0.6%, up to about 0.7%, up to about 0.8%, up to about 0.9%, up to about 1.0%, up to about 1.5%, up to about 2.0%, up to about 2.5%, up to about 3.0%, up to about 3.5%, up to about 4.0%, up to about 4.5%, up to about 5.0%, up to about 5.5%, up to about 6.0%, up to about 6.5%, up to about 7.0%, up to about 7.5%, up to about 8.0%, up to about 8.5%, up to about 9.0%, up to about 9.5%, up to about 10%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10%.

[0080] A conditioning agent or mixture of conditioning agents may be included in the composition at an amount, by weight, of at least about 0.5%, at least about 0.75%, at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, up to about 0.5%, up to about 0.75%, up to about 1.0%, up to about 1.5%, up to about 2.0%, up to about 2.5%, up to about 3.0%, up to about 3.5%, up to about 4.0%, up to about 4.5%, up to about 5.0%, about 0.5%, about 0.75%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5.0%.

[0081] A preservative or mixture of preservatives may be included in the composition at an amount, by weight, of up to about 0.01%, up to about 0.02%, up to about 0.03%, up to about 0.04%, up to about 0.05%, up to about 0.06%, up to about 0.07%, up to about 0.08%, up to about 0.09%, up to about 0.10%, up to about 0.15%, up to about 0.20%, up to about 0.25%, up to about 0.30%, up to about 0.35%, up to about 0.40%, up to about 0.45%, up to about 0.50%,Attorney Docket No. 892593-0003-WO01up to about 0.55%, up to about 0.60%, up to about 0.65%, up to about 0.70%, up to about 0.75%, up to about 0.80%, up to about 0.85%, up to about 0.90%, up to about 0.95%, up to about 1.0%, at least about 0.01%, at least about 0.02%, at least about 0.03%, at least about 0.04%, at least about 0.05%, at least about 0.06%, at least about 0.07%, at least about 0.08%, at least about 0.09%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.30%, at least about 0.35%, at least about 0.40%, at least about 0.45%, at least about 0.50%, at least about 0.55%, at least about 0.60%, at least about 0.65%, at least about 0.70%, at least about 0.75%, at least about 0.80%, at least about 0.85%, at least about 0.90%, at least about 0.95%, at least about 1.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.0%.

[0082] An surfactant or mixture of surfactants may be included in the composition at an amount, by weight, of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%, at least about 10%, up to about 0.1%, up to about 0.2%, up to about 0.3%, up to about 0.4%, up to about 0.5%, up to about 0.6%, up to about 0.7%, up to about 0.8%, up to about 0.9%, up to about 1.0%, up to about 1.5%, up to about 2.0%, up to about 2.5%, up to about 3.0%, up to about 3.5%, up to about 4.0%, up to about 4.5%, up to about 5.0%, up to about 5.5%, up to about 6.0%, up to about 6.5%, up to about 7.0%, up to about 7.5%, up to about 8.0%, up to about 8.5%, up to about 9.0%, up to about 9.5%, up to about 10%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10%.c. Properties of the Compositioni. pHAttorney Docket No. 892593-0003-WO01

[0083] The pH of compositions including the dendrimer-retinoid complex can affect one or more of solubility, stability, and efficacy of the composition. For example, lower pH may result in lower solubility of the retinoid associated with the dendrimer complex. The pH of the composition may be about 7. The pH of the composition may be about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 10, about 7 to about 9, or about 7 to about 8. The pH of the composition may be about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10. The pH of the composition may be about 10 or less, about 9 or less, about 8 or less, about 7 or less, about 6 or less, about 5 or less, about 4 or less, or about 3 or less. The pH of the composition may be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10.

[0084] Composition pH can be adjusted with acid or base, if necessary. Any acid or base compatible with the components of the composition can be used. Exemplary acids include citric acid, gluconic acid, lactic acid, acetic acid, and glycolic acid. Exemplary bases include sodium hydroxide, potassium hydroxide, and triethanolamine.ii. Solubility

[0085] The solubility of the dendrimer-retinoid complex such as the composition of the present disclosure can be enhanced over neat retinoid. The concentration of the retinoid encapsulated in the dendrimer, or the retinoid associated with dendrimer can be determined via laboratory analytical methods such as HPLC. Formulations containing the composition can be manufactured and then tested by these methods. Specifically, the solubility of the retinoid in a composition comprising a retinoid-PAMAM G4-PYR dendrimer complex at pH 7 can be determined.

[0086] The aqueous solubility of the dendrimer-retinoid complex may be at least about 10 times greater, at least about 20 times greater, at least about 30 times greater, at least about 40 times greater, at least about 50 times greater, at least about 60 times greater, at least about 70 times greater, at least about 80 times greater, at least about 90 times greater, at least about 100Attorney Docket No. 892593-0003-WO01times greater, at least about 110 times greater, at least about 120 times greater, at least about 130 times greater, at least about 140 times greater, at least about 150 times greater, at least about 160 times greater, at least about 170 times greater, at least about 180 times greater, at least about 190 times greater, at least about 200 times greater, at least about 210 times greater, at least about 220 times greater, at least about 230 times greater, at least about 240 times greater, at least about 250 times greater, at least about 260 times greater, at least about 270 times greater, at least about 280 times greater, at least about 290 times greater, or at least about 300 times greater than the aqueous solubility of neat retinoid, as measured at pH 7.

[0087] The aqueous solubility of the dendrimer-retinoid complex may be at least about 10 times greater, at least about 20 times greater, at least about 30 times greater, at least about 40 times greater, at least about 50 times greater, at least about 60 times greater, at least about 70 times greater, at least about 80 times greater, at least about 90 times greater, or at least about 100 times greater than the aqueous solubility of neat retinoid, as measured at pH 2, at pH 2.5, at pH 3, at pH 3.5, at pH 4, at pH 4.5, at pH 5, at pH 5.5, at pH 6, at pH 6.5, at pH 7, at pH 7.5, at pH 8, at pH 8.5, at pH 9, at pH 9.5, or at pH 10.

[0088] Dissolution rates of the composition in solid form can also be measured. For example, the dissolution of the composition can be measured in simulated gastric and intestinal fluids. The time to dissolution of the composition in simulated gastric fluid or intestinal fluids may be less than about 1 hour, less than about 55 minutes, less than about 50 minutes, less than about 45 minutes, less than about 40 minutes, less than about 35 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes. The time to dissolution of the composition in simulated intestinal fluid may be less than about 1 hour, less than about 55 minutes, less than about 50 minutes, less than about 45 minutes, less than 40 minutes, less than about 35 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes.iii. Stability

[0089] Forming a dendrimer-retinoid complex may enhance stability over neat retinoid. The concentration of non-degraded retinoid over time in the dendrimer-retinoid complex can be determined via laboratory analytical methods such as HPLC. After determining the initialAttorney Docket No. 892593-0003-WO01amount (or concentration) of retinoid in a manufactured composition, samples containing the manufactured composition can be kept at predetermined temperatures for predetermined amounts of time. The sample can then be analyzed via HPLC to determine the amount of retinoid in the composition. This amount of retinoid can be compared to the initially determined amount. This comparison amount can be used to determine the percent degradation. For example, a sample of a composition may initially contain 1.0 mg / mL retinoid, and after 4 days, the same sample may contain 0.95 mg / mL retinoid. In this hypothetical example, the retinoid has degraded by 5%. Specifically, the stability of retinoid in a composition comprising a retinoid-PAMAM G4-PYR dendrimer complex at pH 7 can be determined at ambient (room), elevated, and reduced temperatures.

[0090] The dendrimer-retinoid complex may degrade less than about 30%, less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than about 25%, less than about 24%, less than about 23%, less than about 22%, less than about 21%, less than about 20%, less than about 19%, less than about 18%, less than about 17%, less than about 16%, less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5% after 4 days at ambient temperature.

[0091] The dendrimer-retinoid complex may degrade less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 79%, less than about 78%, less than about 77%, less than about 76%, less than about 75%, less than about 74%, less than about 73%, less than about 72%, less than about 71%, less than about 70%, less than about 69%, less than about 68%, less than about 67%, less than about 66%, less than about 65%, less than about 64%, less than about 63%, less than about 62%, less than about 61%, or less than about 60% after 11 days at ambient temperature.

[0092] Antioxidant efficacy of the composition can also be measured by use of a DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. In this assay, changes in color of the composition can be measured at certain wavelengths of light using a UV / visible light spectrophotometer. When a DPPH free radical reacts with an antioxidant compound, it is reduced. DPPH is a well-known radical and a trap ("scavenger") for other radicals. Therefore, rate reduction of a chemical reaction upon addition of DPPH is used as an indicator of the radical nature of that reaction. Because of a strong absorption band centered at about 520 nm, the DPPH radical has a deep violet color in solution, and it becomes colorless or pale yellow when neutralized. In particular,Attorney Docket No. 892593-0003-WO01the antioxidant efficacy of a retinoid encapsulated in a dendrimer and / or a retinoid-PAMAM G4-PYR dendrimer complex at pH 7 can be determined at predetermined timepoints.

