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WO2001015777A1 - Administration pulmonaire d'ascorbates mineraux - Google Patents

Administration pulmonaire d'ascorbates mineraux Download PDF

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Publication number
WO2001015777A1
WO2001015777A1 PCT/US1999/019977 US9919977W WO0115777A1 WO 2001015777 A1 WO2001015777 A1 WO 2001015777A1 US 9919977 W US9919977 W US 9919977W WO 0115777 A1 WO0115777 A1 WO 0115777A1
Authority
WO
WIPO (PCT)
Prior art keywords
ascorbate
composition
pharmaceutically acceptable
lung
mineral
Prior art date
Application number
PCT/US1999/019977
Other languages
English (en)
Other versions
WO2001015777A8 (fr
Inventor
Jeffrey Zidichouski
Original Assignee
Oxycal Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oxycal Laboratories, Inc. filed Critical Oxycal Laboratories, Inc.
Priority to PCT/US1999/019977 priority Critical patent/WO2001015777A1/fr
Priority to AU57978/99A priority patent/AU5797899A/en
Publication of WO2001015777A1 publication Critical patent/WO2001015777A1/fr
Publication of WO2001015777A8 publication Critical patent/WO2001015777A8/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • This invention relates to pulmonary-administration treatment methods and compositions.
  • compositions containing pharmaceutically acceptable mineral ascorbates which are specially adapted for pulmonary administration.
  • the invention pertains to treatment methods for applying mineral ascorbates to deep lung tissue surfaces by pulmonary administration.
  • the invention pertains to treatment methods for applying mineral ascorbate to deep lung tissue surfaces by forming an inhalable aerosol of solid mineral ascorbate particles.
  • the invention pertains to treatment methods for applying mineral ascorbates to deep lung tissue surfaces by forming an inhalable aerosol of liquid particles containing mineral ascorbates.
  • “Aerosol” means both a true colloidal dispersion of solid or liquid particles in a gaseous carrier and other dispersions or “sprays", in which the solid or liquid particles are temporarily suspended in the carrier, even though the suspension is not a true colloid.
  • Treatment means prophylaxis, amelioration, prevention or cure of body conditions.
  • “Pulmonary administration” means any mode of administration which delivers a mineral ascorbate to any surface of the lung, including both inhalation and endotracheal administration, as a liquid, a powder or an aerosol, for local action on pulmonary tissues and/or via pulmonary tissues into the circulatory system for systemic action by the mineral and/or ascorbate moieties.
  • “Lung surface” means any of the interior surfaces of the lungs, including alveolar surfaces, bronchiolar surfaces and passage between any of these surfaces, either directly for local action on pulmonary tissues or via pulmonary tissues into the circulatory system for systemic action.
  • Oral administration of a drug may be inefficient to deliver the drug to the intended treatment site in the body.
  • Oral administration of a drug may be inefficient to deliver the drug to the intended treatment site in the body.
  • orally-ingested ascorbic acid to appear in lung tissue and fluids, there must be adequate gastrointestinal absorption, re-distribution, minimal uptake by other tissues and blood cells, minimal influences by first-pass metabolism in the liver and by excretion and, finally, adequate delivery by the circulatory system to the lung tissues.
  • IV infusion of ascorbic acid has been employed in limited clinical settings, but long-term chronic administration is not a practical way to improve lung function.
  • Ascorbic acid has been topically applied to the skin by so-called "transdermal patch” techniques to reduce the appearance of wrinkles.
  • transdermal patch techniques to reduce the appearance of wrinkles.
  • vitamin C in this form would penetrate the stratum corneum in sufficient quantity to gain access to the circulation, and it is more likely that it would cause a high degree of skin irritation before the barrier is penetrated.
  • Benson et al. U.S. Patent 5,006,343. disclosed pulmonary administration of "a wide range of pharmaceutically active substances" in a liposome-alveolar surfactant protein carrier, for both systemic delivery or local delivery.
  • the disclosed pharmaceutically active substances included "anti-oxidants such as vitamin E, vitamin C, superoxide dismutase and catalase” for "treatment of oxygen toxicity", although the only working example of an antioxidant was vitamin E.
  • the mineral ascorbate is a pharmaceutically acceptable alkaline earth metal ascorbate, preferably calcium ascorbate or magnesium ascorbate, a pharmaceutically acceptable transition metal ascorbate such as zinc ascorbate or an alkali metal ascorbate, preferably sodium ascorbate or potassium ascorbate.
