AU2019100771B4

AU2019100771B4 - Ferrous Sulphate Formulations and Uses Thereof

Info

Publication number: AU2019100771B4
Application number: AU2019100771A
Authority: AU
Inventors: Chris Pola
Original assignee: Ferromedica Pty Ltd
Current assignee: Ferromedica Pty Ltd
Priority date: 2018-07-17
Filing date: 2019-07-17
Publication date: 2019-09-26
Anticipated expiration: 2027-07-17
Also published as: WO2020014738A1; AU2019303725A1; AU2019100771A4

Abstract

This invention relates generally to therapeutic and/or nutraceutical formulations comprising ferrous sulphate, and their manufacture, and methods and uses of said formulations in treating iron deficiency or supplementing ones diet which may be iron deficient or treating iron deficient anaemia.

Description

FERROUS SULPHATE FORMULATIONS AND USES THEREOF

FIELD

BACKGROUND

Iron is an essential body mineral, playing various roles in the human body is metabolism and red blood cell production. About 70% of the human body's iron is found in red blood cells as a component of haemoglobin and in muscles as myoglobin, which functions as an oxygen carrier enabling proper respiration. While the daily iron intake for an average human is small (around 1 mg for adult males and 1.5 mg for females), the recommended intake for iron is several times larger (8-27 mg) as the actual absorption of iron in human body is a complex process.

When the human body lacks iron, a condition known as iron deficiency anaemia may result. Anaemia is a result of a decrease in the amount of red blood cells in the blood and causes symptoms such as feeling breathless, fatigued and tired, heart palpitations, tiredness, confusion and looking pale. To treat anaemia caused by iron deficiency, supplementary ferrous sulphate (as a source of iron) is often orally administered. However, there are considerable side effects to taking iron supplements, such as nausea, stomach pain, reflux acid, heartburn, constipation and diarrhoea. To mitigate and decrease side effects and improve patient compliance with orally administered iron supplements it is preferred to prescribe ferrous iron containing oral dose forms in some form of controlled release mechanism.

Controlled release, in the pharmaceutical field, relates to the release of a drug in a controlled manner, either at specific sites (stimuli based) or after some time (time based). Prolong/sustained release is a type of controlled release mechanism where the drug is released at a predetermined rate in order to maintain a constant drug concentration for a

-2specific period of time. The goal here is to provide delivery profiles that can release the active ingredient over longer period of time, afford better patient compliance from reduced dosing, and allow for better control of therapeutic drug concentration. Through this, a reduction or avoidance of side effects can also be effected. Such properties are strongly dependent on the physical and chemical characteristics of the formulation excipients, which results in variations in the release mechanism and profile.

For instance, FERRO-TARDYERON tablets, which are sold as oral prolong release ferrous sulphate formulations, make use of a gel matrix system. This is facilitated by the EUDRAGIT S matrix (methacrylic acid and methylmethacrylate copolymer) in the tablet core which uses a dissolution controlled process. Due to the polymer's anionic nature, the drug leaches out as the tablet swells and dissolves only when it passes through the colon. However, while iron release can be controlled, the absorption of iron in human body is known to mainly occur in the stomach and duodenum, suggesting that most of the iron passes out of the body un-absorbed.

FERROGRAD C is another commercially available ferrous sulphate based tablet which incorporates GRADUMET (methylacrylate methylmethacrylate copolymer) for a prolong release profile. In this diffusion controlled release system, the rate of release is first order as the polymer matrix is non-disintegrating. This can result in a progressively diminishing release rate due to the increasing diffusion distance and decreasing surface area at the penetrating diffusion front. As such, the effective plasma concentration of the drug may be shorter (i.e. not as prolonged as desired).

The present invention seeks to overcome some of the shortcomings of the art to provide a ferrous sulphate oral formulation with a controlled release profile, that minimises or reduces dissolution in the duodenum thus doing away with (or at least minimising) the associated gastric side effects of stomach pain, burning and reflux acid. The tablets disclosed herein are characterised by a smooth and constant release of 60-85% of the active ingredient over the first four hours (and in particular over the first 1 -2 hours) so as to maximise ferrous iron absorption in the duodenum leading to better therapeutic

2019100771 17 Jul 2019

-3 outcomes, thus minimising the unwanted adverse initial dose dumping, which leads to a correspondingly lowering of side effects and in particular stomach irritation.

