WO1995000176A1 - Compositions for treating hypoxia-associated ocular complications - Google Patents
Compositions for treating hypoxia-associated ocular complications Download PDFInfo
- Publication number
- WO1995000176A1 WO1995000176A1 PCT/US1994/006824 US9406824W WO9500176A1 WO 1995000176 A1 WO1995000176 A1 WO 1995000176A1 US 9406824 W US9406824 W US 9406824W WO 9500176 A1 WO9500176 A1 WO 9500176A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- osmoprotectant
- buffer
- heme oxygenase
- hypoxia
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention generally relates to a method for the treatment of eye disorders. More specifically, it relates to a method and composition for preventing or treating hypoxia-associated ocular complications which employs at least two agents selected from the group consisting of an aqueous soluble, solution-stable heme oxygenase inducer, a membrane-permeable anti-acidosis buffer, and an osmoprotectant agent.
- an aqueous soluble, solution-stable heme oxygenase inducer a membrane-permeable anti-acidosis buffer, and an osmoprotectant agent.
- Contact lens wear causes corneal epithelial hypoxia, which results in stimulation of anaerobic glycoiysis and increased production and accumulation of osmotically active lactate in the epithelium.
- the lactate diffuses to the stroma, where it creates an osmotic imbalance leading to increased corneal hydration (swelling).
- Lens wear also produces an increase in CO 2 tension brought on by limited CO 2 lens transmissibility. This increase in CO 2 at the tear-film/lens interface, combined with accumulation of stromal lactate, contributes to a reduction in corneal pH (corneal acidosis). When the eye lids are closed, the CO 2 tension will increase further and the epithelial oxygen availability is further reduced.
- Lactate dehydrogenase (LDH) inhibitors sodium oxalate and sodium oxamate, have been reported to inhibit the progress of experimental edema by reducing the accumulation of stromal lactate without having any effect on corneal thickness in nonedematous cornea in vitro (M.D. Rohde et al., Current Eye Research, 1986, 5, 751-758). See also M. E. Clark, J. A. M. Hinke and M. E. Todd, J. EXD. Biol. (1981 ), 90, 43-63, which is incorporated in its entirety by reference.
- LDH Lactate dehydrogenase
- U.S. Patent No. 5,102,670 to Abraham discloses a method for treating or preventing ocular swelling and corneal-conjunctival inflammation.
- the method involves administration to the eye of an amount of a heme oxygenase inducing agent such as SnCI 2 . See also Nahas, G. G., Pharmacol. Rev.. 14
- a combination of at least two agents selected from the group consisting of an aqueous soluble, solution-stable heme oxygenase inducer, a membrane-permeable anti- acidosis buffer, and an osmoprotectant agent are very effective not only for treating hypoxia-associated ocular complications, but also for preventing the same in a host in need of such treatment or prevention.
- the present invention provides a method of preventing or treating hypoxia-associated ocular complications in a host in need of such prevention or treatment which comprises administering to the eye of the host a prophylactically or therapeutically effective amount of at least two agents selected from the group consisting of an aqueous soluble, solution-stable heme oxygenase inducer, a membrane- permeable anti-acidosis buffer, and an osmoprotectant.
- the present invention provides an ophthalmic composition for preventing or treating hypoxia-associated ocular complications in a host in need of such prevention or treatment which comprises a prophylactically or therapeutically effective amount of at least two agents selected from the group consisting of an aqueous soluble, solution-stable heme oxygenase inducer, a membrane- permeable anti-acidosis buffer and an osmoprotectant, together with a physiologically acceptable carrier.
- the present invention involves administration to the eye of a subject an ophthalmic composition including (a) up to about 2.5% by weight of an aqueous soluble, solution-stable heme oxygenase inducer; (b) up to about 0.5M of a membrane-permeable anti-acidosis buffer; (c) up to about 0.6M of an osmoprotectant; (d) up to about 2.0% by weight per volume of a tonicity adjusting agent; and (e) water, wherein the composition has a pH range of about 6.0 to about 9.0 and wherein at least two components selected from (a), (b) and (c) are present in the composition.
- an ophthalmic composition including (a) up to about 2.5% by weight of an aqueous soluble, solution-stable heme oxygenase inducer; (b) up to about 0.5M of a membrane-permeable anti-acidosis buffer; (c) up to about 0.6M of an osmoprotectant; (d
- compositions of the present invention are physiologically acceptable in that they are safe and tolerable in the eye and have no significant ocular side effects.
