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WO2016037166A1 - Novel anti-oxidant compositions and methods of delivery - Google Patents

Novel anti-oxidant compositions and methods of delivery Download PDF

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Publication number
WO2016037166A1
WO2016037166A1 PCT/US2015/048772 US2015048772W WO2016037166A1 WO 2016037166 A1 WO2016037166 A1 WO 2016037166A1 US 2015048772 W US2015048772 W US 2015048772W WO 2016037166 A1 WO2016037166 A1 WO 2016037166A1
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extract
agents
antioxidants
mixtures
antioxidant
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PCT/US2015/048772
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French (fr)
Inventor
Yu Zhang
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Definitions

  • the present invention relates to methods and compositions for treating respiratory symptoms caused by inhaled particulate matter.
  • Air pollution is made up of a mixture of small particles in the air, and often characterized by obvious smog hanging over places where people live.
  • the problem of air pollution has increased due to the rapid pace at which economies of the world are developing.
  • the components that contribute to the ambient air pollution include fine particles produced during energy production (e.g., coal consumption, fuel burning), ozone (formed by chemical reactions of oxygen molecules under solar ultraviolet radiation).
  • WHO World Health Organization
  • the invention provides a method of treating respiratory symptoms caused by inhaled particulate matter comprising: providing an antioxidant pharmaceutical composition comprising, consisting essentially of, or consists of: a plant extract; and at least one of: vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol- based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, and salts thereof; and
  • the invention provides an antioxidant pharmaceutical composition
  • an antioxidant pharmaceutical composition comprising, consisting essentially of, or consists of: a plant extract; and at least one of: vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, and salts thereof.
  • composition having a plant extract, and vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its
  • antioxidants derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, mixtures thereof.
  • the present invention provides methods and compositions for treating respiratory symptoms caused by inhaled particulate matter.
  • the methods include the administration of the disclosed pharmaceutical compositions before, during, and after exposure to inhaled particulate matter.
  • the pharmaceutical composition comprises a plant extract; and vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, plant extracts, enzyme and small molecule antioxidants, mixtures thereof, and salts thereof.
  • suitable plant extracts include: acai extract, aloe vera extract, astragalus extract, auricularia auricula-judae extract, bilberry extract, bitter orange extract, black cohosh extract, bromelain extract, butterbur extract, cat's claw extract, chamomile extract, chasteberry extract, cinnamon extract, cranberry extract, dandelion extract, dendranthema morifolium extract, echinacea extract, essiac tea extract, Flor Essence tea extract, Sambucus nigra (European elder) extract, Evening Primrose extract, fenugreek extract, feverfew extract, flaxseed extract, ganoderma lucidium (reishi mushroom) extract, garlic extract, ginger extract, ginkgo biloba extract, ginseng extract, glycyrrhiza glabra (licorice) extract, goldenseal extract, grape seed extract, green tea extract, hawthorn extract, hood
  • Extracts from plants may be obtained by any known means.
  • thiol-based antioxidants include isothiocyanates, sulfides, glutathione and its derivatives, thioredoxin, cysteine and N-acetylcysteine, dithiol compounds, prothiol compounds, and mixtures thereof.
  • dithiols include lipoic acid.
  • prothiol compounds include L-2-oxothiazolidine-4-carboxylate.
  • polyphenols examples include phenolic acids, ferulic acid, caffeic acid, cinnamic acid, phenylethyl ester, apigenin, pycnogenol, carotenoids, flavonoids, soy isoflavones, genistein, daidzein, equol, tretinoin, silymarin, quercetin, tannins, resveratrol, tea polyphenols, catechin, epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate, and mixtures thereof.
  • minerals include selenium, sodium, potassium, magnesium, calcium, zinc, copper, iron, chromium, fluorine, chlorine, iodine, phosphorous, and mixtures thereof.
  • Suitable enzyme and small molecule antioxidants include superoxide dismutases, catalase, glutathione peroxidase, NADPH:quinone reductase, thioredoxin system, coenzyme Q, glutathione, bilirubin, melatonin, ferritin, L-carnitine, alpha-lipoic acid, metallothioneins, acetyl-L-carnitine, edaravone, hydroxytyrosol, tyrosol, ladostigil, mofegiline, N-acetylcysteine, N-acetylserotonin, oleocanthal, oleuropein, rasagiline, selegiline, uric acid, butylated hydroxytoluene, 2,6-di-tert-butylphenol, 1,2-diaminopropane, 2,4-dimethyl-6-tert- butylphenol, ethylenedi
  • free form means the original chemical form, not the salt or any other chelating form (like dimers, or polymers).
  • the pharmaceutical composition comprises an active ingredient, wherein the active ingredient consists of: a) a plant extract, and b) an antioxidant.
  • the composition consists of: a) plant extract, b) an antioxidant, and/or salt thereof, and c) at least one carrier and/or excipient.
  • the pharmaceutical composition consisting essentially of the active ingredients of: a) plant extract, and b) an antioxidant and/or salt thereof. That is, any other ingredients that may materially affect the basic and novel characteristics of the active ingredients of the invention are specifically excluded from the composition. Any ingredient which can potentially cause an undesirable effect/side effect, including, for example, an allergic response, may materially affect the basic and novel characteristics of the active ingredients of the invention.
  • nasal decongestant and antihistamines are some examples of components which may materially affect the basic and novel characteristics of the active ingredients of the pharmaceutical compositions and may be excluded from certain embodiments of the present invention: nasal decongestant and antihistamines.
  • the aforementioned ingredients may materially change the characteristics of the present pharmaceutical composition due to unwanted effects and/or potential allergic responses.
  • decongestants are not desired in some embodiments of the invention.
  • a decongestant is pseudoephedrine.
  • unwanted potential effects of pseudoephedrine include nausea, vomiting, trouble sleeping, dizziness, headache, or nervousness may occur.
  • antihistamines are not desired in some embodiments of the invention. Examples of unwanted potential effects of antihistamines include dry mouth, drowsiness, dizziness, nausea, vomiting, restlessness, moodiness, trouble urinating or not being able to urinate, blurred vision, and confusion.