  • compositions for inhalation application to the lung-air interface of lung tissue comprising an inhalable aerosol comprising a pharmaceutically acceptable carrier gas as the continuous phase and a disperse phase of solid particles of the mineral ascorbate.
  • compositions for inhalation application comprise an inhalable aerosol comprising a pharmaceutically acceptable carrier gas as the continuous phase and a disperse phase comprising liquid particles containing a mineral ascorbate.
  • I provide a method for applying a mineral ascorbate directly to the lung-air exchange surface of lung tissue, comprising the steps of forming a composition comprising particulate mineral ascorbate, including particles thereof in the range of from about 0.5 to about 10 microns, aerosolizing this composition with a pharmaceutically acceptable gaseous carrier and applying the aerosolized composition to the lung-air exchange surface of lung tissue.
  • I provide a method for applying a mineral ascorbate directly to the lung-air exchange surface of lung tissue, comprising the steps of forming a liquid composition which includes a mineral ascorbate in a pharmaceutically acceptable liquid carrier, aerosolizing this composition with a pharmaceutically acceptable gaseous carrier and applying the aerosolized composition to the lung-air exchange surface of lung tissue.
  • the solid or liquid component of the aerosol compositions and methods of the invention comprises a mineral ascorbate and a metabolite of vitamin C, preferably metabolites which are members of the group consisting of aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof, dehydroascorbic acid, threose, erythreose, 4-hydroxy-5-methyl-3(2H)-furanone, 3- hydroxykojic acid and 5-hydroxymaltol.
  • the metabolite is preferably a calcium, magnesium, zinc, sodium or potassium salt of threonic acid, lyxonic acid or xyIonic acid and mixtures thereof.
  • I provide an improved method of application of vitamin C to the body, including the heart, including the aortic arch, coronary arteries and arterioles, comprising direct application of a mineral ascorbate to lung tissue, absorption into the blood at the lung-air exchange interface of lung tissue, transport directly to the left atrium of the heart via the pulmonary veins and distribution to other body tissues via the arteriole blood supply.
  • compositions and methods of application thereof to body tissues comprising aerosols which include the above-described vitamin C metabolites and another therapeutically active component (other than vitamin C), in which the metabolites aid in transport of the other active component across the lung-air exchange interface.
  • a wide variety of lung-specific conditions are amenable to treatment in accordance with the invention, including infant and adult respiratory distress syndrome ("ARDS", arising from diminished lung surfactant properties), age- related decrease in lung function (caused by age-dependent reduction in lung tissue elasticity and likely related to collagen/elastin levels in the lung), viral pneumonia, bacterial pneumonia, Group B streptococcal infections, oxygen toxicity, alpha-1-anti-protease deficiency, emphysema, asthma (including exercise-induced asthma and cold-induced asthma), the deleterious effects of smoking, tuberculosis, lung cancer, bronchitis, cystic fibrosis, mucopurulent and purulent exacerbation of simple mucoid bronchitis, bronchorrhea, bronchopneumonia, purulent pneumonia, pneumonic-alveolar-consolidation, bronchiectasis, bronchocoele, post-transplantation obliterative bronchiolitis and allergenic brochi
  • compositions and methods of the invention are effectively employed as a pre-treatment to hyperbaric oxygen therapy (HPT) in which the patient breathes pure oxygen at 3-4 atmospheres pressure, a combination which ineluctably generates high levels of damaging free radicals in the lungs .
  • HPT hyperbaric oxygen therapy
  • other active components of the aerosol compositions of the invention may include, but are not limited to antivirals, such as acyclovir, zidovudine and ribavarin, antibacterials, such as sulfamethoxazole and nalidixic acid, fungicides, such as fungizone and mycostatin, antibiotics such as cephalosporins, penicillin, tetracyclines and aminoglycosides, protease inhibitors such as alpha-1- antiprotease, antioxidants such as vitamin C (in the form of ascorbic acid, to standardize the vitamin C content or pH balance of the final formulation), vitamin E and glutathione, superoxide dismutase and catalase, anti- inflammatory agents such as prostaglandins, salicylates, pyrazolons, propionic acid derivatives and para-aminophenol derivatives, anti-allergenics such as antihistamines, including terfenadine, di
