CA2478137A1 - Metal ion chelate complexes and use thereof - Google Patents
Metal ion chelate complexes and use thereof Download PDFInfo
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- CA2478137A1 CA2478137A1 CA002478137A CA2478137A CA2478137A1 CA 2478137 A1 CA2478137 A1 CA 2478137A1 CA 002478137 A CA002478137 A CA 002478137A CA 2478137 A CA2478137 A CA 2478137A CA 2478137 A1 CA2478137 A1 CA 2478137A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
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- 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
- A61K33/34—Copper; Compounds thereof
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- 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
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The present invention relates to processes for forming metal ion chelate complexes, formulations comprising one or more metal ion chelate complexes, methods of preparation, and use thereof, More particularly, the present invention relates to formulations comprising copper complexes, in particular, formulations comprising copper-EDTA,
Description
I
Metal Ion Chelate Complexes and U~~e Thereof Technical Field The present invention relates to processes for forming metal ion chelate complexes, formulations comprising one or more metal ion chelate complexes, methods of s preparation, and use thereof. More particularly, the preseztt invention relates to formulations comprising copper complexes, in parCicular, formulations compzising copper-IrDTA.
Background of the tnvention Minerals such as metal ions play an important physiological role in animals, io humans and plants. For example, minerals such as zinc, iron, calcium, copper and the like, are important for bone development, energy production and fatty acid oxidation. Tn addition, metal ions may be incorporated into enzymes and proteins, and may also function as co-factors (eg, copper is a co-factor associated with the enzyme superoxide dismutase).
~s Administration of metal ions may be therapeutically useful. Metal ions, such as c-opper ions, have been adnninistered in the form of mineral salts, for example, as metal sulfides, chlorides and nitrates. However, a major limitation of this form of administration is toxic side effects or tissue irritation easing from the high concentration of metal ion released into the system. ' :.n The present invention provides processes for producing metal ioo, chelate complexes and methods of using such complexes.
Summary of the Invention According to a first aspect of the invention there is provided a process for preparing one or more metal ion chelate eomplex(es), comprising zs mixing a chelating agent with an oxidising agent in solution, to obtain a reaction mixture;
adding at Ieast one metal capable of foaming a metal ion ehelate complex to said reaction mixture so as to form said one or more metal ion chelate complex(es), or a mixture thereof.
~o According to a second aspect of the invention there is provided a process for preparing at least one metal ion chelate complex(es), comprising:
dissolving a chelating agent in water to obtain a solution;
adding at least ot~e metal capable of forming a metal ion chelate complex with said chelating agent to said solution, and adding an oxidizing agent to said solution, so as to form at least one metal ion chelate complex, or a mixture thereof.
In one embodiment the chelating agent is dissolved in a suitable solvent, such as water, prior to addition of the oxidising agent.
s The process according to the invention may further include a separation step, e.g., a filtration step, to remove. residual or unreacted metal.
The process according to the invention may further include all additional step of isolating said metal ion chelate complex from solution. Suitable methods of isolation include solvent evaporation, recrystallisation, solvent extraction, and other general ro methods known to those sk-filled in the art.
In one embodiment, the resultant mixture may comprise at Ioast one metal ion chelate complex, unreacted oxidising agent, metal or chelating agent. In one embodiment, the process is continued until at least one of said oxidising agent, said ehelating agent, and said metal is consumed. In one embodiment all of the oxidising agent is consumed.
~s In one embodiment the chelating agent is multidentate. In one embodiment the chelating agent comprises N andlor O donor atoms. In one embodiment the chelating agent comprises at least one carboxylic acid (or carboxylate) group. In one embodiment the chelating agent comprises at Least one amino group, wherein the amino group may be a primary, secondary or tertiary amino group, In one embodiment the chelaring agent may zo comprise at least one., e.g., 1, 2, 3, 4, 5 or G, imidodiacetic acrd [-N((:H.~COZH)i] groups, wherein one or both of the methylene (-CHZ) hydrogen atoms may be replaced with another substituent, such as a Ci-Ca alkyl gxoup. In one embodiment the chelating agent is selected from EDTA, DTPA, HEDTA, ethylenediaminedisuccinic acid (EDDS), salicylic acid, acetyl salicylic. acid, amino acids such as glycine, histidine, Lysine, arginine, as cysteine, methionine, and peptides comprising those amines, and salts thereof. The peptide comprise two, three, four or five amino acids. The respective amino acids may be the same or different. In one embodiment, the peptide is a dipeptide or a tripeptide. In one embodiment the. chelating agent is EDTA or a salt thereof. In one embodiment, the chelating agent is EDTA disodium salt. In another embodiment the chelating agent is ~u DTPA or a salt thereof, e.g., a sodium salt thereof.
In alternate embodiments the oxidising agent may be selected from hydrogen peroxide, ozone, and aqueous solutions, including water and aqueous salt solutions, acidic solutions. Other oxidising agents are well known to those skilled in the art and include, for example, permmganate salts, and dichromate salts. In one embodiment the oxidising agent is an aqueous solution of hydrogen peroxide. For example, the oxidising agent may be a 35wC%, 30wt%, 25wt%, 20wt%, l5wt%, l0wt%, Swt%, 3wt%, lwt% or 0.5 wt%
aqueous solution of hydrogen peroxide.
In one embodiment, the metal is capable of being oxidisc;d to a metal ion capable of forming a metal ion chelate complex with a chelating agent. In one embodiment, the s metal is a transition metal. In one embodiment the metal is selected from Mn, Fe, Co; Ni, Cu, Zn, Cr, Al, Cd, Ag and Se. In one embodiment, the metal is elemental metal. In one embodiment, the metal is a solid. For example, the metal may be in the form of wire, granules, powder, a sold bar having any shape, or any other suitable solid form. The metal may be added to the reaction mixture comprising the c.helating agent andlor ~o oxidising agent all at once. Alternatively, the metal may be added to the reaction mixture comprising the chelating agent and/or the oxidising agent in a portionwise fashion over a period of time. For example, the metal may be added portionwise over about 5 seconds to about 1 hour. Those skilled in the art would be able to ga~xge an appropriate rate of addition of the metal taking into consideration factors such as <;oncentration, temperature, is reagents, etc.
In one embodiment the metal is copper which is oxidised to Cuz+ or Cu+ ions, or a mixture thereof. In another embodiment the metal is iron which is oxidised to Fe2+ or Fe3+ ions, or a mixture thereof. In a further embodiment the metal is zinc which is oxidised to Zn~+ ions. In another embodiment the metal is Ni which is oxidised to Niz+
ao ions, Tn a further embodiment the metal is cobalt which is oxidised to Go2+
or Co3+ ions, or a mixture thereof. In another embodiment the metal is silver which is oxidised to Ag a ons.
Mixtures of different metals may be added to the oxidising solution to produce mixtures of metal ion complexes or salts thereof.
is The metal ion complex or salt thereof may be water soluble.
The amount of metal added may be sufficient to consume substantially all of the oxidising agent. The amount of chelating agent added may be sufficient to complex substantially all of the metal ions.
tn various embodiments, the stoichiometric ratio of the metal to the chelating agent 3o is selected from about 4:1, about 3:1, about 2.8:1, about 2.6:1, about 2.5:1, about 2.4:1, about 2.2:1, about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about l.b:l, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about l.I:l, about 1:1, about 1:1.1, about 1:I.2, about 1:I.3, about 1:1.4, about I:1.5, about 1:1.6, about 1:1.7,, about 1:1.8, about 1:1.9, about 1:2, about I:2,1, about 1:2.2, about 1:2.4, about 1:2.5, about 1;2.6, about 1.:2.8, 3s about I:3, and about 1:4.
Metal Ion Chelate Complexes and U~~e Thereof Technical Field The present invention relates to processes for forming metal ion chelate complexes, formulations comprising one or more metal ion chelate complexes, methods of s preparation, and use thereof. More particularly, the preseztt invention relates to formulations comprising copper complexes, in parCicular, formulations compzising copper-IrDTA.
Background of the tnvention Minerals such as metal ions play an important physiological role in animals, io humans and plants. For example, minerals such as zinc, iron, calcium, copper and the like, are important for bone development, energy production and fatty acid oxidation. Tn addition, metal ions may be incorporated into enzymes and proteins, and may also function as co-factors (eg, copper is a co-factor associated with the enzyme superoxide dismutase).
~s Administration of metal ions may be therapeutically useful. Metal ions, such as c-opper ions, have been adnninistered in the form of mineral salts, for example, as metal sulfides, chlorides and nitrates. However, a major limitation of this form of administration is toxic side effects or tissue irritation easing from the high concentration of metal ion released into the system. ' :.n The present invention provides processes for producing metal ioo, chelate complexes and methods of using such complexes.
Summary of the Invention According to a first aspect of the invention there is provided a process for preparing one or more metal ion chelate eomplex(es), comprising zs mixing a chelating agent with an oxidising agent in solution, to obtain a reaction mixture;
adding at Ieast one metal capable of foaming a metal ion ehelate complex to said reaction mixture so as to form said one or more metal ion chelate complex(es), or a mixture thereof.
~o According to a second aspect of the invention there is provided a process for preparing at least one metal ion chelate complex(es), comprising:
dissolving a chelating agent in water to obtain a solution;
adding at least ot~e metal capable of forming a metal ion chelate complex with said chelating agent to said solution, and adding an oxidizing agent to said solution, so as to form at least one metal ion chelate complex, or a mixture thereof.
In one embodiment the chelating agent is dissolved in a suitable solvent, such as water, prior to addition of the oxidising agent.
s The process according to the invention may further include a separation step, e.g., a filtration step, to remove. residual or unreacted metal.
The process according to the invention may further include all additional step of isolating said metal ion chelate complex from solution. Suitable methods of isolation include solvent evaporation, recrystallisation, solvent extraction, and other general ro methods known to those sk-filled in the art.
In one embodiment, the resultant mixture may comprise at Ioast one metal ion chelate complex, unreacted oxidising agent, metal or chelating agent. In one embodiment, the process is continued until at least one of said oxidising agent, said ehelating agent, and said metal is consumed. In one embodiment all of the oxidising agent is consumed.