  • the pharmaceutical formulation does not include decongestants. In yet another embodiment, the pharmaceutical formulation does not include antihistamines.
  • Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995.
  • an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • pharmaceutically-acceptable carriers include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.
  • the following buffer pairs have been contemplated: citric acid/ potassium citrate, potassium acetate/ acetic acid, sodium hydrogen phthalate/ potassium hydroxide, potassium hydrogen phthalate / potassium dihydrogen orthophosphate, sodium hydrogen phthalate / sodium dihydrogen orthophosphate, sodium dihydrogen orthophosphate / potassium hydroxide, barbitone potassium / hydrochloric acid, tris (hydroxylmethyl) aminomethane / hydrochloric acid, potassium tetraborate/ hydrochloric acid to maintain a pH of the composition within the range of about 6.8 to 8.6.
  • the preferred formulation is that of a liquid.
  • excipients have been contemplated: gums, granulating agents, binders, lubricants, disintegrating agents, sweetening agents, additives, solvents, glidants, anti-adherents, anti-static agents, surfactants, viscosity enhancers, plant cellulosic material coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, antistatic agents, spheronization agents, and any combinations thereof.
  • the preferred formulation is that of a dry powder or a solid aerosol. Accordingly, the following excipients have been contemplated: sugars and saccharides, preferably inhalation grade lactose, preferably alpha monohydrate lactose in the form of crystalline lactose, milled lactose or micronized lactose.
  • a composition of the present invention includes aqueous nasal or oral spray composition having: 0.10-5.0% by weight/volume of an antioxidant and mixtures thereof; 0.10-5.0% by weight/volume of a plant extract and mixtures thereof; 1.0-20.0% by weight/volume of an excipient and mixtures thereof; a sufficient amount of a pharmaceutically acceptable buffer to maintain the pH of the composition within the range of about 6.8 to 8.6; and water.
  • the methods of the present invention comprise the administration of a therapeutically effective amount of the composition to a human in an amount which is effective to inhibit, treat, or alleviate respiratory symptoms caused by inhaled particulate matter.
  • therapeutically effective amount is defined as the amount necessary to achieve the desired outcome.
  • the term “inhibit” includes “reduce and/or “prevent” and/or “shorten duration.” That is, the method of the present invention is considered to be effective if it causes one or more of: a reduction/inhibition/prevention of any symptom associated with inflammation of the respiratory tract.
  • Reduction of symptoms can be assessed by comparing the magnitude and/or duration of at least one respiratory symptom in a subject at two different occasions, that is, i) when administered the pharmaceutical composition, and then the subject is exposed to inhaled particulate matter; and ii) when not administered the composition, and then the subject is exposed to inhaled particulate matter.
  • the respiratory symptoms are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%.
  • compositions of the present invention provide a unique and synergistic combination of effects.
  • the antioxidants provide reduction/prevention of oxidative damage and the plant extracts provide immune support to the body. Accordingly, the combination provides an unexpected efficacy in the treatment of respiratory symptoms caused by inhaled particulate matter.
  • PM Particulate matter
  • PM refers to small solid particles and/or liquid matter existing in the air.
  • PM can be sub-categorized, depending on the particle size and penetration to lung tissue, coarse particles, namely PM10 (inhalable particles less than or equal to 10 ⁇ in diameter), and fine particles, namely PM2.5 (inhalable particles less than or equal to 2.5 ⁇ in diameter), both of which are generated mostly by air pollution.
  • PM2.5 comprises water-soluble inorganic ions (sulfate, nitrate, ammonium and sodium, magnesium, calcium, aluminum, etc.), organic carbon compounds and elements (iron, or lead, zinc, arsenic, cadmium, etc.).
  • PM2.5 Because of the particles size of PM2.5, it can stay in air for a very long time, and increase the likelihood of respiratory symptoms of people who spend time outdoors. These symptoms may be localized to the respiratory system, including the nasal passages and the lungs, or the symptoms may be systemic.
  • Symptoms localized to the respiratory system include inflammation of the lungs or nasal passages. Inflammation of the lungs includes pneumonitis, or inflammation of lung tissue, or asthma. Inflammation of the nasal passages includes sinusitis, or inflammation of nasal tissue. These symptoms may be acute or chronic.
  • Lung disease includes at least for example, chronic obstructive pulmonary disease (COPD), lung cancer, and granulomatous lung diseases.
  • COPD chronic obstructive pulmonary disease
  • the composition is administered before the onset of symptoms.
  • administration is at most about 120 minutes before exposure to inhaled particulate matter, at most about 90 minutes before exposure to inhaled particulate matter, at most about 60 minutes before exposure to inhaled particulate matter, at most about 30 minutes before exposure to inhaled particulate matter, at most about 20 minutes before exposure to inhaled particulate matter, just right before exposure to inhaled particulate matter, or simultaneously exposure to inhaled particulate matter.
  • administration is at most about 120 minutes before exposure to inhaled particulate matter, at most about 90 minutes before exposure to inhaled particulate matter, at most about 60 minutes before exposure to inhaled particulate matter, at most about 30 minutes before exposure to inhaled particulate matter, at most about 20 minutes before exposure to inhaled particulate matter, just right before exposure to inhaled particulate matter, or simultaneously exposure to inhaled particulate matter.
  • the composition is administered before the onset of symptoms.
  • administration is at most about 120 minutes before exposure to
  • composition can be administered up to about 2 hours to about 4 hours after exposure to inhaled particulate matter, but before the onset of symptoms.
  • composition of the present invention can be administered by any inhalation methods known in the art.
  • the pharmaceutical composition can be administered through the nose or the mouth.
  • numerous specific details are set forth in order to provide a thorough understanding of the present embodiments. It will be apparent, however, to one having ordinary skill in the art that the specific detail need not be employed to practice the present
  • the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a process, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, article, or apparatus.
