WO2020257064A1

WO2020257064A1 - Fullerenol xanthophyll adducts and methods

Info

Publication number: WO2020257064A1
Application number: PCT/US2020/037318
Authority: WO
Inventors: Peter Robert BUTZLOFF
Original assignee: Butzloff Peter Robert
Priority date: 2019-06-20
Filing date: 2020-06-11
Publication date: 2020-12-24

Abstract

A retinoid analogue composition includes a carotenoid molecule directly added to a fullerene molecule to form a fullerenol carotenoid. The fullerenol carotenoid includes at least one oxygen- containing carotenoid adduct bonded to a polyhydroxylated fullerene molecule. The fullerenol carotenoid can further include proximal charge induced ascorbic acid associated by adsorption to the fullerenol carotenoid. A carotenoid adduct includes a beta-carotene structurally related to retinol metabolites. The fullerene molecule includes one of C60 or C70. The fullerenol carotenoid includes a xanthophyll having a functional group carbon chain length equal to or greater than beta-carotene. A method of treating an obstructive pulmonary disease or age-related macular degeneration includes delivering the retinoid analogue fullerenol carotenoid composition into the lungs of a patient as a vapor inhalant. Before delivering as a vapor inhalant, the xanthophyll can be heated to 245 degrees C for no more than 1 second.

Description

FULLERENOL XANTHOPHYLL ADDUCTS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is related to, and claims benefit and priority under 35 U.S.C. 119(e) to, U.S Provisional Application 62/864,409, entitled “Fullerenol Xanthophyll Adducts And Methods,” filed on June 19, 2019 and to International Application Serial No.: PCT/US 18/27177, entitled“Anisotropic Nanoparticle Compositions And Methods”, filed April 11, 2018, both of which are hereby incorporated by reference in their entireties.

FIELD OF INVENTION

[0001] The present invention relates, generally, to a composition of xanthophyll-fullerenol nanoparticle adducts and, in particular, to reconfigurable xanthophyll-fullerenol nanoparticle adducts having rigid semi-conductive molecular wire elements that resist degradation to imbed within living cell membranes.

BACKGROUND ART

[0002] New adjuvants and flavor carriers are urgently required to amplify the administration of existing food nutrients as well as to reinforce their long-term preservation. Therefore, new compositions of matter are increasingly required to act simultaneously as a potential food delivery vehicle as well as to serve as a generic cellular anti-oxidant having desirable immunity reinforcement properties.

[0003] Except for some species of aphids, animals are unable to synthesize carotenoids essential for metabolism and vision. Animals therefore need to obtain carotenoids from food. Most carotenoids are not highly effective as antioxidants, because they are unable to function in that capacity more than one time without a secondary mechanism to regenerate their antioxidant capacity. One exception of this is the xanthophylls that have oxygen containing polar end groups on at least one side of an electron conductive and partly unsaturated aliphatic chain. This allows them to orient both parallel and perpendicular to cell membranes to enable releasing a free radical cargo to the extracellular matrix. Oxygen containing carotenoids are oxocarotenoids and xanthophylls, of which astaxanthin is a representative example. Unlike the xanthophylls, carotenoid molecules and other aliphatic hydrocarbons tend to locate parallel with the cell membrane surface within hydrophobic membranes, and are not by themselves able to orient perpendicular to the membrane to be able to conduct electrons or free radicals away from this region. The primary reason for this is that a sufficient length of 40 carbon atoms as well as a stiff molecular structure is required to achieve bridging from the inner cell membrane to the outer cell membrane. Shorter molecules achieve occasional interaction with only one external cell membrane interface. However, the interaction of a carotenoid and an electron conductive antioxidant bridge does create a synergy to regenerate and therefore magnify the effects of an antioxidant that is parallel and confined within the cell lipid membrane. One widely known example of this bridging effect is the interaction of vitamin C with vitamin E at mutually orthogonal orientations. This crossover happens within cellular lipid membranes to afford a random type of antioxidant synergy whenever chance orientation and proximity effects within cellular lipid membranes allow electron and free radical transfer to take place between a parallel oriented carotene and an orthogonal oriented molecules that confers good electron conduction to at least one cell membrane surface. Carotenoid and polyphenol networks are another widely known example of this type of lipid bridging effect. Natural limits arise on random orientation of the electron conductive polyphenol component to be both orthogonal to the cell membrane in a correct position for electron and free radical transport. Interaction effects are sparse when this reliance is a random molecular abutment to a carotene that requires release of a captured free radical to permit regeneration and therefore create an antioxidant synergy.

[0004] Astaxanthin is a red colored xanthophyll carotenoid pigment that commonly occurs in microalgae, yeast, and some of the larger creatures that feed on them. It confers a pink color to shrimp, flamingo birds, trout, and ocean animals such lobsters, at least one species of dolphin, and the flesh of the Pacific salmon. Astaxanthin has a CAS registry number 472-61-7, and a molecular formula of C40H52O4.

[0005] While the presence of astaxanthin of about 3 percent in algae supplements is widely available and inexpensive, the high cost of highly purified astaxanthin has limited its economic exploration in otherwise promising clinical cancer treatment studies. The high anti-oxidant and anti-inflammatory properties of astaxanthin are useful in some types of cosmetic and anti-aging skin treatments, promising 6000 times greater anti-oxidant effectiveness than vitamin C when delivered at about 5 percent by weight for a dosage of about 3 milligrams per topical application in an oil matrix. However, environmental factors such as acidity, food processing, the food matrix, and the substantial irreversible bond interactions among fatty acid food components all have an effect on reducing the efficiency of uptake and absorption of astaxanthin and related xanthophylls. [0006] One disadvantage of astaxanthin is an extremely high affinity for oil as well as a very poor tolerance for trace amounts of water, such as in oil-water emulsions. Efforts to reverse this problem have traditionally focused on the creation of astaxanthin succinate ester, and similar xanthophyll esters. However, the water solubility advantage of the esterified form of astaxanthin or other carotenoid esters are immediately lost where these are metabolized by animals into the non-esterified form as a normal part of the cellular digestion process. In particular, carotenoids such as astaxanthin are metabolized by BCOl (beta-carotene oxygenase 1), which is located in the cytosol, and BC02 (beta-carotene oxygenase 2), which is associated with the inner mitochondrial membrane (the endoplasmic reticulum). Thus, astaxanthin and astaxanthin esters easily precipitate out of oil solution or lipid emulsion carriers on exposure of their metabolites to very low levels of moisture. These limits have therefore placed highly significant physical constraints on the economic exploitation and practical industrial utilization of astaxanthin antioxidant properties in clinical cancer treatment studies as well as in cosmetic and food supplement applications.

