WO2001035966A1 - Composes et complexes de bore utilises comme agents anti-inflammatoires - Google Patents

Composes et complexes de bore utilises comme agents anti-inflammatoires Download PDF

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Publication number
WO2001035966A1
WO2001035966A1 PCT/US2000/031354 US0031354W WO0135966A1 WO 2001035966 A1 WO2001035966 A1 WO 2001035966A1 US 0031354 W US0031354 W US 0031354W WO 0135966 A1 WO0135966 A1 WO 0135966A1
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WO
WIPO (PCT)
Prior art keywords
boron
inflammation
methods
ligands
atom
Prior art date
Application number
PCT/US2000/031354
Other languages
English (en)
Inventor
Dusan Miljkovic
Original Assignee
Topgene, 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 Topgene, Inc. filed Critical Topgene, Inc.
Priority to EP00979177A priority Critical patent/EP1233772A4/fr
Priority to AU16584/01A priority patent/AU1658401A/en
Priority to JP2001537958A priority patent/JP2003514023A/ja
Priority to US10/129,938 priority patent/US6696419B1/en
Publication of WO2001035966A1 publication Critical patent/WO2001035966A1/fr

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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
    • A61K33/22—Boron compounds
    • 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
    • A61K31/69—Boron compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]

Definitions

  • the field of the invention is anti-inflammatory agents.
  • Boron compounds are known to show a variety of different biological activities. Very often, boron compounds show enzyme inhibitory activity, and thus boron compounds can inhibit a number of enzymes alone or in a mixture with various co-inhibitors. For example, borates inhibit L-amino acid oxidase in a mixture with butanedione by interacting with the arginine residue in the active site. (Christman MF, Cardenas JM: Experientia 38 (5): 537-538 (1982)).
  • borates and butanedione inhibit citrate/isocitrate-hydro-lyase, EC 4.2.1.3, again by interacting with the arginine residue from the active site.
  • 2,3-butanedione or 1,2- cyclohexanedione in the presence of borates interact specifically with the guanidino group from arginine, and this fact was used for determination of arginine residues in the active site of the examined enzymes. In this way Dietl, T. and Tschesche, H . (Hoppe Seylers Z Physiol Chem: 357 (5): 657-665 (1976)) proved arginine residue is present in the active site of proteinases.
  • boron as an essential structural element (such as boromycin, an anti-HIV antibiotic (Kohno J, et al : Biosci Biotechnol Biochem (Japan) 60(6), 1036-7 (1996), or tetralons, new boron-containing antibiotics from a myxobacterium, Sorangium cellulosum (Irschik H, Schummer D, Gerth K, Hofle G, Reichenbach H: J Antibiot (Tokyo) (Japan), 48 (1), 26-30 (1995)).
  • organoboron compounds such as cyanotriphenylborate
  • cyanotriphenylborate subtype-specific blockers of glycine receptor chloride channels
  • the known forms of boron supplementation have noticeably undesirable side effects, rendering the known forms of boron supplementation somewhat undesirable as anti-inflammatory agents.
  • the known forms either contain or are readily hydrolyzed in the gut to boric acid. Boric acid is reactive, and tends to accumulate in tissues other than bone or joint.
  • the amount of boron made available by known supplementation is extremely high compared with normal blood values.
  • a typical boron supplement, for example, may make almost 3 mg of elemental boron available to the tissues within a half hour after ingestion, which is about 14 times the normal total blood boron of 213 ⁇ g.
  • the present invention provides methods and compositions in which boron compounds/ complexes having a central tetrahedral boron atom, covalently bound to four ligands (of either identical or different nature), are utilized to provide anti-inflammatory effects.
  • Specifically included among the contemplated anti-inflammatory effects are reduction of inflammation of knees, fingers and other joints, reduction of inflammation from insect bites and other localized traumas to the skin, is reduction of scar tissue and improved wound healing.
  • One particularly useful indication for topical treatment is sunburned or otherwise burned skin.
  • At least one of the ligands is contemplated to include an oxygen, nitrogen, carbon or sulfur atom, and in more preferred embodiments all four ligands are contemplated to include an oxygen, nitrogen, carbon or sulfur atom.
  • boron is complexed with a saccharide or an amino acid having at least two hydroxyl groups, or one amino- and one hydroxyl group in 1,2- or 1,3- position to each other.
  • a spatial arrangement allows formation of stable five- or six-membered rings consisting of one boron atom, two hetero-atoms and 2 or 3 carbon atoms.
  • Such complexes may advantageously comprise fructose, sorbitol, mannitol, xylitol, sorbose, serine or threomne.
  • boron is bound more or less tightly to hetero-atoms.
  • the stability of boron complexes is contemplated to be proportional to their association constants, and in yet another aspect of the invention, preferred complexes have association constants of at least 50, and more preferred complexes have an association constant between 3,000 and 20,000.
  • acidic boron complexes may be further converted to salts having sodium, potassium, magnesium or calcium as a counter ion (cation).
  • cation counter ion
  • an active boron compound/complex is included in a suitable cosmetic formulation wherein the compound/complex is provided in a suitable solvent system, a microemulsion form, or a suitable liposome form.