~s In one embodiment the chelating agent is multidentate. In one embodiment the chelating agent comprises N andlor O donor atoms. In one embodiment the chelating agent comprises at least one carboxylic acid (or carboxylate) group. In one embodiment the chelating agent comprises at Least one amino group, wherein the amino group may be a primary, secondary or tertiary amino group, In one embodiment the chelaring agent may zo comprise at least one., e.g., 1, 2, 3, 4, 5 or G, imidodiacetic acrd [-N((:H.~COZH)i] groups, wherein one or both of the methylene (-CHZ) hydrogen atoms may be replaced with another substituent, such as a Ci-Ca alkyl gxoup. In one embodiment the chelating agent is selected from EDTA, DTPA, HEDTA, ethylenediaminedisuccinic acid (EDDS), salicylic acid, acetyl salicylic. acid, amino acids such as glycine, histidine, Lysine, arginine, as cysteine, methionine, and peptides comprising those amines, and salts thereof. The peptide comprise two, three, four or five amino acids. The respective amino acids may be the same or different. In one embodiment, the peptide is a dipeptide or a tripeptide. In one embodiment the. chelating agent is EDTA or a salt thereof. In one embodiment, the chelating agent is EDTA disodium salt. In another embodiment the chelating agent is ~u DTPA or a salt thereof, e.g., a sodium salt thereof.
In alternate embodiments the oxidising agent may be selected from hydrogen peroxide, ozone, and aqueous solutions, including water and aqueous salt solutions, acidic solutions. Other oxidising agents are well known to those skilled in the art and include, for example, permmganate salts, and dichromate salts. In one embodiment the oxidising agent is an aqueous solution of hydrogen peroxide. For example, the oxidising agent may be a 35wC%, 30wt%, 25wt%, 20wt%, l5wt%, l0wt%, Swt%, 3wt%, lwt% or 0.5 wt%
aqueous solution of hydrogen peroxide.
In one embodiment, the metal is capable of being oxidisc;d to a metal ion capable of forming a metal ion chelate complex with a chelating agent. In one embodiment, the s metal is a transition metal. In one embodiment the metal is selected from Mn, Fe, Co; Ni, Cu, Zn, Cr, Al, Cd, Ag and Se. In one embodiment, the metal is elemental metal. In one embodiment, the metal is a solid. For example, the metal may be in the form of wire, granules, powder, a sold bar having any shape, or any other suitable solid form. The metal may be added to the reaction mixture comprising the c.helating agent andlor ~o oxidising agent all at once. Alternatively, the metal may be added to the reaction mixture comprising the chelating agent and/or the oxidising agent in a portionwise fashion over a period of time. For example, the metal may be added portionwise over about 5 seconds to about 1 hour. Those skilled in the art would be able to ga~xge an appropriate rate of addition of the metal taking into consideration factors such as <;oncentration, temperature, is reagents, etc.
In one embodiment the metal is copper which is oxidised to Cuz+ or Cu+ ions, or a mixture thereof. In another embodiment the metal is iron which is oxidised to Fe2+ or Fe3+ ions, or a mixture thereof. In a further embodiment the metal is zinc which is oxidised to Zn~+ ions. In another embodiment the metal is Ni which is oxidised to Niz+
ao ions, Tn a further embodiment the metal is cobalt which is oxidised to Go2+
or Co3+ ions, or a mixture thereof. In another embodiment the metal is silver which is oxidised to Ag a ons.
Mixtures of different metals may be added to the oxidising solution to produce mixtures of metal ion complexes or salts thereof.
is The metal ion complex or salt thereof may be water soluble.
The amount of metal added may be sufficient to consume substantially all of the oxidising agent. The amount of chelating agent added may be sufficient to complex substantially all of the metal ions.
tn various embodiments, the stoichiometric ratio of the metal to the chelating agent 3o is selected from about 4:1, about 3:1, about 2.8:1, about 2.6:1, about 2.5:1, about 2.4:1, about 2.2:1, about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about l.b:l, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about l.I:l, about 1:1, about 1:1.1, about 1:I.2, about 1:I.3, about 1:1.4, about I:1.5, about 1:1.6, about 1:1.7,, about 1:1.8, about 1:1.9, about 1:2, about I:2,1, about 1:2.2, about 1:2.4, about 1:2.5, about 1;2.6, about 1.:2.8, 3s about I:3, and about 1:4.
In one embodiment the metal ion forms a 1:1 metal ion chelate complex with the chelating agent. In another embodiment the metal ion forms a 2:1 metal ion chelate complex with the chelating agent.
In one embodiment the solution is an aqueous solution. 'The pH of the solution may s be between about 2 and about 14. In another embodiment the solution is a basic aqueous solution wherein the pH of the solution is between about 7.5 .and about I4, for example, pH about 8, 9, 10, 11, I2, or 13. In one embodiment, the pH o:f the solution at completion of the reaction is about 6 to about 8, e.g, about 7.
Modification of the temperature may be used to control the rate of reaction.
ao Accordingly, the process may optionally include one or more cooling steps.
For example, the solution may optionally be cooled prior to addition of the metal, after addition of the metal, during the oxidation step, ox at completion of the oxidation reaction.
The temperature may be maintained less than about 100°C, less than about 80°C, 60°C, for example, between about 0°C and about 50°C, ox between about 10°C and about 40°C. In a one embodiment, the mixture may be cooled to a temperature selected from about 40°C, about 35°C, about 30°C, about 25°C, about 20°C, about 15°C, .about 10°C, and about S°C.
Alternatively, the process may include one or more heating steps.
According to a third aspect of the invention theze is provided a process for pzeparing copper-EDTA, comprising ~a mixing EDTA or a salt thereof with an aqueous solution of hydrogen peroxide to obtain a mixture; and adding copper to said mixture so as to form copper-EDTA or a salt thereof.
Tn one embodiment the process further comprises a separation step, e.g., a filtration step, for removing residual or unreacte.d copper solid(s).
zs rn one embodiment the process further compzises cooling the mixture of hydrogen peroxide and E.DTA or a salt thezeof.
Tn another embodiment, the process may further comprise cooling the mixture after copper has been added. Tn one embodiment the temperature is maintained at a tennperature below about 40°C, eg, between about 5°C and about 40°C.
3a The salt of EDTA may Comprise one or more of sodium ions, potassium ions, lithium ions, calcium ions, magnesium ions, or mixtures thereof In one embodiment the chelating agent is EDTA disodium salt.
In one erzzbodiment the copper is oxidised to Cu2+.
In one embodiment the resultant metal chelate complex is a salt, such as an alkali earth or alkali metal salt. For example, the metal ion chelat.e complex may be Na+, K~, Li+, IvZg2+, or Ca2+ salt. In another embodiment the metal chelate complex is Cu[EDTA]Na2. In one embodiment the metal chelate complex is Cu2[EDTA]. In a s further embodiment the product is a mixture of Cu2[EDTA] and Cu[EDTA]Na2.
In a further embodiment the metal chelate complex or salt thereof, may be a hydrate.
With reference to the first or second aspect of the invent:ian, in one embodiment the resultant mixture may be evaporated or lyophilized to obtain a solid comprising the metal ~o ion cl~elate complex or salt thereof. The metal ion chelate complex may be purired e.g, by recrystallization from a suitable solvent.
According to a fourth aspect of the invention there is provided a metal ion complex or salt thereof prepared according to the. process of the first, second or third aspect of the invention.
~s According to a fifth aspect of the invention there is provided an aqueous solution comprising at least one metal ion complex or salt thereof prepared according to the process of the first, second or third aspect of the invention. In one embodiment the aqueous solution may comprise uncomplexed chelating agent, or residual oxidizing agent.
According to a sixth aspect of the invention there is provided a pharmaceutical Zo formulation comprising a metal ion complex or salt thereof according to the fourth aspect of the invention, or a solution according to the fifth aspect of the invention, together with a suitable adjuvant, diluent or carrier.
According to a seventh aspect of the invention there is provided a process for preparing a pharmaceutical formulation e.omprising mixing at least one metal ion complex Zs or salt thereof according to the fourth aspect of the invention with a suitable carrier, diluent or adjuvant.
According to an eighth aspect of the invention there is provided a process for preparing a pharmaceutical formulation comprising mixing an ;aqueous solution of at least one metal ion comple;~ or salt thereof according to the fifth aspect of the invention with a :o suitable acceptable carrier, diluent or adjuvant.
With reference to any one of the sixth, seventh or eighth aspects of the invention, the carrier, diluent or adjuvant may be pharmaceutically aca~table andlor veterinarily acceptable.
According to a ninth aspect of the invention there is pro ided a method of treafi~nenc 3s of a disease or condition in a mammal, comprising administezing to said mammal an effective amount of at least one metal ion cheIate complex or a salt thereof, or a pharmaceutical composition thexeof.
According to a tenth aspect of the invention there is provided at least one metal ion chelate complex or salt thereof, or a pharmaceutical composition thereof, when used for s treating a disease or condition in a mammal.
According to an eleventh aspect of. the invention there is provided the use of a metal ion chelate complex or salt thereof for the manufacture of a medicament for treating a disease or condition.
With reference to any one of the ninth to eleventh aspects of the invention, in one to embodiment the metal ion chelate complex may be a metal ion chelate connplex according to the fourth aspect of the invenkion. In another embodirnent the metal ion cixelate complex may be in the form of an aqueous solution, for example, an aqueous solution according to the fifth aspect of the invention. In one embodiment the metal ion chelate complex is Cuz[EDTA], Cu[EDTA]Na2, Cu[EDTA-HZ], or a m~i~cture thereof.
a s In one embodiment, the pharmaceutical corraposition is a topical composition according to the sixth aspect of the invention. The composition may be in the form of a cream, lotion, spray or gel.
The disease or condition to be treated may be selected from reducing inflammation, such as inflammation associated with arthritis, including osteoarthritis and rheumatoid 'o arthritis; promoting growth or regrowth of hair; heating psoriasis;
increasing blood flow;
treating chill blains; treating varicose veins; promoting wound healing;
promoting healing of scar tissue, including scar tissue resulting from bums; alleviating or reducing joint or muscular pain; tzeating sinus inflammation andlor sinus pair; treating bacterial andJor fungal infection.
zs Other conditions that may be treated in accordance with the present invention include eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, and onychoschizia tsplit nails).
