Description:FIELD OF THE INVENTION
The present invention relates to oral liquid compositions of sucroferric oxyhydroxide or its pharmaceutically acceptable salts thereof. It further relates to ready to use oral liquid compositions of sucroferric oxyhydroxide and methods for preparing said oral liquid compositions.

BACKGROUND OF THE INVENTION
USFDA has approved sucroferric oxyhydroxide chewable tablets under the brand name Velphoro. Each Velphoro Chewable tablet contains 500 mg iron (equivalent to 2,500 mg sucroferricoxyhydroxide) and approved for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. The recommended starting dose of Velphoro is 3 tablets (1,500 mg) per day, administered as 1 tablet (500 mg) 3 times daily with meals. Based on clinical studies, on average patients required 3 to 4 tablets (1,500 mg to 2,000 mg) a day to control serum phosphorus levels. Velphoro chewable tablets can be crushed to powder and mixed with suitable solvent like water to form an easily administered suspension. But this varies the rate of release of an active ingredient. Most of the patients feel horrid while chewing the tablet as it leaves a bad taste and turns tongue and teeth orange in color.

Sucroferric oxyhydroxide is also available as 125 mg Oral powder in sachet under the trade name Velphoro in Europe. Before administration, Velphoro oral powder should be mixed with a small amount of soft food (such as apple sauce) or with non-carbonated beverage or water and taken with meals. Each sachet of oral powder requires minimum 5 mL of liquid for suspension.

Sucroferric oxyhydroxide is a moisture sensitive drug substance and quickly degrades under humid conditions. Therefore, mixing the sachet content onto soft food might trigger a significant degradation of Sucroferric oxyhydroxide resulting in an under dosing. Furthermore, it appears that there is a change in the solid form of the drug substance, which recrystallizes during the reconstitution of the oral suspension. Such recrystallisation may impair the quality of the medicine, especially with regard to the accuracy of the dose dispensed, the kinetic of solubilization, or the clogging of syringe for oral administration, if the crystals formed are too large. This suggests that the performance of hospital - compounded suspensions, with respect to dose uniformity, dissolution kinetic, may significantly vary from a batch to another. This could result in administering an inappropriate dose to patients.

WO 20101015827 A2 discloses a ferric iron composition for use in a method of treating hyperphosphatemia, wherein the ferric iron composition is a solid ligand-modified poly oxo-hydroxy metal ion material represented by the formula (MxLy(OH)n), wherein M one or more metal ions that comprise Fe3+ Ions, L represents one or more ligands that comprise a carboxylic acid ligand, or an ionised form thereof, and OH represents oxo or hydroxy groups and wherein the material has a polymeric structure in which the ligands L are substantially randomly substituted for the oxo or hydroxy groups and wherein the solid ligand-modified poly oxo-hydroxy metal ion material having one or more reproducible physico-chemical properties. WO 20101015827 A2 does not contain any example of a specific pharmaceutical composition.

U.S. Patent No. 10,624,855 discloses solid oral compositions especially chewable tablets, tablets, mini-tablets (micro-tablets) of sucroferric oxyhydroxide.

Currently available in the market either as tablets or powder. An individual may have difficulty swallowing the usual solid dosage form, and mixing the sachet content onto soft food might trigger a significant degradation of Sucroferric oxyhydroxide resulting in an under dosing. For children, dose management is difficult if tablet to cut or crush because of no accuracy of dose. Thus there exists a need for alternate dosage forms which addresses the above issues and provide ease of administration and patient compliance. Especially, there is no oral liquid Sucroferric oxyhydroxide composition available for the pediatric population, geriatric patients. Thus, there exists a need for ready to use liquid compositions of sucroferric oxyhydroxide. Inventors of the present invention makes the process simple in administering the drug comfortably with much convenience. As there is no chewing involved and the dosage form passes through the throat smoothly with minimal contact with teeth and tongue and cause no or very less tooth discoloration. The present invention provides a ready to use liquid compositions of Sucroferric oxyhydroxide, preferably ready to use oral suspension, which address the issues and maintains its content uniformity for prolonged period.