  • a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • any examples or illustrations given herein are not to be regarded in any way as restrictions on, limits to, or express definitions of any term or terms with which they are utilized. Instead, these examples or illustrations are to be regarded as being described with respect to one particular embodiment and as being illustrative only. Those of ordinary skill in the art will appreciate that any term or terms with which these examples or illustrations are utilized will encompass other embodiments which may or may not be given therewith or elsewhere in the specification and all such embodiments are intended to be included within the scope of that term or terms. Language designating such nonlimiting examples and illustrations includes, but is not limited to: “for example,” “for instance,” “e.g.,” and “in one embodiment.”
  • each member may be combined with any one or more of the other members to make additional sub-groups.
  • additional sub-groups specifically contemplated include any one, two, three, or four of the members, e.g., a and c; a, d, and e; b, c, d, and e; etc.
  • Plants (10.0 g) are added to a mixture of 500 mL of distilled water and 500 mL of methanol in a 2 L round-bottom flask and reflux for 30 minutes.
  • the solution is cooled down to room temperature, filtered through a buchner funnel and the filtrate is collected, followed by passing through a 0.2 ⁇ membrane into a 2 L round-bottom flask.
  • the solution is evaporated under reduced pressure on a rotary evaporator to obtain 1.0 g crude extract.
  • the crude extract is dissolved in ethyl acetate (2.0 mL) and then
  • Total Phenol Count (TPC) assay Folin-Ciocalteu assay is used to determine the total phenol count of the antioxidants. Folin-Ciocalteu reagent is made by dissoving 10 g sodium tungstate and 2.5 g sodium molybdate in 70 mL water, adding 5 mL 85% phosphoric acid and 10 mL concentrated hydrochloric acid, refluxing for 10 hrs, adding 15 g lithium sulfate, 5 mL water and 1 drop bromine, and refluxing for another 15 min, and cooling to room temperature and bringing to 100 mL with water, eventually forming the hexavalent phosphomolybdic-phosphotungstic acid
  • O 2 scavenging activity Nitroblue tetrazolium (NBT) is used as a standard to evaluate the capacity of aliquots of antioxidants (50, 100, 200 and 300 ⁇ g) through the photochemical reduction in the riboflavin-light-NBT system. 3 mL of solution contained 50 mM phosphate buffer, 13 mM methionine, 2 ⁇ riboflavin, 100 ⁇ EDTA, 75 ⁇ NBT and 100 ⁇ ⁇ solution of various concentrations of the antioxidants. The increase in absorbance at 560 nm after 10 min illumination is monitored from a fluorescent lamp with respect to the production. H 2 O 2 scavenging activity: Antioxidants (50, 100, 200 and 300 ⁇ g) are dissolved in H 2 0
  • Rats in Group 5-8 are exposed according to four different daily exposure protocols, 4 h air followed by intratracheal instillation of PM2.5 (0.2, 0.8, 3.2 mg/rat).
  • Bronchoalveolar Lavage Fluids Cell Differentiation and Biochemical Analysis Twenty-four hours after the last intratracheal instillation of air or PM2.5, rats are anesthetized with chloral hydrate (30 mg/kg, i.p.). Aliquot of the recovered lavage fluid is taken and centrifuged (1500 rpm for 10 min at 4 °C) and cells are collected for cell counts by a hemocytometer and differentiation. Standard clinical laboratory method is used to determine the lactate dehydrogenase (LDH) activities in supernatants. ELISA kits are used to determine the activities of interleukin (IL)-2 and tumor necrosis factor alpha (TNF-a).
  • IL interleukin
  • TNF-a tumor necrosis factor alpha
  • the colorimetric assay kits are used to determine the albumin and activity of alkaline phosphatase (AKP). Histopathological Examination with Hemotoxylin and Eosin (HE) Staining: The lung apex is put in a solution of 4% paraformaldehyde for at 4 °C 12 hrs. After fixation, paraffin-embedded tissues are sectioned at 5 ⁇ and are stained with HE, Cuts by ultramicrotome are mounted and stained with lead citrate, and then electron microscopy is used for observation.
  • alkaline phosphatase ADP
  • HE Hemotoxylin and Eosin Staining
  • Buffer sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
  • Antioxidant vitamin E 0.15%
  • Plant extract ziziphus jujuba extract 0.25%
  • Buffer sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
  • Antioxidant Resveratrol 0.20%
  • Buffer sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
  • Antioxidant vitamin B 20%
  • Antioxidant quercetin 15%
  • Plant extract tremella fuciformis extract 15%
  • Plant extract 0.001-2% water soluble polyvinylpyrrolidone having an 0.05-15.00% average molecular weight of about 10,000 to
  • Aromatic alcohol 0.20-5.00%

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Abstract

The present invention provides compositions and methods relating to the treatment of treating respiratory symptoms caused by inhaled particulate matter. In one embodiment, the method includes administering a composition including a plant extract and an anti-oxidant through an inhaled route.

Description

NOVEL ANTI- OXIDANT COMPOSITIONS AND METHODS OF DELIVERY
FIELD OF THE INVENTION
The present invention relates to methods and compositions for treating respiratory symptoms caused by inhaled particulate matter.
BACKGROUND
Air pollution is made up of a mixture of small particles in the air, and often characterized by obvious smog hanging over places where people live. The problem of air pollution has increased due to the rapid pace at which economies of the world are developing. The components that contribute to the ambient air pollution include fine particles produced during energy production (e.g., coal consumption, fuel burning), ozone (formed by chemical reactions of oxygen molecules under solar ultraviolet radiation).
Air pollution can have a negative effect on human health and may lead to diseases that include stroke, lung cancer, acute lower respiratory infections in children. According to the report published by World Health Organization (WHO) on Mar 25, 2014, about 7 million people died in the year of 2012 due to air pollution exposure, which is one eighth of death worldwide.
Accordingly, there is a need for a more effective and accessible manner by which to manage respiratory symptoms caused by inhaled particulate matter.
SUMMARY OF THE INVENTION
In one embodiment, the invention provides a method of treating respiratory symptoms caused by inhaled particulate matter comprising: providing an antioxidant pharmaceutical composition comprising, consisting essentially of, or consists of: a plant extract; and at least one of: vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol- based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, and salts thereof; and
administering said pharmaceutical composition by inhalation route to a person in need thereof.