  • suitable cosmetic formulation wherein the compound/complex is provided in a suitable solvent system, a microemulsion form, or a suitable liposome form.
  • These formulations may advantageously contain other ingredients that are also non-toxic and non-irritating to the skin.
  • the composition is also preferably adapted for efficient penetration through the skin stratum corneum barrier when applied topically.
  • Figure 1 depicts generic chemical structures of boron compounds/complexes according to the present invention.
  • Figures 2A and 2B are chemical structures depicting particularly preferred compounds, calcium fructo-borate complex, and calcium threonine borate complex. Detailed Description
  • boron compounds and complexes containing sugars, sugar polyols, amino acids and other non-toxic boron specific ligands may be used as anti-inflammatory agents.
  • Boron compounds/complexes contemplated herein may be taken orally as nutritional supplements, or may be placed in solution and applied topically to the skin.
  • Boron compounds/complexes contemplated herein have a tetrahedral boron atom covalently bound to four hetero-atoms which can be identical or different from one another.
  • hetero-atom means any chemical element except boron.
  • hetero-atoms include oxygen, nitrogen, carbon and sulfur, but are also contemplated to include hydrogen, and non- metallic elements from groups IVA, VA, VIA and VII A of the periodic table.
  • boron compounds/complexes can be natural, synthetic, or some combination of natural and synthetic.
  • boron complexes which exist in nature such as glyco-borates and sugar polyols complexed with borates, both of which are often found in fruits.
  • these naturally occurring boron compounds are best synthesized, although theoretically they could be extracted from natural sources.
  • Boron compounds/complexes employed according to the present invention can be prepared in any suitable manner.
  • sodium borate/tetraborate is treated with two molar equivalents of sugar polyol (preferably mannitol or xylytol), or two molar equivalents of an amino acid (preferably serine or threonine), in an aqueous solution.
  • sugar polyol preferably mannitol or xylytol
  • an amino acid preferably serine or threonine
  • ligands can be simply mixed in an appropriate solvent (water, acetone, dioxan, tetrahydrofuran, etc), whereupon the complex directly crystallizes out, or stays in a solution.
  • metal ions which charge neutralize the boron anionic complex one can use any of a variety of non-toxic metallic cations, such as sodium, potassium, calcium, or magnesium. However, one can successfully use ammonium cation, protonated amines, as well as quaternary ammonium cations.
  • association constant of the boron complex the less toxic is the complex, and the more advantageous are its biological properties.
  • association constants at or above about 50 are usable, although ones of over 1,000 are preferable. In the most favorable cases, association constants between about 3,000 and about 20,000 are especially beneficial.
  • FIG. 1 The general structure of boron compounds suitable for anti-inflammatory effects is depicted in Figure 1.
  • Residues W, X, Y and Z may be the same as, or different from one another, and are contemplated to include any suitable hetero-atom.
  • the five-membered rings are preferred over six- membered rings, and the six-membered rings are preferred over hepta-membered ring, and so forth.
  • Figure 2A depicts a particularly preferred compound, calcium fructo-borate complex, illustrated in one of several possible structural conformations.
  • Figure 2B depicts another particularly preferred compound, calcium threonine borate complex.
  • Contemplated formulations of boron compounds/complexes contemplated herein may advantageously involve a solution or emulsion of the active material in water, aqueous buffer, a mixture of water and an organic solvent allowed in topical skin treatment (such as ethanol, glycerol, etc), organic non-toxic and non-irritating solvents, or macro- and micro-emulsion forms, liposome forms, or in any other suitable carrier(s) for topical application.
  • Particularly contemplated carriers are liposome and microemulsion formulations, and at present the most preferred carriers are emulsions of a bile acid salt (such as sodium taurocholate) and a soybean oil such as soybean phosphatidyl choline (SPC).
  • boron compound/complex solutions include mixtures of boron containing compounds and/or complexes in all manner of solvents, whether homogeneously or non-homogeneously dispersed, completely or partially solvated, suspended, emulsified, or dispersed in any other manner. Boron compound/complex solutions thus also include all possible carriers.
  • Preferred concentrations of solutions/emulsions have about 10 "6 to 10 weight % of boron, with solutions/emulsions containing 1-5 mg of B/ml. contemplated to be particularly suitable for anti-inflammatory purposes. Such solutions/emulsions are contemplated to be rubbed onto the skin twice per day, morning and evening, preferably after a shower or bath. Other contemplated protocols include applications of greater or lesser frequency, such as daily, every-other day, weekly, or bi-weekly schedules.
  • a particularly preferred method of application is partial or full immersion in a bath.
  • boron compounds/complexes contemplated herein may form all or part of bath salts, which can be added to a bath or other container of water and used for soaking in a manner analogous to that now known for Epsom Salts (magnesium sulfate).
  • Epsom Salts magnesium sulfate
