EP2723353A1

EP2723353A1 - Activated carbon comprising an adsorbed iodide salt for use in the reduction of gastrointestinal uptake of mercury

Info

Publication number: EP2723353A1
Application number: EP12802948.5A
Authority: EP
Inventors: Staffan Skogvall
Original assignee: Pharmalundensis AB
Current assignee: Pharmalundensis AB
Priority date: 2011-06-21
Filing date: 2012-06-14
Publication date: 2014-04-30
Also published as: EP2723353A4; WO2012177210A1

Abstract

The invention provides activated carbon comprising an adsorbed iodide salt selected from the group of alkali metal iodides and earth alkali iodides, for use in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings or other sources of mercury. Furthermore, the invention provides pharmaceutical composition containing such activated carbon as well as methods of using such activated carbon for reducing gastrointestinal uptake of mercury.

Description

ACTIVATED CARBON COMPRISING AN ADSORBED IODIDE SALT FOR USE IN THE REDUCTION OF GASTROINTESTINAL UPTAKE OF MERCURY

FIELD OF THE INVENTION

The invention relates to reduction of gastrointestinal uptake of mercury

5 released from amalgam dental fillings. More specifically, the invention relates to activated carbon comprising an adsorbed iodide salt for use in a method for reducing gastrointestinal uptake of mercury. Furthermore, the invention provides pharmaceutical composition containing such activated carbon as well as methods of using such activated carbon for reducing gastrointestinal 10 uptake of mercury.

BACKGROUND OF THE INVENTION

Silver amalgam has been used for almost 200 years in dentistry (Lorscheider 15 F L et al., Mercury exposure from"silver" tooth fillings: emerging evidence

questions a traditional dental paradigm. FASEB J 1995:9(7):504-8). Silver amalgam contains approximately 50 % metallic mercury. It is today generally accepted that small amounts of mercury vapor are continuously released from the amalgam into buccal air, which is inhaled. The mercury is absorbed by the 20 lungs and then distributed in the body by the circulation.

Dental amalgam has been found to be a major contributing source to Hg body burden in humans. Mercury is thought to negatively affect the central nervous system, the reproductive system, the renal system, and the immune system.

25 In an evaluation of the safety of dental amalgam published in J Occup Med Toxicol 21 1 13:6(1 ):2 the Scientific Committee of the European Commission considered dental amalgam to be the main source of human total body burden of mercury, the evaluation relying on autopsy studies showing that many individuals with amalgam have toxic levels of mercury in their brains or

30 kidneys. The half-life of mercury in the brain was considered to extend from several years to several decades, thus allowing mercury to accumulate to toxic levels. It is also believed that mercury vapor is about ten times more toxic to human neurons than lead.

It has also been stated that fish, tobacco and other sources, in addition to dental amalgam, could constitute important sources of mercury. However, irrespective of whether the mercury originates from amalgam fillings or from any other source, it is for obvious reasons important to minimize the total body burden of mercury. It was previously thought that renal excretion is the dominant way for mercury removal from the body. As stated by Lorscheider et al., supra, this view does not longer hold. At present the dominating path of mercury excretion is considered to be fecal, 90-95 % being excreted by this route mainly in the bile. The thus excreted mercury is however reabsorbed to a large degree further down in the intestinal tract. Thereby the total amount of mercury leaving the body is substantially reduced (Clarkson T W, The toxicology of mercury. Crit Rev Clin Lab Sci 34:369-403, 1997). This phenomenon is called entero-hepatic circulation. In view of the accumulating evidence that amalgam filling can negatively affect human health, many methods have been developed to reduce the burden of amalgam mercury on the human body. The most straightforward of them is removal of amalgam fillings, which are replaced by polymeric and ceramic alternatives. There are however many problems connected with this method, including technical problems, financial cost and pain during the replacement process.

Other ways to cope with a dental amalgam burden is by use of a means for blocking release of mercury from amalgam. Brushing teeth with amalgam fillings with a toothpaste disclosed in U.S. Patent No. 5, 178,541 provides a mercury sulfide protective layer on the amalgam surface and thereby reduces the release of mercury from the surfaces. U.S. Patent No. 4,859,453 discloses a toothpaste composition comprising selenium iodide. U.S. Patent No. 4,534,944 discloses a composition for suppressing the formation of mercury vapor comprising a carrier liquid and a copper ion source, such as copper sulphate or thiosulphate. U.S. Patent No. 4,876,025 discloses a composition for absorption of mercury comprising an iodide, a polyhydric alcohol and, optionally, a Lewis acid.