In alternative embodiments of the invention, th.e metal ion complexes) or salts) thereof, or compositions comprising said metal ion complexes) or salts) thereof may be 3o used to as a means of prow ding mineral supplements, e.g, copper, cobalt, zinc, selenium, etc, to animals, e.g., humans, sheep, cattle, goats, horses, pigs, etc. In various embodiments, compositions may comprise mixtures of different metal ion chelate complexes, or salts thereof.
In further embodiments, the metal ion chelate complex according to the invention, ~s or pharmaceutical compositions comprising the complex, may be used as an alternative to conventional sun screen, eg, for humans or animals suffering from conditions such as vitiligo (lack of pigment in the skin).
In one embodiment the present invention may enable a non-toxic amount of a metal ion to be administered.
s With reference to the eighth or ninth aspects of the invention, the mammal may be.
human, non-human primate, murine, bovine, ovine, equine, caprine, leporine, avian, feline, porcine, or canine. In one embodiment the mammal is human.
The present invention provides a convenient process for prepaxing metal chelate complexes and salts thereof. Metal ion chelate complexes in accordance with the present io invention, including copper complexes such as copper-BDTA complexes or salts thereof, may have a range of beneficial therapeutic properties.
Brief ~escription of the Figures Figure 1 is a Negative ion MALDI mass spectrum of a. sample solution prepared according to the process of the invention shoeing major copper containing ions consistent is with the species Cu[EDTA~~' or Cu[EDTA]~ (m.w 351 Da).
Figure 2 is an e.lectrospray mass spectrum of a sample solution prepared according to the process of the present invention showing a major copper containing ion consistent with a sodium ion of Cu[EDTA]Na2.
Figure 3 is a comparison photograph of a male's hands after treatment of one hand Zo with a cream according to the invention.
p'iguxe 4 is a comparison photograph of a male's hands after treatment of the left hand with a cream according to the. invention.
Figuxe S is a photograph of the hands of an 84 year old woman suffering arthritis before treatment.
is Figure 6 is a photograph of the hands of an 84 year old woman suffering arthritis after treatment with a cream according to the invention for one week.
Definitions The following ate some definitions that may be. helpful in understanding the description of the present invention. These are intended as general definitions and should :o in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.
Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements i clearly encompass both singular and plural forms of the recited integers, steps or elements.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to s imply the inclusion of a stated step or element or integer or group of steps or elements ox integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification., the term "comprising" meats "including principally, but not necessarily solely".
In the context of the present specification, the. term "metal ion complex"
should be m understood to include metal ion complexes, as well as salts, protonated forms, and hydrates thereof.
In the context of this specification, the term "copper-EDTA" should be understood to include within its meaning Cu[EATA]2- andlor salts thereof, e.g, Cu[EDTA]Na2, Cu[EDTA-Hi2]and Cuz[EDTA].
~s Tn the contexi of this specification "Ci-Ca allcyl" refers to straight or branched saturated alkanes having one to four carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tent-butyl, Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to ~o be understood that the. invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specit5cati.on, individually or collectively, and any and all combinations or any two or more of said steps or features.
AlI the references cited in this application are specifically incorporated by reference z: and are incorporated herein in their entirety.
The. language "therapeutically effective amount" is intended to include within its meaning a non-toxic but sufficient amount of a. compound or composition of the invention to provide the desired therapeutic effect. The exact therapeutically effective amount of the compound or composition will vary according to factors such as the type of disease or 3o condition to be treated, the age, sex, and weight of the animal, mode of administration, and the ability of the compound or composition to permeate cell membranes.
Dosage regima may be adjusted to provide the optimum therapeutic; response. For examples several divided doses may be administered one or several times daily or the dose can be proportionally reduced or increased as indicated by the exigencies of the.
therapeutic ~s situation. ' As used herein the term "treatment", refers to any and all uses which remedy a disorder or disease state or symptoms, prevent the establishment of a disorder or disease, or otherwise prevent, hinder, retard, or reverse the progression of a.
disorder or disease or other undesirable symptoms in any way whatsoever.
s Abbreviations EDTA - ethylenediaminetetraacetic acid DTPA - diethylenetriaminepentaacetic acid HEDTA- hydroxyethylethylenediaminetria.cetac acid NSAI:D - non-steroidal anti-inflammatory drug io GOX-2 - cyclooxygenase-2 Detailed pescription ~f Preferred Embodiment: of the Invention The present invention relates to processes for fom~ing metal ion chelate complexes and salts and protonated forms thereof, compositions comprising one or more metal ion chelate complexes, methods of preparation, and use thereof. More particularly, the is present invention relates to compositions comprising copper complexes, including compositions comprising copper-EDTA, copper-DTPA and eopper-HEDTA, and salts and protonated forms thereof.
The process for preparing metal ion chelate complexes according to the invention, comprises oxidising a metal which is in its elemental state to a correspoaiding cation in '0 S~h~ ncino~ an ntiriising agent. In one embodiment, the process of the invention may be carried out as a "one pot" process. Alternatively, the reaction can be carried out i.n a stepwise fashion, including stepwise addition of reagents.
Whilst not seeking to be limited to any one proposed mechanism of action, the process may involve an i~a sits redox reaction between the: elemental metal and the zs oxidising agent, whereby the. metal is oxidised to one or more corresponding cations. The metal cations thus produced may then chelate to the chelating agent to form a metal ion chelate complex, or metal complex anion. Suitable combinations of oxidising agent and metal can be selected based on the reduction potential of the respective reagents.
Reduction potentials would be known to those skilled in the art and are reported, fox ?o example, irt the CRC Hahdboo& of Chemistry and Physics, Weast, R., Ed. SS'h Edition, 1974-1975, the entire contents of which are incorporated herein by cross-reference.
By way of illustration, the following reaction ntay be envisaged, where the oxidising agent is hydrogen peroxide and M is a suitable metal:
M~S~ + HZO~ + 2H* M2* + 2H20 When M is copper, the. follor ing redox reaction may be envisaged:
Cu(s) + Hx02 + 2H+ Cu2' * 2H20 s The resultant MZ+ ions, eg, Cu~* ions, may then form a~ metal i.on complex with a chelating agent, such as EDTA, DTPA, HEDTA, or salt or protonated form thereof.
One or more steps of the process of the present invention may be exothermic arid ' the reaction vessel may optionally be cooled. variation of temperature, reagent concentration, rate of addition of reagents, surface area of the metal (e.g, larger surface ~o areas may lead to an increased reaction rate), and pH may be used as a means of controlling the rate of the eomplexation reaction.
Suitable cheiating agents include multidenta.te ligands capable of forming stable ' metal ion complexes. Examples of suitable chelating agents include ethylenediaminetetra,acetic (EDTA), diethylenetriaminepentaacetic acid (DPTAj and is (HEDTA) hydrvxyethylethyienediaminetriacetic acid, the structures of which are shown below:
Ho 0 0 off o off HO~O 0 OH HOCH
~N ~ 2 ~N~~N~ \N N
0~ ~ O O ''0 O
~O'H OH H HO 'O~H H ON
EDTA DTPA HEDTA
Multidentate ligands such as EDTA, DTPA, HEDTA may be zwitterionic.
ao EDTA is a hexadentate chelating ligand with 6 possible coordination sites.
The pKa of the carboxylic acid residues of EDTA are 1.70, 2.60, 6.30 and 10.60, respectively.
Neutral EDTA can exist as a zwitterion with t'vo of the acid protons being located on the nitrogen atoms.
EDTA, DTPA, and HEDTA have a strong affinity for a wide range of metal ions, zs and, for example, may form complexes with metal ions including Ag+, Caz+, Coat, Cu2+, Fe3~, Fe2+, Mg~'~, Ni2*, and Zn~'-. Metal ion complexes prepared according to the present invention may be stable at low, neutral aridlor high pH. For example, metal ion chelate complexes according to the present invention may be stable at a phl in the range from about 4 to about 12. The metal ion complex may comprise the chelate and metal ion in. a 3e 1:1 stoichiometric ratio or 1:2 stoichiometric ratio. For example, Cu2+ may chelate to EDTA in a I:1 ratio to form the anionic species Cu[EDTAJZ', or a salt or protonated form thereof. Suitable counterions may include sodium ions, pots~ssium ions, calcium ions, magnesium ions, etc.
In accordance with the process of the present invention, appropriate molar ratios of reagents can be determined by those skilled in the art. Thus, it is possible to manipulate molar ratios to ensure any one or more reagents are consumed in the course of the reaction. For example, 1 mole of copper may be oxidised by one mole of hydrogen peroxide to produce one mole of Cu2y ions rfz siW which may then be chelated by one mole of EDTA. Accordingly, to ensure all of the hydrogen peroxide is consumed, an excess of copper can be used. Alternatively, a molar excess of any oa~e or more reagents ~o may be used whereby residual excess reagent Will remain at completion of the reaction process. In one embodiment, excess chelating agent, e.g., EDT A or a salt thereof, may be used. In one embodiment, excess metal, e.g., copper, may be used. Residual reagents may be removed upon completion of the reaction.
One advantage of the present invention is that metal ions, such as iron, zinc, nickel, 2 s cobalt, magnesium, and copper ions (or mixtures thereof), may be administered to a subject in the form of a metal ion complex or salt or hydrate thereof, or a pharmaceutical composition Thereof.
Techniques known to those skilled in the art, such as ion exchange chromatogaphy and reerystallization, may be used to exchange counterions, thus, for examgle, a salt or Zo protonated form of a metal ion ch.elate complex (or mixtures thereof) rt2ay be converted into another salt of choice.
Aqueous solutions of metal ion chelate complexes produced according to the process of the present invention may have a relatively stable shelf life, for example, up to years, 4 years, 3 years, 2 years, 12 months, 6 months, or 3 months. Buffer solutions, zs e.g., ammoniaJammonium chloride, znay be used to stabilise solutions of metal ion chelate complexes.