[0007] Another significant economic problem with the delivery of carotenoids in general, and with astaxanthin in particular, is a sensitive susceptibility to damage by free radicals. Free radicals initiate the chemical degradation process on exposure to sufficient sunlight, or simply by exposure to the heat energy associated with normal food processing conditions or standard medical or food sterilization processes. The use of liquid lipid, and hybrid solid-liquid lipid emulsions in water confers temporary protection of the desirable properties of astaxanthin or related carotenoids. The action of digestion and metabolite formation immediately reduces the stability of these emulsion structures and results in their oxidation. This instability serves to limit bioavailability as well as the potential drug carrier function of astaxanthin and related xanthophylls.

[0008] During the aging process, gastrointestinal absorption of carotenoids is decreased due to age-related gastric disorders like acute and chronic gastritis, abnormal gastric acid secretion, and deviations in intestinal enzyme spectrum. In addition, an age-related change in the intestinal microbiota, which regulates bioavailability of carotenoids and polyphenols in the large intestine, is responsible for depleted level of lycopene level in old age. Xanthophyll carotenoids, like lycopene, can provide benefits to sufferers of certain disease states. However, they are typically rendered useless in the gut. [0009] What is needed is a free-radical scavenging nanotechnology to enhance the protection of cells from oxidative damage, while also providing electromagnetic enhancement of communication and information transfer among neural brain cells that are not in direct contact to enable ephaptic communication at a distance.

SUMMARY OF THE INVENTION

[0010] In select embodiments, the invention provides a chemical composition, which improves cell membrane stability and offers robust anti-oxidant function. This composition is made with at least one oxygen-containing carotenoid adduct-bonded to a polyhydroxylated fullerene molecule.

[0011] The invention provides a retinoid analogue composition including a carotenoid molecule directly added to a fullerene molecule to form a fullerenol carotenoid. The fullerenol carotenoid further includes at least one oxygen-containing carotenoid adduct bonded to a polyhydroxylated fullerene molecule. The fullerenol carotenoid can further include proximal charge induced ascorbic acid associated by adsorption to the fullerenol carotenoid. At least one of the carotenoid adducts includes a beta-carotene structurally related to retinol metabolites. The fullerene molecule includes one of C60 or C70. C60 includes geometrically isotropic polyhydroxylated C60 or geometrically anisotropic polyhydroxylated C60, and C70 includes isotropic C70 or anisotropic C70. The carotenoid includes a xanthophyll. In an embodiment, the xanthophyll is an astaxanthin. The fullerenol carotenoid includes a xanthophyll having a functional group carbon chain length equal to or greater than beta-carotene (C40H56).

[0012] The invention also provides a method of treating an obstructive pulmonary disease including delivering the retinoid analogue composition of a fullerenol carotenoid into the lungs of a patient as a vapor inhalant wherein gastrointestinal decomposition of the carotenoid adduct structure is obviated. An embodiment of the invention provides a method of treating an obstructive pulmonary disease comprising delivering the retinoid analogue composition of a xanthophyll having a functional group carbon chain length equal to or greater than beta-carotene (C40H56) into the lungs of a patient as a vapor inhalant wherein gastrointestinal decomposition of the carotenoid adduct structure is obviated. In an embodiment, before delivering as a vapor inhalant into the lungs of a patient, the method includes heating the xanthophyll to at least 245 degrees C for no more than about 1 second.

[0013] The invention also provides a method of treating an ocular disease comprising delivering as a vapor inhalant into the lungs of a patient the retinoid analogue composition of a xanthophyll having a functional group carbon chain length equal to or greater than beta-carotene (C40H56), wherein ephaptic neural innervation associated with ocular neurons within the structure of and leading to the retina of the eye is stimulated and wherein the ephaptic neural innervation slows the progression of age-related macular degeneration (AMD). In an embodiment, before delivering as a vapor inhalant into the lungs of a patient, the method includes heating the xanthophyll to at least 245 degrees C for no more than about 1 second. In an embodiment, the method also can include one of applying electrical stimulation to the skin surfaces near to the eye during periods of sleep, or applying standard transcranial alternating or direct current stimulation wherein ocular neural tissue growth is stimulated.

[0014] These and other advantages of the present invention will be further understood and appreciated by those skilled in the art by reference to the following written specifications, claims and appended drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Preferred embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings, in which:

[0016] FIG. 1 is a schematic of reaction pathways to different fullerenol geometries based on C60 or C70 core molecules, in accordance with the teachings of the present invention;

[0017] FIG. 2 is an illustration of an anisotropic C60 fullerenol with two astaxanthin adducts, in accordance with the teachings of the present invention;

[0018] FIG. 3 is an illustration of an isotropic C60 fullerenol with two astaxanthin adducts, in accordance with the teachings of the present invention;

[0019] FIG. 4 is an illustration of electron hopping migration along astaxanthin-conjugated bonds, in accordance with the teachings of the present invention;

[0020] FIG. 5 shows the electron collection site at an electron withdrawing anisotropic C70 fullerenol-astaxanthin adduct, in accordance with the teachings of the present invention;

[0021] FIG. 6 is a view of two types of lipids present in human cell membrane bilayers, in accordance with the teachings of the present invention;

[0022] FIG. 7 is a section of cell membrane showing the orientation of lipid bilayers, in accordance with the teachings of the present invention;

[0023] FIG. 8 is a molecular structure view of ascorbic acid, beta-carotene, and lycopene, in accordance with the teachings of the present invention; [0024] FIG. 9 is an illustration of the disposition of beta-carotene inside a cell membrane bilayer, in accordance with the teachings of the present invention;

[0025] FIG. 10 is an illustration of the orientation of anisotropic fullerenol having a single astaxanthin adduct positioned transverse to a cell membrane bilayer, in accordance with the teachings of the present invention;