WO2009067067 A1 and WO2009078782 A1 describe methods for producing bronchorelaxation in a human or an animal affected by airway obstruction comprising administration of a pharmacologically effective amount of elemental iodine on activated charcoal (iodinated activated charcoal) to the intestine of said human or animal. A pharmaceutical composition comprising elemental iodine on activated charcoal and uses thereof is also disclosed. Accordingly, there is also a need for improving existing methods and finding alternative methods for reducing mercury uptake.

OBJECTS OF THE INVENTION An object of the present invention is to provide a method and a means of the aforementioned kind, which is efficient, easy to apply, and acceptable to most persons.

In particular, an object of the present invention is to provide such a method and means by which the load of mercury on the body of a person having dental amalgam fillings can be controlled so as to not increase over time and even decrease over time.

Further objects of the present invention will become obvious from the following summary of the invention, detailed description and preferred embodiments thereof, and the appended claims. SUMMARY OF THE INVENTION

In a first embodiment, the invention provides activated carbon comprising an adsorbed iodide salt selected from the group of alkali metal iodides and earth alkali iodides, for use in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings.

As disclosed herein, the term "activated carbon" also includes "activated charcoal".

Typical examples of such iodides that could be used in the present invention are Nal, Kl, Mgl₂, and Cal₂. Preferably, potassium iodide, Kl, is included as adsorbed such iodide. Preferably, the amount of adsorbed iodide salt is within the range of 0.25 - 10 % (wt.), and preferably within the range of 0.5 - 5 % (wt.).

Preferably, the activated carbon also comprises an adsorbed

pharmaceutically acceptable bromide salt, such as sodium bromide, potassium bromide, magnesium bromide, lithium bromide, ammonium bromide and/or calcium bromide. The amount of bromide salt may be within the range of 1 - 1000 % (wt.) calculated on the weight of the adsorbed iodide salt. In a second embodiment, the present invention provides use of activated carbon comprising an adsorbed iodide salt according to the first embodiment, in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings. In a third embodiment, the present invention provides a pharmaceutical composition comprising activated carbon comprising an adsorbed iodide salt according to the first embodiment, together with a pharmaceutically acceptable excipient. The selection of excipient is not critical and most commonly used pharmaceutically acceptable excipients could be included in the pharmaceutical composition according to the present invention.

Preferably, the pharmaceutical composition is selected from the group of an aqueous suspension, a capsule, a powder for preparing an oral suspension, or a tablet. For instance, when the activated carbon comprising adsorbed iodide salt is administrated in the form of a tablet or capsule, said activated carbon comprising adsorbed iodide salt can be combined with an oral, nontoxic pharmaceutical acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

It is preferred that the pharmaceutical composition also comprises a bile excretion stimulating agent. Typically, said bile secretion stimulating agent is fat.

In a fourth embodiment, the present invention provides use of a

pharmaceutical composition according to the third embodiment, in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the hypothesis that the intestinal mercury excretion/re-absorption steady state should be interfered with in a manner accomplishing irreversible excretion by the feces of mercury excreted into the intestinal lumen by the bile. The present invention is furthermore based on the insight that activated carbon loaded with an alkali metal or earth alkali metal iodide is capable of absorbing mercury from the gastrointestinal tract and of being excreted in a state loaded with mercury with the feces.

Accordingly, if an effective mercury binding amount of activated carbon comprising an adsorbed iodide salt selected from the group of alkali metal iodides and earth alkali iodides is administrated orally to a person in need of having its mercury load reduced, that person would excrete the iodinated charcoal with the feces.

The person to be decontaminated of mercury in the body should preferably adhere to a normal diet, so as to promote excretion of mercury by the feces. The activated carbon loaded with an alkali metal or earth alkali metal iodide should preferably be administered in the interval between two meals, such as one or two or three or more hours after a meal and one or two or three or more hours prior to the next meal. A preferred form of administration comprises per-oral ingestion of an aqueous suspension of particulate activated carbon loaded with an alkali metal or earth alkali metal iodide. The aqueous media can be water but also mineral water, fruit juice or a soft drink.