[0093] The composition may demonstrate greater than about 40% inhibition, greater than about 45% inhibition, greater than about 50% inhibition, greater than about 55% inhibition, greater than about 60% inhibition, or greater than about 64% inhibition, of the DPPH oxidation at 15 minutes. The composition may demonstrate greater than 30% inhibition, greater than about 35% inhibition, greater than about 40% inhibition, greater than about 45% inhibition, greater than about 50% inhibition, or greater than about 51% inhibition, of the DPPH oxidation at 19 hours.iv. Transderma! Permeation

[0094] Compositions comprising the dendrimer-retinoid complex of the present disclosure may improve transdermal permeation of the retinoid when the compositions are applied topically to skin, compared to compositions having uncomplexed neat retinoid. The concentration of dendrimer-retinoid complex that permeates through skin over a period of time can be determined by use of Franz Diffusion Cells (FDC) and rat skin samples. Formulations containing the composition can be manufactured and then tested by these methods.Specifically, the transdermal permeation of the dendrimer-retinoid complex (such as a retinoid-PAMAM G4-PYR dendrimer complex), at pH 7 can be determined.

[0095] At least about 20%, by weight, of the dendrimer-retinoid complex may permeate the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples. At least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 78% by weight, of the dendrimer-retinoid complex may permeate the skin within a period of time in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples. The period of time may be 10 minutes or less, 15 minutes or less, 20 minutes or less, 25 minutes or less, 30 minutes or less, 35 minutes or less, 40 minutes or less, 45 minutes or less, 50 minutes or less, 55 minutes or less, or 60 minutes or less.

[0096] Less than 25%, by weight, of the dendrimer-retinoid complex may be found as a deposit on the skin after 20 minutes in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples. Less than about 22%, less than about 25%, less than about 30%, lessAttorney Docket No. 892593-0003-WO01than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 65%, less than about 70%, or less than about 75% by weight, of the dendrimer-retinoid complex may be found as a deposit on the skin after a period of time in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples. The period of time may be 10 minutes, 15 minutes, 20 minutes, 25 minute, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes or 60 minutes.d. Embodiments of the Composition

[0097] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7.

[0098] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is associated or entrapped in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer.

[0099] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of the retinoid encapsulated in the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition.

[0100] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of theAttorney Docket No. 892593-0003-WO01retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of the retinoid encapsulated in the dendrimer is at least 1000 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1000 pM, as measured according to the total volume of the composition.

[0101] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of the retinoid encapsulated in the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature.

[0102] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of retinoid encapsulated in the dendrimer is at least 1000 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1000 pM, as measured according to the total volume of the composition; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambientAttorney Docket No. 892593-0003-WO01temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature.

[0103] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of retinoid encapsulated in the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1.5 pM, as measured according to the total volume of the composition; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples.

[0004] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the concentration of retinoid encapsulated in the dendrimer is at least 1000 pM, as measured according to the total volume of the composition and / or the concentration of retinoid associated with the dendrimer is at least 1000 pM, as measured according to the total volume of the composition; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4Attorney Docket No. 892593-0003-WO01days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples.

[0105] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; and wherein the composition comprising about 1120 pM dendrimer or less.

[0106] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz DiffusionAttorney Docket No. 892593-0003-WO01Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; and wherein the composition comprising about 100 pM dendrimer or less.

[0107] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; wherein the composition comprising about 1120 pM dendrimer or less; and wherein the dendrimer is PAMAM G4-PYR dendrimer.

[0008] In an embodiment, the composition may comprise a dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples and / or at least 50%, by weight, of the retinoid associated withAttorney Docket No. 892593-0003-WO01dendrimer permeates skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; wherein the composition comprising about 100 pM dendrimer or less; and wherein the dendrimer is PAMAM G4-PYR dendrimer.

[0109] Compositions may include but are not limited to the following:(1) a composition comprising about 4.5 pM dendrimer, about 1.5 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(2) a composition comprising about 4.5 pM dendrimer, about 2500 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(3) a composition comprising about 1120 pM dendrimer, about 1.5 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(4) a composition comprising about 1120 pM dendrimer, about 2500 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(5) a composition comprising about 4.5 pM PAMAM G4-PYR dendrimer, about 1.5 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(6) a composition comprising about 4.5 pM PAMAM G4-PYR dendrimer, about 2500 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol;(7) a composition comprising about 1120 pM PAMAM G4-PYR dendrimer, about 1.5 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol; and(8) a composition comprising about 1120 pM PAMAM G4-PYR dendrimer, about 2500 pM retinoid, and optionally about 10 pM to about 1000 pM resveratrol.3. Methods for Preparing the Compositions

[0110] The disclosure also provides a method of making the compositions. The method may comprise mixing retinoid, dendrimer, and a solvent to form a mixture comprising the dendrimer-retinoid complex; and filtering the mixture. The method may further comprise removing the solvent after forming the mixture comprising the dendrimer-retinoid complex, to form a solid mixture; and adding water to the solid mixture.Attorney Docket No. 892593-0003-WO01

[0111] Suitable equipment for mixing the components include, but are not limited to, magnetic stir bars in conjunction with magnetic stir plates, stirring rods, overhead stirrers, centrifuges, sonicators and shakers. Use of this equipment may promote the dissolving of retinoid in the solvent. The components of the composition may be mixed for up to about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 24 hours.

[0112] Filtration of the final composition may remove excess solids such as free retinoid not encapsulated in and / or associated with the dendrimer-retinoid complex. Suitable equipment for filtering the composition include, but are not limited to, syringe filters, Buchner funnels, fine frit filters, medium frit filters, centrifugal filter, sep-pack columns.

[0113] Without being bound by scientific theory, it is believed that substantially ail dendrimer, which is sufficiently soluble in water, passes through any filtration device used and is part of the final composition. Therefore, it is assumed that all dendrimer used in the first step of the process for making the composition is part of the composition.

[0114] The method may comprise mixing retinoid, dendrimer, and water to form a mixture comprising the dendrimer-retinoid complex; and filtering the mixture to form the composition.

[0005] One embodiment of the method may include adding an excess of retinoid (relative to dendrimer) to a solution of the dendrimer in water in a suitable container. To promote dissolution of the retinoid, the mixture may be sonicated for up to about 10 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. Sonication may be repeated up to about 2 times, about 3 times, about 4 times, or about 5 times. To further promote dissolution of the retinoid, the mixture may be shaken up to about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 24 hours. The mixture may be filtered (e.g., through a syringe filter) to form the composition.Attorney Docket No. 892593-0003-WO01

[0116] The method may comprise mixing retinoid, dendrimer, and water to form a mixture comprising the dendrimer-retinoid complex; removing water after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition.

[0017] To generate a composition that improves the solubility of retinoid and contains a therapeutically effective amount of the dendrimer-retinoid complex, the retinoid may be additionally solubilized in the process so that it may further contact and bind to the dendrimer. One method for further solubilizing the retinoid in the initial mixture with dendrimer is by adding a solvent in addition to water. The additional solvent may be an organic solvent, such as a C Ca alcohol. A C1-C4 alcohol may include methanol, ethanol, propanol, butanol, or a combination thereof.

[0118] The method may comprise mixing retinoid, dendrimer, and a solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and a Ci-04 alcohol.

[0119] Another embodiment of the method may include adding an excess of retinoid (relative to dendrimer) to a solution of the dendrimer in water and methanol. To promote dissolution of the retinoid, the mixture may be sonicated for up to about 10 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. Sonication may be repeated up to about 2 times, about 3 times, about 4 times, or about 5 times. To further promote dissolution of the retinoid, the mixture may be shaken up to about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 24 hours. Solvent may be removed from the resulting solution via lyophilization to remove all water and methanol and form a solid mixture. Water may be added to the solid mixture. The mixture may be manually agitated, such as by the use of a shaker, to promote dissolution and dispersion of the solid. The mixture may be shaken up to about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours,Attorney Docket No. 892593-0003-WO01about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 24 hours. The mixture may be filtered (e.g., through a syringe filter) to form the composition.

[0120] The removal of solvent may include, but is not limited to, removal techniques such as evaporation, evaporation under reduced pressure, rotary evaporation, rotary evaporation under reduced pressure, sublimation, spray drying, atomization drying and lyophilization.

[0001] The solid mixture may be a powder, a sticky solid, a gum, an amorphous solid, a crystalline solid, an oil, a foam, or a combination thereof.

[0122] By adjusting the amount of the C1-C4 alcohol used in the method for making the composition, greater solubilities of the dendrimer-retinoid complex of the composition may be achieved. A significant increase in solubility of the retinoid may be achieved by using less than 50%, by volume, of the C1-C4 alcohol. By using less than 40%, by volume, of the C1-C4 alcohol, greater solubility of the retinoid may be achieved. Specifically, by using less than 20%, by volume, of the C1-C4 alcohol, greater solubility of the retinoid may be achieved. More specifically, by using less than 15%, by volume, of the C1-C4 alcohol, greater solubility of the retinoid may be achieved. It was surprisingly discovered that methanol may be more effective than ethanol for enhancing solubility of the retinoid. In particular, methanol may be more effective than ethanol for enhancing solubility of the retinoid when used in an amount, by volume, of about 1% to about 50%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10%.

[0123] The solvent may comprise less than about 50%, by volume, the C1-C4 alcohol. The solvent may comprise less than about 49%, less than about 48%, less than about 47%, less than about 46%, less than about 45%, less than about 44%, less than about 43%, less than about 42%, less than about 41%, less than about 40%, less than about 39%, less than about 38%, less than about 37%, less than about 36%, less than about 35%, less than about 34%, less than about 33%, less than about 32%, less than about 31%, less than about 30%, less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than aboutAttorney Docket No. 892593-0003-WO0125%, less than about 24%, less than about 23%, less than about 22%, less than about 21%, less than about 20%, less than about 19%, less than about 18%, less than about 17%, less than about 16%, less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, by volume, the Ci-C4alcohol. The solvent may comprise at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%, by volume, the Ci-C4alcohol. The solvent may comprise about 5% to about 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 45% to about 50%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 35% to about 40%, about 35% to about 45%, or about 40% to about 45%, by volume, the Ci-C4alcohol.

