DESC:
Field of the Invention

The present invention relates to a stable pharmaceutical composition comprising Nitisinone and excipients and a stabiliser selected from fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof, wherein said composition is free of lactose and mannitol. It further relates to a method of treating hereditary tyrosinemia type 1 (HT-1) by administering the said composition.

Background of the Invention

Nitisonone is a hydroxyphenyl-pyruvate dioxygenase inhibitor, commercially available as tablets, capsules and oral suspension for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) and Alkaptonuria in combination with dietary restriction of tyrosine and phenylalanine. Chemically it is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione.
HT-1 disease is due to a deficiency of the final enzyme of the tyrosine catabolic pathway fumarylacetoacetate hydrolase. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme which precedes fumarylacetoacetate hydrolase. By inhibiting the normal catabolism of tyrosine in patients with HT-1, Nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate, that in patients with HT-1 are converted to the toxic metabolites Succinylacetone and Succinylacetoacetate, the former inhibiting the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.

Nitisinone is known to be unstable at room temperature, due to stability issues, the Nitisinone capsule must be stored at 2-8°C. There have been various efforts made in the past to prepare stable formulation of Nitisinone. Therefore, there is a continuing need to develop a stable formulation of Nitisinone.

PCT Publication No. 2017137468 discloses highly stable pharmaceutical composition comprising 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as the active ingredient, one stabilizer and at least one excipient. It identifies that Nitisinone with stearic acid as a stabilizer, surprisingly gives rise to highly stable pharmaceutical compositions even at room temperature for long period of time.

PCT Publication No. 2015101794 discloses pharmaceutical composition of Nitisinone which possesses excellent storage stability. Nitisinone composition disclosed are stable under a range of temperature conditions, such that there are no longer any storage implications. It discloses that association with lactose further enhances the stability and prevents formation of the undesired cyclized product.

PCT Publication No. 2013181292, discloses pharmaceutical formulations of Nitisinone which were alleged to be stabilized for long term storage. The application discloses that the presence of citric acid enabled stabilization of the formulation.

CN112107548 discloses pharmaceutical composition comprising Nitisinone, a surface stabilizer, a glidant, a pH regulator and a filler. The composition comprises, 0.1% - 10% of Nitisinone, 0.1%
- 5% of a surface stabilizer, 0% - 1% of a glidant, 0% - 5% of a pH regulator, and 70% - 95% of a filler.

PCT Publication No. 2012177214 discloses oral liquid suspensions of Nitisinone containing citric acid buffer as a stabilizer.

The stability of a drug is of paramount importance and is required so that the drug product meets its acceptance criteria throughout the lifetime and to gain regulatory approval.

In order to avoid unacceptable degradation of Nitisinone, prior art teaches use of specific excipients. However, the prior arts fails to teach a Nitisinone composition wherein the composition is stable for long duration of time and the shelf life of Nitisinone has been increased abruptly. It is however, desirable to provide alternative stable Nitisinone composition, wherein the degradation of Nitisinone is such that the pharmaceutical tablet composition fulfills the regulatory stability criteria for pharmaceutical tablets and can be stored for long duration of time.

It is surprisingly found that Nitisinone compositions comprising various excipients and stabiliser selected from fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof are stable. Additionally, Nitisinone composition is free of lactose, and mannitol and is found to be stable.

Thus, the present invention relates to stable Nitisinone compositions and process of preparation thereof. The compositions have acceptable stability in terms of related substances, even after storage at accelerated conditions.

Summary of the Invention

A first aspect of the present invention provides a stable Nitisinone composition comprising Nitisinone and excipients and a stabiliser selected from the group consisting of fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof, wherein said composition is free of lactose, and mannitol.

According to another embodiment of the present invention, the composition further comprises one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, lubricants, or mixtures thereof.

The present invention relates to pharmaceutical composition of active pharmaceutical ingredients including Nitisinone, diluent including microcrystalline cellulose, acid modifier such as maleic acid and lubricant including Sodium Stearyl fumarate.

According to one embodiment of the present invention, the said composition does not have more than 0.2% of acid impurity and 0.6% of total impurity when stored at 40oC/75% RH for a period of four weeks.

According to another embodiment of the present invention, Nitisinone is present in an amount of 1.0 % to 10%, preferably in an amount of 7.0 % to 9.0 % by weight of the composition.

According to another embodiment of the present invention, the composition is a tablet, capsule minitablets, granules, powder for oral suspension or pellets.

According to another embodiment of the present invention, the composition is prepared by direct compression.

According to another embodiment of the present invention, the composition is prepared by a direct compression comprising the steps of:
(i) preparing a dry blend of Nitisinone, stabilizer and one or more pharmaceutically acceptable excipients, and
(ii) directly compressing the blend of i) to obtain stable Nitisinone composition.