[0026] FIG. 11 is an illustration of the orientation of anisotropic fullerenol having two astaxanthin adducts positioned transverse to a cell membrane bilayer, in accordance with the teachings of the present invention;

[0027] FIG. 12 is an illustration of anisotropic C60 fullerenol xanthophyll esters, in accordance with the teachings of the present invention;

[0028] FIG. 13 is an illustration of a schematic diagram of the molecular components of FIG. 10, in accordance with the teachings of the present invention;

[0029] FIG. 14 is a block diagram of a method to prepare fullerenol xanthophyll adducts for use in exemplary food and beverage or oral solution products, in accordance with the teachings of the present invention;

[0030] FIG 15 is a block diagram of a method to prepare fullerenol carotenoids for use in vapor inhalant fluids, in accordance with the teachings of the present invention;

[0031] FIG. 16 is a tabular view listing non-oxygen containing carotenoids, in accordance with the teachings of the present invention;

[0032] FIG. 17 is an illustration of a method of vapor inhalant use to administer fullerene carotenoids, in accordance with the teachings of the present invention.

[0033] Some embodiments are described in detail with reference to the related drawings. Additional embodiment features and/or advantages will become apparent from the ensuing description or may be learned by practicing the invention. In the FIGURES, which are not drawn to scale, like numerals refer to like features throughout the description. The following description is not to be taken in a limiting sense but is made merely for the purpose of describing the general principles of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The following detailed description, taken in conjunction with the accompanying drawings, is merely exemplary in nature and is not intended to limit the described embodiments or the application and uses of the described embodiments. Any implementation described herein as“exemplary” or“illustrative” is not necessarily to be construed as preferred or advantageous over other implementations.

[0035] Present embodiments relate to a composition of reconfigurable xanthophyll-fullerenol nanoparticle adducts having rigid semi-conductive molecular wire elements that resist degradation to imbed within living cell membranes. The fullerenol portion of the adduct provides a lipid surface anchor to the outside of a cell wall that serves to stabilize the internal crossing of the cell membrane lipids by at least one xanthophyll portion of the molecular adduct. The composition modifies neural and retinal cell membrane electrical and electromagnetic characteristics to improve resistance to, for example, macular degeneration.

[0036] In general, present embodiments are directed to the ability of polyhydroxylated fullerene derivatives, and in particular, to the carotenoid adducts of anisotropic fullerenols, to act as hydrophilic to hydrophobic nano-particulate lipid membrane stabilizers and free radical recombination centers having antioxidant and neuroprotective electrical characteristics. A carotenoid is an isoprenoid provided with at least eight isoprene units and thus having at least 40 carbons, such as a xanthophyll. Provitamin A carotenoids, alpha-carotene, beta-carotene, and beta-cryptoxanthin can be converted by the body to retinol (vitamin A). In contrast, no vitamin A activity can be derived from lutein, zeaxanthin, lycopene, or the xanthophylls. It is not required or necessary that a carotenoid be metabolized into a vitamin for their fullerene nano-particulate adducts to function as novel lipid membrane stabilizers and free radical recombination centers having useful antioxidant and neuroprotective electrical characteristics. The efficiency of carotenoid uptake in the prior art is highly variable, depending on factors like food matrix, food preparation, and digestive or absorptive capacities. The present composition and method of delivery is designed to overcome these limitations and thereby provide useful properties to maintain or improve ocular and retinal health.

[0037] The present embodiments include a composition of fullerenol clusters having one or more carotenoid adducts, where especially xanthophyll adducts have sufficient length to adopt a functional electric characteristic contiguous with the lipid membrane spanning orientation to provide enhanced electromagnetic propagation and organic ephaptic coupling in neurons. Introduction of this composition is to maintain cooperative electron transfer and electromagnetic coupling among a collective of nearby neurons or neural structures. Scientific evidence for ephaptic coupling exists for severed regions of the hypothalamus. Amplification of this mode of information transfer especially in retinal neurons and optic nerve tissue is the type of coupling enabled by this aspect of the embodiments. The composition also can create an electrical structure that functions to enhance and amplify ephaptic communication between non-contacting neural brain cells, which is not reliant on direct neural wiring. Ephaptic information transfer arises from induced electronic currents amplified at frequencies that are resonant with, and characteristic of, the size and shape of a neural cell. The reception and propagation of electrons along the antenna of the oxy-carotenoid adducts promotes ephaptic interaction among fullerenol- xanthophyll doped cells when electrical charges are reversibly stored at and later released by the fullerenol that functions as a battery. The electrons within the cellular circuits are electrically oscillated at frequencies resonant with the capacitive properties of the lipid cell membrane bilayer as modified by the resistive conduction of the transversely disposed adducts in an RC (resistive-capacitive) organic circuit. These functions act to protect the natural electromagnetic resonant frequencies of populations of neural cells by a tuning mechanism that depends partly on ionic charge screening effects arising at the cytosol in contact with the cell membrane of individual brain cells. The features of the design of the fullerenol-xanthophyll adducts embedded within the cell membranes intend to provide a general improvement in overall macular neurons and tissues.

[0038] In a related aspect, a present embodiment provides an artificially and intentionally designed cooperative functional electrical circuit to amplify organic ephaptic neural coupling. In particular, it is the ensemble of light activated electron hopping in the retina that operates at a distance and without a direct neural connection at the lipid cellular interface that functions to avoid the onset of or mitigate the progression of age-related macular degeneration (AMD).

[0039] In another aspect, anisotropic fullerenol clusters anchor to one or more xanthophyll adducts having polar end groups at either end of an electronically conductive alkyl chain while adopting a rigid lipid membrane spanning orientation capable of providing structural reinforcement.

[0040] In yet another aspect of the embodiments, the anisotropic fullerenol adduct obtains a van-der-Waals type of attraction to anchor the carbon surface of the fullerenol portion of the adduct to hydrophobic lipid molecules at or near to the cell membrane surface. In a related aspect, hydroxylated regions of the anisotropic fullerenol nanoparticle forms at least one adduct by means of an electrostatic hydrogen bond to at least one pendant carotenoid, being preferably a xanthophyll molecule such as astaxanthin. [0041] In still another aspect, the adduct of astaxanthin, a particular xanthophyll, is electrostatically hydrogen bonded to the desired anisotropic fullerenol by means of an applied electric current of about 30 amperes applied at about 12 volts, and in a solution of 190 proof ethanol at a temperature of 50°C over a period of about 30 minutes. In yet another aspect, the astaxanthin-fullerenol composition provides a drug delivery vehicle to carry medicaments across the blood-brain barrier and to improve the dispersion and efficacy of existing medical therapeutic compounds.