[0124] The solvent may comprise about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5%, by volume, the Ci-C4alcohol.

[0125] The solvent may comprise less than about 50%, by volume, methanol. The solvent may comprise less than about 49%, less than about 48%, less than about 47%, less than aboutAttorney Docket No. 892593-0003-WO0146%, less than about 45%, less than about 44%, less than about 43%, less than about 42%, less than about 41%, less than about 40%, less than about 39%, less than about 38%, less than about 37%, less than about 36%, less than about 35%, less than about 34%, less than about 33%, less than about 32%, less than about 31%, less than about 30%, less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than about 25%, less than about 24%, less than about 23%, less than about 22%, less than about 21%, less than about 20%, less than about 19%, less than about 18%, less than about 17%, less than about 16%, less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, by volume, methanol. The solvent may comprise at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%, by volume, methanol. The solvent may comprise about 5% to about 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 35% to about 50%, about 40% to about 50%, about 45% to about 50%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 35% to about 40%, about 35% to about 45%, or about 40% to about 45%, by volume, methanol.

[0126] The solvent may comprise about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, aboutAttorney Docket No. 892593-0003-WO0121%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5%, by volume, methanol.

[0127] The solvent may further comprise water. The balance may be water.

[0128] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising a dendrimer-retinoid complex; removing solvent from the mixture to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol.

[0129] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising a dendrimer-retinoid complex; removing solvent from the mixture to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and ethanol.

[0130] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising a dendrimer-retinoid complex; removing solvent from the mixture to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises less than about 50%, by volume, methanol.

[0131] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and ethanol; wherein the solvent comprises less than about 50%, by volume, ethanol.

[0132] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 5% to about 20%, by volume, methanol.

[0133] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming theAttorney Docket No. 892593-0003-WO01mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and ethanol; wherein the solvent comprises about 5% to about 20%, by volume, ethanol.

[0134] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 10%, by volume, methanol.

[0135] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and ethanol; wherein the solvent comprises about 10%, by volume, ethanol.

[0136] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 5%, by volume, methanol.

[0137] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and ethanol; wherein the solvent comprises about 5%, by volume, ethanol.

[0138] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex, to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 10%, by volume, methanol; wherein the composition comprises the dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition isAttorney Docket No. 892593-0003-WO01encapsulated in the dendrimer, and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid, and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature, and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples, and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; and wherein the composition comprising about 1120 pM dendrimer or less.

[0139] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 10%, by volume, methanol; wherein the composition comprises the dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer, and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid, and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature, and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples, and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing FranzAttorney Docket No. 892593-0003-WO01Diffusion Cells and rat skin samples; and wherein the composition comprising about 100 pM dendrimer or less.

[0140] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 10%, by volume, methanol; wherein the composition comprises the dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer, and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoid encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid, and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature, and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in the dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples, and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; wherein the composition comprising about 1120 pM dendrimer or less; and wherein the dendrimer is PAMAM G4-PYR dendrimer.

[0141] In an embodiment, the method may comprise mixing retinoid, dendrimer, and solvent to form a mixture comprising the dendrimer-retinoid complex; removing solvent after forming the mixture of the dendrimer-retinoid complex to form a solid mixture; adding water to the solid mixture; and filtering the mixture to form the composition; wherein the solvent is a mixture of water and methanol; wherein the solvent comprises about 10%, by volume, methanol; the composition may comprise the dendrimer-retinoid complex, the composition being essentially free of organic solvent; wherein the composition comprises water; wherein the pH of the composition is about 7; wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer, and / or at least 0.5%, by weight, of the retinoid in the composition is associated with the dendrimer; wherein the aqueous solubility of the retinoidAttorney Docket No. 892593-0003-WO01encapsulated in the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid, and / or the aqueous solubility of the retinoid associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat retinoid; wherein the retinoid encapsulated in the dendrimer degrades less than 10% after 4 days at ambient temperature, and / or the retinoid associated with the dendrimer degrades less than 10% after 4 days at ambient temperature; wherein at least 50%, by weight, of the retinoid encapsulated in dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples, and / or at least 50%, by weight, of the retinoid associated with dendrimer permeates the skin in 20 minutes or less in a transdermal permeation study utilizing Franz Diffusion Cells and rat skin samples; wherein the composition comprising about 100 pM dendrimer or less; and wherein the dendrimer is PAMAM G4-PYR dendrimer.

[0142] In an embodiment, the method may also include a final step wherein the composition is dried to a solid form.

[0143] The removal of solvent may include removal techniques such as evaporation, evaporation under reduced pressure, rotary evaporation, rotary evaporation under reduced pressure, sublimation, evaporation with stirring and lyophilization. The solid mixture may be a powder, a sticky solid, a gum, an amorphous solid, a crystalline solid, an oil, a foam, or a combination thereof.

[0144] In an embodiment, dendrimer–retinol and dendrimer–surfactant (such as TPGS)–retinol formulations may be prepared and subsequently sprayed into dry, storage-stable powders by spray drying in the presence of one or more pharmaceutically acceptable stabilizing excipients. The pharmaceutically acceptable excipients may include, but are not limited to, trehalose dihydrate, sucrose, mannitol, or combinations thereof. The dendrimer-based retinol formulations may be mixed or admixed with the selected excipient(s) to form a feed solution or suspension and subjected to spray drying to yield free-flowing, amorphous or semi-crystalline powders. The resulting spray-dried compositions may be configured to provide enhanced long¬ term stability of retinol, protection against oxidation and degradation, and preservation of dendrimer–retinol and dendrimer–surfactant–retinol integrity during storage. The dry powders may be readily and rapidly reconstituted in aqueous or hydroalcoholic media prior to use, forming uniform dispersions suitable for pharmaceutical, cosmeceutical, nutraceutical, or topical administration.Attorney Docket No. 892593-0003-WO014. Pharmaceutical Compositions

[0145] The disclosure is further directed to pharmaceutical compositions. The pharmaceutical compositions may comprise the compositions set forth herein, as well as one or more pharmaceutically acceptable carrier, and / or adjuvants. The pharmaceutically acceptable carrier is non-toxic. The pharmaceutical compositions can be formulated for any type of administration, including, but not limited to, oral administration in solid or liquid form, for parenteral injection or for topical administration.

[0146] The pharmaceutically acceptable carrier may be an inert solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.

[0147] The pharmaceutically acceptable carrier may be a natural or a man-made carrier. A natural pharmaceutical carrier requires no chemical or biological manipulation into a carrier state. Some examples of materials which can serve as natural pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; agar; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions, and antioxidants can also be present in the composition, according to the judgment of one skilled in the art of formulations

[0148] The pharmaceutically acceptable carrier may be a synthesized man-made carrier. Some examples of synthesized pharmaceutically acceptable carriers may be cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; propylene glycol; esters such as ethyl oleate and ethyl laurate; buffering agents such as magnesium hydroxide and aluminum hydroxide, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of one skilled in the art of formulations5. Administration

[0149] The pharmaceutical compositions of can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, ocularly,Attorney Docket No. 892593-0003-WO01topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally”, as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection, and infusion.

[0150] Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate, or suitable mixtures thereof. Suitable fluidity of the composition may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0151] These compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.a. Solid Dose Pharmaceutical Compositions

[0152] The pharmaceutical composition may be a solid dose formulation. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, one or more compositions of the disclosure is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate,Attorney Docket No. 892593-0003-WO01magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0153] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0154] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of materials which can be useful for delaying release of the active agent can include polymeric substances and waxes.b. Topical / Transdermal Pharmaceutical Compositions

[0155] The pharmaceutical composition may be in the form of a topical or transdermal composition. Dosage forms for topical or transdermal administration of the composition include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. A desired composition of the disclosure is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this disclosure.

[0156] The ointments, pastes, creams, and gels may contain, in addition to an active composition of this disclosure, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0157] Powders and sprays can contain, in addition to the compositions of this disclosure, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0158] Dosage forms for topical administration of a composition of this disclosure include powders, sprays, ointments, and inhalants. The active composition is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, orAttorney Docket No. 892593-0003-WO01propellants, which can be required. Ophthalmic formulations, eye ointments, powders, and solutions are contemplated as being within the scope of this disclosure. Aqueous liquid compositions comprising compositions of the disclosure also are contemplated.6. Methods of Using the Composition

[0159] The present disclosure provides a method for treating and / or preventing disorders, diseases, or conditions by administering the compositions or pharmaceutical compositions described herein to a subject in need thereof. This includes treatment and / or prevention of disorders or conditions that can be treated or prevented by administration of retinoid and optionally resveratrol as described herein. In other words, administration of a composition or pharmaceutical composition described herein to a subject in need thereof may provide for curative treatment of such a disorder or condition, control the progression of such a disorder or condition, ameliorate the symptoms associated with such a disorder or condition, and / or reduce the risk for such a disorder or condition.

[0160] The pharmaceutical composition may be useful for treating and preventing certain disorders or conditions in humans and animals. Typically, treatment or prevention of such disorders or conditions can be affected by administering a composition of the disclosure, either alone or in combination with another active agent as part of a therapeutic regimen to a subject in need thereof.

[0161] The compositions and pharmaceutical compositions may be used to treat and / or prevent cancer, cardiovascular disease, cardiac failure, diabetes, Alzheimer’s disease, Parkinson’s disease and other brain diseases, fatty liver disease, obesity, cataracts, osteoporosis, muscle wasting, sleep disorders, acoustic trauma, inflammatory disease, psoriasis, arthritis, colitis, aging, viral disease, reproductive disease, and skin conditions or disorders.