  • the mineral ascorbates used in the practice of my invention are substantially pH neutral, thus avoiding problems which are caused by the introduction of highly acidic forms of vitamin C, such as ascorbic acid.
  • the invention takes advantage of the presence of the metal (or cation) moieties of mineral ascorbates which, by themselves, have significant treatment effects.
  • zinc ascorbate advantageously provides biologically active zinc values to lung tissue having rhinoviricidal activity, in addition to the benefits of the ascorbate moiety having vitamin C activity.
  • magnesium ascorbate advantageously provides biologically active magnesium values to lung tissues, with resulting pulmonary benefits.
  • Inclusion of vitamin C metabolites in the treatment compositions which are introduced by pulmonary administration in accordance with my invention provides faster absorption and longer retention of vitamin C and/or other therapeutically active agents which are normally eliminated via the renal tubular secretion pathway for organic anions, which have an acidic functional group and a pKa ⁇ 6, as more fully discussed in co-owned U.S. Patent No. 5,070,085, incorporated herein by reference. These beneficial effects of faster absorption and increased retention of therapeutically active components are obtained whether or not the compositions also contain mineral ascorbates.
  • the vitamin C metabolites are present in the compositions of the invention in an amount effective to increase the absorption rate and/or retention time of the therapeutically active compound which can be from about 0.1 to about 24 wt.% of the metabolite-therapeutic agent composition, preferably in the range of about 1 to about 7 wt . % .
  • the treatment compositions of the invention which can be introduced into the body by pulmonary administration are in the form of solid or liquid particles suspended or carried in a pharmaceutically acceptable carrier gas, illustratively, air, carbon dioxide, nitrogen or other carrier gases known in the art, such as dichlorodifluoromethane. To increase the depth of application in the lungs, it is preferred that a predominant portion of these particles be in the size range of from about 0.5 to about 10 microns.
  • Suitable dispensing apparatus for metered pulmonary administration of solids or liquids suspended in a carrier gas are well known and are effectively employed in the practice of my invention. For example, see U.S.
  • Patents 2,992,645 to Fowler, 3,012,555 to Meshberg, 3,219,533 to Mullins, 3,236,458 to Ramis and 3,897,779 to Hansen are also well known and effective in the practice of my invention, for example, anhydrous ethanol, sorbitan trioleate and the like. Sonication of the suspensions and lyophylization of the particles also improves the stability of these suspensions.
  • the aerosolized solid particles comprise a mineral ascorbate, e.g., calcium ascorbate, magnesium ascorbate, sodium ascorbate, potassium ascorbate or zinc ascorbate and mixtures thereof and vitamin C metabolites such as aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof, preferably a calcium, magnesium, zinc, sodium or potassium salt of threonic acid, lyxonic acid or xyIonic acid and mixtures thereof.
  • a mineral ascorbate e.g., calcium ascorbate, magnesium ascorbate, sodium ascorbate, potassium ascorbate or zinc ascorbate and mixtures thereof
  • vitamin C metabolites such as aldonic acids and the pharmaceutically acceptable salts, aldonolactones and aldonolactides thereof, preferably a calcium, magnesium, zinc, sodium or potassium salt of threonic acid, lyxonic acid or xyIonic acid and mixtures thereof.
  • the aerosolized liquid particles are formed of a shelf-stable liquid composition containing these mineral ascorbates and vitamin C metabolites.
  • these liquid compositions are commercially available as products sold under the registered trademark "Ester-C®” Topical Concentrate from Inter-Cal Corporation of Prescott, Arizona, U.S.A.
  • These shelf-stable liquid vitamin C concentrates are further described in co- owned pending International Applications PCT/US98/02333, filed February 6, 1998 and PCT/US99/02735, filed February 5, 1999, incorporated herein by reference.
  • This example illustrates the preparation of a mineral ascorbate dry powder composition containing an additional therapeutic agent for the treatment of asthma.
  • Example 4 400 milligrams of beclomethasone dipropionate powder, screened to remove particles that are greater than 10 microns in diameter, is added to 9.6 g of the ground calcium ascorbate-threonate composition of Example 1 and the resultant composition is mixed for 5 minutes to yield a uniformly mixed composition.