This summary is not intended to limit the key essential features of the present invention nor its scope and application. Other advantages and details about the composition and the method will become more apparent to a person skilled in the art from the below detailed description of the invention when read in conjugation with the drawings.

DETAIL DESCRIPTION OF THE INVENTION
DEFINITIONS

The term "Nitisinone", as used herein, refers to Nitisinone and one or more pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. The present invention comprises Nitisinone in an amount of from about 1.0% to about 15.0% by weight of the composition. Preferably, Nitisinone present in an amount of from
about 1.5 % to about 9.0 % by weight of the composition. Nitisinone is commercially available as tablets having strength 2.0 mg, 5.0 mg and 10.0 mg, as capsules having strength 2.0 mg, 5.0 mg, and 10.0 mg and as 4mg/ml suspension.

The term "stable" as used herein refers to a negligible reduction in the content of active ingredient with the lapse of time.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "pharmaceutically acceptable excipients", as used herein, includes any physiologically inert additives that are routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients may include, but are not limited to, disintegrant, diluents, and lubricants/glidants.

Suitable stabilizers are selected from group comprising of maleic acid, fumaric acid, glutamic acid and aspartic acid. Maleic and fumaric acid are dibasic organic acid, whereas glutamic acid and aspartic acid are amino acids. According to one embodiment of the invention, the composition is free of citric acid.

Suitable diluents or fillers are selected from the group comprising of magnesium carbonate, calcium silicate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, sucrose, sorbitol, xylitol, erythritol, kaolin, calcium silicate, maltodextrin, microcrystalline cellulose, pregelatinized starch, maize starch, corn starch, or mixtures thereof. The present invention comprises one or more diluents in an amount of from about 60% to about 92% by weight of the composition. Among the diluents, microcrystalline cellulose is the preferred diluent. According to one embodiment of the invention, the composition is free of lactose and mannitol.

Suitable lubricants/glidants/anti-adherents are selected from the group comprising magnesium stearate, calcium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, zinc stearate, aluminum silicate,
talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof. The present invention comprises one or more Lubricants in an amount of from about 1% to about 5% by weight of the composition. Various lubricants are used such as Glyceryl, Sodium Sterayl fumarate etc. Among the lubricant, sodium stearyl fumarate is the preferred lubricant.

DESCRIPTION
The present invention provides a stable Nitisinone composition comprising Nitisinone and excipients and a stabiliser selected from the group consisting of fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof, wherein said composition is free of lactose, and mannitol.

The present invention relates to a pharmaceutical composition which comprises a active pharmaceutical ingredients and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, lubricants, or mixtures thereof.

The present invention relates to pharmaceutical composition of active pharmaceutical ingredients including Nitisinone, diluent including microcrystalline cellulose, acid modifier such as maleic acid and lubricant including Sodium Stearyl fumarate.

The inventors of the present invention have surprisingly found that the stability of the Nitisinone composition has been increased in the instant composition upto 6 months. Additionally, such composition does not have more than 0.2% of acid impurity and 0.6% of total impurity when stored at 40oC/75% RH for a period of six months.

The amount of Nitisinone in the pharmaceutical composition of present invention is in the range of 1-10 %w/w. Further, in the preferred embodiment, the amount of microcrystalline cellulose is in the range of 80-95 %w/w, amount of maleic acid is in the range of 0.5-6.0 %w/w, and the Sodium stearyl fumarate is in the range of 0.8-4 %w/w.

Thus, the details of composition of Nitisinone in Nitisinone tablet is as follows:
Nitisinone Tablets
Ingredients % W/W
Nitisinone 1-10
Microcrystalline Cellulose 80-95
Maleic Acid 0.5-6.00
Sodium Stearyl Fumarate 0.5 -4.0

Suitable diluent which includes but are not limited to microcrystalline cellulose 0.5 - 4%. Further, microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and direct-compression processes. In addition to its use as a binder/diluent, microcrystalline cellulose also has some lubricant and disintegrants properties that make it useful in tablets.

Suitable acid modifier which includes but are not limited to fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures. However, Fumaric acid is the trans and Maleic acid the cis isomer. The physical properties of Maleic acid and fumaric acid are very different. The cis isomer is less stable. Maleic acid is used in the preparation of fumaric acid by catalytic isomerization. Maleic acid is used in the pharmaceutical industry as a pH modifier and a buffering agent. It is also used to prevent rancidity of oils and fats; a ratio of 1 : 10 000 is usually sufficient to retard rancidity. Maleic acid is commonly used as a pharmaceutical intermediate to form the maleate salts of several categories of therapeutic agents, such as salts of antihistamines and other drug substances.

