WO2008001110A2

WO2008001110A2 - Manganese, zinc and selenium compositions, preparations and uses

Info

Publication number: WO2008001110A2
Application number: PCT/GB2007/002442
Authority: WO
Inventors: Stephen Spaulding Hickok
Original assignee: Remedy Research Ltd
Current assignee: Remedy Research Ltd
Priority date: 2006-06-29
Filing date: 2007-06-29
Publication date: 2008-01-03
Anticipated expiration: 2008-12-29
Also published as: GB0612917D0; WO2008001110A3

Abstract

An ionic manganese-containing composition which comprises: (i) one or more water soluble manganese compounds able to form manganese-containing ions when dissolved in water; optionally together with: (ii) one or more water soluble zinc compounds able to form zinc-containing ions when dissolved in water, and/or optionally together with; (iii) one or more water soluble selenium containing compounds able to form selenium-containing ions when dissolved in water; (iv) one or more ammonium agents able to form ammonium ions when dissolved in water; (v) one or more acids; and (vi) water; the composition having: (vii) an acidic pH; and (viii) an electrolytic potential in excess of 50 millivolts and/or (ix) an electrolytic conductivity in excess of 50 millisiemens cm-1(mS/cm).

Description

MANGANESE, ZINC AND SELENIUM COMPOSITIONS, PREPARATIONS AND USES

Minerals, i.e. traces of certain specific metal or semi-metal elements are required as part of the human diet for good health. Mineral deficiencies can lead to poor health and specific disorders. Amongst the minerals that the body requires, there are for example, the metals manganese and zinc and the semi-metal selenium. The human body requires traces of such minerals in soluble form whereby the corresponding metallic or semi-metallic (herein collectively "metallo") ions become bio-available within the bloodstream for cellular uptake.

In addition to nutritional deficiencies in the developing world, the typical western diet may not contain sufficient amounts of these minerals alone or in combination. Accordingly mineral supplements are widely available without prescription as foodstuff supplements.

This invention is particularly concerned with manganese, zinc and selenium mineral compositions, their preparation and uses in treating selective medical indications in humans or animals. Simple mineral compounds such as inorganic mineral salts, e.g. zinc sulphate, manganese sulphate and the like will dissociate in aqueous solution to form the corresponding metallo-ions e.g. Zn²⁺ and Mn²⁺ and dissolved sulphate ions, SO₄ ^2'. However, it has been observed that such metallo-ions by themselves in solution within the bloodstream may not have an optimum bioavailability profile or effect. Mineral binder systems are known which seek to improve bio-availability of at least zinc ions. One such mineral supplement composition is based upon inorganic chelate binders, where the required mineral element, e.g. zinc, is chemically bonded to a chelate. Bio-availability of such chelated zinc still has room for improvement. The digestive system has difficulty in leaching chelated zinc away from the chelate binder for cellular uptake and retention. This still limits their bio-availability. Chelate-based zinc supplements apparently limit the body's absorption of soluble zinc.

Remaining zinc content is apparently not absorbed but passed in faeces. Iron chelated mineral supplements, in particular can cause constipation as the chelate can act as a flocculent in the large intestine. It is desirable that these disadvantages are reduced or preferably minimised by providing an alternative mineral delivery system for one or more of: manganese, zinc and/or selenium with enhanced bioavailability of the dissolved mineral metallo-ions.

Another mineral supplement is based upon a mineral salt combined with an organic gluconate binder. One product based upon the gluconate bound mineral delivery system is a lozenge containing zinc for oral ingestion. However, not only does the gluconate delivery system restrict mineral element/ion bio-availability similarly to chelated minerals described above, but zinc gluconate lozenges in particular can be unpalatable and leave undesirable coloured stains in the mouth. Accordingly it is also desirable to reduce or minimise this disadvantage by providing an alternative mineral delivery system yielding better mineral element bio-availability for ions of at least one of manganese, zinc and selenium.

