WO2014177876A1

WO2014177876A1 - Calcium supplement

Info

Publication number: WO2014177876A1
Application number: PCT/GB2014/051356
Authority: WO
Inventors: Malcolm Geoffrey Green
Original assignee: Calinnova Ltd
Priority date: 2013-05-03
Filing date: 2014-05-01
Publication date: 2014-11-06
Also published as: EP2996495A1; GB201308011D0; AU2014261225A1

Abstract

A calcium supplement is described. The calcium supplement comprises and organic calcium salt and is usable in the treatment of calcium dysregulation.

Description

CALCIUM SUPPLEMENT

This invention relates to calcium supplementation. More particularly, the present invention relates to calcium supplementation with a co-ordinated calcium salt in the calcium supplement.

Supplementation of the diet with calcium salts is a well known practice both in humans and especially in animal husbandry where the provision of a so-called salt-lick has been common practice for a great many years, particularly for large grazing animals such as cattle and horses.

More recently, salts have been added to commercial animal feeds in an attempt to regulate and/or to improve the dietary intake of the animal being fed. In general, the calcium salts added to animal feed include calcium carbonate, for example as limestone flour, and calcium phosphate: the salts currently used are generally inorganic salts or simple salts. The calcium salts may be added directly to the feed or by the use of feed balancers which are added to the main feed to boost the levels of the vitamin, mineral and sometimes herb components of the main feed composition.

However, the present inventor has found that the use of a co-ordinated calcium salt (in the diet) can improve the mobility, gait, hormonal balance, and other physical condition in horses.

More particularly, the inventor has found that the use of chelated organic calcium salts as a dietary supplement has a beneficial effect on the physiology of the horse and may influence the calcium metabolism within the horse. It is postulated that the choice of an organic ligand in the calcium salt rather than the usual inorganic or non-chelated salts has an unexpected beneficial effect on calcium metabolism and may improve conditions associated with calcium dysregulation within the body.

In the description which follows, the invention will be described in relation to its use in horses, however, the invention finds equal utility in other equine mammals such as donkeys, or in other grazing animals and in other animals in general and so the use of the calcium supplement or feed of the present invention is not intended to be restricted to horses. Conditions linked to calcium dysregulation in horses include muscular problems, such as problems with gait, lameness including intermittent lameness, and tying-up, fertility issues such as control of functions in sperm and eggs, or oestrus issues, endocrine problems such as laminitis (also known as founder), PSSM (Polysaccharide Storage Myopathy), insulin resistance, neurological issues such as head shaking, shivers, wobbling etc. and skeletal issues such as osteomalacia, kissing spine, developmental orthopaedic disease (DOD), bran disease, big head disease, splints and the like. Controlling calcium regulation may even have a beneficial effect on the incidences of fits and seizures such as in epileptic horses. Many of these problems are not traditionally associated with calcium regulation, although skeletal disorders are often associated with calcium deficiency even though blood or serum calcium levels in an affected animal may be in the normal range.

Many or all of these conditions may be improved by calcium supplementation with at least one co-ordinated calcium salt, especially at least one chelated organic calcium salt.

Accordingly, the present invention provides a calcium supplement comprising at least one co-ordinated calcium salt. Preferably, the coordinated calcium salt is a chelated organic calcium salt.

Alternatively, the calcium supplement may contain an inorganic or simple, non-chelated calcium salt together with an organic acid or its salt. The organic acid or its salt will generally represent the preferred ligand of the calcium chelate, such as citric acid or sodium citrate (and limestone flour) in place of calcium citrate.

Preferably, the inorganic calcium salt and the organic acid or its salt are co-administered.

The calcium supplements of the invention may be used to balance calcium metabolism in a horse with aberrant calcium metabolism. Thus, in a further aspect, the present invention provides a calcium supplement to balance calcium metabolism in a horse with aberrant calcium metabolism, the supplement comprising at least one co-ordinated calcium salt. Preferably, the co-ordinated calcium salt is a chelated organic calcium salt.