- composition is open to the inclusion of various other ingredients that will not detract from its efficacy, stability or physiological acceptance, preferred examples of the ingredients are provided below for purposes of illustrative clarity.
- prophylactically effective amount means that the amount of the active ingredients contained in the composition is of sufficient quantity to prevent hypoxia-associated complications by administration of the composition prior to, or simultaneously with, exposure of a host to a condition where such complications are anticipated. For example, when contact lens wear is expected to continue for an extended period of time, prior or simultaneous administration of the composition would be required.
- therapeutically effective amount means that the amount of the active ingredients is of sufficient quantity to abrogate or ameliorate hypoxia-associated complications, including reduced wearing time, by administration of the composition before, simultaneously or after a host has developed clinical signs and symptoms resulting from such complications.
- hypoxia-associated ocular complications refers to any adverse conditions in which the eye or parts thereof, such as the cornea and conjunctiva, develop arising from prolonged contact lens wear which causes a state of hypoxia.
- Such complications include, without limitation, conditions such as corneal edema, ocular inflammation and reduced lens wearing time.
- the ophthalmic composition of the present invention principally employs at least two agents selected from the group consisting of an aqueous soluble, solution-stable heme oxygenase inducer, a membrane- permeable anti-acidosis buffer, and an osmoprotectant, together with a physiologically acceptable carrier.
- the aqueous soluble, solution-stable heme oxygenase inducer includes any compound or combination of compounds known to induce heme oxygenase in vivo.
- Representative compounds are aqueous soluble, solution-stable heme derivatives, heavy metal ions or suitable metal-containing compounds, and Vitamin B 12 .
- Suitable heavy metal ions are an ion of a metal selected from the group consisting of Cr, Mn, Fe, Ni, Cu, Zn, Au, Hg, Pb, Cd, Sn, Pt and Sb. The most preferred metal ion is Sn 2+ or Sn 4+ .
- Stannic chloride being physiologically acceptable, is a particularly preferred compound.
- Suitable heme derivatives are various synthetic hemes wherein Fe is replaced by other metals such as Sn, Cr, Co, Zn, or Mn, and analogous compounds wherein the porphyrin ring structure is modified as protoporphyrins or mesoporphyrins.
- Typical synthetic hemes are cobalt protoporphyrin (CoPP), cobalt mesoporphyrin (CoMP), and heme arginate.
- Combinations of heme oxygenase inducers such as Vitamin B 12 , zinc sulfate and a soluble, solution-stable Sn +2 or Sn +4 containing complex can also be used.
- An effective concentration range for the heme oxygenase inducer in the composition of the invention is generally from about 0.0005 to about 1.0 w/v%, more preferably 0.001 to 0.2 w/v% and even more preferably about 0.02 w/v%.
- the membrane-permeable anti-acidosis buffer may be included in the composition to correct corneal acidosis.
- the requirements of the buffer are: (1) it must permeate through the corneal epithelium into the interior of epithelial cells and thus must be able to buffer the intracellular pH of epithelial cells; (2) it must pass through the epithelium into the stroma and buffer acellular stromal tissue; and (3) it must be acceptable from a safety and toxicology point of view.
- suitable buffers should be soluble in tears, physiologically acceptable, act as a proton acceptor in vivo and be capable of permeating through the corneal epithelial cell membranes into the intracellular medium of the epithelial cells and must also be capable of permeating through the entire corneal epithelium into the corneal stroma.
- the most preferred buffer is a weak base, tris(hydroxymethyl)aminomethane (TRIS) or alternatively di(hydroxymethyl)aminomethana TRIS has been used for the treatment of acute respiratory acidosis or metabolic acidosis which develops during cardiac operations because of its low toxicity and excellent buffering ability (G.G. Nahas, Clin. Pharmacol, and Ther.. (1963), 4, 784-802).
- An effective concentration range for the membrane-permeable anti-acidosis buffer is generally from about 0.05M to about 0.50M, more preferably 0.1 OM to 0.30M.
- the osmoprotectant may be included in the composition to regulate intracellular and/or extracellular osmotic pressure.
- the osmoprotectant can thus correct the uneven and/or elevated hydration across the cornea (cornea swelling) caused by the lactate accumulation.
