WO2016162794A1

WO2016162794A1 - Pharmaceutical compositions of ferric citrate

Info

Publication number: WO2016162794A1
Application number: PCT/IB2016/051933
Authority: WO
Inventors: Kocherlakota Chandrashekhar; Banda Nagaraju
Original assignee: Leiutis Pharmaceuticals Pvt Ltd
Priority date: 2015-04-08
Filing date: 2016-04-06
Publication date: 2016-10-13

Abstract

The present invention relates to pharmaceutical compositions of Ferric citrate tablets having specific surface area of Ferric citrate less than 16m²/gm. Further the invention relates to method of preparing Ferric citrate tablets having specific surface area of less than 16m²/gm.

Description

Pharmaceutical compositions of Ferric citrate

Background of the invention

Ferric citrate is chemically described as iron (+3), x (1, 2, 3-propanetricarboxylic acid, 2-hydroxy-), y (H₂0). Ferric citrate has the following structure:

Ferric citrate is an iron (III) citrate salt composed of ferric iron and citrate ions in an undefined molecular composition. Ferric citrate is used as an iron fortificant and hematinic agent.

During storage the chemical composition of the ferric citrate complex does not change. However, even when protected from light, the physical characteristics of Ferric citrate change significantly. For example, the color of Ferric citrate changes from green to garnet red or pale brown. In addition, the solubility of the complex changes from water soluble to water insoluble.

Polymerization of Ferric citrate also adversely changes the biological properties and bioavailability of the Ferric citrate complex. The biological properties and bioavailability of polymeric Ferric citrate more closely resemble those of ferritin, the physiological storage form of iron, than physiologically bioavailable iron, as in iron salts such as ferrous sulfate. Once formed, high molecular weight ferric citrate polymers are very slow to dissociate to low molecular weight chemical entities that provide iron.

The polymerization of freshly prepared Ferric citrate can be prevented or slowly reversed under certain conditions. For instance, if a 20-fold excess of citrate is present in a solution of freshly prepared Ferric citrate, polymerization of the Ferric citrate will be suppressed. Likewise, a 20-fold excess of citrate in solution will reverse polymerization over a period of many days. U.S. Pat. No. 5,753,706 to Chen Hsing discloses the use of ferric containing compounds including Ferric citrate and Ferric acetate in the crystalline form, in an orally effective one gram dosage form, to bind to soluble dietary phosphate.

U.S. Pat. No. 6,903,235 to Hsiao discloses that Ferric citrate is commercially available in the form of a combination of iron and citric acid of indefinite composition. The '235 patent explains pharmaceutical-grade ferric citrate having ferric citrate with a definite hydrate and manufacturing process for preparing the same.

Ferric citrate is commercially available as Auryxia in the US. It is approved by the Food and Drug Administration for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. Auryxia 210 mg Ferric iron tablets, equivalent to lg Ferric citrate, are film-coated, peach-colored oval-shaped tablets.

US patent Nos. 7,767,851; 8,338,642; 8,609,896 and 8,901,349 all assigned to Kwok et al., disclose orally administrable forms of Ferric citrate having a BET active surface area greater than about 16 m²/g. The increased surface area results in a significantly increased dissolution rate, thereby providing rapid onset of action in binding to dietary phosphate.

Summary of the Invention

One aspect of the present invention is to provide Ferric citrate tablets, wherein specific surface area of Ferric citrate is less than 16m²/gm.

Another aspect of the present invention is directed to the preparation of Ferric citrate tablets, wherein the specific surface area of Ferric citrate is less than 16m²/gm.

Yet another aspect of the invention is to provide Ferric citrate tablets with a dissolution profile comparable to the reference listed drug. Yet another aspect of the present invention relates to the manufacturing process for the preparation of ferric citrate tablets. The process may involve wet granulation or dry granulation, otherwise known as slugging.

Detailed description of the Invention

As used here in the term specific surface area is defined as a property of solids which is the total surface area of a material per unit of mass and can be measured using a BET (Brunauer Emmett Teller) surface area measurement.

The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to +15% of the value.

The present invention is directed to the preparation of Ferric citrate tablets having specific surface area of Ferric citrate less than 16m²/gm with a dissolution profile comparable to that of reference listed drug. Reference listed drug of Ferric citrate is Auryxia available as 210 mg (ferric iron) tablets, equivalent to 1 gram ferric citrate.

Yet another aspect of the present invention relates to the manufacturing process for the preparation of ferric citrate tablets such as wet granulation or dry granulation process using suitable excipients which is responsible for its tablet disintegration property.

The inventors of the instant application surprisingly found that it is possible to make Ferric citrate tablets with similar dissolution profile as Auryxia tablets despite having a specific surface area of less than 16m²/gm. Preferably specific surface area of Ferric citrate is about 4m²/gm. More preferably the specific surface area of Ferric citrate is about 12m²/gm. More preferably the specific surface area of Ferric citrate ranges from about 10 to less than 16m²/gm.