In accordance with the present invention, metal ion complexes or salts oz hydrates thereof (e.g., Copper-fiDTA and salts thereof), as well of pharmaceutical formulations of metal ion complexes or salts thereof, may be useful in treating a range of physiological yo conditions or disorders in humans and animals. Examples of therapeutic uses include mineral supplementation, treatment of inflammation, treatment of arthritis, inducing hair growth or regrowth, promoting wool growth in sheep azrd goats, treating psoriasis, alleviation of pain including sinus pain, joint pain, and muscular pain, promoting wound healing including healing of scar tissue, increasing blood flow, treating chill Mains, ;s treatment of varicose veins, and treatment of microbial infection including bacterial, fungal infection, treating eczema, reducing wrinkles, bruises, preventing or alleviating joint degeneration and pain associated therewith, treatizt.g acne, promoting healing of burns, and treating onychoschizia (split nails).
For example, for treatment or alleviation of inflammation., a topical formulation (eg, a cream, lotion, spray or gel) comprising a metal ion complex according to the invention may be rubbed into an inflamed area, e.g, one to three times per day, until inflammation is reduced. Treatment may continue for as long as necessary to reduce or continually alleviate inflammation.
For promoting hair regrowth, a topical formulation (eg, a cream, lotion, gel, spray ~o or shampoo) comprising a metal ion eorrxplex according to the invention may be applied to the scalp, with rubbing or massaging, e.g., once or twice per day for a period of time which is at least sufficient to stimulate or promote hair grov~~th o~r regrowth.
For use as a sunscreen, a topical formulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the invention rtia.y be applied to an area of is skin prior to exposure to the sun or ~V. Additional applications may be made as required.
For relief of sinus pain, a topical farmulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the invention ma.y be applied to an area of skin around the nose andlor under the eyes or across the forehead when pain starts, resulting in pain relief zo To reduce scarring, a topical formulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the. invention may be applied, generally one to three times per day, e.g., twice a day, across the scar tissue with aubbing to work it into the scar tissue and surrounding skin.
For healing of bruising a topical formulation (eg, a cream, lotion, gel or spray) zs comprising a metal ion complex according to the invention may be. applied to and around the bruised area once a day until bruising disappears.
For treatment of onychosc.hizia (split nails) a suitable formulation (eg, a liquid, cream, tincture, or lotion) comprising a metal ion complex according to the invention may be applied once a day until the desired nail quality is attained.
3u For treatment of acne and other skin conditions such as psoriasis, a suitable formulation (eg, a liquid, cream, gel, spray, tincture, or lotion) comprising a metal ion complex according to the invention may be applied to the appropriate area, one to three times per day, e.g, twice per day, in a manner similar to conventional therapies.
Pharmaceutical anc)<lor Therapeutic Formulations In accordance with the present invention, metal ion chelate complexes, such as copper-EDTA or salts thereof, and pharmaceutical formulations thereof, may be administered alone or may be used in combination with other known treatments or s therapeutic agents, including for example, anti-inflammatory agents (eg, NSATDs, cartisones, etc), analgesics and pain killers (eg, NSAIDs, CO~i-2 inhibitors), antibacterial and antifungal agents, hair growth stimulants (eg, radical scavengers, antiandxogens), sunscreens, and antibacterial and antifungal treatments known ao those skilled in the art, including, for example, cephalosporins, penicillins, macrolides, miconazole, etc.
n Pharmaceutical formulations may optionally include a buffer.
Metal ion chelate complexes or salts or hydrates thereof, or fozmulations comprising metal ion chelate complexes in accordance with the present invention may also he used with conventional wound dressings, e.g., as a means of promoting wound healing, zeducing inflammation, promoting healing of scar tissue, preventing or treating is microbial infection, etc, Metal ion ehelate complexes according to the present invention, or formulations thereof, may be applied to one or snore surfaces of a wound dressing. For example, the metal ion chelate complex or salt thereof may be. applied in the form of a liquid, cream, spray, or lotion, etc. Alternatively, the wound dressing may be impregnated with the metal ion complex or formulation thereof according to the ~o invention. In some embodiments, the means of applying the metal ion complex or salt thereof to the wound dressing may include using a carrier medium which is capable of evaporating after application, e.g, an alcohol. Examples of vvound dressings include bandages, swabs, adhesive dressings e.g., BandAid~ adhesive strips, skin replacement dressings, burn dressings, blister dressings, and the like.
is In accordance with the present invention, metal ion chelate complexes may be incorporated into pharmaceutical formulations in the form of their pharmaceutically acceptable salts. By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the 30 like, and are commensurate with a reasonable benefitlrisk ratio.
.Pharmaceutically acceptable salts are well known in the. azt and include alkali and all:.ali earth salts.
In the context of the present invention, the language "pharmaceutically acceptable carrier" is intended to ine.lude solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such 3s media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the metal ion chelate complex, use thereof in the therapeutic compositions and methods of treatment is contemplated. Supplementary active compounds may also be incozporated into the compositions according to the present invention. Dosage unit fozm as used herein refers s to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of metal ion complex. is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carriez. The specification for dosage unit foams of the invention rnay be dependent on (a) the unique characteristics of the metal ion chelate complex and the particular therapeutic effect to be m achieved, and (b) the limitations inherent in the art. The principal metal ion chelate complex is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages may be determined by reference to the usual dose and manner of administration of the said ~ s ingredi ents.
Convenient modes of administration include topical transdermal application.
For example, formulations may corztprise a cream, lotion, a liquid, a. spray, a paste, or a gel.
Dispersions of metal ion chelate complexes may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of ;.o storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms.
Other modes of administration may include injection (subcutaneous, intravenous, etc.), oral administration, aid rectal administration. Depending on the route of administration, the formulation andlor metal ion chelate complex may be coated with a zs material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound. The.
fozznulation andlor metal ion chelate complex may also be administered parenterally or intraperiloneally.
Pharmaceutical compositions suitable for injection include sterile aqueous solutions so (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Ideally, the composition is stable under the conditions of manufacture and storage and ma.y include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi.
In one embodiment of the invention, the formulation and/or metal ion chelate complex according to the invention may be administered orally, for example, with an.
inert diluent or an assimilabIe edible carrier, The formulation and/or metal ion chelate complex and other ingredients can also be enclosed in a hard or soft shell gelatin capsule, s compressed into tablets, or incorporated directly into an in.dividual's diet. For oral therapeutic administration, the formulation andlor metal ion chelate complex can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
Suitably, such compositions and preparations may contain at least 1°,% by weight of active compound.
a The percentage of the active compound in pharmaceutical compositions and preparations can, of course, be varied and, for example, may convenienthr range from about 2% to about 90%, about 5°~° to about 80°f°, about 10% to about 75%, about 15°l° to about 65%;
about 20~/o to about 60%, about 25% to about 50%, about 30'% to about 4S°~o, or about 35°,% to about 45%, of the weight of the dosage unit. The amount of active compound in ~s therapeutically useful compositions is such that a suitable dosage will be obtained.
Single or multiple administrations of a pharmaceutical composition in accordance with the present invention may be carried out. One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels of the metal ion complexes andlor compositions thereof according to the invention and an administration zo pattern which would be suitable for treating the disorders or diseases to which the compounds and compositions are applicable.
Further, it will be apparent to one of ordinary skill in the art that the optimal course of treatment, such as the number of applications or administrations per day for a defined number of days, can be ascertained using conventional course of treatment determination ?= tests.
By way of illustration, a topical formulation in the form of a cream, lotion, spray or gel for treating or reducing inflammation may be applied locally and rubbed into the skin at the site of inflammation. This process could be repeated as necessary over a suitable tin3e period, eg, once, twice, three or four times per day for 1 day, 2-3 days, 4-7 days, 7-30 14 days, up to 3 weeks, up to d. weeks, ete, until the inflammation is suitably reduced.
Application rnay be ongoing or may be discontinued for z period of time and then recommenced.
Generally, an effective dosage per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 rrng to about 750 mg per kg ~s body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight. Still suitably, an effective dosage per ~
hours may be in the range of about 1.0 mg to about 200 mg per kg body weight;
about 1.0 mg to about 100 mg per kg body weight; about 1.0 rng to about 50 mg per kg body s weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kg body weight.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in 'the specific embodiments m without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
The. invention will now be described in greatez detail by reference to specific examples, which should not be construed as in any way limiting the scope of the is mventron.
Example 1 Preparation of Copper-EDTA compalex Method 1:
EDTA disodium salt (140 g, 0.43 rnol) ~~as added tc> an aqueous solution of zo hydrogen peroxide (10 wt%, l L), and the mixture stirred until all of the EDTA disodium salt had dissolved. The solution was cooled to maintain the temperature below 25 °C.
Copper wire (60g, 0.94 mot) was added and the resultant rnixtuze stirred and cooled. A
blue solution was produced. The solution was evaporated to obtain a blue powder comprising copper-EDTA disodium sail. Metal ion complex n'ay optionally be purified zs by recrystallisation. Mass spec (mlz) (Negative Ion MALDI): ?.51 (100%), Method 2;
EDTA disodium salt was added to water and the resultant mixture. heated with stirring to promote dissolution. When all of the EDTA salt vvas dissolved, the solution was cooled to room temperature. Hydrogen peroxide (10 wt°.~o) was then added, followed ac> by coppers) and the mixture stirred, optionally with wazrning but maintaining the temperature to less than 40'C to produce a blue solution comprising copper-EDTA
disodium salt. In a variation of this method the order of addition of the hydrogen peroxide and copper may be reversed.
Example 2 -Pharmaceutical Formul:~tions 2(a) - Topical Cream Formulation (i) 20 mL of the solution prepared in Example. 1 eras mixed into 250 g of commercially available Vitamin E cream.
s (ii} 10 mL of the solution prepared in Example 1 twos mixed into 200g of comrzxercially available Sorbolene cream.
2(b) - Topical Cream Formulation A typical composition formulated as a topical cream is outlined below:
Cu[EDTA]Naz 1.0 g ~o Polawax GP 200 25.0 g Lanolin Anhydrous 3.0 g White $eeswax 4.5 g Methyl hydroxybenzoate 0.1 g Deionised & sterilised Water to 100.0 g ~s The polawax, beeswax and lanolin are heated together at 60°C, a solution of methyl hydroxybenzoate is added and homogenisation achieved using high speed stirring. The temperature is then allowed to fall to 50°C. The compound of the present invention, in this example being Cu[EDTA]Na2, is then added and dispersed throughout, and the composition is allowed to cool with slow speed stirring.
