# Patent

## Title
Mixture of iron and copper salts masking metallic taste

## Abstract

A composition comprising iron pyrophosphate and copper citrate does not exhibit the unpleasant taste and aftertaste usually found with iron supplements.

## Background
This application is a national stage application of PCT Application No. PCT/EP2006/009434, filed on Sep. 28, 2006, which claims priority of PCT Application No. PCT/EP2007/008049, filed Sep. 15, 2007; and European Patent Application No. 07290015.2, filed Jan. 4, 2007.
The present invention relates to an oral composition without metallic taste comprising an iron source which is ferric pyrophosphate and copper citrate as copper source, its process for preparation and its use for balancing the provision of iron as nutritional supplement.
Iron is essential to most life forms and to normal human physiology. Iron is an integral part of many proteins and enzymes that maintain good health. In humans, iron is an essential component of proteins involved in oxygen transport (Dallman, P R, Biochemical basis for the manifestations of iron deficiency, Ann Rev Nutr 1986, 6, 13-40). It is also essential for the regulation of cell growth and differentiation (Andrews N C, Disorders of iron metabolism, N Eng J Med 1999, 341, 1986-95). A deficiency of iron limits oxygen delivery to cells, resulting in fatigue, poor work performance, and decreased immunity (Haa, J D, Brownlie T 4th. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship, J Nutr 2001, 131, 691S-6S,), Bhaskaram P. Immunobiology of mild micronutrient deficiencies, Br J Nutr 2001, 85, S75-80).
Several oral compositions are known for the use as nutritional or dietary supplement containing iron. Known compositions are e.g., multi-vitamin and mineral supplements or oral dosage forms containing a higher dose of iron for treating iron deficiency symptoms. However, in order to avoid a bad metallic taste the amount of iron is limited and the use of a complex and expensive taste masking technology such as coating of iron-containing granules or tablets, admixing taste masking flavours, use of capsules is necessary.
The object of the present invention is to provide an alternative oral composition containing an iron source and/or a copper source having no metallic bad taste and avoiding an expensive taste masking technology.
Surprisingly it is found that a metallic bad taste of the composition according to the present invention can be avoided.
Subject of the present invention is an oral composition comprising an iron source which is ferric pyrophosphate and copper citrate as copper source. The oral composition according to the invention has not a metallic bad taste, in particular aftertaste.
According to the present invention ferric pyrophosphate includes any kind of solvate such as hydrates. Preferably the anhydrous form, the monohydrate or the nonahydrate of ferric pyrophosphate is used. Most preferably the nonahydrate of ferric pyrophosphate is used.
According to the present invention copper citrate includes any kind of solvate such as hydrates. Preferably the hemipentahydrate of copper citrate is used.
The amount of the iron source in the composition according to the invention is from 1 to 60 mg, preferably, from 2 to 20 mg based on iron.
The amount of the copper citrate in the composition according to the invention is from 0.1 to 2 mg, preferably 0.3 to 1.1 mg based on copper.
In particular the ratio between iron and copper in the composition is from 1:2 to 50:1, preferably from 5:1 to 25:1, most from 10:1 to 20:1. “Ratio” means for the purposes of the invention the ratio by weight of the individual components based on iron and copper.
The composition according to the invention can comprise further active ingredients such as vitamins and minerals. Vitamins include, but are not limited to, vitamin A, beta carotene, vitamin C (ascorbic acid), vitamin D3 (cholecalcipherol), vitamin E (tocopherol acetate), vitamin B1 (thiamine), vitamin B2 (riboflavin), nicotinamide, vitamin B5 (panthothenic acid), vitamin B6 (pyridoxine), folic acid, vitamin B12 (cyanocobalamin), vitamin K1 and biotin. Minerals include, but are not limited to, calcium salts such as calcium carbonate, calcium phosphate, calcium glycerophosphate; magnesium salts such as magnesium phosphate, magnesium sulphate (dihydrate) or magnesium oxide; zinc salts such as zinc citrate; selenium salts such as sodium selenate; potassium iodide; manganese salts such as manganese sulphate; molybdate salts such as sodium molybdate; chromium salts such as chromium chloride; sodium chloride and potassium chloride.
Subject of the present invention is an oral composition comprising an iron source which is ferric pyrophosphate and copper citrate as copper source and optionally at least one further mineral and/or vitamin.
The composition according to the invention is administered orally one or more, preferably up to three, more preferably up to two times per day. With each administration the number of dosage forms taken in at the same time should not exceed two.
The composition according to the present invention can be used as nutritional supplement or as dietary supplement for balancing the supply of iron in a patient. A patient, for the purpose of this invention, is a mammal, including a human.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases.