In one embodiment, the invention provides an antioxidant pharmaceutical composition comprising, consisting essentially of, or consists of: a plant extract; and at least one of: vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, and salts thereof.
As a result of the present invention, the treatment of respiratory symptoms caused by inhaled particulate matter can be provided by the administration of composition having a plant extract, and vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its
derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, mixtures thereof.
DETAILED DESCRIPTION
The present invention provides methods and compositions for treating respiratory symptoms caused by inhaled particulate matter. The methods include the administration of the disclosed pharmaceutical compositions before, during, and after exposure to inhaled particulate matter.
In one embodiment, the pharmaceutical composition comprises a plant extract; and vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, plant extracts, enzyme and small molecule antioxidants, mixtures thereof, and salts thereof.
Examples of suitable plant extracts include: acai extract, aloe vera extract, astragalus extract, auricularia auricula-judae extract, bilberry extract, bitter orange extract, black cohosh extract, bromelain extract, butterbur extract, cat's claw extract, chamomile extract, chasteberry extract, cinnamon extract, cranberry extract, dandelion extract, dendranthema morifolium extract, echinacea extract, essiac tea extract, Flor Essence tea extract, Sambucus nigra (European elder) extract, Evening Primrose extract, fenugreek extract, feverfew extract, flaxseed extract, ganoderma lucidium (reishi mushroom) extract, garlic extract, ginger extract, ginkgo biloba extract, ginseng extract, glycyrrhiza glabra (licorice) extract, goldenseal extract, grape seed extract, green tea extract, hawthorn extract, hoodia extract, horse chestnut extract, isatis indigotica extract, kava extract, lavender extract, lycium barbarum extract, mistletoe extract, noni extract, panax pseudo-ginseng extract, peppermint extract, polypodium leucotomos extract, pomegranate extract, prunus persica flower extract, punica granatum extract, red clover extract, robdosia rubescens extract, sage extract, saw palmetto extract, Scutellaria baicalensis extract, serenoa repens (saw palmetto) extract, silybum marianum (milk thistle) extract, soy extract, St. John's wort extract, tea extract, thunder God vine extract, tremella fuciformis extract, valerian extract, yohimbe extract, ziziphus jujuba extract, and mixtures thereof.
Extracts from plants may be obtained by any known means.
Examples of thiol-based antioxidants include isothiocyanates, sulfides, glutathione and its derivatives, thioredoxin, cysteine and N-acetylcysteine, dithiol compounds, prothiol compounds, and mixtures thereof. An example of dithiols include lipoic acid. An example of prothiol compounds include L-2-oxothiazolidine-4-carboxylate.
Examples of polyphenols include phenolic acids, ferulic acid, caffeic acid, cinnamic acid, phenylethyl ester, apigenin, pycnogenol, carotenoids, flavonoids, soy isoflavones, genistein, daidzein, equol, tretinoin, silymarin, quercetin, tannins, resveratrol, tea polyphenols, catechin, epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate, and mixtures thereof.
Examples of minerals include selenium, sodium, potassium, magnesium, calcium, zinc, copper, iron, chromium, fluorine, chlorine, iodine, phosphorous, and mixtures thereof.
Examples of suitable enzyme and small molecule antioxidants include superoxide dismutases, catalase, glutathione peroxidase, NADPH:quinone reductase, thioredoxin system, coenzyme Q, glutathione, bilirubin, melatonin, ferritin, L-carnitine, alpha-lipoic acid, metallothioneins, acetyl-L-carnitine, edaravone, hydroxytyrosol, tyrosol, ladostigil, mofegiline, N-acetylcysteine, N-acetylserotonin, oleocanthal, oleuropein, rasagiline, selegiline, uric acid, butylated hydroxytoluene, 2,6-di-tert-butylphenol, 1,2-diaminopropane, 2,4-dimethyl-6-tert- butylphenol, ethylenediamine, and mixtures thereof.
Any of the components may be present in free form. As used herein free form means the original chemical form, not the salt or any other chelating form (like dimers, or polymers).
In one embodiment, the pharmaceutical composition comprises an active ingredient, wherein the active ingredient consists of: a) a plant extract, and b) an antioxidant.
In one embodiment, the composition consists of: a) plant extract, b) an antioxidant, and/or salt thereof, and c) at least one carrier and/or excipient.
In one embodiment, the pharmaceutical composition consisting essentially of the active ingredients of: a) plant extract, and b) an antioxidant and/or salt thereof. That is, any other ingredients that may materially affect the basic and novel characteristics of the active ingredients of the invention are specifically excluded from the composition. Any ingredient which can potentially cause an undesirable effect/side effect, including, for example, an allergic response, may materially affect the basic and novel characteristics of the active ingredients of the invention.
The following are some examples of components which may materially affect the basic and novel characteristics of the active ingredients of the pharmaceutical compositions and may be excluded from certain embodiments of the present invention: nasal decongestant and antihistamines.
The aforementioned ingredients may materially change the characteristics of the present pharmaceutical composition due to unwanted effects and/or potential allergic responses. For example, decongestants are not desired in some embodiments of the invention. One example of a decongestant is pseudoephedrine. Examples of unwanted potential effects of pseudoephedrine include nausea, vomiting, trouble sleeping, dizziness, headache, or nervousness may occur. For example, antihistamines are not desired in some embodiments of the invention. Examples of unwanted potential effects of antihistamines include dry mouth, drowsiness, dizziness, nausea, vomiting, restlessness, moodiness, trouble urinating or not being able to urinate, blurred vision, and confusion.
In one embodiment, the pharmaceutical formulation does not include decongestants. In yet another embodiment, the pharmaceutical formulation does not include antihistamines.
The components of the delivery system can be administered in vivo by use of a pharmaceutically acceptable carrier in the form of a composition. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the components of the delivery system, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of pharmaceutically-acceptable carriers include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.
To maintain proper pH of the pharmaceutical composition of the present invention, the following buffer pairs have been contemplated: citric acid/ potassium citrate, potassium acetate/ acetic acid, sodium hydrogen phthalate/ potassium hydroxide, potassium hydrogen phthalate / potassium dihydrogen orthophosphate, sodium hydrogen phthalate / sodium dihydrogen orthophosphate, sodium dihydrogen orthophosphate / potassium hydroxide, barbitone potassium / hydrochloric acid, tris (hydroxylmethyl) aminomethane / hydrochloric acid, potassium tetraborate/ hydrochloric acid to maintain a pH of the composition within the range of about 6.8 to 8.6.