~0 2(c) - 'l: opical Lotion Formulation A typical composition formulated as a topical lotion is outlined below:
Cu(E.DTA]Nay 1.2 a Sorbitan Monolaurate 0.8 g Polysorbate 20 0.7 g is Cetostearyl Alcohol 1.5 g Cvlycerin 7.0 g Methyl ~iydroxybenzoate 0.4 g Sterilised Water about to 100.00 ml The methyl hydroxybenaoate a~~d glycerin are dissolved in 70 rnl of the. water at 3n 75oC. The sorbitan monolaurate, polysorbate. 20 and cetostearyl alcohol are melted together at 75°C and added to the aqueous solution. The resulting emulsion is homogenised, allowed to cool with continuous stirring and the Cu[EDTA]Nay is added as a suspension in the remaining eater. The whole suspension is stirred until homogenised.
2(d) - Ointment Formulation A typical composition for delivery as an ointment includes l.Og of Cu[EDTA~Na2, together with white soft paraffin to 100.0 g, dispersed to produce a smooth, homogeneous product.
s 2(e) - Liquid Formulation An example of a liquid formulation can be prepared by diluting ~0 mL of the solution produced in Example 1 with 200n~L of sterilised water and mixing to produce a homogeneous solution.
co 2(f) - Shampoo Formulation An example of a shampoo formulation can be prepared 'by diluting 40 naL of the solution produced in Example 1 with 250mL of commercially available shampoo and mixing to produce a homogeneous product.
Example 2(g) - Capsule Composition !s A composition of copper-EDTA disodium in the form of a. capsule may be prepared by filling a standard two-piece hard gelatin capsule with 250 mg of Cu[EDTA]Naa, in powdered form, 100 mg of lactose, 3S mg of talc and IO mg of magnesium steatite.
Example 3 - Methods of Treatment 3(a) -'Treatment of inflammation 4o Study (i) A cream containing Goppes-EDTA prepared according to example (2a)(i) was applied topically twice per day to an inflamed knee joint of a male aged mid-40s, then rubbed in. Treatment was continued for one week to alleviate inflammation: The duration of treatment time and number of applications per day may be varied as necessary.
a~ Study (ii) A cream containing Copper-EDTA prepared according to example (2a)(i) was applied topically 3 times per day to the hands of an, 84 yeas old woman having severe.
arthritis. Initial relief was felt within 24 hours. Substantial relief from pain and inflammation was felt within a week.
3n Study (iii) A cream containing Copper-EDTA prepared according to example (2a)(i) was applied topically to one hand of a 55 year old male suffering from arthritis.
The cream was applied twice per day for one tveek. The other hand was not treated. After one week there w as a significant reduction in pain and swelliag in the hand which had been treated, in comparison to the hand which had not been treated.
3(b) - Stimulation of Hair Regrowth A cream containing Copper-EDTA prepared accoxdini; to example. (2a}(i} was s applied topically once per day to the scalp of a 42 year old male, then massaged into the scalp until the cream had been absorbed. Treatment was continued for 1 month before fine hairs started to grow. The lairs have continued to grow orrer a. 6 month period (to date) without further treatment.
3(c} - Sunscreen io A female subject (aged early ~lOs) suffering from vitiligo applied a cxeam prepared according to Example (2a)(i) to areas of skin lacking pi~nent. The treated areas regained.
some colour after applying the cream foz about 1 month, After about 1 week of treatment, non-pi~nented patches of skin were able to be exposed to sunlight without the burning sensation usually experienced by the subject. The. cream is currently applied once in the i5 morning to get sun protection for the day.
inc9ustrial Applicability The present invention relates to a process for preparing metal ion complexes and zo plartnaceutical formulations thereof. The invention further relates to methods of treatment of inflammatory disorders, pain, promotion of hair growth or regrowth, and promotion of wound and scar tissue healing.
In one embodiment the solution is an aqueous solution. 'The pH of the solution may s be between about 2 and about 14. In another embodiment the solution is a basic aqueous solution wherein the pH of the solution is between about 7.5 .and about I4, for example, pH about 8, 9, 10, 11, I2, or 13. In one embodiment, the pH o:f the solution at completion of the reaction is about 6 to about 8, e.g, about 7.
Modification of the temperature may be used to control the rate of reaction.
ao Accordingly, the process may optionally include one or more cooling steps.
For example, the solution may optionally be cooled prior to addition of the metal, after addition of the metal, during the oxidation step, ox at completion of the oxidation reaction.
The temperature may be maintained less than about 100°C, less than about 80°C, 60°C, for example, between about 0°C and about 50°C, ox between about 10°C and about 40°C. In a one embodiment, the mixture may be cooled to a temperature selected from about 40°C, about 35°C, about 30°C, about 25°C, about 20°C, about 15°C, .about 10°C, and about S°C.
Alternatively, the process may include one or more heating steps.
According to a third aspect of the invention theze is provided a process for pzeparing copper-EDTA, comprising ~a mixing EDTA or a salt thereof with an aqueous solution of hydrogen peroxide to obtain a mixture; and adding copper to said mixture so as to form copper-EDTA or a salt thereof.
Tn one embodiment the process further comprises a separation step, e.g., a filtration step, for removing residual or unreacte.d copper solid(s).
zs rn one embodiment the process further compzises cooling the mixture of hydrogen peroxide and E.DTA or a salt thezeof.
Tn another embodiment, the process may further comprise cooling the mixture after copper has been added. Tn one embodiment the temperature is maintained at a tennperature below about 40°C, eg, between about 5°C and about 40°C.
3a The salt of EDTA may Comprise one or more of sodium ions, potassium ions, lithium ions, calcium ions, magnesium ions, or mixtures thereof In one embodiment the chelating agent is EDTA disodium salt.
In one erzzbodiment the copper is oxidised to Cu2+.
In one embodiment the resultant metal chelate complex is a salt, such as an alkali earth or alkali metal salt. For example, the metal ion chelat.e complex may be Na+, K~, Li+, IvZg2+, or Ca2+ salt. In another embodiment the metal chelate complex is Cu[EDTA]Na2. In one embodiment the metal chelate complex is Cu2[EDTA]. In a s further embodiment the product is a mixture of Cu2[EDTA] and Cu[EDTA]Na2.
In a further embodiment the metal chelate complex or salt thereof, may be a hydrate.
With reference to the first or second aspect of the invent:ian, in one embodiment the resultant mixture may be evaporated or lyophilized to obtain a solid comprising the metal ~o ion cl~elate complex or salt thereof. The metal ion chelate complex may be purired e.g, by recrystallization from a suitable solvent.
According to a fourth aspect of the invention there is provided a metal ion complex or salt thereof prepared according to the. process of the first, second or third aspect of the invention.
~s According to a fifth aspect of the invention there is provided an aqueous solution comprising at least one metal ion complex or salt thereof prepared according to the process of the first, second or third aspect of the invention. In one embodiment the aqueous solution may comprise uncomplexed chelating agent, or residual oxidizing agent.
According to a sixth aspect of the invention there is provided a pharmaceutical Zo formulation comprising a metal ion complex or salt thereof according to the fourth aspect of the invention, or a solution according to the fifth aspect of the invention, together with a suitable adjuvant, diluent or carrier.
According to a seventh aspect of the invention there is provided a process for preparing a pharmaceutical formulation e.omprising mixing at least one metal ion complex Zs or salt thereof according to the fourth aspect of the invention with a suitable carrier, diluent or adjuvant.
According to an eighth aspect of the invention there is provided a process for preparing a pharmaceutical formulation comprising mixing an ;aqueous solution of at least one metal ion comple;~ or salt thereof according to the fifth aspect of the invention with a :o suitable acceptable carrier, diluent or adjuvant.
With reference to any one of the sixth, seventh or eighth aspects of the invention, the carrier, diluent or adjuvant may be pharmaceutically aca~table andlor veterinarily acceptable.
According to a ninth aspect of the invention there is pro ided a method of treafi~nenc 3s of a disease or condition in a mammal, comprising administezing to said mammal an effective amount of at least one metal ion cheIate complex or a salt thereof, or a pharmaceutical composition thexeof.
According to a tenth aspect of the invention there is provided at least one metal ion chelate complex or salt thereof, or a pharmaceutical composition thereof, when used for s treating a disease or condition in a mammal.
According to an eleventh aspect of. the invention there is provided the use of a metal ion chelate complex or salt thereof for the manufacture of a medicament for treating a disease or condition.
With reference to any one of the ninth to eleventh aspects of the invention, in one to embodiment the metal ion chelate complex may be a metal ion chelate connplex according to the fourth aspect of the invenkion. In another embodirnent the metal ion cixelate complex may be in the form of an aqueous solution, for example, an aqueous solution according to the fifth aspect of the invention. In one embodiment the metal ion chelate complex is Cuz[EDTA], Cu[EDTA]Na2, Cu[EDTA-HZ], or a m~i~cture thereof.
a s In one embodiment, the pharmaceutical corraposition is a topical composition according to the sixth aspect of the invention. The composition may be in the form of a cream, lotion, spray or gel.
The disease or condition to be treated may be selected from reducing inflammation, such as inflammation associated with arthritis, including osteoarthritis and rheumatoid 'o arthritis; promoting growth or regrowth of hair; heating psoriasis;
increasing blood flow;
treating chill blains; treating varicose veins; promoting wound healing;
promoting healing of scar tissue, including scar tissue resulting from bums; alleviating or reducing joint or muscular pain; tzeating sinus inflammation andlor sinus pair; treating bacterial andJor fungal infection.
zs Other conditions that may be treated in accordance with the present invention include eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, and onychoschizia tsplit nails).
In alternative embodiments of the invention, th.e metal ion complexes) or salts) thereof, or compositions comprising said metal ion complexes) or salts) thereof may be 3o used to as a means of prow ding mineral supplements, e.g, copper, cobalt, zinc, selenium, etc, to animals, e.g., humans, sheep, cattle, goats, horses, pigs, etc. In various embodiments, compositions may comprise mixtures of different metal ion chelate complexes, or salts thereof.
In further embodiments, the metal ion chelate complex according to the invention, ~s or pharmaceutical compositions comprising the complex, may be used as an alternative to conventional sun screen, eg, for humans or animals suffering from conditions such as vitiligo (lack of pigment in the skin).