SUMMARY

The present invention provides ferrous sulphate formulations that comprise an effective amount of ferrous sulphate, a controlled release matrix and optionally a coating. The controlled release profile is characterised by a smooth and constant release of the active ingredient throughout the upper gastrointestinal tract but mainly controlling the dissolution of the tablet to occur in the first four hours releasing the active ferrous iron in the gastrointestinal region where it is maximally absorbed. This is assumed to be primarily as a result of the amount of HPMC, which is a non-ionic hydrophilic polymer stable over a wide pH range of 3 - 11, or at least through an actual working interrelationship between HPMC and the other excipients and the active(s). The formulation may also contain ascorbic acid (Vitamin C) to increase the absorption and bioavailability of iron to the subject. The present invention aims to control the rate of delivery of the agent to the subject such that the initial dose dumping is eliminated (or at least minimised).

In the first aspect, the invention provides a controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

a. ferrous sulphate as the Fe (II) source in amount of from about 300 mg to about 400 mg, and wherein the core also comprises the following additional ingredients:

b. about 0.75 to about 2% wt/wt of colloidal anhydrous silica (based on total weight of ferrous-sulphate in the core);

c. about 60 to about 122% wt/wt of HPMC (based on total weight of ferroussulphate in the core);

d. about 7 to about 15% wt/wt of microcrystalline cellulose (based on total weight of ferrous-sulphate in the core); and

e. about 0.75 to about 2% wt/wt of magnesium stearate (based on total weight of ferrous-sulphate in the core).

-4In an embodiment and with reference to the first aspect the tablet coating system also comprises about 0.002 to about 0.004% wt/wt of carnauba wax (based on total weight of ferrous-sulphate in the core).

In a second aspect, the invention provides a controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

a. ferrous sulphate as the Fe (II) source in amount of from about 300 mg to about 400 mg; and

b. ascorbic acid from about 450 mg to about 600 mg, and wherein the core also comprises the following additional ingredients:

c. about 0.75 to about 2% wt/wt of colloidal anhydrous silica (based on total weight of ferrous-sulphate in the core);

d. about 60 to about 122% wt/wt of HPMC (based on total weight of ferroussulphate in the core);

e. about 7 to about 15% wt/wt of microcrystalline cellulose (based on total weight of ferrous-sulphate in the core); and

f. about 0.75 to about 2% wt/wt of magnesium stearate (based on total weight of ferrous-sulphate in the core).

In an embodiment and with reference to this second aspect the tablet coating system also comprises about 0.002 to about 0.004% wt/wt of carnauba wax (based on total weight of ferrous-sulphate in the core.

In another aspect, the invention provides a controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

b. about 1 mg to about 4 mg of colloidal anhydrous silica;

c. about 180 mg to about 280 mg of HPMC;

d. about 20 mg to about 40 mg of micro crystalline cellulose; and

e. about 1 mg to about 4 mg of magnesium stearate.

-5 In a further aspect, the invention provides a controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

c. about 3 mg to about 8 mg of colloidal anhydrous silica;

d. about 200 mg to about 400 mg of HPMC;

e. about 40 mg to about 50 mg of micro crystalline cellulose; and

f. about 3 mg to about 8 mg of magnesium.

In an embodiment and with reference to this above aspect the tablet coating system also comprises about 0.002 to about 0.004% wt/wt of carnauba wax (based on total weight of ferrous-sulphate in the core.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

Figure 1 is graph depicting the dissolution profile comparison between Example 1 Tablet vs commercially available Ferro-Gradumet Tablet

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. For the purposes of the present invention, the following terms are defined below.

Excipients are pharmaceutically inactive substances that serve as the vehicle or medium for a drug or other active substances.

Colloidal anhydrous silica is an excipient and is a fine suspension of amorphous, nonporous and typically spherical silica particles.

-6HPMC is the excipient hydroxypropyl methylcellulose, also known as hypromellose. It is a semisynthetic, inert, viscoelastic polymer. It is a non-ionic, hydrophilic derivative of cellulose ether and is stable over pH range 3 - 11.

Cellulose-microcrystalline is an excipient and is often referred to as refined wood pulp, often used as a texturiser, an anti-caking agent, suspending agent and adsorbent.

Magnesium stearate is an excipient and is often used as a lubricant to prevent pharmaceutical ingredients from adhering to the equipment.