- the osmoprotectant may be included in the composition to regulate intracellular or extracellular osmotic pressure.
- the requirements of the osmoprotectant are: (1 ) it must permeate through the corneal epithelium into the interior of epithelial cells and thus must be able to regulate the intracellular osmotic pressure of epithelial cells; (2) it must pass through the epithelium into the stroma and osmotically regulate acellular stromal tissue; and (3) it must be acceptable from a safety and toxicology point of view.
- suitable osmoprotectants should be soluble in tears, physiologically acceptable, and be capable of permeating through the corneal epithelial cell membranes into the intracellular medium of the epithelial cells and must also be capable of permeating through the entire corneal epithelium into the corneal stroma.
- Suitable osmoprotectants which can be used include trimethylamine N-oxide (TMAO), betaine, sarcosine, glycine and glycine derivatives (e.g., dimethylglycine), N,N-bis(2-hydroxyethyl) glycine, amino acids (e.g., L-alanine, D-alanine and ?-alanine), taurine, glycerol, l-aminocyclopropane-l-carboxylic acid, octopine and trehalose.
- TMAO trimethylamine N-oxide
- betaine sarcosine
- glycine and glycine derivatives e.g., dimethylglycine
- N,N-bis(2-hydroxyethyl) glycine amino acids (e.g., L-alanine, D-alanine and ?-alanine)
- taurine e.g., L-alanine, D-a
- An effective concentration range for the osmoprotectant is generally from about 0.05M to about 0.6M, more preferably 0.10M to 0.40M.
- osmoprotectants such as glycine or its active derivatives (e.g., sarcosine, dimethylglycine and betaine) or other suitable osmoprotectants (e.g., TMAO) can be used alone or with other excipients to treat hypoxia in the form of a tablet to be ingested or other suitable delivery vehicle. The glycine then is believed to build up in the wearer's system to afford protection from the hypoxia induced complications of contact lens wear.
- osmoprotectants e.g., TMAO
- TMAO osmoprotectants
- the heme oxygenase inducer, the membrane-permeable anti- acidosis buffer, and the osmoprotectant of the present invention can be co-administered to the eye of a host in a single combined formulation such as eye drops, eye washes and contact lens multipurpose solutions. Alternatively, they can be administered concurrently as separate dosage forms. Still further, one agent can be administered before or after administration of the other agent(s) provided that the time interval between the two (or three) is not too lengthy, i.e., not more than a few hours. It is, however, for convenience to the patient and the prescribing ophthalmologist or optometrist to use the agents as a single composition or formulation.
- the combined agents are administered in combination with a physiologically acceptable carrier.
- the most preferred carrier is sterile purified water.
- Tonicity adjusting agents are normally required in an ophthalmic composition.
- the function of the tonicity adjusting agents is to make the composition physiologically acceptable to ocular tissues and to increase the comfort level upon administration. Suitable such agents include alkali metal halides, phosphates, hydrogen phosphates, and borates.
- Preferred are sodium chloride, potassium chloride, sodium phosphate monobasic and sodium phosphate dibasic.
- sodium chloride can be present in the composition in an amount of from about 0% to about 2.0% by weight per volume of the total, more preferably in amount of about 0% to about 0.4%.
- the composition of the present invention can be prepared by dissolving the active components directly in the aforementioned vehicle, or the composition of the present invention can be added to known ophthalmic solutions.
- the active agents of the invention may be administered to the eye in the form of a time release system, such as a contact lens, bandage lens or wafer.
- a time release system such as a contact lens, bandage lens or wafer.
- wafer systems are well known to the ophthalmological art, and are used when a uniform, controlled delivery of the active agents is desired.
- These systems may be made of biocompatible and biodegradable materials which degrade in the eye upon contact with a body fluid (tears) or an enzyme, and are subject to the same pharmacologically acceptable requirements as are indicated for the aforementioned solutions.
- an osmoprotectant selected from the group consisting of glycine, L-alanine, D-alanine, ⁇ - alanine, l-aminocyclopropane-l-carboxylic acid, sarcosine dimethylglycine, betaine, taurine, TMAO (trimethylamineoxide) and mixtures thereof can be combined with a heme oxygenase inducer such as stannous or stannic chloride and/or Vitamin B-12, and the resulting composition ingested.
- glycine is preferred.