The tablets made according to the invention comprise one or more excipients selected from the group comprising of binders, disintegrants, glidants, flow control agents, lubricants, surfactants and coating agents. In one embodiment of the invention, the tablets comprise

(i) Ferric citrate with a specific surface area < 16m²/gm

(ii) One or more excipients selected from disintegrants and binders.

(iii) Flow aids like lubricants and glidants and

(iv) Suitable coating

In another embodiment of the invention, the tablets comprise

(i) Ferric citrate with a specific surface area of about 4m²/gm

(ii) One or more excipients selected from disintegrants and binders.

(iii) Flow aids like lubricants and glidants and

(iv) Suitable coating

In a more preferred embodiment, the tablets comprise

(i) Ferric citrate with a specific surface area ranging from about 10 to less thanl6m²/gm.

(ii) Disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch.

(iii) Binder selected from the group of polysaccharides, hydroxy propyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyethylene glycols, pregelatinized starch.

(iv) Lubricants and glidants selected from stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc.

(v) Coating materials selected from hydroxy propyl methyl cellulose, polyvinyl alcohol, hydroxy ethyl cellulose, ethyl cellulose, solvents, plasticizers and the like.

Suitable binders include, but not limited to, celluloses such as microcrystalline cellulose, modified celluloses (such as low substituted hydroxypropyl cellulose, hydroxypropyl cellulose (or HPC), hydroxypropyl methylcellulose (or HPMC or hypromellose-low viscosity), hydroxyethylcellulose, hydroxyethyl methylcellulose, cellulose gum, xantham gum, sugars (such as sucrose, glucose, amilose, maltodextrin, dextrose and the like), polyvinyl alcohol- polyethylene glycol graft copolymer (Kollicoat IR), copovidone, cross-linked polyvinylpyrrolidone, pregelatinized starch, carbomers, polycarbophil, polyethylene oxide, polyethylene glycol or a combination thereof.

Examples of disintegrants include, but not limited to sodium starch glycolate, alginic acid, powdered cellulose, pregelatinized starch, croscarmellose sodium, polyvinylpyrrolidones, including modified polyvinylpyrrolidones such as crospovidone, docusate sodium, guar gum, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, microcrystalline cellulose or a combination thereof.

Examples of glidants include, but are not limited to calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous and the like.

Examples of lubricants include, but are not limited to, calcium stearate, zinc stearate, magnesium stearate, aluminium stearate, stearic acids, sodium stearyl fumarate, hydrogenated castor oil, light mineral oil, magnesium lauryl sulfate and the like.

Solvents used for granulation can be either aqueous or non-aqueous solvents. Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, methanol, ethanol, dichloro methane, acetone and the like. Other Suitable solvents can also be selected from dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), l-methyl-2- pyrrolidone (NMP), l,3-dimethyl-2-imidazolidinone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), glycerine, dimethyl isosorbide and mixtures thereof. Aqueous solvent includes water. Combination of aqueous and non-aqueous solvents can also be used.

Compressed tablets are further film coated by non-aqueous coating or aqueous coating or by hydro alcoholic coating. This film coating contains at least one compound selected from the group comprising film-forming substances, e.g. hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol, optionally being possible for other auxiliary substances, such as plasticizers, solvents, lubricants and colourants, to be present. Preferred plasticizers are polyethylene glycol (Macrogols e.g. Macrogol 6000), triethyl citrate and triacetin. The film coating may also contain excipients such as, excipients for better film adhesion, preferably lactose and/or stearic acid, release agents/antiadhesive agents, preferably talcum and/or glycerol monostearate, and colourants (pigments and lakes). A preferred blend of hydroxypropyl methylcellulose, a plasticizer and a colorant is commercially available under the tradename OPADRY^®.

The present invention provides a method of preparing ferric citrate tablets using wet granulation or dry granulation process.

The wet granulation process for the manufacture of Ferric citrate tablets involves the following steps:

(i) Blending a mixture of ferric citrate and excipients such as binder, disintegrant,

(ii) Granulating the above mixture in a granulator/fluid bed processor by spraying aqueous/non-aqueous solvent onto the powder, followed by sieving of the wet mass,

(iii) Drying the granulated mass,

(iv) Milling the dried mass to form granules of suitable size,

(v) Lubricating the milled granules,

(vi) Compressing the lubricated granules into tablets.

(vii) Coating the compressed tablets

Alternately, the tablets can be made by dry granulation process comprising:

(i) Blending a mixture of ferric citrate and excipients such as disintegrant.

(ii) Slugging or dry granulating the above blend followed by milling.

(iii) Blending the above slugs with excipients such as binder or disintegrant.

(iv) Lubricating the above blend.

(v) Compressing the lubricated material into tablets.