[0042] Another aspect of present embodiments is to enable the charge screening of ambient microwave broadband radiation impinging upon sensitive biological tissues. In this aspect, the fullerenol-xanthophyll adduct is a dopant composition that acts as an electronic filter and dampener having capacitive and voltage smoothing properties which are protective against transient high frequency irradiation in the gigahertz broadband and terahertz radio frequency bands.

[0043] In yet another aspect, a present embodiment provides the soluble delivery of essential antioxidants to the cell. In yet another aspect, the fullerenol-xanthophyll adducts in a vaporized delivery vehicle of fullerenols conferring significant resistance to the carotenoid nutrients to oxidative degradation, and providing stability against salts, proteases, and amylases. In yet other aspects, the antioxidants of the present embodiments can act as chemical prophylaxes to increase resistance to age-related oxidative neurological diseases.

[0044] Referring now to the drawings wherein like elements are represented by like numerals throughout, there is illustrated in FIG. 1 a molecular reaction pathway synthesis 10, where large black arrows show the direction from a fullerene starting material or reactant to the possible configurational isomers in a fullerenol ending material, or product. Buckminsterfullerene or C60 fullerene molecule 12 has 60 carbon atoms in a spherical molecular framework structure. The related C70 fullerene molecule 11 having 70 carbon atoms may be used to substitute for 12 in the generation of any fullerenol or geometric isomer of fullerenol used to create the composition of the present embodiments. Exemplary C60 fullerene 12 is reacted under oxidative conditions to initially form a fullerene epoxide 14. The epoxide functional group is expressed by the bonding of one oxygen atom 13 to two proximal carbon atoms on the fullerene framework of molecule 14. As the oxidative reactions proceed, hydrogen molecules (not shown) extract from the aqueous medium around the fullerene under high shearing rates. This process incorporates a description previously introduced on the subject matter of anisotropic fullerenols. The epoxide ring 13 reacts with an abstracted hydrogen atom to form a hydroxyl group and a singularly hydroxylated fullerene (fullerenol) product. The result of a continuation of this type of reaction can be a geometrically anisotropic fullerenol 18 having locally clustered hydroxyl groups substantially disposed on one face of the fullerene framework molecule at region 17. However, organic solvents (not shown) allow the creation of isotropic fullerenols. Therein, organic peroxides or other oxidative reactants in, for example toluene solvent, will react fullerene 12 to form fullerene epoxides 14 which continue to accrue hydrogen and eventually result in a product having a multiplicity of randomly distributed polyhydroxylations 15 as functional groups on substantially isotropic fullerenol 16. As used herein, C60 includes geometrically isotropic polyhydroxylated C60 or geometrically anisotropic polyhydroxylated C60, and C70 includes isotropic C70 or anisotropic C70.

[0045] Referring now to FIG. 2, a molecular hydrogen bonded cluster 20 is presented. Cluster 20 includes an anisotropic polyhydroxylated fullerene 21 having seven (7) hydroxyl groups. Anisotropic polyhydroxylated fullerene 21 may be configured with eight (8) or more hydroxyl groups to preferentially anchor the fullerenol at the outside of somatic cell membranes. Anisotropic polyhydroxylated fullerene 21 may also be configured with seven (7) or less hydroxyl groups to anchor the fullerenol at the outside of the endoplasmic reticulum of mitochondria in neural cells and to assist with crossing the blood-brain barrier. Hydrogen bonded cluster consists of at least one of a single astaxanthin adduct 24 with a hydrogen bond 22 to the anisotropic fullerenol 21 at any one of the plurality of fullerenol hydroxyl groups. Hydrogen bonded cluster 20 consists of a multiplicity of astaxanthin adducts 24, 26 with hydrogen bonded regions 22, 23 to the anisotropic fullerenol 21 at any one of the plurality of fullerenol hydroxyl groups, up to a maximum number of adducts equal to the maximum number of hydroxyl groups present at the anisotropic fullerenol. The number of adducts 24, 26 are configurable under the conditions of the electrolytic synthesis as is illustrated in FIG. 4 and FIG. 5.

[0046] Referring now to FIG. 3, a molecular hydrogen bonded cluster 30 is illustrated. Cluster 20 is shown composed with conventional isotropic polyhydroxylated fullerene 31 having six (6) hydroxyl groups. Isotropic polyhydroxylated fullerene 31 may be configured with eight (8) or more hydroxyl groups to preferentially anchor the fullerenol at the outside of somatic cell membranes. Isotropic polyhydroxylated fullerene 31 may also be configured with seven (7) or less hydroxyl groups to preferentially anchor the fullerenol at the outside of the endoplasmic reticulum of mitochondria in neural cells and to assist with crossing the blood-brain barrier. Hydrogen bonded cluster 30 can consist of at least one of a single astaxanthin adduct 34 with a hydrogen bond 32 to the anisotropic fullerenol 31 at any one of the plurality of fullerenol hydroxylation groups. Hydrogen bonded cluster consists of a multiplicity of astaxanthin adducts 34, 36 with hydrogen bonded regions 32, 33 to the anisotropic fullerenol 31 at any one of the plurality of fullerenol hydroxyl groups, up to a maximum number of adducts equal to the maximum number of hydroxyl groups present at the isotropic fullerenol. The number of adducts 34, 36 are configurable under the conditions of the electrolytic synthesis as illustrated in FIG. 4 and FIG. 5.