Instead of an aqueous suspension particulate activated charcoal loaded with alkali metal or earth alkali metal iodide can be administered filled in soft or hard gelatin capsules, vegetable or pullulan capsules, or in form of a tablet formed from particulate activated charcoal loaded with alkali metal or earth alkali metal iodide and a suitable pharmaceutically acceptable binder. The binder should be of a kind allowing the tablet to disintegrate in gastrointestinal fluid. Suitable binders comprise chemically modified cellulose such as carboxymethyl cellulose and polyvinylpyrrolidone. Because of the fragile nature of the carbon only slight compression should be used when forming the tablets so as not to crush the carbon particles. A decontamination scheme for substantially lowering the body load of mercury in a person comprises administration of a pharmacologically effective amount of activated charcoal loaded with an alkali metal or earth alkali metal iodide over an extended period of time, such as one or several months and even one or several years. If the person to be decontaminated has amalgam dental fillings administration is indicated at least until removal of the fillings but preferably substantially longer, such as one year or longer.

Preferably administration of the pharmacologically effective amount of activated carbon loaded with an alkali metal or earth alkali metal iodide is daily and even twice or trice daily but can also be intermittent, such as every second or third day or once or several times per week.

DESCRIPTION OF EXPERIMENTAL WORK

EXAMPLE 1 . Preparation of activated carbon samples loaded with alkali metal iodide or earth alkali metal iodide

Materials.

Activated carbon (Sigma C7606), Potassium iodide (Sigma P7744), de- ionized water.

Equipment.

Magnetic stirrer IKA RTC basic, oil bath, reflux condenser, balance XP-300 Denver Instruments, Pyrex glass flask 2 L, polymer-enclosed magnetic bar, vacuum filter flask 2 L, OOH filter paper (Whatman), laboratory drying oven TS80000, Termaks.

Method.

8.0 g Kl is dissolved in 1 L of water. Activated carbon (92 g) is added. The suspension is stirred for 12 hours at room temperature (21 -23 °C). The activated carbon product is separated from the Kl solution by filtration under reduced pressure and dried for 12 h in 75° C. This resulted in a sample consisting activated carbon impregnated with ~1 .6 % Kl.

EXAMPLE 2. Analysis of mercury uptake in activated carbon samples impregnated with Kl

Materials.

Kl-impregnated carbon sample. Trizma, Sigma T1503-100G. Sodium chloride: Sigma, S988-500G. Potassium chloride: Fluka 60130-1000G.

Deionized water. Hydrochloric acid: Sigma 84422-1 L. Mercury (II) chloride 99.5 % min., Alfa Aesar. Nitric acid: Sigma 30702, min. 69 %, puriss.

Equipment.

Water bath with stirrer and thermostat RCT B, IKA, Germany. Magnetic stirring bar. Volumetric glass flask, 100 ml. Glass funnel, 70 mm diameter. Automatic pipette, 1000 μΙ_. Volumetric glass flask, 500 ml. Round bottom glass flask, 1000 ml, with stopper. Safety pipette, 25 ml. Filter paper 00H grade, diameter 150 mm, Whatman. Preparation of saline solution.

A buffer solution is prepared, containing 0.01 M Trizma, 140 mM NaCI and 4 mM KCI, and adjusted to pH 7.4 with HCI. The buffer solution is capped, preheated and kept at 37 ^°C. Preparation of mercury (II) Chloride stock solution (approx. 10^~3 M)

About 0.027 g HgC is weighed on an analytical balance. The exact weight is noted. The HgC is transferred to the 100 ml volumetric flask and diluted with de-ionized water until it has a concentration of 10^"3 M. Preparation of test solution with mercury (II) chloride ( 10^~5 M)

5 ml of HgC stock solution is added to the 500 ml measuring flask using the automatic pipette. Preheated 37 ^°C buffer solution is the added up to the 500 ml mark. The test solution is transferred to the 1000 ml round bottom flask. The flask is closed with a stopper and placed in the water bath at 37 ^°C.

Binding of mercury from the test solution to activated carbon loaded with Kl 50 mg of the activated carbon loaded with Kl is added to the test solution containing 10^"5 M mercury (II) chloride, and absorption of mercury in the impregnated carbon is allowed to proceed for 30 min while stirring at 300 rpm. When the absorption is complete, a 20 ml sample is withdrawn with the safety pipette and filtered. The sample is added to an amber bottle containing 2 % HNO₃ and analyzed.

Analysis

The sample is analyzed by atomic fluorescence spectrometry. The analytical result of mercury (Hg) is reported in mg/L units.