The present inventor has considered existing zinc chelate and gluconate delivery systems and their disadvantages. The present invention provides inter alia, improved mineral delivery compositions based on components which appear to have the capacity to enhance and prolong (gastrointestinal) absorption of ionic zinc, manganese and selenium compositions. The present inventor provides several aspects to his invention, arising from novel mineral element - containing compositions per se, methods for preparing such compositions and therapeutic uses of such compositions which encompass their use in treating and/or preventing specific medical conditions and diseases.

Accordingly in a first aspect of this invention there is provided an ionic manganese- containing composition which comprises:

(i) one or more water soluble manganese compounds able to form manganese- containing ions when dissolved in water;

optionally together with: (a) one or more water soluble zinc compounds able to form zinc-containing ions when dissolved in water,

and/or optionally together with; (b) one or more water soluble selenium containing compounds able to form selenium-containing ions when dissolved in water;

(iv) one or more ammonium agents able to form ammonium ions when dissolved in water;

(v) one or more acids; and

(vi) water;

the composition having: (vii) an acidic pH; and (viii) an electrolytic potential in excess of 50 millivolts and/or

(ix) an electrolytic conductivity in excess of 50 millisiemens cm^"1(mS/cm)

In a second aspect of this invention there is provided a zinc containing composition, which comprises:

(a) as defined above according to the first aspect, together with (b) as defined above according to the first aspect and/or one or more water soluble manganese compounds able to form manganese-containing ions where dissolved in water; and

(iv) ,(v) and (vi) all as defined above according to the first aspect;

the composition having (vii) an acidic pH and (viii) an electrolytic potential of at least 50 millivolts; and/or (ix) an electrolytic conductivity in excess of 50 mS/cm.

In a third aspect of this invention there is provided a selenium containing composition which comprises (b) as defined above according to the first aspect together with (a) as defined above according to the first aspect and/or one or more water soluble manganese compounds able to form manganese-containing ions when dissolved in water and (iv), (v) and (vi) all as defined above according to the first aspect, the composition having (vii) an acidic pH and (viii) an electrolytic potential of at least 50 millivolts and/or (ix) an electrolytic conductivity in excess of 50 mS/cm.

Such compositions preferably essentially consist of the specified components with any optional but preferred additives (if required) and more preferably consist of such specified components optional additives and the balance (if any) being any inevitable impurities.

In a second aspect of this invention there is provided a method of making a composition as defined in the first aspect comprising dissolving (i) (with (a) and/or (b) if required) in pure distilled water (vi), adding agent(s) (iv) and mixing or allowing to dissolve, then adding acid(s) (v) whilst simultaneously monitoring the pH and electrolytic potential and/or conductivity of the composition until a required value of each measurement is obtained.

A third aspect of this invention provides an antimicrobial and/or antiviral, and/or antiinflammatory formulation as defined herein. The present compositions can have useful benefits in medicine, for example the compositions can be for use in enhancing immune system function, in the treatment or prevention of inflammation and as an antioxidant in the scavenging of potentially harmful free radicals circulating within the bloodstream.

Compositions as defined in the first, second and third aspects may be useful in the preparation of a medicament for use in the prevention and/or treatment of immune disorders and/or inflammation. Manganese compositions alone or with either or both of zinc and selenium mineral components can be useful as immunomodulators such as immunostimulants and immunoboosters, pre-vaccination response enhancers, immunoenhancers and immunoactivators. Similarly the zinc composition with or without either or both of selenium and manganese components, or the selenium compositions alone may show the same activity and practical medical applications. IfTaTOϋrth^" aspect the ^"present invention provides^" the use of a composition as defined in the first, second or third aspects as an immunomodulatory and/or anti inflammatory preparation and/or anti-oxidant preparation.

The ammonium agent acts as an ammonium ion donor into the aqueous compositions and may assist transport of metallo-ions containing the required ionic mineral through the digestive (or mucous membrane) system into the bloodstream. It is preferred to use ammonium agents which are water-soluble inorganic ammonium compounds such as for example ammonium hydroxide aqueous solution or one or more of the following ammonium salts: e.g. one or more of ammonium chloride, sulphate, phosphate, nitrate, citrate or tartrate.