The composition according to the invention comprises suitable administration forms which deliver the compound of the invention and which include, but are not limited to, tablets, tablets which disintegrate rapidly in the oral cavity (orodispersible tablets), powders, sachets, granules, pellets, chewable tablets, chewing gums, dispersible tablets, effervescent compositions such as for example effervescent tablets or effervescent granules, liquids, solutions, emulsions, gels, syrups or drops.
Preference is given to tablets, granules, orodispersible tablets, chewable tablets, chewing gums, dispersible tablets, effervescent tablets and effervescent granules. More preferably the application forms are chewable tablets, orodispersible tablets, chewing gums, dispersible tablets, effervescent tablets and effervescent granules.
Ingredients of the oral dosage forms are those which are accepted for pharmaceuticals and nutritional supplements and physiologically unobjectionable, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g. polyvinylpyrrolidone, gelatin, starch derivatives and cellulose derivatives), and all other excipients required to produce formulations of pharmaceuticals and nutritional supplements of the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g. crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose), e.g. wetting agents (e.g. sodium lauryl sulphate), e.g. release slowing agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. stabilizers, e.g. sweeteners, e.g. antioxidants, e.g. preservatives, e.g. flavourings, e.g. coloured pigments, e.g. effervescent couples preferably citric acid as acid component and sodium carbonate and/or sodium hydrogen carbonate as basic component.
Liquid formulations are likewise produced by a standard method using excipients which are usual for pharmaceuticals and nutritional supplements and contain the active ingredients either dissolved or suspended. Typical administration volumes of these pharmaceutical and nutritional supplement preparations are 1 to 10 ml. Examples of excipients in these liquid formulations are: solvents (e.g. water, alcohol, and natural and synthetic oils, e.g. medium chain-link triglycerides), solubilizers (e.g. glycerol, glycol derivatives), wetting agents (e.g. polysorbate, sodium lauryl sulphate), and further excipients required to produce formulations of pharmaceuticals and nutritional supplements of the desired properties, e.g. viscosity-increasing agents, e.g. pH-correcting agents, e.g. sweeteners and flavourings, e.g. antioxidants, e.g. stabilizers, e.g. preservatives.
Excipients for pharmaceuticals and nutritional supplements familiar to the skilled person are also described for example in the following handbook: “Handbook of Pharmaceutical Excipients,” Rowe R. C., Sheskey P. J. & Weller, P. J., American Pharmaceutical Association, Washington, 4th edition 2003.
The dosage forms mentioned herein are produced by standard processes. E.g. Tablets or chewable tablets can be produced by mixing and/or granulating the active ingredients together with the excipients to form a blend which is finally pressed to tablets. Optionally different blends containing different ingredients and excipients can be premixed and combined to a final blend which is then pressed to tablets. In the case of an effervescent formulation the acid/base couple can be add e.g. to final blend or the acid and the base are added at different times to the blend. Also the base and the acid can be added to different blends which are finally combined.
Advantage of the composition of the present invention is that for the preparation of the composition a complex and expensive taste masking technology known in the prior art such as coating of tablets or coating of granules or putting the iron component into a capsule is not needed. The composition of the present invention can be prepared by simple and well-known standard procedures. Another well-known taste masking method is the addition of flavours in order to cover and mask the bad taste. This taste masking method is normally restricted to only a few applicable flavours which have to be selected in each case. However, flavouring ingredients are not needed for taste masking in the composition of the present invention.
Subject of the present invention is an oral composition comprising an iron source which is ferric pyrophosphate and copper citrate as copper source which has no metallic taste in particular after taste and which is not a coated tablet, coated granule or capsule.
Subject of the present invention is an oral composition comprising an iron source which is ferric pyrophosphate and copper citrate as copper source and optionally at least one further mineral and/or vitamin wherein the composition has no metallic taste and is not a coated tablet, coated granule or capsule.
Preference is given to a fast disintegrating orodispersible tablet, a chewable tablet or an effervescent formulation. The disintegration time of the disintegrating orodispersible tablet is less equal than 100 sec., preferably less equal than 80 sec.