[0162] Examples of skin conditions or disorders include skin cancer, hyperpigmentation, inflammation, burns, psoriasis, eczema, cellulitis, hives, dermatitis, acne, aging, UV light mediated aging, an inflammatory disorder, or a hyper-proliferative disorder.

[0163] To treat and / or prevent skin conditions or disorders such as those listed above, the pharmaceutical composition may be topically administered to the skin or mucous membrane.Attorney Docket No. 892593-0003-WO01

[0164] The present disclosure also provides a method of providing personal and / or cosmetic care, the method comprising topically administering the compositions or pharmaceutical compositions as described herein to a skin or mucous membrane of a subject in need thereof. The methods of providing personal and / or cosmetic care may further comprise administering an anti-aging product, a body lotion, a body treatment, a toner, a facial moisturizer, a facial treatment, makeup foundation, or any skin care product.a. General Dosage Regimens

[0165] When used in the above or other treatments, a therapeutically effective amount of one of the compositions disclosed can be employed. The phrase "therapeutically effective amount" of the composition of the disclosure means a sufficient amount of the composition to bring about a desired in vivo effect and treat disorders or conditions, at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound and / or composition employed; the specific compound and / or composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound and / or composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound and / or composition employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound and / or composition at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0166] The pharmaceutical composition can be between 1 pg to 10 mg active component / kg body weight / time and can be 20 pg to 10 mg component / kg body weight / time. The pharmaceutical composition can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or31 days. The pharmaceutical doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses.b. Combination TherapiesAttorney Docket No. 892593-0003-WO01

[0167] The composition comprising the dendrimer-retinoid complex, as described above may be used in combination with one or more additional therapeutic agents or drugs in the treatment, prevention, control, amelioration, or reduction of risk of disorders or conditions for which the composition or the other drugs may have utility as described above, where the combination of the drugs together are safer or more effective than either drug alone. Such additional therapeutic agents or drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the composition. When the composition is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the composition is preferred. However, the combination therapy may also include therapies in which the composition and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compositions of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients, in addition to the composition comprising the dendrimer-retinoid complex. The above combinations include combinations of a composition of the present disclosure not only with one other active compound, but also with two or more other active compounds. For example, the composition can be combined with a variety of different anti-cancer drugs such as chemotherapeutics, anti-tumor agents, and anti-proliferative agents, such as fluorouracil, imiquimod, vismodegib, aldesleukin, dacarbazine, vemurafenib (Zelboraf), and ipilimumab.

[0168] The weight ratio of the composition of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a composition of the present disclosure is combined with another agent, the weight ratio of the composition of the present disclosure to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a composition of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0169] The compositions and processes of the disclosure will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the disclosure.Attorney Docket No. 892593-0003-WO017. Examples

[0170] The foregoing may be better understood by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention. The present disclosure has multiple aspects and embodiments, illustrated by the appended non-limiting examples.

[0171] Formulations of the dendrimer-retinoid complexes are referred to herein as a weight / volume %. This weight / volume % is defined as milligram (mg) of dendrimer per total microliters (pL) of the formulation. For example, a 1% formulation comprises 10 mg in 1,000 pL, and a 0.1% formulation comprises 1 mg in 1,000 pL. The 1% formulation has a dendrimer concentration of 700 pM, and the 0.1% formulation has a dendrimer concentration of 70 pM.Example 1Analytical HPLC method for estimation of Vitamin A (i.e., Retinol)

[0172] The estimation of vitamin A (i.e., retinol) was carried out using HPLC system (Alliance ™-2695, Waters, Milford, MA) with a Waters XBridge C18 reverse phase column (4.6 mm × 150 mm, 3.5 pm), equipped with photodiode array detector-2996 and refractive index detector-2414. The mobile phase consisted of acetonitrile (95%) and water (5%) at pH 7. The flow rate was adjusted to 0.5 mL / min having an injection volume of 10 pL and the column temperature was maintained at 25±0.5 °C. The retinol eluate from the column was monitored at 324.8 nm using Empower™ 2 chromatography data software. The retention time for retinol was found to be 7.438±0.025 minute. The calibration graph was rectilinear in the concentration range of 10 pg / mL to 100 pg / mL with a correlation coefficient of 0.995 (FIGS. 2A-B). The inter and intraday accuracy and precision was within ≤ 5%.Example 2Formulation Development: Dendrimer-Retinol (Aqueous solution of Retinol concentrate)

[0173] Dendrimer-Retinol complexes were formulated according to methods (with modifications) disclosed in U. S. Patent No. 9,855,223, U. S. Patent No. 10,406,119, U. S. Patent No. 11,110,068, and U. S. Patent No. 11,931,321, each of which is incorporated herein by reference. Dendrimer-retinol complexes can be prepared by two methods:Attorney Docket No. 892593-0003-WO01

[0174] Protocol 1 (0.1% w / v formulation): Briefly, 5 mg of retinol was added into 20 mL amber color vials containing a total volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and deionized water preadjusted to pH 7.0 using 0.1 N HCI. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0175] Protocol 2 (0.1% w / v formulation): Briefly, 5 mg of retinol was added into 20 mL amber color vials containing a total volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and deionized water preadjusted to pH 7.0 using 0.1 N HCI. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0176] 0.1% w / v Dendrimer Formulations: An examination will be made into the effect that a decreased amount of PAMAM dendrimer would have on retinoid solubility in water. These formulations will be prepared according to Protocol 1 and Protocol 2. Each formulation will contain 1 mg PAMAM PYR dendrimer as 0.1% w / v preparations described above and may vary up to 10 mg PAMAM PYR as 1% w / v. The method of preparation is otherwise identical between the 1% and 0.1% formulations.

[0177] pH 2.5 Formulations: An examination of the effect of pH on the solubility of retinoid in the PAMAM dendrimer formulations will be approached in two ways. Two 0.1% dendrimer formulations will be created according to Protocol 2. In the first formulation, HCI will be used to lower the pH of the PAMAM PYR dendrimer to 2.5 prior to the introduction of retinoid to make aAttorney Docket No. 892593-0003-WO01formulation. In the second formulation the pH of dendrimer-retinoid prepared at pH 7.0 will be lowered to 2.5. Additionally, a control formulation of retinoid in water with the pH lowered to 2.5 will be analyzed.Example 3Formulation Development: Dendrimer-Retinol with Excipient

[0178] Further, 5 mg of retinol dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 5 mg of vitamin E-TPGS (D-a-Tocopheryl Polyethylene Glycol Succinate). Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0179] A separate formulation was again made with 5 mg of retinol dissolved in 200 pL of ethanol and adding into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 50 mg of Vitamin E-TPGS (D-a-Tocopheryl Polyethylene Glycol Succinate). Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.Example 4Attorney Docket No. 892593-0003-WO01Formulation Development: Dendrimer-Retinol with Paraffin Oil

[0180] 5 mg of retinol was dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 0.1% paraffin oil. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.Example 5Formulation Development: Nanosuspension of Dendrimer-Retinol with Surfactants (Tween 80 and Span 80)

[0181] 5 mg of retinol was dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 0.1% Tween 80. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0182] 5 mg of retinol was dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 0.1 % Span 80. Each formulation was sonicated for 2 minutes in four 30-secondAttorney Docket No. 892593-0003-WO01increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0183] 5 mg of retinol was dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made with a combination of 5 mg of dendrimer and (0.1%) of Tween 80, and Span 80. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. The insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.Example 6Formulation Development: Dendrimer-Retinol with Surfactants & Excipients

[0184] 5 mg of retinol was dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer, 5 mg TPGS, 0.1% Tween 80, and 0.1% Span 80. Each formulation was sonicated for 2 minutes in four 30-second increments. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova® 4230, New Brunswick Scientific, Edison, NJ) and then allowed to stand at room temperature for 12 hours to attain equilibrium. Vials underwent lyophilization to remove water and methanol and were reconstituted with water. Formulations were placed in an orbital shaker at an ambient temperature and shaken for 4 hours. TheAttorney Docket No. 892593-0003-WO01insoluble retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of solubility. Controls were prepared by adding pure retinol in vial containing 5 mL deionized water.

[0185] Thus, the solubility profile of retinol associated with dendrimer, TPGS, paraffin oil, Tween 80, Span 80, and their combination is represented in TABLE 1.TABLE 1. The Solubility profile of retinol associated with dendrimer, TPGS, paraffin oil, Tween 80, Span 80, and their combination. _ _ _Formulation Code with (0.1% w / v Dendrimer;Formulation Solubility (pg / mL) i.e. 1 mg / mL Dendrimer)Trans-Retinol Aqueous Solution BQL-HPLC* Dendrimer-Retinol Aqueous Solution 0.5 Dendrimer-Retinol-TPGS Aqueous Solution 208.96 Dendrimer-Retinol-Paraffin Oil Emulsion 150.80 Dendrimer-Retinol-Tween 80 Emulsion 899.37 Dendrimer-Retinol-Span 80 Emulsion 575.30 Dendrimer-Retinol-Tween 80-Span 80 Emulsion 615.23 Dendrimer-Retinol-Tween 80-Span 80-TPGS Emulsion 713.47Formulation Code with (1% w / v Dendrimer; i.e.Formulation Solubility (pg / mL) 10 mg / mL Dendrimer)Dendrimer-Retinol-TPGS Aqueous Solution 1036.66*BQL-HPLC: Below the quantification limit of HPLC.Example 7Stability Studies

[0186] The long-term storage stability studies of Dendrimer-Retinol complexes were carried out in amber color vials at room temperature (20±2 °C / 60 ±5% RH) for a period of 365 days. The Retinol content was examined, and the stability profile was plotted as a function of time (days) (FIG. 3).