When the route of administration is through a nasal cavity, the preferred formulation is that of a liquid. Accordingly, the following excipients have been contemplated: gums, granulating agents, binders, lubricants, disintegrating agents, sweetening agents, additives, solvents, glidants, anti-adherents, anti-static agents, surfactants, viscosity enhancers, plant cellulosic material coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, antistatic agents, spheronization agents, and any combinations thereof.
When the route of administration is via the mouth, the preferred formulation is that of a dry powder or a solid aerosol. Accordingly, the following excipients have been contemplated: sugars and saccharides, preferably inhalation grade lactose, preferably alpha monohydrate lactose in the form of crystalline lactose, milled lactose or micronized lactose.
In one embodiment, a composition of the present invention includes aqueous nasal or oral spray composition having: 0.10-5.0% by weight/volume of an antioxidant and mixtures thereof; 0.10-5.0% by weight/volume of a plant extract and mixtures thereof; 1.0-20.0% by weight/volume of an excipient and mixtures thereof; a sufficient amount of a pharmaceutically acceptable buffer to maintain the pH of the composition within the range of about 6.8 to 8.6; and water. The methods of the present invention comprise the administration of a therapeutically effective amount of the composition to a human in an amount which is effective to inhibit, treat, or alleviate respiratory symptoms caused by inhaled particulate matter.
As used herein, therapeutically effective amount is defined as the amount necessary to achieve the desired outcome.
In the present specification, the term "inhibit" includes "reduce and/or "prevent" and/or "shorten duration." That is, the method of the present invention is considered to be effective if it causes one or more of: a reduction/inhibition/prevention of any symptom associated with inflammation of the respiratory tract.
Reduction of symptoms can be assessed by comparing the magnitude and/or duration of at least one respiratory symptom in a subject at two different occasions, that is, i) when administered the pharmaceutical composition, and then the subject is exposed to inhaled particulate matter; and ii) when not administered the composition, and then the subject is exposed to inhaled particulate matter. Typically, the respiratory symptoms are reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%.
Without wishing to be bound by theory, it is believed that the compositions of the present invention provide a unique and synergistic combination of effects. In particular, it is believed that the antioxidants provide reduction/prevention of oxidative damage and the plant extracts provide immune support to the body. Accordingly, the combination provides an unexpected efficacy in the treatment of respiratory symptoms caused by inhaled particulate matter.
Particulate matter is a component of air pollution. Particulate matter (PM) refers to small solid particles and/or liquid matter existing in the air. According to United States Environmental Protection Agency website, PM can be sub-categorized, depending on the particle size and penetration to lung tissue, coarse particles, namely PM10 (inhalable particles less than or equal to 10 μιη in diameter), and fine particles, namely PM2.5 (inhalable particles less than or equal to 2.5μιη in diameter), both of which are generated mostly by air pollution. In particular, PM2.5 comprises water-soluble inorganic ions (sulfate, nitrate, ammonium and sodium, magnesium, calcium, aluminum, etc.), organic carbon compounds and elements (iron, or lead, zinc, arsenic, cadmium, etc.). Because of the particles size of PM2.5, it can stay in air for a very long time, and increase the likelihood of respiratory symptoms of people who spend time outdoors. These symptoms may be localized to the respiratory system, including the nasal passages and the lungs, or the symptoms may be systemic.
Symptoms localized to the respiratory system include inflammation of the lungs or nasal passages. Inflammation of the lungs includes pneumonitis, or inflammation of lung tissue, or asthma. Inflammation of the nasal passages includes sinusitis, or inflammation of nasal tissue. These symptoms may be acute or chronic.
Other symptoms associated with by inhaled particulate matter include the common cold, allergic rhinitis (swelling of the lining of the nose), nasal polyps (small growths in the lining of the nose), a deviated septum (a shift in the nasal cavity), shortness of breath, decreased ability to exercise, feeling like not getting enough air inhaled, coughing, wheezing, coughing up mucus, pain or discomfort when breathing in or out, chest tightness.
Further symptoms include, but not limited respiratory disease, lung disease and aggravation of cardiovascular diseases, all of which are caused by the inflammation of respiratory system. Lung disease includes at least for example, chronic obstructive pulmonary disease (COPD), lung cancer, and granulomatous lung diseases.
In the methods of the present invention, the composition is administered before the onset of symptoms. For example, administration is at most about 120 minutes before exposure to inhaled particulate matter, at most about 90 minutes before exposure to inhaled particulate matter, at most about 60 minutes before exposure to inhaled particulate matter, at most about 30 minutes before exposure to inhaled particulate matter, at most about 20 minutes before exposure to inhaled particulate matter, just right before exposure to inhaled particulate matter, or simultaneously exposure to inhaled particulate matter. In some embodiments, the
pharmaceutical composition can be administered up to about 2 hours to about 4 hours after exposure to inhaled particulate matter, but before the onset of symptoms.
The composition of the present invention can be administered by any inhalation methods known in the art. For example, the pharmaceutical composition can be administered through the nose or the mouth. In the specification, numerous specific details are set forth in order to provide a thorough understanding of the present embodiments. It will be apparent, however, to one having ordinary skill in the art that the specific detail need not be employed to practice the present
embodiments. In other instances, well-known materials or methods have not been described in detail in order to avoid obscuring the present embodiments.
Throughout this specification, quantities are defined by ranges, and by lower and upper boundaries of ranges. Each lower boundary can be combined with each upper boundary to define a range. The lower and upper boundaries should each be taken as a separate element.
Reference throughout this specification to "one embodiment," "an embodiment," "one example," or "an example" means that a particular feature, structure or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present embodiments. Thus, appearances of the phrases "in one embodiment," "in an
embodiment," "one example," or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures or characteristics may be combined in any suitable combinations and/or subcombinations in one or more embodiments or examples. In addition, it is appreciated that the figures provided herewith are for explanation purposes to persons ordinarily skilled in the art and that the drawings are not necessarily drawn to scale.