Carnauba wax is an excipient and consists mainly of fatty acid esters.

The present invention provides a ferrous sulphate formulation that comprises an effective amount of active ingredient, a controlled release matrix of specific excipients in specific amounts and a film coating.

In the present formulation, the main active ingredient is ferrous sulphate. The amount of ferrous sulphate included in the formulation is effective to provide a therapeutic plasma concentration in a subject for up to 24 h. In an embodiment, the formulation comprises between about 300 mg to about 400 mg of active ingredient. In another embodiment, the formulation comprises about formulation comprises about formulation comprises about formulation comprises about

300 mg of active ingredient.

325 mg of active ingredient.

350 mg of active ingredient.

375 mg of active ingredient.

In another embodiment, the

In another embodiment, the formulation comprises about 400 mg of active ingredient.

In an embodiment, the formulation may comprise between about 450 mg to about 600 mg of ascorbic acid (Vitamin C). In another embodiment, the formulation comprises about 450 mg of ascorbic acid. In another embodiment, the formulation comprises about 500 mg of ascorbic acid. In another embodiment, the formulation comprises about 550 mg of ascorbic acid. In another embodiment, the formulation comprises about 600 mg of ascorbic acid.

2019100771 17 Jul 2019

-7In further embodiments the formulations discussed above may also comprise amounts of folic acid 40-800mg, Vitamin B12 and other B Group Vitamins, all may be present at doses with ± 50% of the recommended daily dose or intake (RDI). Other additional minerals which may be present include Magnesium (for instance 300 mg ±50%), Zinc (for instance, 25 mg ± 50%) and/or Calcium (for instance, 600 mg ± 50%).

The controlled release matrix comprises of a combination of formulation excipients which allows for a smooth and constant release of the active ingredient throughout the gastrointestinal tract. It is thought to exert its effect via a dissolution controlled process, by swelling under the influence of a media and erosion of the matrix to release the active ingredient. To ensure the smooth release of active ingredient, the controlled release matrix cannot be affected by the varying pH of gastrointestinal fluids (i.e. stomach, duodenum, ileum, colon). The present invention also aims to control the rate of delivery of the agent to the subject such that the initial dose dumping is eliminated.

The formulations discussed herein comprise Hypromellose or hydroxypropyl methyl cellulose (HPMC), and preferably HPMC with the following specifications:

Methoxy (-OCH3; Μ_τ 31.03) and hydroxypropoxy (-OC3H6OH; Μ_τ 75.09) groups (dried substance) conforming to the types of hypromellose set forth in the accompanying table:

Substitution type	Methoxy (per cent)	Hydroxypropoxy (per cent)
1828	16.5 to 20.0	23.0 to 32.0
2208	19.0 to 24.0	4.0 to 12.0
2906	27.0 to 30.0	4.0 to 7.5
2910	28.0 to 30.0	7.0 to 12.0

The viscosity grades range from 4000-100,000 mPa s.

In an embodiment, the formulation comprises between about 60% to about 122% (%wt/wt, based on total weight of ferrous sulphate) of HPMC. In another embodiment, the formulation comprises about 60% (%wt/wt) of HPMC. In another embodiment, the

-8formulation comprises about 74% (%wt/wt) of HPMC. In another embodiment, the formulation comprises about 86% (%wt/wt) of HPMC. In another embodiment, the formulation comprises about 98% (%wt/wt) of HPMC. In another embodiment, the formulation comprises about 113% (%wt/wt) of HPMC. In another embodiment, the formulation comprises about 122% (%wt/wt) of HPMC.

The formulation also comprises colloidal anhydrous silica in an amount for instance of 99.0% to 100.5% of SiO₂ (ignited substance).

In an embodiment, the formulation comprises between about 0.75% to about 2% (%wt/wt, based on total weight of ferrous sulphate) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 0.75% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 0.9% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.05% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.2% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.35% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.5% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.65% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 1.8% (%wt/wt) of colloidal anhydrous silica. In another embodiment, the formulation comprises about 2% (%wt/wt) of colloidal anhydrous silica.

The formulation also comprises microcrystalline cellulose which is known in the art to be purified, partly depolymerised cellulose prepared by treating α-cellulose, obtained as a pulp from plant materials with mineral acids.