[0187] Briefly, In the case of Formulation A: 10 mg TPGS was dissolved in 1 mg / mL Dendrimer solution followed by addition of Retinol.Attorney Docket No. 892593-0003-WO01

[0188] In case of Formulation B: 1mg TPGS was dissolved in 1 mg / mL Dendrimer solution followed by addition of Retinol.

[0189] Thus, the comparative stability profile of Retinol associated with Dendrimer and TPGS, is represented in FIG. 3. The data suggests the adding of TPGS concentration (10 mg and 1mg) significantly impact Retinol stabilization and better stability in amber color vials at room temperature (20±2 °C / 60 ±5% RH) for a period of 365 days compared to native Retinol (which is not stable at room temperature). Formulation A comprising 10 mg TPGS and 1 mg dendrimer retains approximately 50.12% of retinol at Day 150 and 21.4% at Day 365, demonstrating sustained preservation of retinol over prolonged storage. In contrast, Formulation B comprising 1 mg TPGS and 1 mg dendrimer retains only 30.93% of retinol at Day 150 and declines to approximately 0.51% at Day 365, indicating substantially reduced stability. These data establish that higher TPGS content in combination with dendrimer significantly enhances protection of retinol against degradation during long-term storage. In certain embodiments, such formulations provide improved shelf life, reduced oxidative loss, and superior compositional integrity of retinol for pharmaceutical, cosmeceutical, nutraceutical, and topical applications.Example 8Solubility Studies

[0190] PAMAM G4-PYR, PAMAM G4-NH2, PAMAM-G4-OH and PAMAM G3.5-COOH dendrimers were used to prepare retinoid formulations. Of the above four dendrimers, PAMAM G4-PYR dendrimer, PAMAM G4-NH2, (0.1% w / v formulation) enhanced water solubility of neat retinoid using protocols 1 and 2. PAMAM-G4-OH and PAMAM-G3.5-COOH dendrimers showed slight water solubility enhancement of retinoid. Native retinol showed extremely low aqueous solubility (0.017 pg / mL, reported value). Complexation with PAMAM dendrimers markedly enhanced solubility, with G4-PYR showing the highest solubilization (0.24 pg / mL), followed by G4-NH2 (0.19 pg / mL), G4-OH (0.16 pg / mL), and G3.5-COOH (0.13 pg / mL). This trend indicates that surface functionality and internal cavity environment strongly influence retinol loading, with pyrrolidone- and amine-terminated dendrimers providing superior hydrophobic accommodation. (FIG. 4).

[0191] Additionally, retinol was complexed with (0.1% w / v) combinations of two PAMAM dendrimers, including G4-PYR + G4-NH2, G4-NH2+ G3.5-COOH, and G4-OH + G3.5-COOH,Attorney Docket No. 892593-0003-WO01as well as with three-dendrimer systems comprising G4-PYR + G4-OH + G3.5-COOH and G4-NH2+ G4-OH + G3.5-COOH, using the same preparation protocol. All formulations were allowed to equilibrate under controlled conditions to facilitate effective host-guest complexation. Further improvement in retinol solubility was observed when two dendrimers were combined. The G4-PYR + G4-NH2 system achieved the highest solubility (0.51 pg / mL), followed by G4-NH2 + G3.5-COOH (0.46 pg / mL) and G4-OH + G3.5-COOH (0.39 pg / mL). These results demonstrate a synergistic effect, where complementary surface chemistries enhance retinol partitioning and stabilization within the dendritic network (FIG. 5). The greatest enhancement was achieved using three-dendrimer combinations. G4-PYR + G4-OH + G3.5-COOH yielded the highest solubility (0.67 pg / mL), while G4-NH2 + G4-OH + G3.5-COOH also showed substantial improvement (0.54 pg / mL). This clearly indicates that multi-dendrimer architecture provides additive and cooperative effects, creating a more favorable microenvironment for retinol encapsulation (FIG. 6).

[0192] Solubility Profile of PAMAM G4 PYR Dendrimer. A solubility profile was created with different concentrations of PAMAM G4-PYR dendrimer (pH 7) in water using Protocol 1. The dendrimer concentrations were 0, 0.25, and 1 mg / mL. An increase in retinoid solubility associated with the dendrimer was observed with increasing concentrations of PAMAM G4-PYR dendrimer in the formulation at pH 7.

[0193] Each formulation was sonicated for 2 minutes in 30-second increments (four times) and placed in an orbital shaker overnight at ambient temperature. Formulations then underwent lyophilization to remove all water and organic solvent and reconstituted with 1000 pL Millipore water. Formulations were placed in an orbital shaker for 4 hours at an ambient temperature and then filtered through a 13 mm membrane syringe filter and analyzed for dendrimer-associated drug by HPLC / UV spectroscopy at 324.8 nm.Example 9Antioxidant Efficacy Evaluation of PAMAM-Retinoid

[0194] DPPH Assay: Antioxidant efficacy was determined by a DPPH (1, 1 -diphenyl-2-picrylhydrazyl) assay, in which changes in color (from a deep violet to light yellow) was measured at 515 nm using a UV / visible light spectrophotometer. 0.1% PAMAM G4-PYR dendrimer (pH 7)-retinoid complexes were compared against the control of retinoid in water, MeOH and DMSO alone. Measurements were taken at 0.25, 0.5, 1, 2, and 19 hours. FreeAttorney Docket No. 892593-0003-WO01retinol exhibited negligible DPPH scavenging activity in aqueous medium due to its poor solubility, while moderate activity was observed in methanol (18.36%) and DMSO (22.41%) at 100 pM (equivalent to 28.65 pg / mL retinol), in contrast, dendrimer-based systems significantly enhance antioxidant efficacy, with Dendrimer-Retinol and Dendrimer-TPGS-Retinol demonstrating 31.56% and 39.49% inhibition, respectively, highlighting the role of dendrimer- mediated solubilization and synergistic stabilization (FIG. 7).Example 10Transdermal Permeation Study of PAMAM-Retinoid

[0195] Transdermal permeation studies were conducted using Franz Diffusion Cells (FDC) and rat skin samples. The diffusion cells with a 5 mL receptor chamber was provided by Permegear. The formulations examined were a 0.1% PAMAM-G4 PYR dendrimer-retinoid formulation, a 0.1% PAMAM-G4 PYR dendrimer-TPGS retinoid formulation, and a control of free retinoid in water. For each formulation, the receptor chamber of the FDC was filled with 5 mL of a PBS (pH 7.4): methanol 90:10 mixture. Skin samples from Dahl Salt Sensitive rats were cut to size and placed at the interface of the donor and receptor chambers. 0.5 mL of the desired formulation was placed in the donor chamber and the FDC was stirred on a stir plate set to 6 (on an arbitrary 10-point scale). At various intervals over a 24-hour period 400 pL was removed from the receptor chamber by means of the sampling arm and analyzed by HPLC. The volume was replaced by an equal amount of fresh PBS: Methanol mixture. After 24 hours, an aliquot was taken from the donor chamber and the skin was removed and retinoid recovered by soaking skin in 2 mL methanol and sonicating for 10 minutes followed by filtration and HPLC analysis as discussed before. The permeability of free retinol was negligible and remained below the limit of quantification throughout the study, confirming its poor aqueous permeability. In contrast, dendrimer-retinol exhibited a time-dependent increase in permeability from 7.45 % at 0.5 h to 25.53% at 12 h. Notably, dendrimer-TPGS-retinol demonstrated the highest enhancement, increasing from 9.59% at 0.5 h to 35.58% at 12 h. This indicates that dendrimer significantly improves retinol permeability, further amplified by TPGS-mediated transport facilitation (FIG. 8).

[0196] Additional transdermal permeation studies were performed that examine the effects of the dendrimer on a retinoid suspension. For these studies, a 1% PAMAM G4-PYR dendrimer-retinoid formulation was prepared according to Protocol 2 except that the formulationAttorney Docket No. 892593-0003-WO01was not filtered through 13 mm syringe filter prior to being added to the donor compartment, leaving a suspension. A control suspension was prepared in a similar manner, without filtration. These formulations were analyzed and compared according to the procedures described above.

[0197] Strat-M® membrane (EMD, Millipore) is a synthetic membrane-based model with diffusion characteristics well-correlated to human skin. Strat-M® membrane is used as a screening tool for transdermal diffusion studies in the development of cosmetic products. The preceding permeation studies was conducted using Strat-M® membranes.Example 11Dissolution Studies

[0198] Dissolution of retinoid in simulated gastric (pH 1.2) and intestinal environments (pH 6.8) was examined. 1 mL of a 0.1% PAMAM G4-PYR dendrimer-retinoid formulation and 1 mL of a 0.1% PAMAM-G4 PYR dendrimer-TPGS retinoid formulation were prepared using Protocol 2 and analyzed via HPLC. The formulation was divided into 2 equal aliquots and lyophilized. Simulated gastric and intestinal fluids were prepared, with the simulated gastric fluid consisting of HCI, NaCI, Pepsin, and water while the simulated intestinal fluid consisted of NaOH, KH2PO4, and water. 10 mL of these simulated solutions were added to all the above lyophilized formulations, and the fluids were stirred at a low speed (1 on an arbitrary 10-point scale stir plate). This experiment was protected from light. At various time points, 0.5 mL aliquots of fluid were removed from the chambers and analyzed via HPLC. The volume removed was replaced with fresh simulated fluid. Control formulations of retinoid alone, was analyzed simultaneously and compared to the dendrimer-containing formulations.