As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, article, or apparatus.
Further, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not to an exclusive "or". For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Additionally, any examples or illustrations given herein are not to be regarded in any way as restrictions on, limits to, or express definitions of any term or terms with which they are utilized. Instead, these examples or illustrations are to be regarded as being described with respect to one particular embodiment and as being illustrative only. Those of ordinary skill in the art will appreciate that any term or terms with which these examples or illustrations are utilized will encompass other embodiments which may or may not be given therewith or elsewhere in the specification and all such embodiments are intended to be included within the scope of that term or terms. Language designating such nonlimiting examples and illustrations includes, but is not limited to: "for example," "for instance," "e.g.," and "in one embodiment."
In this specification, groups of various parameters containing multiple members are described. Within a group of parameters, each member may be combined with any one or more of the other members to make additional sub-groups. For example, if the members of a group are a, b, c, d, and e, additional sub-groups specifically contemplated include any one, two, three, or four of the members, e.g., a and c; a, d, and e; b, c, d, and e; etc.
EXAMPLES
1. ) Plant Extraction :
Plants (10.0 g) are added to a mixture of 500 mL of distilled water and 500 mL of methanol in a 2 L round-bottom flask and reflux for 30 minutes. The solution is cooled down to room temperature, filtered through a buchner funnel and the filtrate is collected, followed by passing through a 0.2 μιη membrane into a 2 L round-bottom flask. The solution is evaporated under reduced pressure on a rotary evaporator to obtain 1.0 g crude extract. The crude extract is dissolved in ethyl acetate (2.0 mL) and then
chromato graphed on Si02 with methanol, ethyl acetate and hexane (1:5: 15) solutions as eluents to give different fractions. Fractions are dried through rotary evaporation and stored at -20°C and re-suspended in DMSO to give a final concentration of 1 mM for use in the assays.
2. ) Total Phenol Count (TPC) assay: Folin-Ciocalteu assay is used to determine the total phenol count of the antioxidants. Folin-Ciocalteu reagent is made by dissoving 10 g sodium tungstate and 2.5 g sodium molybdate in 70 mL water, adding 5 mL 85% phosphoric acid and 10 mL concentrated hydrochloric acid, refluxing for 10 hrs, adding 15 g lithium sulfate, 5 mL water and 1 drop bromine, and refluxing for another 15 min, and cooling to room temperature and bringing to 100 mL with water, eventually forming the hexavalent phosphomolybdic-phosphotungstic acid
3Η2θ·Ρ2θ5·13 νθ3·5Μοθ3·10Η2θ/3Η2θχΡ2θ5·14 νθ3·4Μοθ3·10Η2Ο in the solution. Stock solutions of antioxidants are prepared in DMSO at concentrations of 1, 5, 10, 25, 50, 100, 250 and 500 μΜ. ΙΟΟμί solution containing 5 μΐ^ of Folin-Ciocalteu reagent and 20 μΐ^ of sodium carbonate solution are added first to the 96-well plate, followed by the addition of different concentrations of antioxidants. Due to the maximum UV absorption of the blue coloration, it can be detected in the region of 750 nm, and is proportional to the total phenol count. O2 scavenging activity: Nitroblue tetrazolium (NBT) is used as a standard to evaluate the capacity of aliquots of antioxidants (50, 100, 200 and 300 μg) through the photochemical reduction in the riboflavin-light-NBT system. 3 mL of solution contained 50 mM phosphate buffer, 13 mM methionine, 2 μΜ riboflavin, 100 μΜ EDTA, 75 μΜ NBT and 100 μΐ^ solution of various concentrations of the antioxidants. The increase in absorbance at 560 nm after 10 min illumination is monitored from a fluorescent lamp with respect to the production. H2O2 scavenging activity: Antioxidants (50, 100, 200 and 300 μg) are dissolved in H20
(100 μΙ_), followed by the addition of 0.01 % hydrogen peroxide (100 μΙ_), 0.1 M phosphate buffer (700 μί) and 0.1 M sodium chloride (100 μί). After incubation for 20 min at 37 °C, the phenol red dye (0.2 mg/mL, 1 mL) with 0.1 mg/mL horseradish peroxidase in 0.1 M phosphate buffer is added to the reaction mixture. 0.5 M NaOH (100 μν> is added after 15 min and the UV absorbance is measured at 610 nm. Percentage of reduction of H202 adsorption can be calculated for test samples. CoUagenase assay: CoUagenase from Clostridium histolyticum is dissolved in 50 mM
Tricine buffer for use at an initial concentration of 0.8 units/mL. N-[3-(2-furyl) acryloyl]- Leu-Gly-Pro-Ala (FALGPA) is used as the substrate, and dissolved in Tricine buffer to a final concentration of 2 mM. Antioxidants are incubated with coUagenase in buffer for 15 minutes before substrate is added to the reaction mixture. The final reaction mixture contains 25% w/v test antioxidants. UV absorbance is measured at 335 nm when substrate is added. 6.) Animal study: Male Wistar rats (150-180 g) are kept at 22 °C with 40-60% humidity. The rats are randomly assigned to 8 groups (n = 6), and a dark - light cycle of 12-12 h. Food and water are available ad libitum. After a week acclimation, all rats are exposed according to study design: Group 1 (Air exposure), Group 2 (Air exposure + nasal spray antioxidants), Group 3 (Air exposure + orally-dosed antioxidants), Group 4 (Air exposure + pulmonary inhaled antioxidants), Group 5 (PM2.5 exposure), Group 6 (PM2.5 exposure + nasal spray antioxidants), Group 7 (PM2.5 exposure + orally-dosed antioxidants), Group 8 (PM2.5 exposure + pulmonary inhaled antioxidants). Rats in Group 5-8 are exposed according to four different daily exposure protocols, 4 h air followed by intratracheal instillation of PM2.5 (0.2, 0.8, 3.2 mg/rat). Bronchoalveolar Lavage Fluids Cell Differentiation and Biochemical Analysis: Twenty-four hours after the last intratracheal instillation of air or PM2.5, rats are anesthetized with chloral hydrate (30 mg/kg, i.p.). Aliquot of the recovered lavage fluid is taken and centrifuged (1500 rpm for 10 min at 4 °C) and cells are collected for cell counts by a hemocytometer and differentiation. Standard clinical laboratory method is used to determine the lactate dehydrogenase (LDH) activities in supernatants. ELISA kits are used to determine the activities of interleukin (IL)-2 and tumor necrosis factor alpha (TNF-a). The colorimetric assay kits are used to determine the albumin and activity of alkaline phosphatase (AKP). Histopathological Examination with Hemotoxylin and Eosin (HE) Staining: The lung apex is put in a solution of 4% paraformaldehyde for at 4 °C 12 hrs. After fixation, paraffin-embedded tissues are sectioned at 5 μηι and are stained with HE, Cuts by ultramicrotome are mounted and stained with lead citrate, and then electron microscopy is used for observation.