Such ammonium agents appear to assist effectiveness of the aqueous mineral compositions of (or containing) manganese, zinc and/or selenium, which compositions preferably demonstrate beneficial high levels of electrolytic potential and/or conductivity in the prepared aqueous compositions containing dissolved metallo-ions. The aqueous compositions formed appear to behave as acidic aqueous electrolytic solutions with preferably high electrolyte potential and/or conductivity.

An improved metallic (or semi-metallic) mineral delivery system in the form of aqueous compositions for ingestion can surprisingly be formulated from a selection of but a few highly specific metals and/or semi-metals, and even more specific metallo- ionic combinations thereof (in acidic aqueous media), which compositions demonstrate significant maintained electrolytic potential and/or conductivity which properties can be stable for a surprisingly long period of time - months or even years. Such compositions have surprisingly been found, inter alia, when ingested from oral dosage form or absorbed through e.g. the buccal or sublingual mucosa to make the beneficial mineral ions bio-available with apparently enhanced cellular retention but without significant adverse affect upon surrounding human tissue. The metailo-ions (in aqueous solution) which are or which comprise the metallic mineral element appear to be more effective in treatments than comparable mineral compositions in which ammonium agents are excluded. Accordingly, within the present compositions, the metallic and/or semi-metallic element effects (depending which of the three mineral species are present) of manganese, with or without zinc and/or selenium, appear to be synergistically improved by the presence of at least one ammonium agent. In particular this appears to be the case with manganese-only, zinc-only and selenium-only metal or semi-metal compositions, as well as acidic aqueous electrolytic solutions that contain combinations of at least two of manganese, zinc and selenium.

In preferred embodiments of the invention, the compositions are derived from manganese with or without zinc and selenium, or are derived from selenium with at least one of zinc and manganese or are derived from zinc with at least one of manganese and selenium. These compositions can act if required through the buccal/sublingual mucosa, i.e. mucous membrane, for rapid absorption into the bloodstream.

Accordingly such compositions in the form of acidic aqueous (optionally mixed) metallo-ion electrolyte solutions for medical uses can provide for rapid mineral element ion delivery to the body for cellular uptake, with less wastage of the desirable mineral(s). In the case of preferred compositions which contain at least one of manganese, zinc and selenium as the mineral element, it is possible to reduce the disadvantages of chelated zinc gluconate mentioned above, whilst simultaneously providing soluble and effective manganese, zinc and/or selenium, in an improved ionic form.

The present compositions for human (or animal) medical use are based upon the presence of water soluble manganese, zinc and/or selenium compound(s) such as a readily available salt thereof in aqueous acidic solution, which further contains components [as defined in the above aspects] and appearing in the US Pharmacopoeia designated GRAS (generally regarded as safe) food additives or other chemicals by the US-FDA regulatory authority.

In order to make the present compositions for human (or animal) medical uses, it is preferred for the following general preparative procedure to be adopted:

General Procedure

(a) The required metal and/or semi-metal such as a mineral element or elements, e.g. zinc, manganese and/or selenium is included as a water soluble mineral salt such as zinc sulphate or semi-metal compound. This is to be completely dissolved in pure distilled water (in contrast to deionised water) preferably 1 litre by mixing the salt into the.water at ordinary room temperature, e.g. about 20⁰C by vigorous stirring. The corresponding metallic mineral ions (metallo- ions) thereby form in the aqueous solution.

(b) When all the metallic salt and/or semi metal compound has been completely dissolved in the distilled water, at least one ammonium agent is added such as ammonium hydroxide or one or more soluble ammonium salts is added for example one or more of: ammonium sulphate, ammonium chloride, ammonium citrate, and ammonium phosphate, which is mixed into the solution obtained in step (a) to dissolve therein.