Alternatively, the present invention provides a calcium supplement to balance calcium metabolism in a horse with aberrant calcium metabolism, the supplement comprising non-chelated calcium salt together with an organic acid or its salt. Preferably, the non-chelated calcium salt and the organic acid or its salt are co-administered.

The provision of an organically complexed calcium salt or the coadministration of an inorganic calcium salt with an organic acid or its salt has a beneficial effect on the well-being of the animal receiving the supplement. It is postulated that calcium dysregulation in animals manifests as a multitude of varying ailments, illnesses and problems, both behavioural and physical, in the animal as shown in the list above. Without wishing to be bound by theory, the present inventors postulate that the administration of the organically complexed calcium (directly or by co-administration) corrects the dysregulation of the calcium metabolism and "normalises" the calcium functions of the animal. The term "normalise" as used herein is intended to define a situation in which the calcium metabolism of the animal is returned to a stable or homeostatic level rather than is returned to a blood concentration range which is generally considered to be acceptable or normal.

The calcium supplement of the invention may be provided as a separate supplement, or it may be incorporated into commercially prepared feed, a feed balancer, a salt lick, a paste or other traditional foodstuffs. When in powdered form the supplement may be compressed into tablet form, optionally with flavourings such as mint.

Accordingly, the present invention also provides a commercially prepared animal feed, a feed balancer, a salt lick, or paste comprising at least one co-ordinated calcium salt or an inorganic or non-chelated calcium salt together with an organic acid or its salt, such as limestone flour with citric acid or sodium citrate. Preferably, the co-ordinated calcium salt is a chelated organic calcium salt. The co-ordinated calcium salt is preferably a chelate and the ligand of the chelate is preferably an amino acid, such as methionine, glycine, lysine, a carbohydrate such as gluconate, lactate, malate, another organic molecule, an organic acid salt such as citrate, ascorbate, acetate or a fatty acid. The chelate may be derived or concentrated from milk.

The calcium chelate may be selected from the following non- exhaustive list: calcium citrate, calcium gluconate, calcium citrate malate, calcium malate, calcium lactate, a calcium amino acid chelate, calcium aspartate, calcium ascorbate dihydrate, calcium aspartate, calcium borogluconate, calcium bromolactobionate hexahydrate, calcium citrate hydrate, calcium D-saccharate, calcium glubionate, calcium gluconate, calcium lactate gluconate, calcium lactobionate, calcium levulinate dihydrate, calcium magnesium lactate gluconate, calcium orotate dihydrate, calcium pidolate, calcium palmitate and/or other calcium salts of fatty acids.

The organic acid or salt may be citric acid, lactic acid, malic acid, or gluconic acid, or an amino acid salt, or a salt of a fatty acid or may be an amino acid or a fatty acid.

Currently, the more preferred chelated calcium compounds are calcium citrate and calcium gluconate and the most preferred compound is a calcium citrate compound.

When provided separately the preferred organic acid or its salt is citric acid or sodium citrate and the preferred non-chelated calcium salt is limestone flour or chalk.

The calcium coordination compound may be bonded to or associated with protein, such as whey protein, casein, soy protein, pea protein, and cereal protein or other plant, algal, yeast, fungal, bacterial or animal derived proteins.

The calcium may be deliberately incorporated at high levels in living organisms such as plants, algae, yeasts, fungi, bacteria or single celled or multicellular animals which are then added to the supplement or feed. The actual amount of the supplement provided to the horse per day (the feed dose) will depend upon the calcium coordination complex/calcium chelate present in the supplement.

Advantageously, the feed dose for a 550kg horse is between 6 to 125 grams of supplement per day; 1 1 to 222 grams of supplement per day; or 5 to 95 grams of supplement per day.