In an embodiment, the formulation comprises between about 7% to about 15% (%wt/wt, based on total weight of ferrous sulphate) of microcrystalline cellulose. In another embodiment, the formulation comprises about 7% (%wt/wt) of microcrystalline cellulose.

-9In another embodiment, the formulation comprises about 8% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 9% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 10% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 11% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 12% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 13% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 14% (%wt/wt) of microcrystalline cellulose. In another embodiment, the formulation comprises about 15% (%wt/wt) of microcrystalline cellulose.

In an embodiment, the formulation comprises between about 0.75% to about 2% (%wt/wt, based on total weight of ferrous sulphate) of magnesium stearate. In another embodiment, the formulation comprises about 0.75% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 0.9% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.05% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.2% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.35% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.5% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.65% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 1.8% (%wt/wt) of magnesium stearate. In another embodiment, the formulation comprises about 2% (%wt/wt) of magnesium stearate.

In certain embodiments the coating comprises a polymer, plasticiser and pigment mixed together and dispersed finely as a film over the tablet to protect the tablet, maintain the shape of the tablet, aid in swallowing and for a lustre appearance. In the above formulations, poly(vinyl alcohol) (PVA) based coating formulations are used.

In an embodiment, the formulation comprises between about 4% to about 13% (%wt/wt, based on total weight of ferrous sulphate) of PVA. In another embodiment, the

- 10formulation comprises about 4% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 5.5% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 7% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 8.5% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 10% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 11.5% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 12% (%wt/wt) of PVA. In another embodiment, the formulation comprises about 13% (%wt/wt) of PVA.

One commercially available PVA based coating is OPADRY complete film coating system. In an embodiment, the formulation comprises between about 4% to about 13% (%wt/wt, based on total weight of ferrous sulphate) of OPADRY film coating. In another embodiment, the formulation comprises about 4% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 5.5% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 7% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 8.5% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 10% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 11.5% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 12% (%wt/wt) of OPADRY film coating. In another embodiment, the formulation comprises about 13% (%wt/wt) of OPADRY film coating.

In one embodiment, the coating comprises between about 0.002% to about 0.004% (%wt/wt, based on total weight of ferrous sulphate) of carnauba wax. In another embodiment, the coating comprises about 0.002% (%wt/wt) of carnauba wax. In another embodiment, the coating comprises about 0.0025% (%wt/wt) of carnauba wax. In another embodiment, the coating comprises about 0.003% (%wt/wt) of carnauba wax. In another embodiment, the coating comprises about 0.0035% (%wt/wt) of carnauba wax. In another embodiment, the coating comprises about 0.004% (%wt/wt) of carnauba wax.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an

- 11 acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase consisting essentially of', and variations such as consists essentially of' will be understood to indicate that the recited element(s) is/are essential i.e. necessary elements of the invention. The phrase allows for the presence of other nonrecited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the method defined.

Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

Further features of the present invention are more fully described in the following nonlimiting examples.

EXAMPLES

EXAMPLE 1 Iron Tablet

Preparation of Iron tablet

- 122019100771 17 Jul 2019

- 13 2019100771 17 Jul 2019

Formulation of Iron tablet

MASTER FORMULATION

	Approved Name	Amount per tablet	Unit
	ACTIVE INGREDIENTS
1	Ferrous sulphate-dried	325.00	mg
	EXCPIENT INGREDIENTS		mg
2	Colloidal anhydrous silica	3.00	mg
3	Hypromellose	240.00	mg
4	Cellulose-microcrystalline	29.00	mg
5	Magnesium stearate	3.00	mg
6	OPADRY Complete film coating system 85G86592-Brown (PI 11445)	18.00	mg
7	Carnauba Wax	qs	mcg

EXAMPLE 2 Iron/Vitamin C Tablet

Preparation ofIron/Vitamin C tablet

142019100771 17 Jul 2019


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2019100771 17 Jul 2019

- 162019100771 17 Jul 2019

Formulation ofIron/Vitamin C tablet

MASTER FORMULATION

	Approved Name	Amount per tablet	Unit
	ACTIVE INGREDIENTS
1	Ferrous sulfate-dried	325.00 (105.00 equivalent of iron)	mg
2	Ascorbic acid	537.5	mg
3	Colloidal anhydrous silica	6.00	mg
4	Hypromellose	366.125	mg
5	Cellulose-microcrystalline	46.00	mg
6	Magnesium stearate	6.00	mg
7	OPADRY Complete film coating system 85G86592-Brown (PI 11445)	23.16	mg
8	OPADRY Complete film coating system 85G58921 White (PI 4455)	15.44	mg

EXAMPLE 3 Comparative data with competitor’s formulation

A dissolution study was performed between the commercially available product (FerroGrad) vs the Tablet of Example 1. Figure 1 identifies that in Example 1 there is less iron released initially minimising dose dumping and associated gastric effects.