  • Such immersion may then advantageously be followed by topical application of a cream at or near sites of particular inflammation.
  • the boron compounds/complexes contemplated herein affect inflammation through interaction with a broad range of enzymes and enzyme systems, as opposed to targeting a single enzyme or enzyme system.
  • Such systems are present to a greater or lesser extent across a broad range of animals, and it is thus contemplated that the inventive subject matter is broadly applicable to humans, other mammals, as well as other animals.
  • boron compounds/complexes from this invention are considerably less toxic than boric acid and its simplest derivatives, and are thus safer than boric acid itself or its simple derivatives for prolonged topical applications, including long term anti-inflammatory effects on joints.
  • Another advantage is that many of the boron compounds/complexes contemplated herein are stable at ambient temperatures, storable in their suitable formulations for a long time and are commercially readily available.
  • Still another advantage is that many of the boron compounds/complexes contemplated herein are expected to show multifunctional synergistic biological activity. This represents a great advantage in relation to other previously described anti-inflammatory agents, all of which were specifically active towards one particular enzyme.
  • a ligand When synthesizing boron compounds/complexes according to the present disclosure, one should generally follow accepted rules of chemical synthesis. Thus, if a ligand contains only one hetero-atom in its B-binding site, one takes four or more molar equivalents of it in respect to one molar equivalent of the starting boron compound. Further, if a ligand contains two or three hetero-atoms in its B-binding sites, one takes two or more molar equivalents of it in respect to one molar equivalent of the starting boron compound. Still further, if a ligand contains four or more hetero-atoms in its B-binding sites, one takes one or more equivalents of the ligand to one molar equivalent of the starting boron compound.
  • the molar equivalent of the starting boron compound corresponds to its molecular formula if it contains one boron atom in it. If molecular formula contains more than one boron atom one divides molecular formula with a number of boron atoms containing in it. For example, if one starts with sodium tetraborate decahydrate, its molecular formula should be divided by four to obtain its molar equivalent.
  • the selected ligand in the corresponding or slightly higher molar ratio to the starting boron compound and the starting boron compound (most often boric acid or borax), is mixed in water to make a rather concentrated solution (usually in the range from 10 to 30%).
  • the reaction mixture is stirred or shaken at room temperature for 0.5 to 1 hour, whereupon all solid components go completely to a solution. If boric acid is used, then subsequent neutralization is needed, such as with NaHCO 3 , KHCO 3 , CaHCO 3 , etc.
  • Sodium tetraborate (0.804 g; 4 mmoles) and serine (3.2 g; 32 mmoles) are mixed in water (ml) at room temperature. After. stirring or shaking for 0.5 to 1 hour at room temperature, all components go into solution. The final concentration is adjusted to the desired level (usually 2-4 mg B/ml).
  • phosphatidyl choline (PC) in chloroform is evaporated at room temperature in vacuum with a rotary evaporator at room temperature to provide a uniform transparent lipid film.
  • the water solution of calcium fructo-borate is added at once to a lipid PC-film. After shaking the mixture for 2 hours at 37 C, and sonicating the mixture for an additional 0.5 hour at room temperature, preparation of the calcium fructo-borate liposome formulation is finished.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'inflammation est modifiée par l'application locale d'un composé/complexe contenant du bore, dans lequel un atome de bore tétraédrique central est lié de manière covalente à quatre ligands. Au moins un des ligands comprend, de préférence, un atome d'oxygène, d'azote, de carbone ou de soufre et, de préférence les quatre ligands possèdent au moins un de ces atomes. Les ligands préférés sont les saccharides et les acides aminés, dont le fructose, le sorbitol, le mannitol, le xylitol, le sorbose, la sérine et la thréonine. Les ligands spécialement préférés sont formés d'au moins deux groupes hydroxyles, ou d'un groupe hydroxyle et d'un groupe amino en position 1,2- et 1,3- l'un par rapport à l'autre, une constante d'association élevée de l'ordre d'environ 3 000 à 20 000 étant ainsi produite. Les composés/complexes sont de préférence fournis en formulations permettant une bonne administration transdermique, dont des systèmes de solvants appropriés, des microémulsions, des liposomes. Les inflammations particulièrement concernées sont les inflammations des articulations et de la peau, dont les brûlures, telles que les coups de soleil.
PCT/US2000/031354 1999-11-19 2000-11-14 Composes et complexes de bore utilises comme agents anti-inflammatoires WO2001035966A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00979177A EP1233772A4 (fr) 1999-11-19 2000-11-14 Composes et complexes de bore utilises comme agents anti-inflammatoires
AU16584/01A AU1658401A (en) 1999-11-19 2000-11-14 Boron compounds and complexes as anti-inflammatory agents
JP2001537958A JP2003514023A (ja) 1999-11-19 2000-11-14 抗炎症剤としてのホウ素化合物および複合体
US10/129,938 US6696419B1 (en) 1999-11-19 2000-11-14 Boron compounds and complexes as anti-inflammatory agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16693899P 1999-11-19 1999-11-19
US60/166,938 1999-11-19