In an embodiment in which the supplement comprises a calcium amino acid chelate, the feed dose for a 550 kilogram horse is 6 to 125 grams of the supplement per day. On this dosage of between 1 and 20 grams of calcium is available for absorption by the horse.

In an embodiment in which the supplement comprises calcium gluconate, the feed dose for a 550 kilogram horse is 1 1 to 222 grams of the supplement per day. On this dosage of between 1 and 20 grams of calcium is available for absorption by the horse.

In an embodiment in which the supplement comprises calcium citrate, the feed dose for a 550 kilogram horse is 5 to 95 grams of the supplement per day. On this dosage of between 1 and 20 grams of calcium is available for absorption by the horse.

Advantageously, a maintenance dose of the supplement can be determined according to individual need and may be calculated by trial and error based on the re-emergence of symptoms from providing too low a dose.

The present inventor has carried out a number of blood trials (taking blood samples before and after supplementing) which indicate that the calcium supplements of the invention can alter the balance of the different calcium components in the blood (protein bound, ionised, organically complexed and inorganically complexed calcium).

Specifically, blood tests have shown that use of a chelated calcium supplement leads to a decrease in the levels of ionised calcium in blood samples (14 of the 18 horses tested showed a decrease in blood ionised calcium levels after taking a chelated calcium supplement).

These changes will be described in more detail in the following examples. Without wishing to be bound by theory, it is presently believed that organically chelated calcium salts are metabolically processed by a different mechanism to the inorganic or non-chelated calcium salts traditionally used in feeds or feed supplements and that this has a beneficial effect on the calcium regulation and homeostasis of calcium in the body. It may even be that the organically chelated calcium salts act differently at a cellular or subcellular level (calcium channel) within the animal. For example some citrate pumps operate only when the citrate anion is bound to a divalent cation, of which calcium is the most common. Certainly, anecdotal evidence suggests that the calcium salts excreted in horse urine change when the horse receives organically chelated calcium salts as a feed supplement. It is also possible that the chelated calcium is entering the blood as a chelate, or is re-chelating after entering the blood, and so is not present in the blood as dissociated or ionised calcium: this is one interpretation of the fall in blood ionised calcium levels after supplementation. This also follows from the decrease in the absolute level of ionised calcium in the blood (with supplementation) despite the increase in calcium that is being provided by the dietary supplementation with chelated calcium.

Additionally, the inventor believes that chelated calcium supplements may have an effect on blood magnesium levels too (chelated calcium seems to help horses to regulate magnesium, both increasing and decreasing blood magnesium levels).

The present invention will now be described in more detail with reference to and as illustrated by the accompanying drawings of which,

Figure 1 is a chart of the Total Calcium levels of the blood of two horses before and after supplementing with a chelated calcium supplement,

Figure 2 is a graph showing the Ionised Blood Calcium (iCa) levels of the blood of these two horses before and after the supplementation change,

Figure 3 shows the levels of complexed calcium (inorganic and organic complexes) as estimated by the Nernst equation,

Figure 4 is the Total Blood calcium levels of two Australian horses grazing oxalate rich tropical pastures, Figure 5 shows the changes in iCa in the same horses as Figure 4; in contrast to horses 1 and 2 (Figures 1 -3) these horses both showed decreases in iCa levels during the trial,

Figure 6 shows estimated complexed calcium levels in the same horses as Figures 4 and 5,

Figure 7 is a stylised graph showing changes in blood magnesium levels following chelated calcium supplementation, where +1 = top of "normal range" and -1 = "bottom of normal range",

Figure 8 shows the total blood calcium concentration in a test group supplemented with limestone + citric acid (horses 1 to 4), citric acid (horses 5 to 7) and calcium citrate (horses 8 to 1 1 );

Figure 9 shows the ionised calcium levels of the horses of Figure 8,

Figure 10 shows the complexed calcium levels of the horses of Figure

8, and

Figure 1 1 shows the changes in ionised blood calcium levels before and after supplementing with chelated calcium where "0" represents the centre of the normal range, "+Γ the top of the normal range and "- the bottom of the normal range.