SUMMARY OF THE INVENTION
In one general aspect, there is provided an oral liquid composition comprising sucroferric oxyhydroxide and one or more pharmaceutically acceptable excipients.

In another aspect, there is provided an oral liquid composition of sucroferric oxyhydroxide with improved taste having high patient compliance.

In another aspect, there is provided an oral liquid composition of sucroferric oxyhydroxide, offering dose flexibility for patients who need special doses of the drug and have difficulties in swallowing oral solid dosage forms.

In another aspect, there is provided process of preparation of oral liquid composition of sucroferric oxyhydroxide.

In another aspect, there is provided a ready to use oral liquid composition comprising sucroferric oxyhydroxide and one or more pharmaceutically acceptable excipients selected from suspending agents, preservatives, solvents or cosolvents, buffering agents, sweeteners, anti-foaming agents, wetting agents, coloring agents, flavoring agents. and combinations thereof.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to Oral liquid composition comprising sucroferric oxyhydroxide as an active ingredient.

The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, suspending agents, preservatives, vehicles and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.

The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.

The term “liquid composition” as used herein refers to a liquid dosage form suitable for oral administration, such as a suspension, solution, emulsion, syrup and the like; preferably, oral suspension.

The term “about” as used herein refers to +/- 20%, +/- 10%, +/- 5%, or +/- 2% of a value.
As used herein, the term “ready for use” refers to a mixture of particles containing an active substance and a suspension base.

The present invention relates to pharmaceutical stable oral liquid compositions of Sucroferric oxyhydroxide and one or more pharmaceutically acceptable excipients.

The pharmaceutical liquid composition of the present invention may include a variety of excipients and vehicle. Excipients of the present invention selected from suspending agents, preservatives, solvents or cosolvents, buffering agents, sweeteners, anti-foaming agents, wetting agents, coloring agents, flavoring agents. and combinations thereof.

Suspending agents according to the present invention include but are not limited to xanthan gum, Tragacanth, microcrystalline cellulose and carboxymethylcellulose sodium, pectin, lecithin, agar, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, gellan gum, bentonite, Kaolin, carrageenan, propylene glycol alginate, sodium alginate, gum acacia, carbomer and the like, and combinations thereof.

In some embodiments of present invention, suspending agent is in the range of 0.01%w/v to 4.00%w/v. Preferably in the concentration range of 0.10%w/v to 0.50%w/v.

Preservatives according to the present invention include but are not limited to sodium benzoate, benzyl alcohol, potassium sorbate, sorbic acid, benzoic acid, benzalkonium chloride, cetrimide, ethyl alcohol, para hydroxyl benzoic acid esters like methyl paraben, propyl paraben, and combinations thereof. In some embodiments of present invention, preservative is in the range of 0.01%w/v to 4.0 %w/v. Preferably in the concentration range of 0.10%w/v to 2.0 %w/v.

Solvents or cosolvents are water-miscible organic solvents used in liquid drug formulations to increase the solubility of poorly water-soluble substances and enhance the chemical stability of a drug. Solvent or cosolvents can be selected from but not limited to ethanol, polyethylene glycols (PEG), sorbitol, glycerin, propylene glycol, benzyl alcohol and water.

Buffering agents provide stability and pH control to the pharmaceutical compositions. Suitable buffering agents can be selected from but not limited to sodium acetate, sodium citrate, ammonium sulfate, sodium phosphate, disodium hydrogen phosphate, potassium citrate, citric acid monohydrate, trisodium citrate dihydrate.

In some embodiments of present invention, buffering agent is in the range of 0.01%w/v to 5.0 %w/v. Preferably in the concentration range of 0.05%w/v to 2.0%w/v.