- Additional ingredients may be added to the composition, as long as they are physiologically acceptable and not deleterious to the eye or ocular tissue. Further, they should not adversely affect the efficacy of the above-noted active components as well as should not deteriorate the stability of the composition. Additional ingredients are, for example, stabilizers, preservatives, disinfecting agents, buffering agents (when the anti-acidosis buffer is not present in the composition) and the like. Such ingredients are known to those skilled in the ophthalmological art.
- suitable preservatives and disinfecting agents include polyhexamethylene biguanide, polyquad (Onamer M), and polyoxyalkylene diamine biguanides.
- preservatives and disinfecting agents may be used at a concentration level of about 0.5 to 100 ppm.
- Suitable buffers include sodium or potassium citrate, citric acid, boric acid, sodium borate, sodium bicarbonate, various mixed phosphate buffers including combinations of Na 2 HPO 4 , NaH 2 PO 4 , Na 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 and HCO 3 .
- buffers may be used in an amount from about 0.05% to 2.5% by weight per volume of the total and preferably 0.1 % to 2.0%.
- the pH of the present composition is buffered to prevent irritation to the eye by adding the buffer to the composition for pH adjustment.
- compositions can be buffered with ordinary buffers to impart pH-stability and ocular-acceptability in addition to the requirement to provide a unique membrane-permeable anti-acidosis buffer.
- the active components of the invention can be provided in solid form such as tablets or powders.
- Effervescing agents are typically employed when the composition is provided in solid form.
- suitable effervescing agents include tartaric or citric acid used in combination with a suitable alkali metal salt such as sodium carbonate.
- the effectiveness of the compositions of the present invention to prevent or ameliorate hypoxia-associated ocular complications can be determined by their ability to pass two or more of the following standard biological and/or pharmacological tests, viz., (1 ) measuring their ability to induce heme oxygenase to a level which adequately controls inflammation and swelling; (2) measuring their ability to reduce or eliminate corneal swelling (e.g. osmotically-induced swelling); and (3) measuring their ability to shift corneal epithelial and stromal pH to a physiologically acceptable value
- EXAMPLE 1 The following ingredients were combined and mixed uniformly together to produce an ophthalmic composition having a pH of 7.5:
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94920755A EP0707495A1 (en) | 1993-06-18 | 1994-06-16 | Compositions for treating hypoxia-associated ocular complications |
AU71742/94A AU7174294A (en) | 1993-06-18 | 1994-06-16 | Compositions for treating hypoxia-associated ocular complications |
JP7502956A JP2000507200A (en) | 1993-06-18 | 1994-06-16 | Compositions for treating ocular complications associated with hypoxia |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/079,025 US5389383A (en) | 1993-06-18 | 1993-06-18 | Method for treating hypoxia-associated ocular complications |
US08/079,025 | 1993-06-18 | ||
US18555694A | 1994-01-24 | 1994-01-24 | |
US08/185,556 | 1994-01-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995000176A1 true WO1995000176A1 (en) | 1995-01-05 |
Family
ID=26761550
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/006824 WO1995000176A1 (en) | 1993-06-18 | 1994-06-16 | Compositions for treating hypoxia-associated ocular complications |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0707495A1 (en) |
JP (1) | JP2000507200A (en) |
AU (1) | AU7174294A (en) |
HU (1) | HUT75679A (en) |
IL (1) | IL109762A0 (en) |
WO (1) | WO1995000176A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015281A1 (en) * | 1996-10-08 | 1998-04-16 | Hartford Hospital | Induction of a cellular stress response with heavy metal salts |
WO1998017265A1 (en) * | 1996-10-17 | 1998-04-30 | Achille Sandoli | Pharmaceutical composition containing tromethamine for the topical treatment of acne vulgaris |