In one embodiment the present invention may enable a non-toxic amount of a metal ion to be administered.
s With reference to the eighth or ninth aspects of the invention, the mammal may be.
human, non-human primate, murine, bovine, ovine, equine, caprine, leporine, avian, feline, porcine, or canine. In one embodiment the mammal is human.
The present invention provides a convenient process for prepaxing metal chelate complexes and salts thereof. Metal ion chelate complexes in accordance with the present io invention, including copper complexes such as copper-BDTA complexes or salts thereof, may have a range of beneficial therapeutic properties.
Brief ~escription of the Figures Figure 1 is a Negative ion MALDI mass spectrum of a. sample solution prepared according to the process of the invention shoeing major copper containing ions consistent is with the species Cu[EDTA~~' or Cu[EDTA]~ (m.w 351 Da).
Figure 2 is an e.lectrospray mass spectrum of a sample solution prepared according to the process of the present invention showing a major copper containing ion consistent with a sodium ion of Cu[EDTA]Na2.
Figure 3 is a comparison photograph of a male's hands after treatment of one hand Zo with a cream according to the invention.
p'iguxe 4 is a comparison photograph of a male's hands after treatment of the left hand with a cream according to the. invention.
Figuxe S is a photograph of the hands of an 84 year old woman suffering arthritis before treatment.
is Figure 6 is a photograph of the hands of an 84 year old woman suffering arthritis after treatment with a cream according to the invention for one week.
Definitions The following ate some definitions that may be. helpful in understanding the description of the present invention. These are intended as general definitions and should :o in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.
Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements i clearly encompass both singular and plural forms of the recited integers, steps or elements.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to s imply the inclusion of a stated step or element or integer or group of steps or elements ox integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification., the term "comprising" meats "including principally, but not necessarily solely".
In the context of the present specification, the. term "metal ion complex"
should be m understood to include metal ion complexes, as well as salts, protonated forms, and hydrates thereof.
In the context of this specification, the term "copper-EDTA" should be understood to include within its meaning Cu[EATA]2- andlor salts thereof, e.g, Cu[EDTA]Na2, Cu[EDTA-Hi2]and Cuz[EDTA].
~s Tn the contexi of this specification "Ci-Ca allcyl" refers to straight or branched saturated alkanes having one to four carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tent-butyl, Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to ~o be understood that the. invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specit5cati.on, individually or collectively, and any and all combinations or any two or more of said steps or features.
AlI the references cited in this application are specifically incorporated by reference z: and are incorporated herein in their entirety.
The. language "therapeutically effective amount" is intended to include within its meaning a non-toxic but sufficient amount of a. compound or composition of the invention to provide the desired therapeutic effect. The exact therapeutically effective amount of the compound or composition will vary according to factors such as the type of disease or 3o condition to be treated, the age, sex, and weight of the animal, mode of administration, and the ability of the compound or composition to permeate cell membranes.
Dosage regima may be adjusted to provide the optimum therapeutic; response. For examples several divided doses may be administered one or several times daily or the dose can be proportionally reduced or increased as indicated by the exigencies of the.
therapeutic ~s situation. ' As used herein the term "treatment", refers to any and all uses which remedy a disorder or disease state or symptoms, prevent the establishment of a disorder or disease, or otherwise prevent, hinder, retard, or reverse the progression of a.
disorder or disease or other undesirable symptoms in any way whatsoever.
s Abbreviations EDTA - ethylenediaminetetraacetic acid DTPA - diethylenetriaminepentaacetic acid HEDTA- hydroxyethylethylenediaminetria.cetac acid NSAI:D - non-steroidal anti-inflammatory drug io GOX-2 - cyclooxygenase-2 Detailed pescription ~f Preferred Embodiment: of the Invention The present invention relates to processes for fom~ing metal ion chelate complexes and salts and protonated forms thereof, compositions comprising one or more metal ion chelate complexes, methods of preparation, and use thereof. More particularly, the is present invention relates to compositions comprising copper complexes, including compositions comprising copper-EDTA, copper-DTPA and eopper-HEDTA, and salts and protonated forms thereof.
The process for preparing metal ion chelate complexes according to the invention, comprises oxidising a metal which is in its elemental state to a correspoaiding cation in '0 S~h~ ncino~ an ntiriising agent. In one embodiment, the process of the invention may be carried out as a "one pot" process. Alternatively, the reaction can be carried out i.n a stepwise fashion, including stepwise addition of reagents.
Whilst not seeking to be limited to any one proposed mechanism of action, the process may involve an i~a sits redox reaction between the: elemental metal and the zs oxidising agent, whereby the. metal is oxidised to one or more corresponding cations. The metal cations thus produced may then chelate to the chelating agent to form a metal ion chelate complex, or metal complex anion. Suitable combinations of oxidising agent and metal can be selected based on the reduction potential of the respective reagents.
Reduction potentials would be known to those skilled in the art and are reported, fox ?o example, irt the CRC Hahdboo& of Chemistry and Physics, Weast, R., Ed. SS'h Edition, 1974-1975, the entire contents of which are incorporated herein by cross-reference.
By way of illustration, the following reaction ntay be envisaged, where the oxidising agent is hydrogen peroxide and M is a suitable metal:
M~S~ + HZO~ + 2H* M2* + 2H20 When M is copper, the. follor ing redox reaction may be envisaged:
Cu(s) + Hx02 + 2H+ Cu2' * 2H20 s The resultant MZ+ ions, eg, Cu~* ions, may then form a~ metal i.on complex with a chelating agent, such as EDTA, DTPA, HEDTA, or salt or protonated form thereof.
One or more steps of the process of the present invention may be exothermic arid ' the reaction vessel may optionally be cooled. variation of temperature, reagent concentration, rate of addition of reagents, surface area of the metal (e.g, larger surface ~o areas may lead to an increased reaction rate), and pH may be used as a means of controlling the rate of the eomplexation reaction.
Suitable cheiating agents include multidenta.te ligands capable of forming stable ' metal ion complexes. Examples of suitable chelating agents include ethylenediaminetetra,acetic (EDTA), diethylenetriaminepentaacetic acid (DPTAj and is (HEDTA) hydrvxyethylethyienediaminetriacetic acid, the structures of which are shown below:
Ho 0 0 off o off HO~O 0 OH HOCH
~N ~ 2 ~N~~N~ \N N
0~ ~ O O ''0 O
~O'H OH H HO 'O~H H ON
EDTA DTPA HEDTA
Multidentate ligands such as EDTA, DTPA, HEDTA may be zwitterionic.
ao EDTA is a hexadentate chelating ligand with 6 possible coordination sites.
The pKa of the carboxylic acid residues of EDTA are 1.70, 2.60, 6.30 and 10.60, respectively.
Neutral EDTA can exist as a zwitterion with t'vo of the acid protons being located on the nitrogen atoms.
EDTA, DTPA, and HEDTA have a strong affinity for a wide range of metal ions, zs and, for example, may form complexes with metal ions including Ag+, Caz+, Coat, Cu2+, Fe3~, Fe2+, Mg~'~, Ni2*, and Zn~'-. Metal ion complexes prepared according to the present invention may be stable at low, neutral aridlor high pH. For example, metal ion chelate complexes according to the present invention may be stable at a phl in the range from about 4 to about 12. The metal ion complex may comprise the chelate and metal ion in. a 3e 1:1 stoichiometric ratio or 1:2 stoichiometric ratio. For example, Cu2+ may chelate to EDTA in a I:1 ratio to form the anionic species Cu[EDTAJZ', or a salt or protonated form thereof. Suitable counterions may include sodium ions, pots~ssium ions, calcium ions, magnesium ions, etc.
In accordance with the process of the present invention, appropriate molar ratios of reagents can be determined by those skilled in the art. Thus, it is possible to manipulate molar ratios to ensure any one or more reagents are consumed in the course of the reaction. For example, 1 mole of copper may be oxidised by one mole of hydrogen peroxide to produce one mole of Cu2y ions rfz siW which may then be chelated by one mole of EDTA. Accordingly, to ensure all of the hydrogen peroxide is consumed, an excess of copper can be used. Alternatively, a molar excess of any oa~e or more reagents ~o may be used whereby residual excess reagent Will remain at completion of the reaction process. In one embodiment, excess chelating agent, e.g., EDT A or a salt thereof, may be used. In one embodiment, excess metal, e.g., copper, may be used. Residual reagents may be removed upon completion of the reaction.
One advantage of the present invention is that metal ions, such as iron, zinc, nickel, 2 s cobalt, magnesium, and copper ions (or mixtures thereof), may be administered to a subject in the form of a metal ion complex or salt or hydrate thereof, or a pharmaceutical composition Thereof.
Techniques known to those skilled in the art, such as ion exchange chromatogaphy and reerystallization, may be used to exchange counterions, thus, for examgle, a salt or Zo protonated form of a metal ion ch.elate complex (or mixtures thereof) rt2ay be converted into another salt of choice.
Aqueous solutions of metal ion chelate complexes produced according to the process of the present invention may have a relatively stable shelf life, for example, up to years, 4 years, 3 years, 2 years, 12 months, 6 months, or 3 months. Buffer solutions, zs e.g., ammoniaJammonium chloride, znay be used to stabilise solutions of metal ion chelate complexes.
In accordance with the present invention, metal ion complexes or salts oz hydrates thereof (e.g., Copper-fiDTA and salts thereof), as well of pharmaceutical formulations of metal ion complexes or salts thereof, may be useful in treating a range of physiological yo conditions or disorders in humans and animals. Examples of therapeutic uses include mineral supplementation, treatment of inflammation, treatment of arthritis, inducing hair growth or regrowth, promoting wool growth in sheep azrd goats, treating psoriasis, alleviation of pain including sinus pain, joint pain, and muscular pain, promoting wound healing including healing of scar tissue, increasing blood flow, treating chill Mains, ;s treatment of varicose veins, and treatment of microbial infection including bacterial, fungal infection, treating eczema, reducing wrinkles, bruises, preventing or alleviating joint degeneration and pain associated therewith, treatizt.g acne, promoting healing of burns, and treating onychoschizia (split nails).