  • the resultant ground material comprised of calcium ascorbate, calcium threonate, and beclomethasone dipropionate, is loaded into gelatin, plastic or other capsules and delivered to the respiratory tract using a dry powder inhaler device as indicated in Example 1.
  • the configuration of the inhaler device is adjusted to deliver the desired dose of beclomethasone for each actuation of the inhaler.
  • Example 3 400 milligrams of beclomethasone dipropionate powder, screened to remove particles that are greater than 10 microns in diameter, is added to 9.6 g of the ground calcium ascorbate-threonate composition of Example 1 and the resultant composition is mixed for 5 minutes to yield a uniformly
  • the MDI is designed to deliver a dose of 200 mgs of aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11 or CFC-12 or non-chlorofluorocarbon propellants known as fluorocarbons such as HFC131A or HFC-227 per activation.
  • chlorofluorocarbon propellants such as CFC-11 or CFC-12
  • fluorocarbons such as HFC131A or HFC-227 per activation.
  • This example illustrates the preparation of a mineral ascorbate aerosol composition containing an additional therapeutic agent for the treatment of asthma.
  • Example 400 milligrams of beclomethasone dipropionate powder is screened to remove particles that are greater than 10 microns in diameter.
  • the screened powder is added to 9.8 gms of the ground and screened calcium ascorbate/calcium threonate composition of Example 1 and the resultant composition is mixed for 5 minutes to yield a uniformly mixed composition.
  • the resultant blended material of calcium ascorbate, calcium threonate, and beclomethasone dipropionate is loaded into the pulmonary dispenser of Example 3 and pressurized with an appropriate carrier gas/propellant as described in Example 3.
  • the dispenser's orifice and the activation mechanism are sized to deliver 200.4 mgs of the ground powder composition as an inhalable suspension in the carrier gas such that 400 ⁇ g of beclomethasone dipropionate and 200 mgs of Ester-C® dry powder are delivered upon the activation of the device.
  • This example illustrates the preparation of a nebulizing solution or an aerosol composition of liquid mineral ascorbate solution useful in the practice or other presently preferred embodiments of the invention.
  • This example illustrates the preparation of a nebulizing solution or an aerosol composition of a liquid mineral ascorbate composition containing an additional therapeutic agent for the treatment of asthma.
  • This example illustrates other dry powder compositions useful in the practice of the invention.
  • Powdered mineral ascorbates are substituted in whole or in part for lactose or glucose powders as diluent-carriers in MDI and in other dry powder drug formulations containing drugs, e.g., Beta-agonists used in pulmonary therapy, in which the dose per activation of the inhaler dispenser is very small, e.g., in the range of 5-20 micrograms per activation.
  • Such formulations provide the therapeutic benefit of the introduction of the pH neutral form of vitamin C in addition to the delivery of the other drug(s) carried by the mineral ascorbate.
  • This example illustrates the use in adult patients of the compositions of Examples 1-7.
  • Example 1 Up to 6 doses per day of the dry powder composition of Example 1 are self-administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced.
  • Example 4 Up to 6 metered doses per day of the aerosol composition of Example 4 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced. Up to 6 doses per day of the nebulizing composition of Example 5 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of the patient will be reduced.
  • Example 7A-70 Up to 6 doses per day of the dry powder composition of Example 7A-70 are self administered by an adult patient diagnosed with chronic pulmonary distress syndrome. Within 21 days symptoms of chronic pulmonary distress syndrome of the patient will be reduced.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions et des procédés destinés au traitement d'inhalation pulmonaire. La composition est constituée d'un ascorbate minéral acceptable sur le plan pharmaceutique et, éventuellement, d'un ou plusieurs métabolites de vitamine C.
PCT/US1999/019977 1999-08-31 1999-08-31 Administration pulmonaire d'ascorbates mineraux WO2001015777A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1999/019977 WO2001015777A1 (fr) 1999-08-31 1999-08-31 Administration pulmonaire d'ascorbates mineraux
AU57978/99A AU5797899A (en) 1999-08-31 1999-08-31 Pulmonary-adminstration of mineral ascorbates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1999/019977 WO2001015777A1 (fr) 1999-08-31 1999-08-31 Administration pulmonaire d'ascorbates mineraux