EXAMPLES
Example 1














Amount based

Amount of the



on the active

form of the


Orodispersible tablet
ingredient
Tablet weight 1000 mg
active ingredient


Active Ingredients
[mg]
Form of the active ingredient
[mg]


















vit A
400
vitamin A palmitate 100000 IU/g
13.33


vit C
30
ascorbic acid
30


Vit D3
2,5
cholecalciferol 100000 IU/g
0.8


vit E
5
tocopherol acetate 50% CWS/F
14


thiamin (B1)
1,05
thiamin nitrate 33% Rocoat
3.9


riboflavin (B2)
1,2
riboflavine 33% Rocoat
3.6


nicotinamide (PP)
13,5
nicotinamide
13.5


pantothenic acid (B5)
3
calcium pantothenate
3.26


pyridoxine (B6)
1,5
pyridoxine hydrochloride 33%
5.46




Rocoat



folic acid
150
folic acid 10% trituration
1.5


Cyanocobalamin
0,75 
dry vit B12 0,1% WS
0.75


(B12)





biotin
75
biotin 1% trituration
7.5


calcium
60
calcium carbonate DCCS90L
166.53


magnesium
25
magnesium oxide
41.45


iron
4
Ferric pyrophosphate
16.0


zinc
3,75 
Zinc citrate trihydrate
12.02


iodine
37,5 
potassium iodide 5% trituration
0.75


selenium
25
sodium selenate anhydrous 1%
2.5




trituration



copper
0,45
copper citrate 2.5 H2O
1.28


manganese
0,9 
manganese sulfate monohydrate
2.77


molybdenum
22,5 
sodium molybdate dihydrate 1%
2.25




trituration



chromium
12,5 
chromic chloride hexahydrate 1%
1.25




trituration



Pharmaburst C1


qs 1 tablet


anhydrous citric acid


16


magnesium stearate


25


sodium


20


hydrogencarbonate





pineapple flavour


3


passion fruit flavour


3


aspartame


13


iron oxide


2.5









Pharmaburst C1 is commercially available (SPI Pharma, US Drug Masterfile Number:17044; U.S. Pat. No. 7,118,765).
Example 2














Amount based

Amount of the



on the active

form of the


Orodispersible tablet
ingredient
Tablet weight 1000 mg
active ingredient


Active ingredients
[mg]
Form of the active ingredient
[mg]


















vit A
400 
vitamin A palmitate 100000 IU/g
13.33


vit C
30
ascorbic acid
30


Vit D3
2,5
cholecalciferol 100000 IU/g
0.8


vit E
5
tocopherol acetate 50% CWS/F
14


thiamin (B1)
1,05 
thiamin nitrate 33% Rocoat
3.9


riboflavin (B2)
1,2
riboflavine 33% Rocoat
3.6


nicotinamide (PP)
13,5 
nicotinamide
13.5


pantothenic acid (B5)
3
calcium pantothenate
3.26


pyridoxine (B6)
1,5 
pyridoxine hydrochloride 33%
5.46




Rocoat



folic acid
150
folic acid 10% trituration
1.5


Cyanocobalamin
0,75 
dry vit B12 0.1% WS
0.75


(B12)