(c) To the aqueous mixture, obtained after step (b), at least one acid component, (e.g. sulphuric and/or citric acid and/or hydrochloric acid) is added carefully and slowly, preferably by measured metering, to create an acidic pH and then further lower the pH of the mixture to a preferred level preferably below 2 and to simultaneously exhibit a measurable electrolytic potential and/or conductivity until a preferred level thereof is also reached. The value of electrolytic potential is conveniently measured and monitored throughout this stage by milli-voltmeter. Several commercially available instantaneous readout pH meters can function as a milli-voltmeter by simple adjustment. Sufficient acid should be added to control the values of pH and electrolytic potential and/or electrolytic conductivity. This process for completing preparation of the aqueous metal- and/or semi-metal containing ionic compositions can be likened to a form of electrometric titration. Commercially available conductivity meters can be utilised to measure, monitor and control the obtained valves of conductivity.

The inventor has observed in several preferred embodiments, in stage (c) in the general procedure the addition of one or more acids, preferably one or more acids designated 'GRAS' generally regarded as safe by the US-FDA as noted above, an exothermic reaction can be observed which may simply represent the heat of diluting strong acids. In order that the invention in all its aspects may be further elucidated a plurality of non-limiting examples are now presented in tabular form for a more complete appreciation of the invention, and to enable preferred embodiments of the invention to be reduced to practice by one of ordinary skill in the art. The preparative procedure in each example corresponds to the general procedure already outlined above, using 1 litre of distilled water, or 86OmIs in the case of example 2.

The formulations can be administered orally, e.g. in the range of about 1 to 100, preferably 1 to 50, more preferably 1 to 30, such as 1 drop to 15 drops, dissolved in more water or aqueous beverage other than milk, once, twice or three times daily, depending upon the severity of the condition.

It will be appreciated that the most preferred embodiments are those wherein there is an ionic consistency amongst the selected components. Hence where the mineral compound present is a sulphate, then the ammonium agent is preferably also a sulphate and the acid preferably is sulphuric. Ammonium hydroxide may also work well in view of the presence of hydroxyl ions in the water.

Similarly where the mineral compound is a chloride, the ammonium agent is preferably also ammonium chloride and the acid is preferably hydrochloric. Where the ammonium agent is a phosphate, it is preferred to use phosphoric acid as the acid, whatever mineral salt is used as the source of metallic ions.

Reference is now made to the accompanying Table 1.

NB variable denotes amount adjusted to obtain required specific pH, mV, and mScrrV¹ values, low pH with high mV and mScrrϊ¹ and being preferred.

From these examples it will be appreciated that the compositions may include one or more other additional components, besides the metal compound such as a preferred mineral compound, ammonium agent, acid and water.

Zinc mineral compositions may optionally contain one or more of the following or other stimulants: caffeine, nicotine and ginseng.

Additional medical benefits have surprisingly been found above and beyond benefits that would typically be ascribed to mineral replacement regimes. The present compositions have application as immunostimulants, immunoboosters, immunomodulators, anti-oxidants and/or pre-vaccination enhancers. Manganese- containing compositions in particular appear to have application as anti-inflammatory agents, although anti-inflammatory effects may be observed in the zinc and/or selenium compositions in the presence or absence of a manganese component.

The present compositions may be formulated as aqueous solutions and presented for use and/or sale within dropper bottles for convenient dilution in more water or other aqueous beverages other than milk for oral ingestion. Alternatively the compositions can be applied directly to the buccal and/or sublingual mucosa for even more rapid ionic mineral absorption into the bloodstream.

Alternatively the composition may be formulated as capsules containing a unit dose.

The present compositions may alternatively or additionally function as effective antiviral agents. In particular the present compositions may be useful in preventing and/or treating for example humans or animals affected by or likely to encounter: common cold, SARS, West Nile virus, Influenza, Influenza, (e.g. H5W, H5N1 , H7N2, H7N7) Papillomavins, Herpes simplex, Cytomegalovirus MCMV and human CMV, respiratory syncytial virus, Parainfluenza, human meta pneumovirus, measles, yellow fever, western equine encephalitis, Venezuelan equine encephalitis, HIV.