Results

In this model activated carbon impregnated with 1 .6 % by weight of Kl was found to bind 97 % of available HgC . EXAMPLE 3. Further analysis of mercury uptake in activated carbon comprising adsorbed potassium iodide

The experiment of Example 2 was repeated but the amount of potassium iodide adsorbed on the activated carbon was varied. Similar to example 2, mercury was present as HgC dissolved in de-ionized water. The amount of remaining dissolved mercury was determined by atomic fluorescence spectrometry in the same way as in Example 2. The results obtained are provided below. Kl in Adsorbed Kl in Remaining Remaining impregnation activated carbon amount of amount of solution (%) (% (wt.)) mercury in mercury in solution solution

(mg/l) (% (wt.))

No activated 2.0 100 carbon

Activated 0 0.66 33 carbon without

adsorbed Kl

0.5 0.27 0.49 24

1 .0 0.55 0.34 17

3.0 1 .09 0.14 7

8.0 1 .62 0.047 2

Kl in Adsorbed I2 in Remaining Remaining impregnation activated carbon amount of amount of solution (%) (% (wt.) mercury in mercury in solution solution

(mg/l) (% (wt.))

No activated 20 100 carbon

Activated 8 40 carbon without

adsorbed I2

1 1 7.8 39

3 3 5.3 26

8 8 0.78 2 As is evident from the above experiments, impregnation of carbon with Kl strongly increases the mercury binding capacity by more than ten-fold

(remaining amount of mercury in solution with non-impregnated active carbon 33 %, compared to 2 % when using carbon impregnated with 8 % Kl).

Surprisingly, it has been found that only a small portion of the Kl in the impregnation solution actually binds to the activated carbon. Thus, only 1 ,62 % Kl actually binds to the carbon when exposed to an impregnation solution with 8 % Kl. Nevertheless, this small amount of Kl makes the impregnated carbon as effective in binding mercury as activated carbon impregnated with 8 % l₂. Since iodine can be harmful in high concentrations, this may by a substantial advantage compared to l₂-impregnated carbon when using impregnated carbons for pharmaceutical purposes. EXAMPLE 4. Mercury absorption by activated carbon loaded with 1.6 % of potassium iodide in humans

Three adult persons with an average of 8 amalgam fillings were tested by letting them drink a suspension comprising 2 g of activated carbon loaded with 1 .6 % potassium iodide in 100 ml water once daily for a week. The feces excreted over a day were collected and homogenized. Weighed samples were taken from the homogenized feces. The total amount of mercury in the feces excreted over a day was determined by use of ICPMS. Prior to the start of administration the persons excreted an average of 24 micrograms Hg/day. On the seventh day of treatment with activated carbon loaded with 1 .6 % potassium iodide, the persons excreted an average of 65 micrograms/day. Administration of Kl-impregnated activated charcoal of the invention thus increased the mercury content of the feces by more than 100 %.

Claims

1 . Activated carbon comprising an adsorbed iodide salt selected from the group of alkali metal iodides and earth alkali iodides, for use in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings or other sources of mercury.

2. Activated carbon according to claim 1 , characterized in that the amount of adsorbed iodide salt is within the range of 0.25 - 10 % (wt.), and preferably within the range of 0.5 - 5 % (wt.).

3. Activated carbon according to any of claims 1 and 2, characterized in that the adsorbed iodide is potassium iodide.

4. Activated carbon according to any of claims 1 - 3, characterized in that the activated carbon also comprises a pharmaceutically acceptable bromide salt, such as sodium bromide, potassium bromide, lithium bromide, ammonium bromide and/or calcium bromide.

5. Use of activated carbon comprising an adsorbed iodide salt according to any of claims 1 - 4, in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings.

6. A pharmaceutical composition comprising activated carbon comprising an adsorbed iodide salt according to any of claims 1 - 4, together with a pharmaceutically acceptable excipient.

7. A pharmaceutical composition according to claim 6, which is selected from the group of an aqueous suspension, a capsule, a powder for preparing an oral suspension, or a tablet.

8. A pharmaceutical composition according to any of claim 6 or claim 7, characterized in that it also comprises a bile excretion stimulating agent.

9. A pharmaceutical composition according to claim 8, characterized in that the bile secretion stimulating agent is fat.

10. Use of a pharmaceutical composition according to any of claims 6 - 9, in a method for reducing gastrointestinal uptake of mercury released from amalgam dental fillings.