biotin
75
biotin 1% trituration
7.5


calcium
60
calcium carbonate DCCS9OL
166.53


magnesium
25
magnesium oxide
41.45


iron
4
ferric pyrophosphate
16.0


zinc
3,75 
Zinc citrate trihydrate
12.02


iodine
37,5 
potassium iodide 5% trituration
0.75


selenium
25
sodium selenate anhydrous 1%
2.5




trituration



copper
0,45 
Copper citrate 2.5 H2O
1.28


manganese
0,9
manganese sulfate monohydrate
2.77


molybdenum
22,5 
sodium molybdate dihydrate 1%
2.25




trituration



chromium
12,5 
chromic chloride hexahydrate 1%
1.25




trituration



F-melt grade C


qs 1 tablet


anhydrous citric acid


16


magnesium stearate


25


sodium


20


hydrogencarbonate





pineapple flavour


3


Passion fruit flavour


3


aspartame


13


iron oxide


2.5









F-Melt grade C is commercially available (Fuji Chemical Industry Co., Ltd., Japan) and contains D-mannitol, xylitol, microcrystalline cellulose, crospovidone and dibasic calcium phosphate.
Manufacturing Process for Orodispersible Tablets
Premix:
In a drum dry vitamin D3, thiamine mononitrate, riboflavin, pyridoxine hydrochloride, folic acid, vitamin B 12, calcium pantothenate, biotin, copper citrate 2,5 H2O, manganese sulphate monohydrate, iodine, selenium, chromium, molybdenum, pineapple flavour, passion fruit flavour, iron oxide yellow, aspartame and a part of the disintegrant (e.g. Pharmaburst C1, F-Melt grade C) are mixed for 15 minutes.
Final Blend:
Premix, vitamin A palmitate, nicotinamide, dry vitamin E, ascorbic acid, calcium carbonate, magnesium oxide heavy, iron source, zinc citrate 3 H2O, anhydrous citric acid, sodium hydrogen carbonate and the rest of the pharmaburst C1 or F-melt are mixed for 20 minutes. Thereafter magnesium stearate is added and is mixed again for 5 additional minutes.
Compression:
The homogeneous final blend is compress to tablets on a rotary tablet press.
Example 3














Amount





based on

Amount of the


Effervescent tablet
the active
Tablet weight 4800 mg
form of the active


Active ingredients
ingredient
Form of the active ingredient
ingredient




















vit A as retinol
(2667.7 
IU)
vitamin A palmitate 100000 IU/g
(2266.7 
IU)



800 
μg

22.67 
mg





beta carotene as betatab 10%E
(400 
IU)






7.20 
mg


vitamin D3
(200 
IU)
Cholecalciferol concentrate (water
2.0 
mg



5 
μg
dispersible powder form) 100000







IU/g




Vitamin E
10 
mg
D-alpha-tocopherol acetate
29.80 
mg





concentrate (powder form) 50%




Vitamin K
0.03 
mg 
vitamin K1 5% SD
0.60 
mg


Vitamin B1
4.20 
mg 
Thiamin monophosphoric acid
6.59 
mg





ester chloride dehydrate




Vitamin B2
4.80 
mg 
Sodium riboflavin 5′-phosphate
6.56 
mg


Niacin
54.0 
mg 
nicotinamide
54.0 
mg


Pantothenic acid
18.0 
mg 
Calcium D-pantothenate
19.57 
mg


Vitamin B6
6.0 
mg 
Pyridoxine hydrochloride
7.3 
mg


Folic acid
0.60 
mg 
Pteroylmonoglutamic acid
0.60 
mg


Vitamin B12
3.0 
μg
Cyanocobalamin powder 0.1%
3.0 
mg





water soluble




Biotin
30 
μg
D-biotin
30 
μg


Vitamin C
180 
mg 
Ascorbic acid fine powder
180 
mg


Calcium
120 
mg
Calcium carbonate
295.61 
mg





(see calcium pantothenate)