Additionally the zinc, selenium or copper formulations specifically set out in the example of our US Patent 7,060,302 may be useful as antiviral formulations in the treatment and/or prevention of the specifically identified virus diseases set out above.

Amongst the known antiviral pharmaceutical preparations, there are anti-influenza inhibitors oseltamivir, ramantidine and ribavirin. There are also known anti-HIV and anti-Herpes drugs. The compositions provided herein or the aforementioned compositions exemplified in our US Patent 7,060,302 may be used in conjunction with these known antiviral preparations or the known anti-HIV and anti-Herpes drugs so as to limit the dose thereof. This may especially be the case for the presently disclosed zinc-based compositions.

Preferred embodiments of antiviral compositions are based on a combination of metal-ion components. For example, in treating and/or preventing viruses of the type specified above, it can be preferred to incorporate into the composition the zinc component with either the selenium or manganese components or both, or to incorporate the manganese component with either the selenium or zinc component or both, or to incorporate the selenium component with either the manganese component or the zinc component or both.

Compositions comprising a combination of two (or more) different metallo-ion components are referred to herein as 'combination' compositions. Other preferred compositions for use as antiviral agents within the scope of the invention are based on a combination of active agents for example - a 'combination' composition as herein defined in admixture with at least one known other antiviral preparation such as one or more of: osteltamivir, ramantidine and ribavirin..

Such combination therapies against the selected viruses may lead to enhancement of activity of at least one active component, may allow the use of lower dosages and potentially lessen the development of drug-resistant viruses.

Claims

1. An ionic manganese-containing composition which comprises:

(i) one or more water soluble manganese compounds able to form manganese-containing ions when dissolved in water;

optionally together with:

(ii) one or more water soluble zinc compounds able to form zinc- containing ions when dissolved in water,

and/or optionally together with;

(iii) one or more water soluble selenium containing compounds able to form selenium-containing ions when dissolved in water;

(v) one or more acids; and

(vi) water;

the composition having: (vii) an acidic pH; and (viii) an electrolytic potential in excess of 50 millivolts and/or (ix) an electrolytic conductivity in excess of 50 millisiemens cm^"1(mS/cm)

2. An ionic mineral element-containing aqueous composition for use in modulation and/or stimulation of the immune system, which comprises a composition as claimed in Claim 1.

3. A zinc-containing composition which comprises: (ii) as defined in Claim 1 ; together with (iii) as defined in Claim 1, and/or (i) as defined in Claim 1, together with (iv), (v) and (vi) as defined in Claim 1 , the composition having the properties (vii), (viii) and/or (ix) all as defined in Claim 1.

4. A selenium-containing composition which comprises (iii) as defined in claim 1 together with (i) as defined in Claim 1 and/or (ii) as defined in Claim 1 , together with (iv), (v) and (vi) as defined in Claim 1 , the composition having the properties (vii), (viii) and/or (ix) as defined in Claim 1.

5. A composition as claimed in any one of Claims 2 to 4 for use in modulation or stimulation of the immune system.

6. An immunomodulator or immunostimulant ionic mineral element-containing aqueous composition which comprises (i) to (iv) inclusive as defined in Claim 1 , the composition having an acidic pH no higher than 2.5, an electrolytic potential of at least 100 mV and an electrolytic conductivity in excess of 50 mS/cm^"1.

7. An ionic mineral element-containing aqueous composition for use as an antiinflammatory which comprises (i) to (iv) inclusive as defined in Claim 1 , the composition having an acidic pH no higher than 2.5, an electrolytic potential of at least 100 mV and an electrolytic conductivity in excess of 50 mS/cm^'1.

8. An ionic mineral element-containing aqueous composition for use as an antioxidant which comprises at least one of (i), (ii) and (Hi) as defined in Claim 1 together with (iv), (v) and (vi) as defined in Claim 1 , the composition having an acidic pH no higher than 2.5, an electrolytic potential of at least 100 mV and an electrolytic conductivity in excess of 50 mS/cm^"1.