Examples

Referring to Figure 1 of the above described drawings these two horses were selected for the trial because they were grazing tropical pastures known to cause calcium problems in horses and they both showed symptoms of poor mobility. Horse 2 also had some skeletal issues. Both horses had been on traditional (non-chelated) calcium supplements for a prolonged period.

As can be seen from Figure 1 the Total Calcium level of the blood did not change significantly as a result of the withdrawal inorganic calcium supplements and the replacement with a chelated calcium supplement that provided roughly half the amount of calcium. This supports the concept that Total Blood Calcium is carefully regulated by the hormonal homeostatic system. Referring to Figure 2, both of these horses had extremely low Ionised Blood Calcium levels (normal range 1 .58 - 1 .90). Both horses experienced a normalisation of these levels during the supplementation process despite being supplemented with a chelate which ionises less easily than the inorganic supplements it replaced.

Whilst it is not possible to compare the absolute figures involved the direction and magnitude of the changes are clear - the amount of complexed calcium in the blood has dropped dramatically (see Figure 3). Both of these horses showed little or no calcium passed in their urine before the supplement change but after supplementation both were excreting crystals of calcium carbonate and calcium oxalate in their urine. This suggests that these two compounds were retained while the horses were desperate to retain any calcium but excreted when their calcium balance was normalised.

It should be noted that both horses showed substantial improvements in mobility during the trial and horse 2 also showed skeletal improvements.

Figures 4 to 6 show how chelated calcium corrects blood composition that starts with the opposite problems.

Horse 4 was clearly struggling to maintain its Total Blood Calcium level and indeed had a high Parathyroid Hormone (PTH) level at the beginning of the trial. As can be seen the Total Blood Calcium level normalised with the removal of non-chelated calcium supplements and the replacement with half as much calcium from a chelated supplement. The PTH level also normalised. Like horses 1 & 2 earlier horse 5 showed little change in Total Blood calcium as a result of supplementation.

These changes brought the ionised calcium (iCa) levels right into the middle of the normal range.

As with the first series the estimation of Complexed calcium is not exact. However the change with the supplementation is clear. Here the amount of complexed calcium has risen.

What these tests cannot tell us is how the composition of the complexed calcium has changed. Our current belief is that the addition of chelated calcium has actually increased the amount of organically complexed calcium in the blood and reduced the amount of inorganically complexed calcium.

Chelated calcium also seems to have an effect on other components of the blood. Figure 7 shows how blood magnesium levels change with chelated calcium supplementation. In the vast majority of cases high blood magnesium levels drop with chelated calcium and low ones rise. It was found that best mobility in the horse appeared to correlate with horse blood magnesium levels of between -0.5 (minus 0.5) and 0 (zero).

Additionally, the inventors have anecdotal evidence of an improvement in motility from the owner of a horse with Kissing Spine after using the supplement of the invention in that horse. Kissing Spine, also called dorsal spinous process impingement (DSPI) or Basstrup's disease, occurs when the bony 'spikes' of the dorsal spinous processes - and/or, to a lesser extent, the transverse spinous processes at the top (or sides) of the horse's vertebrae start to rub together, causing pain and swelling, especially on moving. The Kissing Spine in that horse affected 5 vertebrae and was considered to be untreatable by the normal treatment of severing the tendon which runs along the spine. After using the supplement of the invention, the owner noticed that the horse had better mobility.

Example 1 : Mobility/movement issues

Ten horses were recruited to the trial. All were ex racehorses and ranged in age from 4-14. The horses all had movement problems such as poor gait or lameness. The horses were fed a diet supplemented with a calcium supplement or feed comprising 12 g of calcium (from calcium citrate) as the calcium coordination compound. No inorganic or other calcium salt was given to the horses during the test period. The calcium supplement or feed was magnesium-free but the horses' complete diets would have contained "normal" levels of magnesium. The supplement given to the horses otherwise mimicked their previous feed/ feed balancer or supplement in that the same proportions of trace minerals and other ingredients were present. Six of the ten horses showed a distinct improvement in movement at the end of the trial. The improvement in two of them was described as "amazing".