[0047] Referring now to FIG. 4, there is illustrated an oxygen containing carotenoid of the class of oxocarotenoids and xanthophylls, of which astaxanthin 42 is illustrated as a representative example because it can be a highly antioxidant carotenoid. Astaxanthin 42 has a functional high stiffness or modulus to resist compression and folding, and an excellent electrical conduction path enabled by a series of conjugated double bonds along a substantial length of the molecule. Electron hopping from one conjugated double bond to the next conjugated double bond is shown by the presence of thin curved black arrows among the conjugated double bonds of astaxanthin 42. Cyclic end-groups 42, 43 express polar character and interact to preferably bond or form adducts with polar charged regions having electrostatic dipole characteristics. The system of conjugated double bond along the central chain of astaxanthin 42 carries electrons, symbolized as e(-), in the direction of the large straight black arrow 44, in the presence of an applied electric field which introduces a net positive electric charge at first distal end 43 and a net negative charge at second distal end 41. The strength of the applied electric field causes more electrons to migrate along the direction 44 of the molecular wire of astaxanthin 42, where separation of negative charged region 41 in space from that of positive charged region in first distal end 43 arises because the system of conjugated double bonds has semi-conductive properties that are partially resistive.

[0048] Referring now to FIG. 5, there is illustrated an anisotropic fullerenol astaxanthin adduct 50 that contains at least one xanthophyll shown here by the representative oxy-carotenoid molecule of astaxanthin 54. An applied electric field causes electron withdrawal and a net positive charge at distal astaxanthin polar end group 53. The presence of abutting anisotropic C70 fullerenol 54 having eight (8) hydroxyl groups is shown to create adducts by means of the hydrogen bond 56 at one of the hydroxyl groups expressing dipole characteristics. Anisotropic C70 fullerenol 54 is provided with electron charge storage properties at the bare carbon nanoparticle face 54 which acts as an energy reservoir or battery to store at least one and as many as six electrons. Region 55 may therefore accrue as many as seven (7) adducts corresponding with the maximum number of hydroxyl groups at 54. The number of oxy-carotenoid adducts depends on the strength of the applied electric field, as well as the availability of free oxy- carotenoids such as astaxanthin 52, and the availability of hydroxyl groups on the anisotropic fullerenol nanoparticle 54. It is understood that the clustering of adducts will be anisotropic in accordance with the geometric structure of the fullerenol 54. However isotropic clustering is also possible when the fullerenol used as the center of adduction is an isotropic fullerenol as shown in FIG. 3. The replacement of C70 fullerenol 54 with a C60 fullerenol, as illustrated in FIG. 1, can be used in replacement or as a mixture in the creation of this composition with substantially similar effect.

[0049] Referring now to FIG. 6, there is illustrated a phosphatidylserine lipid molecule 62 that is capable of tight packing to create an inner cell membrane of collectively negative charged interfacial layer at the inside of human cells. The tight packing is achieved by the strong van-der- Waals attraction of a pair of adjacent parallel abutting aliphatic molecular backbones 64 provided with the ability to bend and conform because of the lack of stiffness in the mostly single bonded carbon to carbon bonds of the tail region 64. The exposed distal oxygen groups residing at the phosphorus atom and at the carboxylic functional group within the structure that is bounded by the dotted line 62 to indicate the collective net negative polar charge of this region, referred to as the negative polar head of the phosphatidylserine lipid molecule. There also is shown a phosphatidylcholine lipid molecule 66 that is capable of tight packing to create an outer cell membrane of collectively positive charged interfacial layer at the outer lipid boundary of human cells. The tight packing can be achieved by the strong van-der-Waals attraction of a pair of adjacent parallel abutting aliphatic molecular backbones 68 provided with the ability to bend and conform because of the lack of stiffness in the mostly single bonded carbon to carbon bonds of the tail region 68. The exposed distal nitrogen atom residing within the structure that is bounded by the dotted line 66 is used to indicate the collective net positive polar charge of this region, referred to as the positive polar head of the phosphatidylcholine lipid molecule. The positive head 66 becomes less tightly packed than the negative head 62 because the number of proximal oppositely charged atoms is less, and therefore the charge density of opposing charge and the resultant electrostatic attractive forces are weaker in 66 as compared with 62. [0050] Referring now to FIG. 7, there is illustrated a representative section of a human cell membrane 70 having loosely packed phosphatidylcholine lipid external layer 71, and phosphatidylserine lipid internal layer 74. Lipids 71, 72 have respective local orientation and mutual attraction of the aliphatic tail regions 72, 73 responsible for the cell membrane stability and maintenance of continuity along their interpenetrating intersection at region 75. The inside of the cell typically accrues electrons at region 76. An excess of electrons in the cytosol at region 76 may cause undesirable hyperpolarization as well as excess charge storage across cell membrane 70. Cell membrane 70 structure and the opposing charges it carries at either lipid membrane 71 and 74 represent a capacitive function. The electrical resistance between the lipid bilayer 71 and 74 extends across and through region 75 to convey an electrically resistive function (R) that is in parallel to the capacitive function (C) of these structures, as shown in FIG. 13.

[0051] Referring now to FIG. 8, there is illustrated a molecule of ascorbic acid 82 that is preferentially added to the mixture of the composition to confer oxidative protection to the oxy- carotenoid components such as the astaxanthin adducts. Also shown is a beta-carotene molecule 84, and a lycopene molecule 86, both of which represent examples of a non-oxygen containing carotenoid as alternative carotenoid components that can be used to create the composition of the present embodiments. These aliphatic carotenoids typically orient themselves between and parallel to the dual exterior interfaces of cellular lipid bilayers, as shown in FIG. 9.

[0052] Referring now to FIG. 9, there is illustrated an exemplary entrapped aliphatic carotenoid 90, being a beta carotene 92 that is oriented between and parallel to the dual exterior interfaces of cellular lipid bilayers of cell membrane 70. Carotenoid molecule 92 is capable of accepting an electrical charge as well as a free radical. This may result in the reversible oxidation of 92 according to the sacrificial function of oxidation to provide anti-oxidant properties to cell membrane 70.