Publications (2)

Publication Number Publication Date
WO2001015777A1 true WO2001015777A1 (fr) 2001-03-08
WO2001015777A8 WO2001015777A8 (fr) 2001-10-11

Family

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Family Applications (1)

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PCT/US1999/019977 WO2001015777A1 (fr) 1999-08-31 1999-08-31 Administration pulmonaire d'ascorbates mineraux

Country Status (2)

Country Link
AU (1) AU5797899A (fr)
WO (1) WO2001015777A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080427A3 (fr) * 2003-03-12 2005-05-06 Daniel J Schneider Methode de prevention et de traitement d'infections attaquant la muqueuse et d'aide a la readaptation ulterieure au moyen d'acide ascorbique applique localement
WO2005123064A1 (fr) * 2004-06-10 2005-12-29 Board Of Trustees Of Michigan State University Inhalateur de complements adrenergiques comprenant des composes tels que ascorbates, tocopherols ou chelateurs d'acide polycarboxylique
EP1693058A4 (fr) * 2003-11-20 2010-02-17 Morishige Fumie Agent et mesures pour la prevention d'une infection virale
US7718694B2 (en) * 1997-10-16 2010-05-18 Children's Hospital & Research Center At Oakland Compositions and methods for therapy for diseases characterized by defective chloride transport
GB2525626A (en) * 2014-04-29 2015-11-04 Alexander Francois Robert Templet Composition and method for inhalable nutritional element

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU1819138C (ru) * 1987-07-15 1993-05-30 Юрий Викторович Востриков Способ лечени неспецифической бронхопневмонии тел т
US5944012A (en) * 1996-03-25 1999-08-31 Pera; Ivo E. Method for dispensing antioxidant vitamins by inhalation background of the invention

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU1819138C (ru) * 1987-07-15 1993-05-30 Юрий Викторович Востриков Способ лечени неспецифической бронхопневмонии тел т
US5944012A (en) * 1996-03-25 1999-08-31 Pera; Ivo E. Method for dispensing antioxidant vitamins by inhalation background of the invention

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE DWPI ON WEST, VOSTRIKOV YU. V.: "Method for treatment of non-specific bronchial pneumonia in calves - using an aerosol of furazolidone, oxacillin and vitamin C dissolved in propylene glycol" *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718694B2 (en) * 1997-10-16 2010-05-18 Children's Hospital & Research Center At Oakland Compositions and methods for therapy for diseases characterized by defective chloride transport
US8138158B2 (en) 1997-10-16 2012-03-20 Children's Hospital & Research Center At Oakland Compositions and methods for therapy for diseases characterized by defective chloride transport
WO2004080427A3 (fr) * 2003-03-12 2005-05-06 Daniel J Schneider Methode de prevention et de traitement d'infections attaquant la muqueuse et d'aide a la readaptation ulterieure au moyen d'acide ascorbique applique localement
EP1693058A4 (fr) * 2003-11-20 2010-02-17 Morishige Fumie Agent et mesures pour la prevention d'une infection virale
WO2005123064A1 (fr) * 2004-06-10 2005-12-29 Board Of Trustees Of Michigan State University Inhalateur de complements adrenergiques comprenant des composes tels que ascorbates, tocopherols ou chelateurs d'acide polycarboxylique
GB2525626A (en) * 2014-04-29 2015-11-04 Alexander Francois Robert Templet Composition and method for inhalable nutritional element

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Publication number Publication date
WO2001015777A8 (fr) 2001-10-11
AU5797899A (en) 2001-03-26

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