For example, for treatment or alleviation of inflammation., a topical formulation (eg, a cream, lotion, spray or gel) comprising a metal ion complex according to the invention may be rubbed into an inflamed area, e.g, one to three times per day, until inflammation is reduced. Treatment may continue for as long as necessary to reduce or continually alleviate inflammation.
For promoting hair regrowth, a topical formulation (eg, a cream, lotion, gel, spray ~o or shampoo) comprising a metal ion eorrxplex according to the invention may be applied to the scalp, with rubbing or massaging, e.g., once or twice per day for a period of time which is at least sufficient to stimulate or promote hair grov~~th o~r regrowth.
For use as a sunscreen, a topical formulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the invention rtia.y be applied to an area of is skin prior to exposure to the sun or ~V. Additional applications may be made as required.
For relief of sinus pain, a topical farmulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the invention ma.y be applied to an area of skin around the nose andlor under the eyes or across the forehead when pain starts, resulting in pain relief zo To reduce scarring, a topical formulation (eg, a cream, lotion, gel or spray) comprising a metal ion complex according to the. invention may be applied, generally one to three times per day, e.g., twice a day, across the scar tissue with aubbing to work it into the scar tissue and surrounding skin.
For healing of bruising a topical formulation (eg, a cream, lotion, gel or spray) zs comprising a metal ion complex according to the invention may be. applied to and around the bruised area once a day until bruising disappears.
For treatment of onychosc.hizia (split nails) a suitable formulation (eg, a liquid, cream, tincture, or lotion) comprising a metal ion complex according to the invention may be applied once a day until the desired nail quality is attained.
3u For treatment of acne and other skin conditions such as psoriasis, a suitable formulation (eg, a liquid, cream, gel, spray, tincture, or lotion) comprising a metal ion complex according to the invention may be applied to the appropriate area, one to three times per day, e.g, twice per day, in a manner similar to conventional therapies.
Pharmaceutical anc)<lor Therapeutic Formulations In accordance with the present invention, metal ion chelate complexes, such as copper-EDTA or salts thereof, and pharmaceutical formulations thereof, may be administered alone or may be used in combination with other known treatments or s therapeutic agents, including for example, anti-inflammatory agents (eg, NSATDs, cartisones, etc), analgesics and pain killers (eg, NSAIDs, CO~i-2 inhibitors), antibacterial and antifungal agents, hair growth stimulants (eg, radical scavengers, antiandxogens), sunscreens, and antibacterial and antifungal treatments known ao those skilled in the art, including, for example, cephalosporins, penicillins, macrolides, miconazole, etc.
n Pharmaceutical formulations may optionally include a buffer.
Metal ion chelate complexes or salts or hydrates thereof, or fozmulations comprising metal ion chelate complexes in accordance with the present invention may also he used with conventional wound dressings, e.g., as a means of promoting wound healing, zeducing inflammation, promoting healing of scar tissue, preventing or treating is microbial infection, etc, Metal ion ehelate complexes according to the present invention, or formulations thereof, may be applied to one or snore surfaces of a wound dressing. For example, the metal ion chelate complex or salt thereof may be. applied in the form of a liquid, cream, spray, or lotion, etc. Alternatively, the wound dressing may be impregnated with the metal ion complex or formulation thereof according to the ~o invention. In some embodiments, the means of applying the metal ion complex or salt thereof to the wound dressing may include using a carrier medium which is capable of evaporating after application, e.g, an alcohol. Examples of vvound dressings include bandages, swabs, adhesive dressings e.g., BandAid~ adhesive strips, skin replacement dressings, burn dressings, blister dressings, and the like.
is In accordance with the present invention, metal ion chelate complexes may be incorporated into pharmaceutical formulations in the form of their pharmaceutically acceptable salts. By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the 30 like, and are commensurate with a reasonable benefitlrisk ratio.
.Pharmaceutically acceptable salts are well known in the. azt and include alkali and all:.ali earth salts.
In the context of the present invention, the language "pharmaceutically acceptable carrier" is intended to ine.lude solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such 3s media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the metal ion chelate complex, use thereof in the therapeutic compositions and methods of treatment is contemplated. Supplementary active compounds may also be incozporated into the compositions according to the present invention. Dosage unit fozm as used herein refers s to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of metal ion complex. is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carriez. The specification for dosage unit foams of the invention rnay be dependent on (a) the unique characteristics of the metal ion chelate complex and the particular therapeutic effect to be m achieved, and (b) the limitations inherent in the art. The principal metal ion chelate complex is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of compositions containing supplementary active ingredients, the dosages may be determined by reference to the usual dose and manner of administration of the said ~ s ingredi ents.
Convenient modes of administration include topical transdermal application.
For example, formulations may corztprise a cream, lotion, a liquid, a. spray, a paste, or a gel.
Dispersions of metal ion chelate complexes may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of ;.o storage and use, pharmaceutical preparations may contain a preservative to prevent the growth of microorganisms.
Other modes of administration may include injection (subcutaneous, intravenous, etc.), oral administration, aid rectal administration. Depending on the route of administration, the formulation andlor metal ion chelate complex may be coated with a zs material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound. The.
fozznulation andlor metal ion chelate complex may also be administered parenterally or intraperiloneally.
Pharmaceutical compositions suitable for injection include sterile aqueous solutions so (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Ideally, the composition is stable under the conditions of manufacture and storage and ma.y include a preservative to stabilise the composition against the contaminating action of microorganisms such as bacteria and fungi.
In one embodiment of the invention, the formulation and/or metal ion chelate complex according to the invention may be administered orally, for example, with an.
inert diluent or an assimilabIe edible carrier, The formulation and/or metal ion chelate complex and other ingredients can also be enclosed in a hard or soft shell gelatin capsule, s compressed into tablets, or incorporated directly into an in.dividual's diet. For oral therapeutic administration, the formulation andlor metal ion chelate complex can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
Suitably, such compositions and preparations may contain at least 1°,% by weight of active compound.
a The percentage of the active compound in pharmaceutical compositions and preparations can, of course, be varied and, for example, may convenienthr range from about 2% to about 90%, about 5°~° to about 80°f°, about 10% to about 75%, about 15°l° to about 65%;
about 20~/o to about 60%, about 25% to about 50%, about 30'% to about 4S°~o, or about 35°,% to about 45%, of the weight of the dosage unit. The amount of active compound in ~s therapeutically useful compositions is such that a suitable dosage will be obtained.
Single or multiple administrations of a pharmaceutical composition in accordance with the present invention may be carried out. One skilled in the art would be able, by routine experimentation, to determine effective, non-toxic dosage levels of the metal ion complexes andlor compositions thereof according to the invention and an administration zo pattern which would be suitable for treating the disorders or diseases to which the compounds and compositions are applicable.
Further, it will be apparent to one of ordinary skill in the art that the optimal course of treatment, such as the number of applications or administrations per day for a defined number of days, can be ascertained using conventional course of treatment determination ?= tests.
By way of illustration, a topical formulation in the form of a cream, lotion, spray or gel for treating or reducing inflammation may be applied locally and rubbed into the skin at the site of inflammation. This process could be repeated as necessary over a suitable tin3e period, eg, once, twice, three or four times per day for 1 day, 2-3 days, 4-7 days, 7-30 14 days, up to 3 weeks, up to d. weeks, ete, until the inflammation is suitably reduced.
Application rnay be ongoing or may be discontinued for z period of time and then recommenced.
Generally, an effective dosage per 24 hours may be in the range of about 0.0001 mg to about 1000 mg per kg body weight; suitably, about 0.001 rrng to about 750 mg per kg ~s body weight; about 0.01 mg to about 500 mg per kg body weight; about 0.1 mg to about 500 mg per kg body weight; about 0.1 mg to about 250 mg per kg body weight; or about 1.0 mg to about 250 mg per kg body weight. Still suitably, an effective dosage per ~
hours may be in the range of about 1.0 mg to about 200 mg per kg body weight;
about 1.0 mg to about 100 mg per kg body weight; about 1.0 rng to about 50 mg per kg body s weight; about 1.0 mg to about 25 mg per kg body weight; about 5.0 mg to about 50 mg per kg body weight; about 5.0 mg to about 20 mg per kg body weight; or about 5.0 mg to about 15 mg per kg body weight.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in 'the specific embodiments m without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
The. invention will now be described in greatez detail by reference to specific examples, which should not be construed as in any way limiting the scope of the is mventron.
Example 1 Preparation of Copper-EDTA compalex Method 1:
EDTA disodium salt (140 g, 0.43 rnol) ~~as added tc> an aqueous solution of zo hydrogen peroxide (10 wt%, l L), and the mixture stirred until all of the EDTA disodium salt had dissolved. The solution was cooled to maintain the temperature below 25 °C.
Copper wire (60g, 0.94 mot) was added and the resultant rnixtuze stirred and cooled. A
blue solution was produced. The solution was evaporated to obtain a blue powder comprising copper-EDTA disodium sail. Metal ion complex n'ay optionally be purified zs by recrystallisation. Mass spec (mlz) (Negative Ion MALDI): ?.51 (100%), Method 2;
EDTA disodium salt was added to water and the resultant mixture. heated with stirring to promote dissolution. When all of the EDTA salt vvas dissolved, the solution was cooled to room temperature. Hydrogen peroxide (10 wt°.~o) was then added, followed ac> by coppers) and the mixture stirred, optionally with wazrning but maintaining the temperature to less than 40'C to produce a blue solution comprising copper-EDTA
disodium salt. In a variation of this method the order of addition of the hydrogen peroxide and copper may be reversed.
Example 2 -Pharmaceutical Formul:~tions 2(a) - Topical Cream Formulation (i) 20 mL of the solution prepared in Example. 1 eras mixed into 250 g of commercially available Vitamin E cream.
s (ii} 10 mL of the solution prepared in Example 1 twos mixed into 200g of comrzxercially available Sorbolene cream.
2(b) - Topical Cream Formulation A typical composition formulated as a topical cream is outlined below:
Cu[EDTA]Naz 1.0 g ~o Polawax GP 200 25.0 g Lanolin Anhydrous 3.0 g White $eeswax 4.5 g Methyl hydroxybenzoate 0.1 g Deionised & sterilised Water to 100.0 g ~s The polawax, beeswax and lanolin are heated together at 60°C, a solution of methyl hydroxybenzoate is added and homogenisation achieved using high speed stirring. The temperature is then allowed to fall to 50°C. The compound of the present invention, in this example being Cu[EDTA]Na2, is then added and dispersed throughout, and the composition is allowed to cool with slow speed stirring.