Sweeteners are added in liquid compositions that impart sweetness and improve patient compliance through taste masking. Suitable sweeteners can be selected from but not limited to sucralose, saccharin, erythritol, xylitol, sorbitol, mannitol, aspartame, maltitol, fructose, glucose, sucrose, maltose, or combinations thereof.

In some embodiments of present invention, sweetener is in the range of 0.01%w/v to 1.00 %w/v. Preferably in the concentration range of 0.05%w/v to 0.40%w/v.

Antifoaming agents are added in oral suspension pharmaceutical dosage form to lower the surface tension and cohesive binding of liquid phase. Antifoaming agents can be selected from but not limited to simethicone, dimethicone, organic phosphates, alcohols, paraffin oils, sterates and glycols. In the present invention, preferably simethicone emulsion is used as antifoaming agent.

In some embodiments of present invention, antifoaming agent is in the concentration range of 0.01%w/v -1.0%w/v. Preferably, in the concentration range of 0.05%w/v -0.70%w/v.

Wetting agents are surfactants that lower the interfacial tension and contact angle of solid particles and liquid vehicle in suspensions. Wetting agents can be selected from but not limited to propylene glycol, glycerol, Docisate Sodium, sodium lauryl sulphate, polysorbate 80, spans and lecithins.

In some embodiments of present invention, wetting agent is in the concentration range of 0.1%w/v to 7.0 %w/v. Preferably, in the concentration range of 0.5%w/v to 5.0%w/v.

Flavoring agents are added to increase patient acceptance of the drug by masking the specific taste sensations. Flavoring agent can be selected but not limited to essential oils including peppermint oil, orange oil, and lemon oil or can be selected from fruit flavors.

In some embodiments of present invention, flavoring agent is in the concentration range of 0.01%w/v -2.0%w/v. Preferably, in the concentration range of 0.05%w/v -1.0%w/v.

Suitable colorants include, but are not limited to, titanium dioxide pigments, lake pigments and iron oxide pigments. In some embodiments of present invention, colorant is in the concentration range of 0.01%w/v -2.0%w/v. Preferably, in the concentration range of 0.05%w/v -1.0%w/v.

Suitable antioxidants include, but not limited to, tocopherol, gallic acid and gallate, butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, maleic acid, sodium bisulfate, sodium metabisulfite, sodium formaldehyde sulfoxylate. In some embodiments of present invention, antioxidant is in the concentration range of 0.01%w/v -2.0%w/v. Preferably, in the concentration range of 0.05%w/v -1.0%w/v.

In an embodiment of the invention, the composition is administered by oral route as a drinkable dosage form.

In another embodiment, the composition is administered by gastric route via nasogastric tube (NG) or via other enteral feeding tube.

Advantageously the composition of the invention is compatible with polymers used in the manufacture of oral administration devices such as syringes for oral use or feeding tubes. Advantageously, the composition of the invention is stable in contact with polypropylene and polyethylene. Of particular interest, the administration of the composition using a syringe for oral use allows a precise dosing and mitigates the risks of inappropriate dosing regimen.

In another embodiment of the present invention, the ready to use aqueous oral suspension comprises sucroferric oxyhydroxide in the range of about 0.5% to 50%, preferably about 1% to 20%.

In another embodiment of the present invention, the ready to use aqueous oral suspension comprises sucroferric oxyhydroxide, suspending agent, preservative, sweetener, buffering agent, flavoring agent and solvent/cosolvent.

In another embodiment of the present invention, process for the preparation of ready to use oral suspension comprises:

i. Taking 60%, of total volume of purified water and dissolving preservatives with the aid of heating at above 90°C to get a clear, colourless solution. Adding additional 10% purified water and keeping aside to cool at room temperature. Adding and dispersing antifoaming agent into the solution and mix by using suitable mixer to get dispersion.
ii. Dissolving sweetener into above dispersion and mix by using suitable mixer. Adding and dispersing suspending agent into above dispersion and mix by using suitable mixer, under nitrogen purging to get dispersion.
iii. Adding sucroferric oxyhydroxide to propylene glycol slowly by stirring using a suitable mixer to get a homogeneous dispersion and were added to step ii under continuous stirring.
iv. Adding and mixing buffering agent in above dispersion and mix.
v. Coloring agent and flavours were added to above step iv , under continuous stirring, followed by checking the pH, making-up the volume with purified water and finally homogenizing to achieve a uniform and homogenous suspension.
In another embodiment of the present invention, the ready to use aqueous oral suspension comprises sucroferric oxyhydroxide, xanthan gum, glycerin, propylene glycol, methyl paraben, sorbitol, sodium citrate, xanthan gum.

In another embodiment of the present invention, the ready to use aqueous oral suspension comprises 1% -10 %w/v of sucroferric oxyhydroxide, 0.01%-2% w/v of glycerin, 0.01%-2% w/v of methyl paraben, 0.01%-2% w/v of sorbitol, 0.1%-1% w/v of xanthan gum, 0.01% – 2% w/v of sodium citrate and 0.01% – 1% w/v of fruit flavor.

In another embodiment of the present invention, the ready to use aqueous oral suspension comprises 500 mg to 10000 mg of sucroferric oxyhydroxide, which equivalent to 100 mg to 2000 mg iron.

In another embodiment of the present invention, the d90 particle size of sucroferric oxyhydroxide suspended t dispersed in the ready to use oral suspension is less than about 50 μm, preferably less than about 30 μm, more preferably less than about 10 μm.

For the purposes of the present invention, the particle size of the sucroferric oxyhydroxide particles is measured using a light scattering technique (Mastersizer Hydro 2000S from Malvern).

In another embodiment of the present invention, the pH of the ready to use oral suspension ranges from about 4.0 to about 9.0.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1:
Ingredient % (w/v)
Sucroferric oxyhydroxide 1.00 -25.00
Propylene Glycol 40.00-95.00
Methyl Paraben 0.01 – 2.00
Sorbitol 0.01 – 2.00
Sodium citrate 0.01 – 2.00
Xanthan gum 0.1 – 1.00
Fruit Flavour 0.01 - 1.00
Purified water q.s

Manufacturing Process:
1. Add Methyl paraben in a part of water under stirring
2. Dissolve Sorbitol to step 1, under continuous stirring
3. Disperse xanthan gum to step 2, under continuous stirring
4. Add Sucroferric oxyhydroxide to propylene glycol under stirring and add to step 3.
5. Add Sodium citrate to step 4, under stirring.
6. coloring agent and flavors were added to step 5, under continuous stirring, followed by checking the pH, making-up the volume with purified water and finally homogenizing to achieve a uniform and homogenous suspension.
Example 2:
Ingredient % w/v
Sucroferric Oxyhydroxide 1.0% to 20.0%
Propylene Glycol 10.0% to 70.0%
Ethanol 0.0% to 20.0%
Methyl Paraben 0.01% to 2.0%
Sorbitol 0.5% to 10.0%
Sodium Citrate 0.1% to 1.0%
Xanthan Gum 0.1% to 3.0%
Glycerin 0.5% to 10.0%
Flavoring Agent 0.01% to 2.0%
Ascorbic acid 0.01% to 1.0%
Purified Water q.s. to 100%