Magnesium
80 
mg
Magnesium carbonate
163 
mg





Magnesium sulphate dihydrate
257.4 
mg


Iron
14 
mg
Ferric pyrophosphate
56 
mg


copper
0.9 
mg
Copper citrate 2.5 hydrate
2.57 
mg


iodine
0.075 
mg
Potassium iodine
0.098 
mg


zinc
8 
mg
Zinc citrate trihydrate
25.63 
mg


manganese
1.8 
mg
Manganese sulphate monohydrate
5.54 
mg


potassium
20.4 
mg
Potassium chloride
38.96 
mg


selenium
50 
μg
Sodium selenate anhydrous
0.12 
mg


chromium
0.025 
mg
Chromium chloride hexahydrate
0.128 
mg


molybdenum
0.045 
mg
Sodium molybdate dihydrate
0.113 
mg


Coenzyme Q10
3.0 
mg
Coenzyme Q10 10 %
30 
mg









Further excipients can be added to example 3:














excipients
Amount [mg]









Mannitol 100 mesh 2)
qs



Mannitol SD 200 1)
qs



Sorbitol 1)
qs



Anhydrous citric acid
1,800



Sodium hydrogen carbonate
950



Orange juice flavour
77



Sodium carbonate
65



Passion fruit flavour
30



aspartame
35



Potassium acesulfam
20



crospovidone
7



beet red juice powder
5



sucrose ester of fatty acids
0.15







qs: quantum satis = quantity to add to reach the tablet weight



1) Half of mannitol SD 200 and half of sorbitol are used to obtain the theoretical tablet weight of 4800 mg.



2) The quantity of mannitol 100 mesh is adjusted according to mineral contents in the granule.






Example 4












Effervescent tablet
Tablet weight 4400 mg



Active ingredients
Form of the active ingredient
Amount


















Vitamin A
vitamin A 100 WS
28.929 
mg


vitamin D3
Vitamin D3 100 SD/S
3.6 
mg


Vitamin E
Vitamin E 50 % CWS/S
98.34 
mg


Vitamin B6
Vitamin B6 HCl
8.701 
mg


Vitamin C
Vitamin C
207.9 
mg


Vitamin B12
Vitamin B12 0.1% WS
3.9 
mg


Folic acid
Folic acid
0.5 
mg


Zinc citrate
Zinc citrate
32.04 
mg


iron
Ferreous pyrophosphate
21 
mg


copper
Copper citrate 2.5 hydrate
2.678 
mg


Selen
Selen trituration 1%
10.5 
mg


Citric acid
Citric acid
1500 
mg


Sodium
Sodium hydrogencarbonate
1000 
mg


hydrogencarbonate





Sodium carbonate
Sodium carbonate
65 
mg


isomalt
Isomalt DC100
1208.912 
mg


aspartame
aspartame
40 
mg


acesulfame
Potassium acesulfame
20 
mg


betacaroten
Betacaroten 1% CWS
10 
mg


Red beet
Red beet
13 
mg


riboflavine
Riboflavine phosphate
10 
mg


Orange flavor
Orangeultraseal
105 
mg


tangerine
tangerine
10 
mg









Example 4 is manufactured corresponding to example 3.
Manufacturing Process for Example 3:
Vitamin Blend:
In a drum vitamin D3 100 CWS, biotin, folic acid, vitamin B12 0.1% WS, vitamin K1 5% SD, coenzyme Q10 10% CWS/S, sodium molybdate dihydrate, sodium selenate anhydrous and mannitol (a part) are mixed together to the premix 1. Into the tank of the blender the following ingredients are introduced and mixed: premix 1, vitamin A palmitate, nicotinamide, calcium pantothenate, vitamin E powder, pyridoxine hydrochloride, riboflavin sodium phosphate, thiamin monophosphoric, betatab 10% E, crospovidone, beet red juice powder and mannitol (a part).
Mineral Granule:
The following ingredients are mixed: copper citrate 2.5 H2O, zinc citrate trihydrate, iron source, manganese sulfate monohydrate, calcium carbonate, magnesium carbonate, magnesium sulfate dihydrate, sodium hydrogen carbonate, potassium chloride, anhydrous citric acid and mannitol (rest). Thereafter the mixture is granulated by spraying a binding solution made of ethanol, sucrose esters of fatty acids, potassium iodide and chromium chloride hexahydrate. The granule is dried, cooled and sieved.
Final Blend:
In the tank of the tumble mixer the mineral granule, the vitamin blend, ascorbic acid, sodium hydrogen carbonate, sorbitol, anhydrous sodium carbonate, sodium chloride, orange flavour, passion fruit flavour, potassium acesulfame, aspartame and mannitol SD 200 are mixed to the final blend.
Tabletting:
The homogeneous final blend is compressed to tablets on a rotary tablet press.
Results:
Examples 1 and 3 do not show a metallic bad taste when administered orally.
The disintegration time for example 1 (orodispersible tablets) is 67 sec.