[0199] At pH 1.2 (simulated gastric conditions), free retinol showed almost negligible dissolution, with only 0.23% at 2 h and 0.26% at 4 h, confirming its extremely poor aqueous solubility. In contrast, dendrimer-retinol exhibited a marked improvement, dissolving 21.54% at 2 h and 35.98% at 4 h. A further enhancement in dissolution was observed with dendrimer- TPGS-retinol, which achieved 31.45% dissolution at 2 h and 47.52% at 4 h. This demonstrates that dendrimer significantly improves retinol dissolution under acidic conditions, and TPGS provides an additional synergistic solubilization effect. At pH 6.8 (simulated intestinal conditions), a similar but more pronounced trend was observed. Free retinol again remained practically insoluble (0.34% at 2 h and 0.39% at 4 h), whereas dendrimer-retinol achieved 39.52% and 46.71% dissolution at 2 h and 4 h, respectively. The highest performance wasAttorney Docket No. 892593-0003-WO01recorded for dendrimer-TPGS-retinol, with 41.53% at 2 h and 55.62% at 4 h. Overall, these results clearly demonstrate that dendrimer-based delivery systems, particularly when combined with TPGS, substantially enhance retinol dissolution across both gastric and intestinal pH, supporting their potential for improved oral bioavailability. (FIGS. 9A-B).Example 12Dendrimer-Drug Complex as a Solid Dosage Form

[0200] Dendrimer (0.1%)-Resveratrol and Dendrimer (0.1%)-Retinol formulations were prepared by protocol 1 and methods described above. The drug concentration was estimated by HPLC. The formulation was divided into 1 mL aliquots and 5% and 1% cryoprotectant (mannitol, sucrose, trehalose) was added, freeze dried, and lyophilized overnight. The lyophilized powder was reconstituted with 1.1 mL water, stirred, and drug concentration was estimated by HPLC again. Drug concentration recovered was calculated as a percentage (TABLE 2). Almost 100% of the drug (active ingredient) was recovered in the solid forms with cryoprotectants.TABLE 2. Resveratrol recovery.Resveratrol (RSV) Recovered (compared to the original Lyophilized Formulations formulation)5% Cryoprotectant 1% Cryoprotectant D-RSV Alone 99% 100%D-RSV+ Trehalose Dihydrate 100% 100 %D-RSV+ Sucrose 100% 100 %D-RSV+ Mannitol 99% 100 %Example 13Analytical HPLC Method for Simultaneous Estimation of Resveratrol and Vitamin A (i.e.,Retinol)

[0201] The estimation of resveratrol and vitamin A (i.e., retinol) was carried out using HPLC system (Alliance-2695, Waters, USA) with a Waters XBridge C18 reverse phase column (4.6 xAttorney Docket No. 892593-0003-WO01150 mm, 3.5 pm), equipped with photodiode array detector-2996 and refractive index detector- 2414. The mobile phase consisted of acetonitrile (95%) and water (5%) at pH 7. The flow rate was adjusted to 0.5 mL / min having an injection volume of 10 pL and the column temperature was maintained at 25±0.5 °C. The retention time for resveratrol and retinol was found at 3.042±0.025 and 7.332 ±0.025 minute. The calibration graph was rectilinear in the concentration range of 10 pg / mL to 100 pg / mL with a correlation coefficient of 0.994. The inter and intraday accuracy and precision was within ≤ 5% (FIGS. 10A-B).Example 14Analytical HPLC Method for Estimation of Vitamin C (i.e., Ascorbic Acid)

[0202] An HPLC method was developed to analyze ascorbic acid in deionized (DI) water. A calibration graph was prepared as following: Waters XBridge C18 reverse phase column (4.6 mm × 150 mm, 3.5 pm), mobile phase was 0.15 mM EDTA and 25 mM NaH2PO4. Flow rate was 1 mL / min at 265 nm and concentration range was 10-100 pg / mL.Example 15Formulation Development: Dendrimer-Resveratrol and Vitamin A (i.e., Retinol; Aqueous solution of Resveratrol and Retinol Concentrate)

[0203] Dendrimer-resveratrol and retinol complexes were formulated according to methods (with modifications) disclosed in U. S. Patent No. 9,855,223, U. S. Patent No. 10,406,119, U. S. Patent No. 11,110,068, and U. S. Patent No. 11,931,321, each of which is incorporated herein by reference. Briefly, 5 mg of each resveratrol and retinol was added into 20 mL amber color vials containing a total volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and deionized water preadjusted to pH 7.0 using 0.1 N HCI. These vials were shaken in dark at 37±0.5 °C for 12 hours in an incubator shaker (Innova 4230, New Brunswick Scientific, USA) and then allowed to stand at room temperature for 12 hours to attain equilibrium. The insoluble resveratrol and retinol in supernatant was removed by filtration through a 13 mm membrane syringe filter. Aliquots (1 mL) of filtrates were diluted with appropriate quantity of acetonitrile and injected into HPLC for estimation of their concentration. Controls were prepared by adding pure resveratrol and retinol in vial containing 5 mL deionized water.Example 16Attorney Docket No. 892593-0003-WO01Formulation Development: Dendrimer-Resveratrol-Retinol with Excipients such as Vitamin E and Vitamin C

[0204] Further, 5 mg of each resveratrol and retinol dissolved in 200 pL of ethanol and added into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 5 mg of vitamin E-TPGS (D-a-Tocopheryl Polyethylene Glycol Succinate). The remaining steps were similar to the method described above.

[0205] A separate formulation was again made with 5 mg of each resveratrol and retinol dissolved in 200 pL of ethanol and adding into 20 mL amber color vials containing same volume of 5 mL of deionized water, made of a combination of 5 mg of dendrimer and 50 mg of vitamin E-TPGS (D-a-Tocopheryl Polyethylene Glycol Succinate) and 5 mg of vitamin C. The remaining steps were similar to the method described above. The concentration profile of Resveratrol (RSV), Retinol (RET), Vitamin C (VC) associated with Dendrimer, TPGS, and their combination is represented in TABLE 3.TABLE 3. Concentration profiles of Resveratrol (RSV), Retinol (RET), Vitamin C (VC) associated with Dendrimer, TPGS, and their combinations. _Formulation Code with (0.1% w / v Dendrimer)Concentration (i.e. 1mg / mL Dendrimer) Formulation(pg / mL) Dendrimer-Retinol Retinol crystals BQL-HPLC* floating in waterDendrimer-Retinol-TPGS Aqueous Solution 209 Dendrimer-Resveratrol Aqueous Solution 109 Dendrimer- Resveratrol-TPGS Aqueous Solution 149 Dendrimer- Resveratrol-Retinol Aqueous Solution 75 & 1 Dendrimer- Resveratrol-Retinol- TPGS Aqueous Solution 125 & 169Formulation Code withConcentration 0.1% w / v Dendrimer & 1% w / v TPGS Formulation(pg / mL) (i.e. 1mg / mL Dendrimer & 10 mg / mL TPGSDendrimer-Retinol-TPGS Aqueous Solution 1036 Dendrimer-Resveratrol-TPGS Aqueous Solution 990 Dendrimer- Resveratrol- Retinol- TPGS Aqueous Solution 1004 (RSV) & 998(RET) Dendrimer- Resveratrol- Retinol- TPGS+ Vitamin C Aqueous Solution 1004 (RSV), 998(RET) & 1000 (VC) *BQL-HPLC: Below the quantification limit of HPLC.Attorney Docket No. 892593-0003-WO01Example 17Stability study: Dendrimer-Resveratrol-Retinol with Excipients such as Vitamin E and Vitamin C

[0206] Additionally, short-term stability studies were also carried out for combination of dendrimer-TPGS-retinol and resveratrol along with vitamin C in amber color vials at room temperature (20±2 °C / 60 ±5% RH) for a period of 60 days. The Retinol and Resveratrol content was examined, and the stability profile was plotted as a function of time (days). The data clearly demonstrated that the dendrimer-TPGS based retinol-resveratrol combination exhibits strong stability under room temperature, with both actives retaining high levels over time. While retinol alone is known to be chemically labile, the presence of resveratrol in the combination appears to support improved stability, as evidenced by 85.46% resveratrol retention and 49.87% retinol retention at Day 60. This highlights the protective and synergistic effect of co-formulation, validating the strategy of combining dendrimer-TPGS retinol with resveratrol to enhance overall formulation stability and shelf-life (FIG. 11).Example 18Dendrimer- Retinol coated Beads for better Stability

[0207] In certain embodiments, dendrimer-retinol and dendrimer-TPGS-retinol formulations will be prepared and subsequently sprayed into dry, storage-stable powders by spray drying in the presence of one or more pharmaceutically acceptable stabilizing excipients. The excipients may include, but are not limited to, trehalose dihydrate, sucrose, mannitol, or combinations thereof. The dendrimer-based retinol formulations are admixed with the selected excipient(s) to form a feed solution or suspension and subjected to spray drying to yield free-flowing, amorphous or semi-crystalline powders. The resulting spray-dried compositions are configured to provide enhanced long-term stability of retinol, protection against oxidation and degradation, and preservation of dendrimer-retinol and dendrimer-TPGS-retinol integrity during storage. The dry powders are readily and rapidly reconstituted in aqueous or hydroalcoholic media prior to use, forming uniform dispersions suitable for pharmaceutical, cosmeceutical, nutraceutical, or topical administration.Example 19On Demand Retinol release from a cleavable linkerAttorney Docket No. 892593-0003-WO01

[0208] In certain embodiments, retinol will be chemically conjugated to surface-functionalized dendrimers through one or more linker moieties to form dendrimer-retinol and dendrimer-TPGS retinol conjugates. The dendrimers may include, but are not limited to, NH2 terminated, COOH-terminated, OH-functionalized, and PYR-functionalized dendrimers. The hydroxyl functionality of retinol will be derivatized and coupled to reactive groups on the dendrimer surface through ester, carbonate, carbamate, amide, hydrazone, disulfide, peptide, or other suitable linker chemistries. In certain embodiments, the linker will be selected to be cleavable under predetermined physiological, enzymatic, pH-responsive, or redox conditions to enable controlled release of retinol from the dendrimer scaffold. The resulting conjugates will be designed to enhance solubility, stability, bioavailability, and targeted delivery of retinol. In further embodiments, the cleavable linker solution will be provided separately and combined with the dendrimer-retinol or dendrimer-TPGS retinol conjugates prior to administration or use.***

[0209] Although the disclosure above has been described in terms of various aspects and specific embodiments, it is not so limited. A variety of suitable alterations and modifications for operation under specific conditions will be apparent to those skilled in the art. It is therefore intended that the following claims be interpreted as covering all such alterations and modifications as fall within the spirit and scope of the disclosure.