[0053] Referring now to FIG. 10, there is illustrated a structurally supportive anisotropic fullerenol adduct imbedded in a cell membrane 1070, wherein the astaxanthin molecule extends from 1030 to 1040 and has negative charged distal end embedded at the inner membrane interface at 1040. The transverse orientation of astaxanthin from 1030 to 1040 with respect to the lipid bilayer of 1070 allows the migration of electrons along the direction of the conjugated double bonds as indicated by the direction of the large black arrow towards distal end 1030. These electrons continue along hydrogen bond 1010, and accumulate to allow electron storage at the exposed carbon atoms in the structure of the exposed face of the anisotropic fullerenol nanoparticle 1020. Fullerenol 1020 can be a geometrically anisotropic polyhydroxylated C60 fullerenol molecule, but fullerenol 1020 may be substituted by a geometrically anisotropic C70 fullerenol molecule. In some embodiments, geometrically isotropic polyhydroxylated C60 fullerenol may be used, as may a geometrically anisotropic C70 fullerenol molecule. The dotted line between ascorbic acid 1025 and fullerenol 1020 indicates proximal charged induced ascorbic acid 1025 is associated by adsorption to the fullerenol carotenoid. One source of migrating free electrons and free radicals is a chemical potential expressed by the living cell housed within the inner cell membrane. Another source of migrating free electrons initiates by the extracellular voltage gradient in the environment where the outside of the cell membrane is located. Another source of migrating free electrons initiates by a sufficient intensity of ambient electromagnetic radiation interacting with matter that induces electron migration along the semi-conductive pathways present within or among the structures of FIG. 10. The representative anisotropic fullerenol nanoparticle 1020 is provided with seven hydroxyl groups. It is understood that either more or less numbers of hydroxyl groups may be provided or desirable in alternative anisotropic fullerenol nanoparticles in place of 1020 that may be used or called out. Aliphatic carotenoids such as lycopene or beta-carotene shown in FIG. 9 may be present within the cell membrane 1070 to confer synergistic anti oxidant properties to enable improvement to the electrical and free radical transfer by abutment with the transversely oriented astaxanthin-anisotropic fullerenol adduct among the combined structures of 1000.

[0054] Referring now to FIG. 11, there is illustrated anisotropic fullerenol carotenoid imbedded within the bilayer of cell membrane 1100. Two astaxanthin molecules 1140, 1150 extend transversely from the region of the outer lipid layer 1170 at exemplary molecular distal ends 1140 and 1150 towards the negative charged layer at the inner cell membrane represented by the plurality of electrons illustrated as e(-) and collectively illustrated with bracketed region and a negative polarity (-). Two polar end groups of two astaxanthin molecules 1140, 1150 are hydrogen bonded as indicated by 1110, 1120 to two of the available eight hydroxyl groups of the anisotropic fullerene molecule 1120. The representative anisotropic C60 fullerenol nanoparticle 1120 is provided with eight hydroxyl groups. Either more or less numbers of hydroxyl groups may be provided or desirable in alternative anisotropic fullerenol nanoparticles in place of 1120 that may be used or called out in present embodiments. The desired configuration of hydroxyl groups pendant from the fullerenol nanoparticle may differ from those shown at 1120, such that for example, a conventional isotropic fullerol may be used. Also, C60 fullerenol 1120 can be replaced by a C70 fullerenol to create this composition. Furthermore, a multiplicity of hydrogen bonded astaxanthin molecules such as 1140, 1150 may provide additional bonded adducts to the fullerenol nanoparticle 1120 up to the number of available pendant hydroxyl groups on 1120.

[0055] Referring now to FIG. 12, there is illustrated anisotropic fullerenol astaxanthin ester 1200. The core molecular polyhydroxylated fullerene 1210 has five (5) residual hydroxyl groups, and two ester groups 1220, 1230 as adducts binding two pendant astaxanthin functional groups 1240, 1260. Anisotropic polyhydroxylated fullerene 1210 had been configured with seven (7) hydroxyl groups as illustrated in FIG. 2, however to preferentially stabilize and anchor the fullerenol to the two originally hydrogen bonded astaxanthin functional groups 1240, 1260, the optional application of irradiation 1290 by a conventional microwave operating at 2.45 GHz for about 1 minute is sufficient to drive off two of the original hydroxyl groups by release of two water molecules as steam 1270, where the upward direction of the black arrow indicates the upward release of this hot water vapor. The resulting fullerenol astaxanthin ester 1200 can be served as an oral solution, however the digestion process by stomach acid at low pH always returns structure 1200 back into the hydrogen bonded moiety illustrated in FIG. 2. Therefore, there has been no prior economic or pharmaceutical interest to expend the brief energy of microwaves 1290 to drive off water and create the fullerenol carotenoid ester 1200, because this product reversibly returns to the original structure at low pH with no essential functional difference to the patient or the outcome of such oral supplementation as measured by analysis of the residues found in the blood plasma. A heated aerosolized inhalant can be created by raising a non-aqueous solvent mixture of this composition to at least about 245 degrees C for no more than about 1 second. This thermal aerosolization process is an alternative way to create esterification between fullerenols and carotenoids. Thermally-treated xanthophyll fullerenol esters can administered by vapor inhalant administration, which is illustrated in FIG. 17. This method presently allows for the direct introduction of the esterified fullerenol carotenoids such as fullerenol xanthophyll 1200 into the blood via the lungs and airways as a desirable alternative delivery to the patient without exposure of this composition to stomach acids or low pH conditions. The result is a more effective therapeutic outcome in the utilization of the molecules of this composition, when applied and delivered as an ester. Direct introduction of thermally-treated esterified fullerenol carotenoids can be used to treat ocular diseases such as age-related macular degeneration (AMD). Direct introduction of thermally-treated esterified fullerenol carotenoids also can be used to treat pulmonary diseases including, without limitation, obstructive pulmonary diseases.

[0056] Referring now to FIG. 13, there is illustrated an electric circuit diagram representative of the electrical properties of the structure of 1000 in FIG. 10. Electron storage source and sink 1310 provides an electronic battery function representative of a fullerene nanoparticle, where the wire 1312 represents the potential for electron conduction along the pathway of at least one hydrogen bond forming the adducts to a distal polar group at least one astaxanthin molecule at 1320. The astaxanthin molecule provides a semiconducting and resistive electrical pathway along 1330 that includes the series of conjugated double bonds shown in FIG. 4. The astaxanthin or other xanthophyll 1330 anchors to the positive charged external lipid layer at 1320 of cell membranes. The cell membrane bilayer shown in Figure 7 represents the capacitive function at 1350. The astaxanthin or other xanthophyll 1330 anchors to the negative internal charged lipid layer at 1340 of cell membranes. The negative charged face of the fullerenol nanoparticle is in proximal abutment to the positive charged polar head groups of loosely packed phosphatidylcholine membrane layer represented by wire 1314, wherein the resistive electrical property of the cell membrane represents the resistive element 1360. A charge-screening layer of water molecules is always present at the cytosol containing electrons at the cell membrane interface with the interior of the cell, represented by the capacitive function 1360. The charge screening layer of water molecules grounds into the ionic medium of the cell cytosol represented by the electrical ground symbol 1370. Under electrostatic conditions, the electrical charges represented by the circuits 1300 of FIG. 13 arrive at homeostasis. The application of light energy at the cells of the retina, or the application of electromagnetic energy by artificial stimulation will supplement the natural electromagnetic energy produced by neural cells, and is provided to supplement and maintain a steady state of charge polarization and charge localization required to maintain ocular health and energize the retinal neurons in an ephaptic manner, in accordance with the composition and the teachings of the present embodiments.