~0 2(c) - 'l: opical Lotion Formulation A typical composition formulated as a topical lotion is outlined below:
Cu(E.DTA]Nay 1.2 a Sorbitan Monolaurate 0.8 g Polysorbate 20 0.7 g is Cetostearyl Alcohol 1.5 g Cvlycerin 7.0 g Methyl ~iydroxybenzoate 0.4 g Sterilised Water about to 100.00 ml The methyl hydroxybenaoate a~~d glycerin are dissolved in 70 rnl of the. water at 3n 75oC. The sorbitan monolaurate, polysorbate. 20 and cetostearyl alcohol are melted together at 75°C and added to the aqueous solution. The resulting emulsion is homogenised, allowed to cool with continuous stirring and the Cu[EDTA]Nay is added as a suspension in the remaining eater. The whole suspension is stirred until homogenised.
2(d) - Ointment Formulation A typical composition for delivery as an ointment includes l.Og of Cu[EDTA~Na2, together with white soft paraffin to 100.0 g, dispersed to produce a smooth, homogeneous product.
s 2(e) - Liquid Formulation An example of a liquid formulation can be prepared by diluting ~0 mL of the solution produced in Example 1 with 200n~L of sterilised water and mixing to produce a homogeneous solution.
co 2(f) - Shampoo Formulation An example of a shampoo formulation can be prepared 'by diluting 40 naL of the solution produced in Example 1 with 250mL of commercially available shampoo and mixing to produce a homogeneous product.
Example 2(g) - Capsule Composition !s A composition of copper-EDTA disodium in the form of a. capsule may be prepared by filling a standard two-piece hard gelatin capsule with 250 mg of Cu[EDTA]Naa, in powdered form, 100 mg of lactose, 3S mg of talc and IO mg of magnesium steatite.
Example 3 - Methods of Treatment 3(a) -'Treatment of inflammation 4o Study (i) A cream containing Goppes-EDTA prepared according to example (2a)(i) was applied topically twice per day to an inflamed knee joint of a male aged mid-40s, then rubbed in. Treatment was continued for one week to alleviate inflammation: The duration of treatment time and number of applications per day may be varied as necessary.
a~ Study (ii) A cream containing Copper-EDTA prepared according to example (2a)(i) was applied topically 3 times per day to the hands of an, 84 yeas old woman having severe.
arthritis. Initial relief was felt within 24 hours. Substantial relief from pain and inflammation was felt within a week.
3n Study (iii) A cream containing Copper-EDTA prepared according to example (2a)(i) was applied topically to one hand of a 55 year old male suffering from arthritis.
The cream was applied twice per day for one tveek. The other hand was not treated. After one week there w as a significant reduction in pain and swelliag in the hand which had been treated, in comparison to the hand which had not been treated.
3(b) - Stimulation of Hair Regrowth A cream containing Copper-EDTA prepared accoxdini; to example. (2a}(i} was s applied topically once per day to the scalp of a 42 year old male, then massaged into the scalp until the cream had been absorbed. Treatment was continued for 1 month before fine hairs started to grow. The lairs have continued to grow orrer a. 6 month period (to date) without further treatment.
3(c} - Sunscreen io A female subject (aged early ~lOs) suffering from vitiligo applied a cxeam prepared according to Example (2a)(i) to areas of skin lacking pi~nent. The treated areas regained.
some colour after applying the cream foz about 1 month, After about 1 week of treatment, non-pi~nented patches of skin were able to be exposed to sunlight without the burning sensation usually experienced by the subject. The. cream is currently applied once in the i5 morning to get sun protection for the day.
inc9ustrial Applicability The present invention relates to a process for preparing metal ion complexes and zo plartnaceutical formulations thereof. The invention further relates to methods of treatment of inflammatory disorders, pain, promotion of hair growth or regrowth, and promotion of wound and scar tissue healing.
Claims (30)
1. A process for preparing a metal ion chelate complex, comprising:
mixing a chelating agent with an oxidising agent in solution, to obtain a mixture;
and adding at least one metal capable of forming a metal ion chelate complex with said chelating agent to said mixture, so as to form at least one metal ion chelate complex, or a mixture thereof.
mixing a chelating agent with an oxidising agent in solution, to obtain a mixture;
and adding at least one metal capable of forming a metal ion chelate complex with said chelating agent to said mixture, so as to form at least one metal ion chelate complex, or a mixture thereof.
2. A process for preparing a metal ion chelate complex, comprising;
dissolving a chelating agent in water to obtain a solution;
adding at least one metal capable of forming a metal ion chelate complex with said chelating agent to said solution, and adding an oxidizing agent to said solution, so as to form at least one metal ion chelate complex, or a mixture thereof.
dissolving a chelating agent in water to obtain a solution;
adding at least one metal capable of forming a metal ion chelate complex with said chelating agent to said solution, and adding an oxidizing agent to said solution, so as to form at least one metal ion chelate complex, or a mixture thereof.
3. The process according to claim 1 or 2, wherein the chelating agent comprises at least one carboxylate group.
4. The process according to claim 1 or 2, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetetraacetic acid (HEDTA), ethylenediaminedisuccinic acid (EDDS), salicylic acid, acetyl salicylic acid, amino acids, peptides, and salts thereof.
5. The process according to claim 4, wherein said amino acid is selected from glycine, histidine, lysine, arginine, cysteine, and methionine.
6. The process according to claim 4, wherein said peptide comprises at least two amino acids selected from glycine, histidine, lysine, arginine, cysteine, and methionine, and salts thereof, or mixtures thereof.
7. The process according to claim 1 or 2, wherein said chelating agent is EDTA
or a salt thereof.
or a salt thereof.
8. The process according to claim 7, wherein said chelating agent is EDTA
disodium salt.
disodium salt.
9. The process according to claim 1 or 2, wherein said oxidising agent is selected from aqueous hydrogen peroxide, ozone, aqueous salt solutions and aqueous acidic solutions.
10. The process according to claim 9, wherein said oxidising agent is aqueous hydrogen peroxide.
11. The process according to any one of claims 1 to 10, wherein the metal is selected from Mn, Fe, Co, Ni, Cu, Zn, Cr, Al, Cd, Ag, Se, and mixtures thereof.
12, The process according to claim 11, wherein the metal is copper.
13. A process for preparing copper-EDTA or a salt thereof, comprising mixing EDTA or a salt thereof with aqueous hydrogen peroxide to obtain a mixture;
and adding copper to said mixture so as to form copper-EDTA or a salt thereof.
and adding copper to said mixture so as to form copper-EDTA or a salt thereof.
14. The process according to claim 13, wherein copper-EDTA disodium salt is formed.
15. A metal ion complex or salt thereof prepared according to the process of any one of claims 1 to 14.
16. An aqueous solution comprising a metal ion complex or salt thereof prepared according to the process of any one of claims 1 to 14.
17. A pharmaceutical composition comprising a metal ion complex or salt thereof according to claim 15, or a solution according to claim 16, together with a adjuvant, diluent or carrier.
18. The composition according to claim 17, wherein said adjuvant, diluent or carrier is pharmaceutically acceptable.
19. A process for preparing a pharmaceutical formulation comprising mixing a metal ion complex or salt thereof according to claim 15 with a carrier, diluent or adjuvant.
20. A process for preparing a pharmaceutical formulation comprising mixing an aqueous solution of a metal ion complex or salt thereof according to claim 16 with a suitable acceptable carrier, diluent or adjuvant.
21. The process according to claim 19 or 20, wherein the carrier, diluent or adjuvant is pharmaceutically acceptable.
22. A method of treatment of a mammal comprising administering to said mammal, a therapeutically effective amount of Cu[EDTA)2- complex or a salt thereof, or a pharmaceutical composition thereof.
23. The method according to claim 22, wherein said Cu[EDTA]2- complex or a salt thereof is produced according to the process of any one of claims 1 to 14.
24. The method according to claim 22, comprising administering a pharmaceutical composition according to claim 17.
25. The method according to any one of claims 22 to 24, wherein said treatment is for reducing inflammation; promoting growth or regrowth of hair; treating psoriasis;
increasing blood flow; treating chill blains; treating varicose veins;
promoting wound healing; promoting healing of scar tissue, treating burns; alleviating or reducing joint or muscular pain; treating sinus inflammation and/or sinus pain; treating bacterial and/or fungal infection, treating eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, or onychoschizia (split nails).
increasing blood flow; treating chill blains; treating varicose veins;
promoting wound healing; promoting healing of scar tissue, treating burns; alleviating or reducing joint or muscular pain; treating sinus inflammation and/or sinus pain; treating bacterial and/or fungal infection, treating eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, or onychoschizia (split nails).
26. The. method according to claim 25, wherein said inflammation is associated with osteoarthritis or rheumatoid arthritis.
27. Use of an effective amount of Cu[EDTA]2- complex or a salt thereof for the manufacture of a medicament for treating a disease or condition.
28. The use according to claim 27, wherein said Cu[EDTA]2- complex or a salt thereof is produced according to the process of any one of claims 1 to 14
29. The use according to claim 27 or 28, wherein said treatment is for reducing inflammation; treating chill blains; promoting growth or regrowth of hair;
treating psoriasis; increasing blood flow; treating varicose veins; promoting wound healing;
promoting healing of scar tissue, treating burns; alleviating or reducing joint or muscular pain; treating sinus inflammation and/or sinus pain; treating bacterial and/or fungal infection, treating eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, or onychoschizia (split nails).
treating psoriasis; increasing blood flow; treating varicose veins; promoting wound healing;
promoting healing of scar tissue, treating burns; alleviating or reducing joint or muscular pain; treating sinus inflammation and/or sinus pain; treating bacterial and/or fungal infection, treating eczema, wrinkles, bruises, joint degeneration, including cartilage degeneration, acne, burns, or onychoschizia (split nails).
30. The use according to claim 25, wherein said inflammation is associated with osteoarthritis or rheumatoid arthritis.
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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2004
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