Sample formulations
Formulation A:
Figure imgf000012_0001
Excipient: polyethylene glycol (PEG-300) 0.01%
Buffer: sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
Water: QS
Formulation B
Ingredient Wt%
Antioxidant: vitamin E 0.15%
Plant extract: ziziphus jujuba extract 0.25%
Excipient: polyethylene glycol (PEG-300) 0.01%
Buffer: sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
Water: QS
Formulation C
Ingredient Wt%
Antioxidant: Resveratrol 0.20%
Plant extract: ganoderma lucidum (reishi 0.20% mushroom) extract
Excipient: polyethylene glycol (PEG-600) 0.02%
Buffer: sodium dihydrogen orthophosphate / 0.50-1.0% potassium hydroxide
Water: QS
Formulation D
Ingredient Wt%
Antioxidant: vitamin B 20%
Plant extract: ginseng extract 20%
Excipient: cyclodextrin 60% Formulation E
Ingredient Wt%
Antioxidant: vitamin B 20%
Plant extract: ginseng extract 20%
Excipient: cyclodextrin 60%
Formulation F
Ingredient Wt%
Antioxidant: quercetin 15%
Plant extract: tremella fuciformis extract 15%
Excipient: trehalose 70%
Formulation G
Ingredient Wt%
Antioxidant 0.001-2%
Plant extract 0.001-2% water soluble polyvinylpyrrolidone having an 0.05-15.00% average molecular weight of about 10,000 to
360,000 and mixtures thereof
Polyethylene glycol 1.00-10.00%
Moisturizing agent other than polyethylene 1.00-10.00% glycol
EDTA 0.01-0.05%
Antimicrobial preservative 0.001-0.3%
Aromatic alcohol 0.20-5.00%

Claims

1. A method of treating respiratory symptoms caused by inhaled particulate matter
comprising: providing an antioxidant pharmaceutical composition comprising:
a plant extract; and
at least one of: vitamin A, vitamin B, vitamin C, vitamin E, minerals, ubiquinone and its derivatives, thiol-based antioxidants, saccharide-containing antioxidants, polyphenols, enzyme and small molecule antioxidants, salts thereof, and mixtures thereof; and
administering a therapeutically effective amount of said pharmaceutical composition by inhalation route to a person in need thereof.
2. The method according to claim 1, wherein said respiratory symptoms comprise: asthma, sinusitis, or pneumonitis.
3. The method according to claim 1, wherein said minerals are selected from the group consisting of: selenium, sodium, potassium, magnesium, calcium, zinc, copper, iron, chromium, fluorine, chlorine, iodine, phosphorous, and mixtures thereof.
4. The method according to claim 1, wherein said thiol-based antioxidants are selected from the group consisting of: isothiocyanates, sulfides, glutathione and its derivatives, thioredoxin, cysteine and N-acetylcysteine, dithiol compounds, prothiol compounds, and mixtures thereof.
5. The method according to claim 1, wherein said enzyme and small molecule antioxidants are selected from the group consisting of: superoxide dismutases, catalase, glutathione peroxidase, NADPH:quinone reductase, thioredoxin system, coenzyme Q, glutathione, bilirubin, melatonin, ferritin, L-carnitine, alpha-lipoic acid, metallothioneins, acetyl-L- carnitine, edaravone, hydroxytyrosol, tyrosol, ladostigil, mofegiline, N-acetylcysteine, N- acetylserotonin, oleocanthal, oleuropein, rasagiline, selegiline, uric acid, butylated hydroxytoluene, 2,6-di-tert-butylphenol, 1,2-diaminopropane, 2,4-dimethyl-6-tert- butylphenol, ethylenediamine, and mixtures thereof.
6. The method according to claim 1, wherein said polyphenols are selected from the group consisting of: phenolic acids, ferulic acid, caffeic acid, cinnamic acid, phenylethyl ester, apigenin, pycnogenol, carotenoids, flavonoids, soy isoflavones, genistein, daidzein, equol, tretinoin, silymarin, quercetin, tannins, resveratrol, tea polyphenols, catechin, epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate, and mixtures thereof.
7. The method of according to claim 1, wherein said pharmaceutical composition further comprises an excipient.
8. The method of claim 1, wherein said inhalation route is through at least one nasal cavity.
9. The method of claim 1, wherein said inhalation route is through the mouth.
10. The method of claim 1, wherein said pharmaceutical composition comprises at least one, acceptable salt, solvate, or physiologically functional derivative thereof, with at least one compatible excipient.
11. The method of claim 1, wherein said composition is in the form of a liquid.
12. The method of claim 7, wherein said excipient is selected from the group consisting of: gums, granulating agents, binders, lubricants, disintegrating agents, sweetening agents, additives, solvents, glidants, anti-adherents, anti-static agents, surfactants, viscosity enhancers, plant cellulosic material coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, antistatic agents, spheronization agents, and any combinations thereof.
13. The method of claim 1, wherein said composition is in the form of a dry powder or a solid aerosol.
14. The method of claim 7, wherein said excipient is selected from the group consisting of: alpha monohydrate lactose, wherein said alpha monohydrate lactose is in the form of crystalline lactose, milled lactose, or micronized lactose.