[0210] All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.

[0211] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0212] Clause 1. A composition comprising a dendrimer-retinoid complex.

[0213] Clause 2. The composition of clause 1, wherein the dendrimer-retinoid complex is a retinoid associated with the dendrimer, a retinoid encapsulated by the dendrimer, a retinoid entrapped by the dendrimer, ora combination thereof.

[0214] Clause 3. The composition of clause 1, further comprising resveratrol, which forms a dendrimer-resveratrol complex with the dendrimer.Attorney Docket No. 892593-0003-WO01

[0215] Clause 4. The composition of any one of clauses 1-3, wherein the composition is essentially free of organic solvent.

[0216] Clause 5. The composition of any one of clauses 1-4, wherein the dendrimer comprises poly(amidoamine) (PAMAM), poly(propyleneimine) (PPI), poly(lysine), poly(glycerol) or a hyperbranched structure; wherein the hyperbranched structure is selected from the group consisting of dendrigrafts, polyesters, polyamides, and polyalcohols.

[0217] Clause 6. The composition of any one of clauses 1 -5, wherein the dendrimer comprises more than one dendrimer, which form a hybrid dendrimer.

[0218] Clause 7. The composition of any one of clauses 1-6, wherein the dendrimer comprises pyrrolidinone or amine surface groups.

[0219] Clause 8. The composition of any one of clauses 1 -7, wherein the dendrimer comprises pyrrolidinone surface groups.

[0220] Clause 9. The composition of any one of clauses 1-8, wherein the dendrimer comprises amine surface groups.

[0221] Clause 10. The composition of any one of clauses 1-9, wherein the dendrimer is a generation 0 to generation 10 dendrimer.

[0222] Clause 11. The composition of any one of clauses 1-10, wherein the dendrimer is a generation 4 PAMAM dendrimer comprising a diaminobutane, diamonoethane, or similar branched core.

[0223] Clause 12. The composition of any one of clauses 1-11, wherein the retinoid is retinol.

[0224] Clause 13. The composition of any one of clauses 1-12, wherein the composition comprises water.

[0225] Clause 14. The composition of any one of clauses 1-13, wherein the pH of the composition is from about 5 to about 8.

[0226] Clause 15. The composition of any one of clauses 1-14, wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer.Attorney Docket No. 892593-0003-WO01

[0227] Clause 16. The composition of any one of clauses 1-15, wherein the aqueous solubility of the retinoid in the dendrimer-retinoid complex is at least 10 times greater than the aqueous solubility of neat retinoid, as measured at pH 7; and the concentration of the retinoid in the dendrimer-retinoid complex is at least 1.5 pM, as measured according to the total volume of the composition.

[0228] Clause 17. The composition of any one of clauses 1-15, wherein the aqueous solubility of the retinoid in the dendrimer-retinoid complex is at least 10 times greater than the aqueous solubility of neat retinoid, as measured at pH 2.5.

[0229] Clause 18. The composition of any one of clauses 1-17, wherein the composition comprises: about 4.5 pM dendrimer and about 1.5 pM retinoid; about 4.5 pM dendrimer and about 2500 pM retinoid; about 1120 pM dendrimer and about 1.5 pM retinoid; or about 1120 pM dendrimer and about 2500 pM retinoid.

[0230] Clause 19. The composition of any one of clauses 1 and 3-18, wherein the composition further comprises resveratrol and at least 0.5%, by weight, of the resveratrol in the composition is associated with the dendrimer.

[0231] Clause 20. The composition of any one of clauses 1 and 3-19, wherein the aqueous solubility of the resveratrol associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat resveratrol, as measured at pH 7; and the concentration of resveratrol associated with the dendrimer is at least 10 pM, as measured according to the total volume of the composition.

[0232] Clause 21. The composition of any one of clauses 1 and 3-20, wherein the aqueous solubility of the resveratrol associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat resveratrol, as measured at pH 2.5.

[0233] Clause 22. The composition of any one of clauses 1 and 3-21, wherein the composition comprises: about 4.5 pM dendrimer and about 10 pM resveratrol; about 4.5 pM dendrimer and about 1000 pM resveratrol; about 1120 pM dendrimer and about 10 pM resveratrol; or about 1120 pM dendrimer and about 1000 pM resveratrol.

[0234] Clause 23. The composition of any one of clauses 1 and 3-22, wherein the composition comprises from about 4.5 pM to about 1120 pM dendrimer and from about 5 pM to about 5500 pM ascorbic acid.Attorney Docket No. 892593-0003-WO01

[0235] Clause 24. The composition of any one of clauses 1-23, wherein the composition further comprises an antioxidant selected from the group consisting of ascorbic acid, hyaluronic acid, niacinamide, niacin, bakuchiol, squalane, vitamin D3 (cholecalciferol, calcitriol) and salts and esters thereof, epichlorocatechin, including epigallocatechin-3-gallate (EGCG), epicatechin (EC), epicatechin-3-gallate (ECg), epigallocatechin (EGC), catechin, gallocatechin (GC), curcumin, kaempferol, quercetin, myricitin, tranexamic acid, axelaic acid, phenoxyethanol, allantoin, aloe vera, minerals (zinc oxide, titanium dioxide), avobenzone, octocrylene, homosalate, tocopherol and salts and esters thereof, butylated hydroxyl benzoic acids and salts thereof, butylated hydroxytoluene, butylated hydroxyanisole, 6-hydroxy-2, 5,7,8-tetramethylchroman-2-carboxylic acid, gallic acids and alkyl esters thereof, uric acid and salts and alkyl esters thereof, sorbic acid and salts thereof, amines, sulfhydryl compounds, sodium metabisulfite, dihydroxy fumaric acid and salts thereof, glutathione, ferulic acid, dimethylaminoethanol, peptides, coenzyme (CoQ10), exfoliants (alpha-hydroxy acid, alpha hydroxy carboxylic acids, beta-hydroxy acid, para alpha-hydroxy acid) and cannabinoids.

[0236] Clause 25. The composition of any one of clauses 1 -24, further comprising an additional therapeutic agent.

[0237] Clause 26. The composition of any one of clauses 1-25, wherein the composition comprises one or more surfactants selected from the group consisting of D-a-tocopheryl polyethylene glycol succinate (TPGS), paraffin oil, Tween 80, and Span 80.

[0238] Clause 27. The composition of clause 26, wherein the composition comprises from about 0.1% to about 10% of the one or more surfactants.

[0239] Clause 28. The composition of any one of clauses 1 -27, wherein stability of the retinoid in the dendrimer-retinoid complex is increased by about 2 times to about 100 times as compared to the stability of neat retinoid.

[0240] Clause 29. The composition of any one of clauses 19-28, wherein stability of the resveratrol associated with the dendrimer is increased by about 2 times to about 100 times as compared to the stability of neat resveratrol.

[0241] Clause 30. A pharmaceutical composition comprising a therapeutically effective amount of the composition of any one of clauses 1-29 and a pharmaceutically acceptable carrier.Attorney Docket No. 892593-0003-WO01

[0242] Clause 31. The composition of any one of clauses 1-30, wherein the dendrimer and the retinoid are coated on solid particles.

[0243] Clause 32. The composition of any one of clauses 1-31, wherein the retinoid is conjugated to the dendrimer with a labile linker.

[0244] Clause 33. The composition of clause 32, wherein the linker is cleaved before use of the composition.

[0245] Clause 34. The composition of any one of clauses 1 -33, wherein the dendrimer and the retinoid are a powder.

[0246] Clause 35. A method of treating a skin condition or disorder, the method comprising topically administering a therapeutically effective amount of the pharmaceutical composition of clause 30 to a skin or mucous membrane of a subject in need thereof.

[0247] Clause 36. The method of clause 35, wherein the skin condition or disorder is skin cancer, hyperpigmentation, inflammation, burns, psoriasis, eczema, cellulitis, hives, dermatitis, acne, aging, UV light mediated aging, an inflammatory disorder, or a hyper-proliferative disorder.

[0248] Clause 37. A method of providing personal and / or cosmetic care, the method comprising topically administering the composition of clause 1 or the pharmaceutical composition of clause 30 to a skin or mucous membrane of a subject in need thereof.