Manufacturing Process:
1. Heat about 60% of the total volume of purified water to about 90°C and dissolve Methyl Paraben by stirring until a clear, colorless solution is obtained.
2. Add about 10% of purified water after the preservative is completely dissolved and allow the solution to cool to room temperature.
3. Add sorbitol and glycerin into the step 2 dispersion and mix thoroughly.
4. Add Ethanol as a co solvent to the above mixture and mix well
5. Gradually add Xanthan Gum to the above dispersion while mixing to ensure without clumping.
6. Slowly add Sucroferric Oxyhydroxide into the mixture while stirring continuously to prevent sedimentation and ensure a homogeneous blend.
7. Add Sodium Citrate to the mixture and stir well. Monitor and adjust the pH as necessary.
8. Add the selected ascorbic acid to the mixture and stir until fully dissolved and evenly distributed.
9. Add flavoring agent and any coloring agents to the mixture, ensuring that they are evenly dispersed throughout the composition.
10. Make up the total volume of the suspension with the remaining purified water to 100% w/v.
Component Example 3 %w/v Example 4 %w/v Example 5 %w/v
Sucroferric Oxyhydroxide 10.00% 1.0% - 20.0% 5.00% 1.0% - 20.0% 8.00% 1.0% - 20.0%
Propylene Glycol 5.00% 0.01% - 15.0% - - 4.00% 0.01% - 15.0%
Methyl Paraben 0.10% 0.01% - 2.0% 0.05% 0.01% - 2.0% 0.20% 0.01% - 2.0%
Sorbitol 1.00% 0.01% - 1.0% - 0.01% - 1.0% 1.50% 0.01% - 1.0%
Glycerin - - 5.00% 1.0% - 15.0% 3.00% 1.0% - 15.0%
Sodium Citrate 0.50% 0.05% - 2.0% 0.20% 0.05% - 2.0% 0.50% 0.05% - 2.0%
Xanthan Gum 0.30% 0.1% - 1.0% 0.40% 0.1% - 1.0% 0.30% 0.1% - 1.0%
Antifoaming Agent 0.05% 0.01% - 1.0% - - 0.08% 0.01% - 1.0%
Wetting Agent 0.10% 0.1% - 7.0% - - 0.20% 0.1% - 7.0%
Flavoring Agent Fruit Flavor: 0.2% 0.01% - 2.0% Peppermint Oil: 0.1% 0.01% - 2.0% Lemon Flavor: 0.15% 0.01% - 2.0%
Coloring Agent - - - - Iron Oxide Pigment: 0.05% 0.01% - 2.0%
Sweetener Sucralose: 0.1% 0.01% - 1.0% - - Aspartame: 0.15% 0.01% - 1.0%
Purified Water q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Manufacturing process: Same as Example 2
, Claims:We Claim:
1. An Oral liquid composition comprising sucroferric oxyhydroxide and at least one pharmaceutically acceptable excipient.
2. The Oral liquid composition as claimed in claim 1, wherein the sucroferric oxyhydroxide is present in an amount of from 0.5% w/v to 20% w/v.
3. The Oral liquid composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from suspending agents, preservatives, solvents, sweeteners, and flavoring agents.
4. The Oral liquid composition as claimed in claim 1, wherein the suspending agent is selected from xanthan gum, carboxymethylcellulose sodium, and microcrystalline cellulose, present in the range of from 0.01% w/v to 3.0% w/v.
5. The Oral liquid composition as claimed in claim 1, wherein the preservative is sodium benzoate, benzyl alcohol, potassium sorbate, sorbic acid, benzoic acid, benzalkonium chloride, cetrimide, ethyl alcohol, para hydroxyl benzoic acid esters like methyl paraben, propyl paraben, and combinations thereof, present in a concentration range of from 0.01% w/v to 2.0% w/v.
6. The Oral liquid composition as claimed in claim 1, wherein the pH of the composition ranges from 4.5 to 9.
7. The Oral liquid composition as claimed in claim 1, wherein the solvent/ vehicle is selected from glycerin, ethanol, propylene glycol, water or mixtures thereof in a concentration range of 30% w/v to 60% w/v.
8. The Oral liquid composition as claimed in claim 1, wherein the composition comprising:
Sucroferric oxyhydroxide in an amount of from 1%w/w to 20% w/w;
a suspending agent in an amount of about 2.0% w/w;
a preservative in an amount of from 0.01% to 2.0% w/w;
a sweetener in an amount of about 0.1% w/w to 2% w/w
and solvent/ co-solvent.
9. The Oral liquid composition as claimed in claim 1, wherein the sucroferric oxy hydroxide has a d90 particle size of about 10 µm.