(vi) Coating the compressed tablets. The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Examples

Example 1

Manufacturing process:

Ferric citrate, pregelatinized starch and crospovidone were cosifted from sieve #40 and blended. Granulation was carried out using a binder solution of pregelatinized starch dissolved in water using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55°C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry.

Example 2

Film coating ingredients

6 Opadry (non aqueous coating) suspension q.s

Coated tablet weight 1200

Manufacturing process:

Ferric citrate, pregelatinized starch and crospovidone were cosifted from sieve #40 and blended. Granulation was carried out by spraying water using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55°C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry.

Example 3

Manufacturing process:

Ferric citrate and pregelatinized starch were cosifted from sieve #40 and blended. Granulation was carried out by spraying water using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55°C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry. Example 4:

Ferric citrate and crospovidone were co sifted through sieve #40 and blended. The blended material was compressed into slugs and milled and passed through sieve # 10. The slugs were blended with L-hydroxy propyl cellulose. The blend was lubricated with magnesium stearate and compressed into tablets. The compressed tablets were coated using opadry coating material.

Example 5

Manufacturing process:

Ferric citrate and pregelatinized starch were cosifted from sieve #40 and blended. Granulation was carried out by spraying isopropyl alcohol: water mixture using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55°C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry. Example 6

Manufacturing process:

Ferric citrate, pregelatinized starch and crospovidone were cosifted from sieve #40 and blended. Granulation was carried out by spraying isopropyl alcohol: water mixture using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55 °C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry.

Example 7

Manufacturing process:

Ferric citrate, hydroxy propyl methyl cellulose/L hydroxy propyl cellulose/partially pregelatinized starch were cosifted from sieve #40 and blended. Granulation was carried out by spraying water using a rapid mixer granulator. The wet mass was passed through sieve#10 and the granules were dried at 55°C and subsequently milled. The granules were lubricated with calcium stearate and the blend was compressed as tablets. The compressed tablets were coated using opadry.

Example 8

Manufacturing process:

Ferric citrate and crospovidone were cosifted through sieve #40 and blended. The blended material was compressed into slugs and milled and passed through sieve # 10. The slugs were blended with L-hydroxy propyl cellulose. The blend was lubricated with magnesium stearate and compressed into tablets. The compressed tablets were coated using opadry coating material.

Various trials were carried out with different surface areas in the ranges described above. It has been found that the Ferric citrate tablets prepared according to the invention produced comparative dissolution profile to that of reference listed drug. The dissolution data of the Ferric citrate tablets prepared according to the invention is compared to commercially available Auryxia^® tablets (Batch No. 458593). Dissolution tests were performed with USP apparatus Type II paddle method at 100 RPM in 900 ml in various dissolution media at 37+0.5°C. The comparative data is summarized in tables 1 and 2.

Table 1: Comparative dissolution data of ferric citrate tablets prepared according to the invention with RLD in Mcilvaine buffer.

Table 2: Comparative dissolution data of ferric citrate tablets prepared according to the invention with RLD in EDTA dissolution media.

RPM: Rotations per minute

RLD: Reference listed drug

Example 9

Manufacturing process:

Claims

We Claim

Claim 1: A pharmaceutical tablet dosage form of ferric citrate, prepared from ferric citrate having a specific surface area less than 16m²/g.

Claim 2: A pharmaceutical tablet dosage form of ferric citrate according to claim 1, wherein said ferric citrate has a specific surface area of about 12m²/g.

Claim 3: A pharmaceutical tablet dosage form of ferric citrate according to claim 1, wherein said ferric citrate has a specific surface area of about 4m²/g.

Claim 4: A pharmaceutical tablet dosage form of ferric citrate according to claim 1, wherein said ferric citrate has a specific surface area ranging from about 10 to less than 16m²/g.

Claim 5: A pharmaceutical tablet dosage form of ferric citrate prepared from ferric citrate having a specific surface area less than 16m²/g and having comparative dissolution profile with reference listed drug.

Claim 6: A pharmaceutical tablet according to claim 1 and 5 comprises of Ferric citrate and other pharmaceutically acceptable excipients thereof.

Claim 7: A pharmaceutical tablet according to claim 6, wherein said pharmaceutically acceptable excipient is selected from the group consisting of binder, disintegrant, lubricant, glidant, and other pharmaceutically acceptable excipients or combinations thereof.

Claim 8: A pharmaceutical tablet according to claim 7, wherein the disintegrant is selected from one or more of crospovidone, sodium starch glycolate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch. Claim 9: A pharmaceutical tablet according to claim 7, wherein the binder is selected from one or more of polysaccharides, pregelatinized starch, hydroxy propyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyethylene glycols.

Claim 10: A pharmaceutical tablet according to claim 7, wherein lubricants and glidants are selected from one or more of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal silicon dioxide and talc.

Claim 11: The composition according to claim 1 and 5, wherein the tablet comprises of atleast one coating.