Example 2: Laminitis

A 16yr Anglo Arab mare, which had had laminitis for about 3 weeks was recruited to trial using similar doses of supplement as for mobility issues in Example 1 . Before starting supplementation, this horse was having a lot of trouble moving around and was typical of a horse with laminitis stance, leaning backwards to ease the foot pain. She also had a strong digital pulse.

Due to the wet weather she was stabled and walked twice a day: the horse was reluctant to move due to the discomfort of the laminitis. However, even after the first day of treatment a slight improvement could be seen in that the horse was more willing to move. On Day 3 of supplementation, the ring pattern normally observed in laminitis was noted not to have developed. By Day 5 the horse was able to trot, though some discomfort or pain was evident. By day 10 the horse was moving more comfortably although the feet were still believed to be sore from the gait. On day 1 1 the mare began to come into oestrus (season), exhibiting the behavioural patterns associated with oestrus such as kicking and biting, however, the horse was noted to be better behaved with other mares during this oestrus when compared to previous ones, and her oestrus was of normal duration. It was noted that this was the first normal oestrus in this mare for several years and this is taken to be indicative of the supplementation having an endocrine effect.

By day 30 of the trial, the hooves were normal and the movement of the horse was noted as being free and elastic, thus exhibiting a return to normal horse movement.

From these examples the inventor believes that the horses receiving supplementation with organically chelated calcium salts display improved movement and other physical improvements which are considered to result from improved calcium biochemistry or calcium metabolism. It is considered that it is the organic ligand which results in this improvement either through increased bioavailability, or, more likely, due to different bioprocessing by the body.

The examples show that chelated calcium alone can be used to alleviate, ameliorate or even remove problems associated with movement; this is shown by the improvement to behaviour and handling in the treated horses.

Although the specific examples used a calcium supplement or feed comprising calcium citrate only, it is appreciated that the supplement can further comprise one or more components. It is appreciated that the horses will have a number of dietary requirements and, as such, a single calcium supplement or feed may be preferred.

The calcium supplement or feed described above may further comprise vitamin D. It is known that vitamin D is required for calcium absorption. It may be preferable to provide additional vitamin D, particularly when the horse does not have sufficient exposure to sunlight such as when rugged or stabled for long periods of time.

The calcium supplement or feed described above may further comprise magnesium, sodium, potassium, tryptophan, B group vitamins, neurotransmitters and/or their precursors and/or herbal preparations.

Example 3

A 5 week trial was conducted to show that the co-administration of inorganic or non-chelated calcium salts and organic ligand is also effective. 1 1 horses with previously identified mobility issues from skeletal, muscular problems, gait problems or problems with lameness were recruited to trial. In a blind study the horses were supplemented with co-administration of limestone and citric acid (horses 1 to 4), citric acid only (horses 5 to 7) and calcium citrate (horses 8 to 1 1 ) in their normal feed for 5 weeks and their mobility was assessed by their owners against their previous mobility.

Blood calcium levels were taken before and after treatment and the results are shown in Figures 8 to 10. The results of the total blood calcium shown in Figure 8 indicates that all of the horses had similar total blood calcium starting concentrations and that this varied little over the course of the trial.

The levels of ionised blood calcium are shown in Figure 9 where it can be seen that there were little difference between the changes in ionised calcium levels of the limestone and citric acid co-administration group and the calcium citrate group, whereas the administration of citric acid alone showed a greater lowering of ionised calcium levels.

Similarly, Figure 10 shows a similar trend in lowering complexed calcium blood levels between the limestone and citric acid co-administration group and the calcium citrate group.

This shows that co-administration of limestone and citric acid can also be beneficial to the animal.