9. A composition as claimed in any preceding Claim, which further comprises one or more other optional additives which are known immunomodulators and/or antioxidants and/or anti inflammatory agents.

10. A composition as claimed in any preceding Claim wherein (i), (ii) and (iii) are present and respectively comprise inorganic salt of: manganese, zinc and selenium.

11. A composition as claimed in Claim 10, in which said salts comprise at least one of sulphate, chloride, nitrate, citrate, tartrate and/or phosphate.

12. A composition as claimed in Claim 8 in which (i) comprises zinc sulphate, (ii) comprises manganese sulphate, and/or (iii) comprises selenite, selenate, selenic, selenous or selenious acid.

13. A composition as claimed in any preceding Claim, wherein the ammonium agent comprises at least one water soluble inorganic ammonium compound capable of dissociating in water into ammonium ions, said agent preferably selected from the group consisting of ammonium sulphate, ammonium chloride, ammonium phosphate, ammonium citrate, ammonium nitrate and ammonium hydroxide.

14. A composition as claimed in Claim 13, wherein the soluble ammonium agent comprises an inorganic salt such as ammonium sulphate, chloride or phosphate.

15. A composition as claimed in any preceding Claim in which the at least one acid (iii) comprises one or more of sulphuric, hydrochloric, phosphoric, citric, tartaric and nitric acids.

16. A composition as claimed in Claim 15, wherein the at least one acid (iii) is concentrated sulphuric acid or hydrochloric acid or phosphoric acid.

17. A composition as claimed in any preceding Claim in which the water (iv) consists of distilled water.

18. A composition as claimed in any preceding Claim whose pH is less than 5, more preferably less than 4, even more preferably less than 2.5, still preferably less than 2, most preferably less than 1.

19. A composition as claimed in Claim 18, whose pH is in the range of 0 to 2, preferably 0 to 1.

20. A composition as claimed in any preceding Claim, whose electrolytic potential is in excess of 100, preferably in excess of 150, more preferably in excess of 200, even more preferably in excess of 250, most preferably in excess of 300 millivolts.

21. A composition as claimed in Claim 20, whose electrolytic potential is in the range of 310 to 500 millivolts.

22. A composition as claimed in any preceding Claim, whose electrolytic conductivity is in excess of 50 millisiemens/cm, preferably in excess of 100 millisiemens/cm, more preferably in excess of 150 millisiemens/cm, even more preferably in excess of 200 millisiemens/cm yet more preferably in excess of 250 millisiemens/cm.

23. A method of making a composition as claimed in any preceding Claim comprising dissolving (i) as defined in Claim 1 and/or in distilled water, adding if required (ii) as defined in Claim 1 and mixing or allowing to dissolve, then adding if required (iii) as defined in Claim 1 then sequentially adding (iv), (v) and (vi) all as defined in Claim 1 , whilst simultaneously monitoring the pH, electrolytic potential and/or conductivity of the composition until discontinuing the addition of acid when required values of pH, electrolytic potential and/or conductivity are obtained optionally followed by delivering the resultant composition into containers adapted for subsequent use.

24. A method as claimed in Claim 23 in which (i) is present and is as defined in any one of Claims 8 to 10.

25. A method as claimed in Claim 20 to 21 in which (ii) is present and is as defined in Claim 11 or 12.

26. A method as claimed in any one of Claims 20 to 22, wherein (iii) is present and is as defined in Claim 13 or 14.

27. An immunostimulant or immunomodulator formulation comprising a composition as claimed in any one of Claims 1 to 22 together with a pharmaceutically acceptable carrier, diluent or excipient.

28. An ionically modified mineral composition as claimed in any one of Claims 1 to 22 substantially as herein exemplified in any example.

29. A method as claimed in any one of Claims 22 to 26 substantially as herein exemplified in any example.