EP1331902A2 (en) * | 2000-11-08 | 2003-08-06 | Bio-Concept Laboratories | Improved ophthalmic and contact lens solutions containing forms of vitamin b |
EP1675600A2 (en) * | 2003-10-03 | 2006-07-05 | Judith Boston | Methods, compositions,, apparatuses containing tetrameric oxygen |
US9308264B2 (en) | 2000-11-08 | 2016-04-12 | Fxs Ventures, Llc | Ophthalmic contact lens solutions containing forms of vitamin B |
US9492582B2 (en) | 2000-11-08 | 2016-11-15 | Fxs Ventures, Llc | Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers |
US9492581B2 (en) | 2000-11-08 | 2016-11-15 | Fxs Ventures, Llc | Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5616616B2 (en) * | 2008-12-10 | 2014-10-29 | ロート製薬株式会社 | Eye drops for silicone hydrogel contact lenses |
JP2015147759A (en) * | 2014-01-08 | 2015-08-20 | 日油株式会社 | eye drops |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992004905A1 (en) * | 1990-09-14 | 1992-04-02 | Abraham Nader G | Method for treating eye disorders by reducing 12(r)-hydroxyeicosatetraenoic acid and 12(r)-dihydroxyeicosatrienoic acid levels |
-
1994
- 1994-05-24 IL IL10976294A patent/IL109762A0/en unknown
- 1994-06-16 HU HU9502003A patent/HUT75679A/en unknown
- 1994-06-16 AU AU71742/94A patent/AU7174294A/en not_active Abandoned
- 1994-06-16 JP JP7502956A patent/JP2000507200A/en not_active Ceased
- 1994-06-16 EP EP94920755A patent/EP0707495A1/en not_active Withdrawn
- 1994-06-16 WO PCT/US1994/006824 patent/WO1995000176A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992004905A1 (en) * | 1990-09-14 | 1992-04-02 | Abraham Nader G | Method for treating eye disorders by reducing 12(r)-hydroxyeicosatetraenoic acid and 12(r)-dihydroxyeicosatrienoic acid levels |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015281A1 (en) * | 1996-10-08 | 1998-04-16 | Hartford Hospital | Induction of a cellular stress response with heavy metal salts |
US5955111A (en) * | 1996-10-08 | 1999-09-21 | Hartford Hospital | Methods and compositions for inducing production of stress proteins |
AU735055B2 (en) * | 1996-10-08 | 2001-06-28 | Hartford Hospital | Induction of a cellular stress response with heavy metal salts |
WO1998017265A1 (en) * | 1996-10-17 | 1998-04-30 | Achille Sandoli | Pharmaceutical composition containing tromethamine for the topical treatment of acne vulgaris |
US9492581B2 (en) | 2000-11-08 | 2016-11-15 | Fxs Ventures, Llc | Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers |
EP1331902A4 (en) * | 2000-11-08 | 2006-02-08 | Bio Concept Lab | Improved ophthalmic and contact lens solutions containing forms of vitamin b |
EP1992340A1 (en) | 2000-11-08 | 2008-11-19 | FXS Ventures, LLC | Improved ophthalmic and contact lens solution |
US9308264B2 (en) | 2000-11-08 | 2016-04-12 | Fxs Ventures, Llc | Ophthalmic contact lens solutions containing forms of vitamin B |
EP3045168A1 (en) * | 2000-11-08 | 2016-07-20 | FXS Ventures, LLC | Improved ophthalmic and contact lens solution |
US9492582B2 (en) | 2000-11-08 | 2016-11-15 | Fxs Ventures, Llc | Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers |
EP1331902A2 (en) * | 2000-11-08 | 2003-08-06 | Bio-Concept Laboratories | Improved ophthalmic and contact lens solutions containing forms of vitamin b |
US9585394B2 (en) | 2000-11-08 | 2017-03-07 | Fxs Ventures, Llc | Ophthalmic contact lens solutions containing forms of vitamin B |
US10064410B2 (en) | 2000-11-08 | 2018-09-04 | Fxs Ventures, Llc | Ophthalmic contact lens solutions containing forms of vitamin B |
US10595532B2 (en) | 2000-11-08 | 2020-03-24 | Fxs Ventures, Llc | Ophthalmic contact lens solutions containing forms of vitamin B |
EP1675600A2 (en) * | 2003-10-03 | 2006-07-05 | Judith Boston | Methods, compositions,, apparatuses containing tetrameric oxygen |
EP1675600A4 (en) * | 2003-10-03 | 2009-09-02 | Judith Boston | Methods, compositions,, apparatuses containing tetrameric oxygen |
Also Published As
Publication number | Publication date |
---|---|
HU9502003D0 (en) | 1995-09-28 |
IL109762A0 (en) | 1994-08-26 |
JP2000507200A (en) | 2000-06-13 |
AU7174294A (en) | 1995-01-17 |
HUT75679A (en) | 1997-05-28 |
EP0707495A1 (en) | 1996-04-24 |
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