EXAMPLE 4 Various trials to arrive at Tablet of Example 1

Several trials using differing matrix formulations were carried out.

Trial 1.

Initial results using a round biconvex shape with a cellulose base matrix were not satisfactory in that initial dose dumping of >50% 1 hour was achieved and total active 15 release (100%) at T3.

Trial 2.

Initial results using a round biconvex shape with a cellulose base matrix and alternate lubricant and without a silica component were not satisfactory in that initial dose

- 17dumping of >50% 1 hour was still achieved and total active release (100%) at T3. Dissolution profile overall was similar to trial one notwithstanding changes to lubricant and colloidal silica.

Trial 3.

Determined to conduct trial using a diamond shaped tablet form and for comparison using the same base formula as trial 2. The dissolution profile improved however initial dose dumping remained similar with the only improvement being the total active release (100%) at T5. The release linearity did show sufficient improvement such as to form a conclusion that dose shape, total surface area, has an impact on dissolution.

Trial 4/5/6/7.

Required a change to the dissolution matrix composition by making change to the primary matrix component and reverting to lubricant and colloidal silica components (see Example 1, for instance). This being (in part) a cellulose having a content of both methoxy and hydroxypropoxy with a specified nominal viscosity This was used in addition to a purified partly depolymerise cellulose derived from plant material. The various trials conducted under this heading were carried out with a view to optimising the dissolution profile by varying the percentage composition of the matrix component parts. The resulting dissolution profiling resulting in a significant reduction in the dose dump occurring (See Figure 1).

EXAMPLE 5 Dissolution profile of Example 2 tablet

Dissolution studies were performed in the same manner as the USP method disclosed for Example 1 tablet comparison (Paddle at 50 rpm). Results are as follows:

hours - 25 to 45 of LC% hours - 60 to 85 of LC% hours - NLT 85 of LC%

Claims

WHAT IS CLAIMED IS:

1. A controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

a. ferrous sulphate as the Fe (II) source in amount of from about 300 mg to about 400 mg, and wherein the core comprises the following additional ingredients:

b. about 0.75 to about 2% wt/wt of colloidal anhydrous silica (based on total weight of ferrous sulphate in the core);

c. about 60 to about 122% wt/wt of HPMC (based on total weight of ferrous sulphate in the core);

d. about 7 to about 15% wt/wt of microcrystalline cellulose (based on total weight of ferrous sulphate in the core); and

e. about 0.75 to about 2% wt/wt of magnesium stearate (based on total weight of ferrous sulphate in the core.
2. A controlled release Fe (II) tablet comprising a core which is coated with a PVA based film coating system, said core comprising:

a. ferrous sulphate as the Fe (II) source in amount of from about 300 mg to about 400 mg; and

b. ascorbic acid from about 450 mg to about 600 mg, and wherein the core comprises the following additional ingredients:

c. about 0.75 to about 2% wt/wt of colloidal anhydrous silica (based on total weight of ferrous-sulphate in the core);

d. about 60 to about 122% wt/wt of HPMC (based on total weight of ferroussulphate in the core);

e. about 7 to about 15% wt/wt of microcrystalline cellulose (based on total weight of ferrous-sulphate in the core); and

f. about 0.75 to about 2% wt/wt of magnesium stearate (based on total weight of ferrous-sulphate in the core).

- 192019100771 17 Jul 2019
3. A controlled release formula according to any one of claim 1 and claim 2 wherein the %wt/wt ratio ranges of the ferrous sulphate to HPMC is from about 5 : 3 to about

5 : 6.

5 4. A controlled release formula according to any one of claim 1 to 3 wherein the %wt/wt ratio ranges of the ferrous sulphate to microcrystalline cellulose is from about

6 : 1 to about 14 : 1.

5. A controlled release formula according to any one of claims 2 to 4 wherein the 10 %wt/wt ratio ranges of the ferrous sulphate to ascorbic acid is from about 4 : 5 to about
4 : 8.