## Claims

1. An oral nutritional supplement comprising ferric pyrophosphate and copper citrate, wherein the nutritional supplement is in the form of an effervescent composition.

2. The oral nutritional supplement of claim 1, wherein the effervescent composition is a tablet or effervescent granules.

3. The oral nutritional supplement of claim 1, comprising from about 0.1 to about 2 mg of copper.

4. The oral nutritional supplement of claim 1, comprising from about 0.3 to about 1.1 mg of copper.

5. The oral nutritional supplement of claim 1, comprising from about 1 to about 60 mg iron.

6. The oral nutritional supplement of claim 1, further comprising at least one additional ingredient selected from the group consisting of minerals and vitamins.

7. The oral nutritional supplement of claim 1, in the form of an effervescent tablet of about 4800 mg comprising the following composition of active ingredients:















Amount based 



Active
on the active



ingredients
ingredient




















vit A as retinol
(2667.7 
IU )




800 
μg



vitamin D 3
(200 
IU)




5
μg



Vitamin E
10 
mg



Vitamin K
0.03 
mg



Vitamin B1
4.20 
mg



Vitamin B2
4.80 
mg



Niacin
54.0 
mg



Pantothenic acid
18.0 
mg



Vitamin B6
6.0 
mg



Folic acid
0.60 
mg



Vitamin B12
3.0 
μg



Biotin
30 
μg



Vitamin C
180 
mg



Calcium
120 
mg



Magnesium
80 
mg



Iron
14 
mg



copper
0.9 
mg



iodine
0.075 
mg



zinc
8 
mg



manganese
1.8 
mg



potassium
20.4 
mg



selenium
50 
μg



chromium
0.025 
mg



molybdenum 
0.045 
mg



Coenzyme Q10
3.0 
mg









and at least one excipient.

8. The nutritional supplement of claim 7, wherein the active ingredients are present in the following form and amount:















Amount of the form of



Form of the active ingredient
the active ingredient




















vitamin A palmitate 100000 IU/g
(2266.7 
IU) 




22.67
mg



beta carotene as betatab 10% E
(400 
IU) 




7.20
mg



Cholecalciferol concentrate (water
2.0 
mg



dispersible powder form) 100000 IU/g





D-alpha-tocopherol acetate
29.80 
mg



concentrate (powder form) 50%





vitamin K1 5% SD
0.60 
mg



Thiamin monophosphoric acid ester
6.59 
mg



chloride dihydrate





Sodium riboflavin 5′-phosphate
6.56 
mg



nicotinamide
54.0 
mg



Calcium D-pantothenate
19.57 
mg



Pyridoxine hydrochloride
7.3 
mg



Pteroylmonoglutamic acid
0.60 
mg



Cyanocobalamin powder 0.1% water
3.0 
mg



soluble





D-biotin
30 
μg



Ascorbic acid fine powder
180 
mg



Calcium carbonate
295.61 
mg



Magnesium carbonate
163 
mg



Magnesium sulphate dihydrate
159 
mg



Ferric pyrophosphate
56 
mg



Copper citrate 2.5 hydrate
2.57 
mg



Potassium iodine
0.098 
mg



Zinc citrate trihydrate
25.63 
mg



Manganese sulphate monohydrate
5.54 
mg



Potassium chloride
38.96 
mg



Sodium selenate anhydrous
0.12 
mg



Chromium chloride hexahydrate
0.128 
mg



Sodium molybdate dihydrate
0.113 
mg



Coenzyme Q10 10%
30 
mg










and at least one excipient.