[0057] Under local conditions of externally applied broadband high frequency excitation, circuit 1300 functions as an electrical oscillator having a capacitive reactance at 1350 that is of different value than the capacitive reactance at 1360. The high frequency broadband excitation applied to the cell and the characteristic electrical reactance is likely out of phase and displaced in space with respect to that of nearby cells having similar but not equivalent electrical characteristics. Therefore, high frequency broadband signal propagations will be highly localized and otherwise attenuated beyond the cell membrane, so that their collective ensemble electrical activation will provide random orientation and phases that will cancel over large distances. This cancellation of electrical function over large scales provides electronic protection from externally applied broadband gigahertz and terahertz radio frequency irradiation. The electronic characteristic of cellular circuit 1200 is localized and capable of characterization with appropriately placed electromagnetic sensors to assist with monitoring neural and retinal health.

[0058] Low frequency electromagnetic excitation includes the approximate“gamma” band of about 20 Hertz to about 100 Hertz. In this range, the ensemble of circuits 1300 function as an electrical amplifier for the patterns of neural oscillation in humans, having a capacitance at 1350 associated with the cell membrane bilayer and another capacitance at 1360 associated with the corona of hydroxyl groups pendant from the fullerenol. The electrical oscillations arise from electromagnetic signal transduction among a population of excited neural cells that do not necessarily have a direct electrical neural connection, known as ephaptic coupling, which is required to maintain retinal and ocular neuronal health. The reinforced cell membrane structure shown in FIG. 10 and related structures such as FIG. 11 have functional electrical circuit characteristics shown in FIG. 13 for the fullerenol carotenoid composition, wherein these functions are designed to extend and maintain ocular neuronal health and vitality.

[0059] Referring now to FIG. 14, there is illustrated a schematic method to prepare oral supplements of fullerenol carotenoids. To begin in step 1410, C60 or C70 fullerenols are introduced to a mixture of alcohol soluble carotenoids such as astaxanthin and related xanthophylls, where the carotenoids may be obtained from natural algae as a raw material source of these compounds, or a synthetic source of these same type of compounds. This mixture is subjected to intermediate voltage and current sufficient to cause electrostatic adduct formation between the fullerenols and the oxo-carotenoids, along with ultrasonic agitation at 200 watts and 40 kilohertz for about 30 minutes at 50 degrees C. These adducts can be stabilized for long-term shelf life storage in step S 1420 by mixing with ascorbic acid and a lipid or oil carrier at sufficient shear rates of greater than 1000 revolutions per second to produce an emulsion with particle sizes of about 400 nanometers in average diameter. The xanthophyll fullerenol adducts are sufficiently stable to allow their admixture into solid foods in step S1430. One of these solid foods may include the use of a solid gelatins such as those used in gel capsule supplements or in“gummi bear” types of candy. Another one of these foods can be a mixture of cocoa butter and sugar to create a sweet solid vegetable fat type of candy, to which additional flavoring is added. Alternately, step S1440 indicates the transfer of the xanthophyll fullerenol adducts to a watery beverage. Additional fluids such as edible pure grain alcohol (ethanol that has not been denatured) can be useful to create an alcoholic beverage for adults, having the advantage of alcohol as a carrier for the composition of the present embodiments. It is notable here that in sufficient concentration, the fullerenol adducts will form a red color in alcoholic solution. Such a beverage is useful for the purpose of solubilizing, detoxifying, and removal of otherwise recalcitrant and difficult to dissolve organic toxins and plaques that tend to resist digestion and therefore accumulate in the body, especially in retinal tissues, over a period of years. Step S1440 shows the aseptic bottling and distribution of other exemplary beverages, such as porridge yogurt, or smoothies useful for enhancing the conversion of chemical energy from glucose and complex sugars in energy drinks, or fruit juices. The utility of such beverages are to benefit by the addition of fullerenol carotenoid adducts to improve them as functional foods with beneficial neuroprotective properties.

[0060] Referring now to FIG. 15, there is illustrated a schematic method to prepare and use a vapor inhalant from the fullerene carotenoid composition 1500. To begin in step S1510, add the desired quantity of carotenoids such as xanthophylls to carbon fullerenol (C60 or C70) into propylene glycol solvent to create a dispersion. In step S1520, apply high shearing rate to the mixture of step S 1510 to bond the fullerenols in the combined mixture with carotenoids by the formation of stable hydrogen bonded adducts at about 55°C for about 15 minutes during this process, it is acceptable to apply optional ultrasonic agitation at about 40 KHz and about 200 watts of power while shearing to assist in creating a uniformly homogenous product. In step S1530, dilute the homogenous propylene glycol mixture of step S1520 into enough glycerol to create a 30% propylene glycol and 70% glycerol fluid containing the desired fullerenol carotenoids. In step S1540, dispense about 0.5 to 1 ml of the fullerenol into a vapor inhalant cartridge for aspirated electronic delivery as a vapor inhalant to transfer the fullerenol carotenoids such as C60 xanthophylls to the bloodstream for the intended purpose of promoting retinal and ocular health. In optional step S1550, apply about 6 volts to about 10 volts at a few milliamperes of transcranial electric current for ephaptic innervation of the retina and ocular neurons while sleeping to confer additional protective neurostimulation.