[0249] Clause 38. The method of clause 35, further comprising administering an anti-aging product, a body lotion, a body treatment, a toner, a facial moisturizer, a facial treatment, makeup foundation, or any skin care product.

[0250] Clause 39. A method of preparing a composition comprising a dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex, the method comprising: mixing retinoid, optionally resveratrol, dendrimer, and a solvent to form a mixture comprising the dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex; and filtering the mixture.Attorney Docket No. 892593-0003-WO01

[0251] Clause 40. The method of clause 39, further comprising: removing the solvent after forming the mixture comprising dendrimer-retinoid complex, optionally further comprising the dendrimer-resveratrol complex, to form a solid mixture; and adding water to the solid mixture.

[0252] Clause 41. The method of clause 39, further comprising: admixing one or more excipients with the mixture comprising dendrimer-retinoid complex, optionally further comprising the dendrimer-resveratrol complex, to form a suspension; and spray drying the suspension to form a powder.

[0253] Clause 42. The method of clause 41, wherein the one or more excipients are trehalose dihydrate, sucrose, mannitol, or combinations thereof.

Claims

Attorney Docket No. 892593-0003-WO01CLAIMS1. A composition comprising a dendrimer-retinoid complex.

2. The composition of claim 1, wherein the dendrimer-retinoid complex is a retinoid associated with the dendrimer, a retinoid encapsulated by the dendrimer, a retinoid entrapped by the dendrimer, or a combination thereof.

3. The composition of claim 1, further comprising resveratrol, which forms a dendrimer-resveratrol complex with the dendrimer.

4. The composition of any one of claims 1-3, wherein the composition is essentially free of organic solvent.

5. The composition of any one of claims 1-4, wherein the dendrimer comprises poly(amidoamine) (PAMAM), poly(propyleneimine) (PPI), poly(lysine), poly(glycerol) or a hyperbranched structure;wherein the hyperbranched structure is selected from the group consisting of dendrigrafts, polyesters, polyamides, and polyalcohols.

6. The composition of any one of claims 1 -5, wherein the dendrimer comprises more than one dendrimer, which form a hybrid dendrimer.

7. The composition of any one of claims 1-6, wherein the dendrimer comprises pyrrolidinone or amine surface groups.

8. The composition of any one of claims 1-7, wherein the dendrimer comprises pyrrolidinone surface groups.

9. The composition of any one of claims 1 -8, wherein the dendrimer comprises amine surface groups.

10. The composition of any one of claims 1-9, wherein the dendrimer is a generation 0 to generation 10 dendrimer.Attorney Docket No. 892593-0003-WO0111. The composition of any one of claims 1-10, wherein the dendrimer is a generation 4 PAMAM dendrimer comprising a diaminobutane, diamonoethane, or similar branched core.

12. The composition of any one of claims 1-11, wherein the retinoid is retinol.

13. The composition of any one of claims 1-12, wherein the composition comprises water.

14. The composition of any one of claims 1-13, wherein the pH of the composition is from about 5 to about 8.

15. The composition of any one of claims 1-14, wherein at least 0.5%, by weight, of the retinoid in the composition is encapsulated in the dendrimer.

16. The composition of any one of claims 1-15, wherein the aqueous solubility of the retinoid in the dendrimer-retinoid complex is at least 10 times greater than the aqueous solubility of neat retinoid, as measured at pH 7; and the concentration of the retinoid in the dendrimer-retinoid complex is at least 1.5 pM, as measured according to the total volume of the composition.

17. The composition of any one of claims 1-15, wherein the aqueous solubility of the retinoid in the dendrimer-retinoid complex is at least 10 times greater than the aqueous solubility of neat retinoid, as measured at pH 2.5.

18. The composition of any one of claims 1-17, wherein the composition comprises:about 4.5 pM dendrimer and about 1.5 pM retinoid;about 4.5 pM dendrimer and about 2500 pM retinoid;about 1120 pM dendrimer and about 1.5 pM retinoid; orabout 1120 pM dendrimer and about 2500 pM retinoid.

19. The composition of any one of claims 1 and 3-18, wherein the composition further comprises resveratrol and at least 0.5%, by weight, of the resveratrol in the composition is associated with the dendrimer.Attorney Docket No. 892593-0003-WO0120. The composition of any one of claims 1 and 3-19, wherein the aqueous solubility of the resveratrol associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat resveratrol, as measured at pH 7; and the concentration of resveratrol associated with the dendrimer is at least 10 pM, as measured according to the total volume of the composition.

21. The composition of any one of claims 1 and 3-20, wherein the aqueous solubility of the resveratrol associated with the dendrimer is at least 10 times greater than the aqueous solubility of neat resveratrol, as measured at pH 2.5.

22. The composition of any one of claims 1 and 3-21, wherein the composition comprises:about 4.5 pM dendrimer and about 10 pM resveratrol;about 4.5 pM dendrimer and about 1000 pM resveratrol;about 1120 pM dendrimer and about 10 pM resveratrol; orabout 1120 pM dendrimer and about 1000 pM resveratrol.

23. The composition of any one of claims 1 and 3-22, wherein the composition comprises from about 4.5 pM to about 1120 pM dendrimer and from about 5 pM to about 5500 pM ascorbic acid.

24. The composition of any one of claims 1-23, wherein the composition further comprises an antioxidant selected from the group consisting of ascorbic acid, hyaluronic acid, niacinamide, niacin, bakuchiol, squalane, vitamin D3 (cholecalciferol, calcitriol) and salts and esters thereof, epichlorocatechin, including epigallocatechin-3-gallate (EGCG), epicatechin (EC), epicatechin-3-gallate (ECg), epigallocatechin (EGC), catechin, gallocatechin (GC), curcumin, kaempferol, quercetin, myricitin, tranexamic acid, axelaic acid, phenoxyethanol, allantoin, aloe vera, minerals (zinc oxide, titanium dioxide), avobenzone, octocrylene, homosalate, tocopherol and salts and esters thereof, butylated hydroxyl benzoic acids and salts thereof, butylated hydroxytoluene, butylated hydroxyanisole, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acids and alkyl esters thereof, uric acid and salts and alkyl esters thereof, sorbic acid and salts thereof, amines, sulfhydryl compounds, sodium metabisulfite, dihydroxy fumaric acid and salts thereof, glutathione, ferulic acid, dimethylaminoethanol, peptides, coenzyme (CoQ10), exfoliants (alpha-hydroxy acid, alpha hydroxy carboxylic acids, beta-hydroxy acid, para alpha-hydroxy acid) and cannabinoids.Attorney Docket No. 892593-0003-WO0125. The composition of any one of claims 1-24, further comprising an additional therapeutic agent.

26. The composition of any one of claims 1-25, wherein the composition comprises one or more surfactants selected from the group consisting of D-a-tocopheryl polyethylene glycol succinate (TPGS), paraffin oil, Tween 80, and Span 80.

27. The composition of claim 26, wherein the composition comprises from about 0.1% to about 10% of the one or more surfactants.

28. The composition of any one of claims 1-27, wherein stability of the retinoid in the dendrimer-retinoid complex is increased by about 2 times to about 100 times as compared to the stability of neat retinoid.

29. The composition of any one of claims 19-28, wherein stability of the resveratrol associated with the dendrimer is increased by about 2 times to about 100 times as compared to the stability of neat resveratrol.

30. A pharmaceutical composition comprising a therapeutically effective amount of the composition of any one of claims 1-29 and a pharmaceutically acceptable carrier.

31. The composition of any one of claims 1-30, wherein the dendrimer and the retinoid are coated on solid particles.

32. The composition of any one of claims 1-31, wherein the retinoid is conjugated to the dendrimer with a labile linker.

33. The composition of claim 32, wherein the linker is cleaved before use of the composition.

34. The composition of any one of claims 1-33, wherein the dendrimer and the retinoid are a powder.Attorney Docket No. 892593-0003-WO0135. A method of treating a skin condition or disorder, the method comprising topically administering a therapeutically effective amount of the pharmaceutical composition of claim 30 to a skin or mucous membrane of a subject in need thereof.

36. The method of claim 35, wherein the skin condition or disorder is skin cancer, hyperpigmentation, inflammation, burns, psoriasis, eczema, cellulitis, hives, dermatitis, acne, aging, UV light mediated aging, an inflammatory disorder, or a hyper-proliferative disorder.

37. A method of providing personal and / or cosmetic care, the method comprising topically administering the composition of claim 1 or the pharmaceutical composition of claim 30 to a skin or mucous membrane of a subject in need thereof.

38. The method of claim 35, further comprising administering an anti-aging product, a body lotion, a body treatment, a toner, a facial moisturizer, a facial treatment, makeup foundation, or any skin care product.

39. A method of preparing a composition comprising a dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex, the method comprising:mixing retinoid, optionally resveratrol, dendrimer, and a solvent to form a mixture comprising the dendrimer-retinoid complex, optionally further comprising a dendrimer-resveratrol complex; andfiltering the mixture.

40. The method of claim 39, further comprising:removing the solvent after forming the mixture comprising dendrimer-retinoid complex, optionally further comprising the dendrimer-resveratrol complex, to form a solid mixture; and adding water to the solid mixture.

41. The method of claim 39, further comprising:admixing one or more excipients with the mixture comprising dendrimer-retinoid complex, optionally further comprising the dendrimer-resveratrol complex, to form a suspension; andspray drying the suspension to form a powder.Attorney Docket No. 892593-0003-WO0142. The method of claim 41, wherein the one or more excipients are trehalose dihydrate, sucrose, mannitol, or combinations thereof.

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