Example 4

18 horses were recruited to a 5 week trial.

Blood samples were collected and tested for levels of ionised calcium before and at the end of the 5 week trial.

Horses were fed a chelated calcium supplement using 57g calcium citrate providing a dose of 12g of calcium per feed for 5 days each week.

Before the trial started the average ionised calcium levels for the 18 horses were towards the middle of the normal range. At the end of the trial 14 of the 18 horses showed a decrease in blood ionised calcium levels, with the average value for blood ionised calcium levels falling towards the lower quartile of the normal range as shown in Figure 1 1 .

Claims

1 . A calcium supplement to balance calcium metabolism in a mammal with aberrant calcium metabolism, the calcium supplement comprising one of a co-ordinated calcium salt, a chelated organic calcium salt, or the combination of an inorganic or non-chelated calcium salt and an organic acid or its salt.

2. A calcium supplement to balance calcium metabolism in a horse with aberrant calcium metabolism, the supplement comprising one of a coordinated calcium salt, a chelated organic calcium salt, or the combination of an inorganic or non-chelated calcium salt and an organic acid or its salt.

3. A supplement according to claim 1 or claim 2 in which the organic acid or its salt is selected from the group comprising citric acid, lactic acid, malic acid, or gluconic acid, citrate, lactate, malate or gluconate salts, amino acid salts, and salts of a fatty acid.

4. A commercially prepared animal feed, a feed balancer, a salt lick, or paste comprising at least one of a co-ordinated calcium salt or an inorganic or non-chelated calcium salt and organic acid or its salt according to any one of the previous claims.

5. A commercially prepared feed, a feed balancer, a salt lick, or paste according to claim 4, in which the co-ordinated calcium salt is a chelated organic calcium salt.

6. A commercially prepared feed, a feed balancer, a salt lick, or paste according to claim 4, in which the inorganic or non-chelated calcium salt is limestone or chalk and the organic acid or its salt is citric acid, lactic acid, malic acid, or gluconic acid, citrate, lactate, malate or gluconate salts, or an amino acid salt, or a salt of a fatty acid.

7. A calcium supplement according to any one of claims 1 to 3 or a feed according to any one of claims 4 to 6, in which the calcium chelate is selected from the group consisting of calcium citrate, calcium gluconate, calcium citrate malate, calcium malate, calcium lactate, a calcium amino acid chelate, calcium aspartate, calcium ascorbate dihydrate, calcium aspartate, calcium borogluconate, calcium bromolactobionate hexahydrate, calcium citrate hydrate, calcium D- saccharate, calcium glubionate, calcium gluconate, calcium lactate gluconate, calcium lactobionate, calcium levulinate dihydrate, calcium magnesium lactate gluconate, calcium orotate dihydrate, calcium pidolate, calcium palmitate and or other calcium salts of fatty acids.

8. A calcium supplement according to any one of claims 1 to 3 or a feed according to any one of claims 4 to 6, in which the chelated calcium is a calcium amino acid chelate, calcium gluconate and/or calcium citrate.

9. A calcium supplement or feed according to any one of the preceding claims in which the calcium supplement or feed is administered orally.

10. A calcium supplement or feed according to any one of the preceding claims, in which the load dose of calcium is of between 1 to 20 grams of calcium per day.

1 1 . A calcium supplement or feed according to any one of the preceding claims, in which the calcium supplement or feed is used in feed and the feed dose, or loading dose is administered five days a week.

12. A method of balancing calcium metabolism in a horse with aberrant calcium metabolism, the method comprising administering to the horse in need of treatment a calcium supplement or feed according to any one of claims 1 to 1 1 .

A calcium supplement or feed according to any one of claims 1 to 1 1 for use in balancing calcium metabolism in a mammal with aberrant calcium metabolism.

Use according to claim 12, in which the mammal is a horse.

A horse feed comprising a calcium supplement, a feed or a feed balancer according to any one of claims 1 to 1 1 .