15. The method of claim 1, wherein said natural product based antioxidant is a free form natural product based antioxidant.
16. The method of claim 1, wherein said plant extract is selected from the group consisting of: acai extract, aloe vera extract, astragalus extract, auricularia auricula-judae extract, bilberry extract, bitter orange extract, black cohosh extract, bromelain extract, butterbur extract, cat's claw extract, chamomile extract, chasteberry extract, cinnamon extract, cranberry extract, dandelion extract, dendranthema morifolium extract, echinacea extract, essiac tea extract, Flor Essence tea extract, Sambucus nigra (European elder) extract, Evening Primrose extract, fenugreek extract, feverfew extract, flaxseed extract, ganoderma lucidium ( reishi mushroom) extract, garlic extract, ginger extract, ginkgo biloba extract, ginseng extract, glycyrrhiza glabra (licorice) extract, goldenseal extract, grape seed extract, green tea extract, hawthorn extract, hoodia extract, horse chestnut extract, isatis indigotica extract, kava extract, lavender extract, lycium barbarum extract, mistletoe extract, noni extract, panax pseudo-ginseng extract, peppermint extract, polypodium leucotomos extract, pomegranate extract, prunus persica flower extract, punica granatum extract, red clover extract, robdosia rubescens extract, sage extract, saw palmetto extract, Scutellaria baicalensis extract, serenoa repens (saw palmetto) extract, silybum marianum (milk thistle) extract, soy extract, St. John's wort extract, tea extract, thunder God vine extract, tremella fuciformis extract, valerian extract, yohimbe extract, ziziphus jujuba extract, and mixtures thereof.
17. The method of claim 1, wherein said pharmaceutical composition comprises:
0.10-5.0% by weight/volume of at least one antioxidant;
0.10-5.0% by weight/volume of at least one plant extract;
1.0-20.0% by weight/volume of at least one excipient; and
wherein said pharmaceutical composition has a pH in the range of 6.8 to 8.6.
18. An aqueous nasal or oral spray composition comprising:
0.10-5.0% by weight/volume of at least one antioxidant;
0.10-5.0% by weight/volume of at least one plant extract;
1.0-20.0% by weight/volume of at least one excipient; and
a sufficient amount of a pharmaceutically acceptable buffer to maintain the pH of the composition within the range of about 6.8 to 8.6; and water.
9. A particulate composition comprising: 5-25% antioxidant;
5-25% plant extract; and
50-90% saccharide.
PCT/US2015/048772 2014-09-07 2015-09-07 Novel anti-oxidant compositions and methods of delivery Ceased WO2016037166A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2717304C1 (en) * 2019-05-21 2020-03-19 Федеральное государственное бюджетное образовательное учреждение высшего образования "Кузбасская государственная сельскохозяйственная академия" Method for production of biologically active additive
US10717825B2 (en) 2015-07-01 2020-07-21 California Instite of Technology Cationic mucic acid polymer-based delivery system
US11285212B2 (en) 2013-03-01 2022-03-29 California Institute Of Technology Targeted nanoparticles
CN115029326A (en) * 2022-05-27 2022-09-09 湖南福来格生物技术有限公司 Enzyme cross-linked aggregate and preparation method and application thereof
US11890315B2 (en) 2017-11-17 2024-02-06 Renovion, Inc. Stable ascorbic acid compositions and methods of using same
US11998616B2 (en) 2018-06-13 2024-06-04 California Institute Of Technology Nanoparticles for crossing the blood brain barrier and methods of treatment using the same
US12097238B2 (en) 2022-01-04 2024-09-24 Renovion, Inc. Aqueous solution comprising a glutathione salt
WO2025108530A1 (en) * 2023-11-23 2025-05-30 Sarl Laboratoire Beker Formulation of an inhalable quercetin solution for the management of respiratory diseases
US12427180B2 (en) 2016-11-17 2025-09-30 Renovion, Inc. Treatment of respiratory tract diseases and infections with ascorbic acid compositions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040115309A1 (en) * 2000-09-22 2004-06-17 Harris Patricia Anna Food supplement
US20070053843A1 (en) * 2003-10-28 2007-03-08 Dawson Michelle L Inhalable pharmaceutical formulations employing lactose anhydrate and methods of administering the same
US20090060878A1 (en) * 2007-09-04 2009-03-05 The Procter & Gamble Company Oral Compositions, Products And Methods Of Use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040115309A1 (en) * 2000-09-22 2004-06-17 Harris Patricia Anna Food supplement
US20070053843A1 (en) * 2003-10-28 2007-03-08 Dawson Michelle L Inhalable pharmaceutical formulations employing lactose anhydrate and methods of administering the same
US20090060878A1 (en) * 2007-09-04 2009-03-05 The Procter & Gamble Company Oral Compositions, Products And Methods Of Use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US10717825B2 (en) 2015-07-01 2020-07-21 California Instite of Technology Cationic mucic acid polymer-based delivery system
US11041050B2 (en) 2015-07-01 2021-06-22 California Institute Of Technology Cationic mucic acid polymer-based delivery systems
US12427180B2 (en) 2016-11-17 2025-09-30 Renovion, Inc. Treatment of respiratory tract diseases and infections with ascorbic acid compositions
US11890315B2 (en) 2017-11-17 2024-02-06 Renovion, Inc. Stable ascorbic acid compositions and methods of using same
US12350307B2 (en) 2017-11-17 2025-07-08 Renovion, Inc. Stable ascorbic acid compositions and methods of using same
US11998616B2 (en) 2018-06-13 2024-06-04 California Institute Of Technology Nanoparticles for crossing the blood brain barrier and methods of treatment using the same
RU2717304C1 (en) * 2019-05-21 2020-03-19 Федеральное государственное бюджетное образовательное учреждение высшего образования "Кузбасская государственная сельскохозяйственная академия" Method for production of biologically active additive
US12097238B2 (en) 2022-01-04 2024-09-24 Renovion, Inc. Aqueous solution comprising a glutathione salt
US12419932B2 (en) 2022-01-04 2025-09-23 Renovion, Inc. Aqueous solution comprising a glutathione salt
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