[0061] Referring now to FIG. 16, there is illustrated a non-limiting list of carotenoids 1600 having a 40-carbon basal structure that is typical of most carotenoids, where these molecular species are based on variations of the tetraterpenoid pigment phytoene. There are over 600 known carotenoids. These and other carotenoids are useful as antioxidants for the intended purpose. Based on their composition, carotenoids may classify into two general types, carotenes containing only carbon and hydrogen atoms, and carotenes that contain at least one oxygen atom within their molecular structure. The latter are termed oxy-carotenoids. A carotenoid having sufficient length to penetrate all retinal and neural cell membranes are the xanthophylls, therefore these are a preferred embodiment of the composition.

[0062] Referring now to FIG. 17, there is illustrated a method 1700 of using an electronic vapor inhaler to administer the composition of present embodiments. Exemplary C60 fullerene xanthophylls 1710 are charged into a solution for electronic inhalation at the electronic vapor generating device 1720. Xanthophylls 1710 are being aspirated or breathed in by patient or user 1750 into the airways and lungs as indicated by large white arrow 1760. Exhalation of this vapor 1710 out of the nose and airways is indicated by the two narrow black arrows and the cloud shape of exhaled vapors 1730, 1740. It is understood that any of C60 or C70 fullerenols may be used as inhalant carriers for the carotenoids and xanthophylls of the present embodiments to deliver these neuroprotective substances in the form of vapors for inhalation, in accordance with a method of use. Other types of fullerenol configurations and compositions are possible and may create analogous ephaptic stimulation for retinal and ocular neuroprotection presented herein.

[0063] The illustrated inhalant method 1700 of delivering a composition 1710 of the present embodiments can be used to slow the worsening of a pulmonary condition, or to prevent future harm to prospective client 1750 by otherwise unavoidable exposure to pulmonary disease risk factors. For example, chronic obstructive pulmonary disease (COPD) risk factors include microparticulate air pollution in or near cities, exposure to smoke including tobacco aerosols, and genetic factors. COPD is a chronic inflammatory lung disease that causes obstructed lung airflow from the lungs. COPD is characterized by long-term breathing problems including cough, mucus production, wheezing, and poor airflow as measured by lung function tests. No cure is known. By introducing composition 1710 into the airways and lungs of a patient, improvement in breathing, or a reduction of breathing declension may be realized. The direction of large white arrow 1760 can indicate the action of inhalant ingress to the airways and lungs where the pulmonary benefit is to be accorded, especially to avoid, or to treat, for example, COPD. Other obstructive pulmonary diseases, including without limitation, asthma, bronchiectasis, bronchitis, or cystic fibrosis also may benefit from composition embodiments. [0064] Inhaler 1720 may be an existing, appropriate electronic device with a metered-dosage pharmaceutical inhalant delivery system that monitors, adjusts, and limits delivery of a prescribed pharmaceutical composition. Device 1720 can facilitate a non-invasive out-patient home treatment for pulmonary conditions, such as COPD, where real time dosage monitoring can be electronically adjusted by the remote action of a physician using an encrypted big-data cloud interface.

[0065] Any of C60 or C70 fullerenols may be used as inhalant carriers for the carotenoids and xanthophylls of the present embodiments to deliver these neuroprotective substances in the form of vapors for inhalation, in accordance with a method of use. Other types of fullerenol configurations and compositions are possible and may create analogous ephaptic stimulation for retinal and ocular neuroprotection presented herein.

[0066] As variations, combinations and modifications may be made in the construction and methods herein described and illustrated without departing from the scope of the invention, it is intended that all matter contained in the foregoing description or shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments but defined in accordance with the foregoing claims appended hereto and their equivalents.

Claims

1. A retinoid analogue composition, comprising: a carotenoid molecule directly added to a fullerene molecule to form a fullerenol carotenoid.

2. The retinoid analogue composition of Claim 1, wherein the fullerenol carotenoid further comprises: at least one oxygen-containing carotenoid adduct bonded to a polyhydroxylated fullerene molecule.

3. The retinoid analogue composition of Claim 2, wherein the fullerene molecule includes one of C60 or C70.

4. The retinoid analogue composition of Claim 3, wherein C60 includes geometrically isotropic polyhydroxylated C60 or geometrically anisotropic polyhydroxylated C60, and C70 includes isotropic C70 or anisotropic C70.

5. The retinoid analogue composition of Claim 2, wherein the carotenoid includes a xanthophyll.

6. The retinoid analogue composition of Claim 5, wherein the xanthophyll is an astaxanthin.

7. The retinoid analogue composition of claim 2, further comprising proximal charge induced ascorbic acid associated by adsorption to the fullerenol carotenoid.

8. The retinoid analogue composition of claim 2, wherein at least one of the carotenoid adducts includes a beta-carotene structurally related to retinol metabolites.

9. The retinoid analogue composition of claim 5, wherein the fullerenol carotenoid comprises a xanthophyll having a functional group carbon chain length equal to or greater than beta-carotene (C40H56).

10. A method of treating an obstructive pulmonary disease comprising delivering the retinoid analogue composition of Claim 1 into the lungs of a patient as a vapor inhalant wherein gastrointestinal decomposition of the carotenoid adduct structure is obviated.

11. A method of treating an obstructive pulmonary disease comprising delivering the retinoid analogue composition of Claim 9 into the lungs of a patient as a vapor inhalant wherein gastrointestinal decomposition of the carotenoid adduct structure is obviated.

12. The method of treating an obstructive pulmonary disease of Claim 11 further comprising: before delivering as a vapor inhalant into the lungs of a patient, heating the xanthophyll to at least 245 degrees C for no more than about 1 second.

13. A method of treating an ocular disease comprising delivering as a vapor inhalant into the lungs of a patient the retinoid analogue composition of Claim 9, wherein ephaptic neural innervation associated with ocular neurons within the structure of and leading to the retina of the eye is stimulated and wherein the ephaptic neural innervation slows the progression of age- related macular degeneration (AMD).

14. The method of treating an ocular disease of Claim 13 further comprising: before delivering as a vapor inhalant into the lungs of a patient, heating the xanthophyll to at least 245 degrees C for no more than about 1 second.

15. The method of treating the ocular disease of Claim 13, further comprising: one of applying electrical stimulation to the skin surfaces near to the eye during periods of sleep, or applying standard transcranial alternating or direct current stimulation wherein ocular neural tissue growth is stimulated.