Publications (1)

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WO2001035966A1 true WO2001035966A1 (fr) 2001-05-25

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JP (1) JP2003514023A (fr)
AU (1) AU1658401A (fr)
WO (1) WO2001035966A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6720012B2 (en) * 2001-05-30 2004-04-13 A & L Of Michigan, Inc. Boric acid analgesic composition and method of treatment using the same
WO2005123094A2 (fr) 2004-06-14 2005-12-29 Anacor Pharmaceuticals, Inc. Composes renfermant du bore et procedes d'utilisation de ceux-ci
WO2006052733A1 (fr) * 2004-11-05 2006-05-18 Alza Corporation Preparations de liposomes de bortezomib (ps-341)
US11160819B2 (en) 2014-08-29 2021-11-02 Vdf Futureceuticals, Inc. Compositions and methods for borocarbohydrate complexes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4849220A (en) * 1988-04-20 1989-07-18 The United States Of America As Represented By The Secretary Of Agriculture Use of boron supplements to increase in vivo production of hydroxylated steroids
US5312816A (en) * 1991-09-13 1994-05-17 Boron Biologicals, Inc. Method of combatting osteoporosis in mammalian subjects, utilizing organic boron compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962049A (en) * 1997-03-31 1999-10-05 Miljkovic; Dusan Boron carbohydrate complexes and uses thereof
US5985842A (en) * 1998-05-14 1999-11-16 Miljkovic; Dusan Boron compounds/complexes to control hair growth, and methods of use
US6080425A (en) * 1998-05-26 2000-06-27 Topgene, Inc. Boron compounds and complexes as skin-rejuvenating agents
WO2002028869A1 (fr) * 2000-10-05 2002-04-11 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health Inhibiteurs de la gamma-glutamyle transpeptidase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4849220A (en) * 1988-04-20 1989-07-18 The United States Of America As Represented By The Secretary Of Agriculture Use of boron supplements to increase in vivo production of hydroxylated steroids
US5312816A (en) * 1991-09-13 1994-05-17 Boron Biologicals, Inc. Method of combatting osteoporosis in mammalian subjects, utilizing organic boron compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1233772A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6720012B2 (en) * 2001-05-30 2004-04-13 A & L Of Michigan, Inc. Boric acid analgesic composition and method of treatment using the same
WO2005123094A2 (fr) 2004-06-14 2005-12-29 Anacor Pharmaceuticals, Inc. Composes renfermant du bore et procedes d'utilisation de ceux-ci
WO2005123094A3 (fr) * 2004-06-14 2006-02-23 Anacor Pharmaceuticals Inc Composes renfermant du bore et procedes d'utilisation de ceux-ci
US7652000B2 (en) 2004-06-14 2010-01-26 Anacor Pharmaceuticals, Inc. Boron-containing compounds and methods of use
WO2006052733A1 (fr) * 2004-11-05 2006-05-18 Alza Corporation Preparations de liposomes de bortezomib (ps-341)
WO2006052734A1 (fr) * 2004-11-05 2006-05-18 Alza Corporation Formulation liposomale d'acides boroniques peptidiques
US11160819B2 (en) 2014-08-29 2021-11-02 Vdf Futureceuticals, Inc. Compositions and methods for borocarbohydrate complexes

Also Published As

Publication number Publication date
AU1658401A (en) 2001-05-30
EP1233772A4 (fr) 2004-06-16
JP2003514023A (ja) 2003-04-15
EP1233772A1 (fr) 2002-08-28

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