Suitable lubricant which includes but are not limited to Sodium Stearyl Fumarate,0.5-4%. Sodium stearyl fumarate is used as a lubricant in capsule and tablet formulations at 0.5–4.0% w/w concentration. Sodium stearyl fumarate is supplied in a pure form and is often of value when the less pure stearate-type lubricants are unsuitable owing to chemical incompatibility. Sodium stearyl fumarate is less hydrophobic than magnesium stearate or stearic acid and has a less retardant effect on tablet dissolution than magnesium stearate.

The present invention comprises one or more lubricants in an amount from about 0.5% to about 4% by weight of the composition.

The pharmaceutical composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, powder for oral suspension or pellets. The compositions in the form of tablets may be prepared by conventional processes known to a person skilled in the art such as wet granulation, dry granulation or direct compression. Preferably the process involves direct compression.

In one embodiment, there is provided a stable pharmaceutical composition of Nitisinone which is prepared by direct compression methods.
The pharmaceutical compositions of the present invention are prepared by a direct compression comprising the steps of:
(i) preparing a dry blend of Nitisinone, stabilizer and one or more pharmaceutically acceptable excipients, and
(ii) directly compressing the blend of i) to obtain stable Nitisinone compositions.

The pharmaceutical composition of Nitisinone may be manufactured by using various compression technique and specifically with direct compression methods. The manufacturing method of preparation of Nitisinone composition includes:
• Dispense all the raw materials such as Nitisinone, Microcrystalline Cellulose, Maleic Acid, Sodium Stearyl Fumarate.
• Mix Nitisinone and Microcrystalline Cellulose in geometrical order and sift through #40 mesh fitted to vibro sifter and collect in double poly-lined containers.
• Co-sift the above step and Maleic acid through #40 mesh fitted to vibro sifter and collect in double poly-lined containers.
• Load the Co-sifted blend of Step-5.3 in suitable capacity of blender and mix for 20 minutes at 10 RPM.
• Sift quantity of Sodium Stearyl Fumarate through 60# mesh and add it to step-5.4 blend, lubricate for 3 minutes at 10 RPM.
• Unload the lubricated blend in double poly-lined containers.

Following examples are further illustrated and are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1:

Ingredients mg/tablet mg/tablet mg/tablet mg/tablet
Example 1 2 3 4
Nitisinone 10.00 10.00 10.00 10.00
Microcrystalline cellulose 108.68 108.20 108.68 108.20
Aspartic Acid/Glutamic Acid/ Maleic Acid 0.12 0.60 0.12 0.60
Sodium Stearyl Fumrate 1.20 1.20 - -
Glycerol Dibehenate - - 1.20 1.20
Total weight of Core Tablet 120.00 120.00 120.00 120.00

Procedure:

1. Nitisinone, stabilizer (aspartic acid or glutamic acid or maleic acid) and microcrystalline cellulose are blended in a blender followed by lubrication with sodium stearyl fumarate or glyceryl behenate.

2. The lubricated blend of step 1 is then compressed to obtain Nitisinone tablets.

Example 5-10:
Ingredients mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet
Example 5 6 7 8 9 10
Nitisinone 10.00 10.00 5.00 5.00 2.00 2.00
Aspartic acid/Glutamic acid /Maleic acid
108.80
108.80
113.80
113.80
116.80
116.80
Sodium Stearyl Fumrate 1.20 - 1.20 - 1.20
Glycerol Dibehenate - 1.20 1.20 - 1.20 -
Total weight of Core Tablet 120 120 120.00 120.00 120.00 120.00

Procedure:

1. Nitisinone and stabilizer (aspartic acid or glutamic acid or maleic acid) is blended in a blender followed by lubrication with sodium stearyl fumarate (example 5, 8 and 10) or glyceryl behenate (example 6, 7 and 9).

2. The lubricated blend of step 1 is then compressed to obtain Nitisinone tablets.

Example 11-16

Ingredients mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet
Example 11 12 13 14 15 16
Nitisinone 10.00 10.00 5.00 5.00 2.00 2.00
Maleic Acid 54.40 54.40 56.90 56.90 58.40 58.40
Glutamic Acid 54.40 54.40 56.90 56.90 58.40 58.40
Sodium Stearyl Fumrate 1.20 1.20 - 1.20 -
Glycerol Dibehenate - 1.20 - 1.20 1.20
Total weight of Core Tablet 120.00 120.00 120.00 120.00

Procedure:

1. Nitisinone, glutamic acid and maleic acid are blended in a blender followed by lubrication with sodium stearyl fumarate/ glycerol dibehenate.

2. The lubricated blend of step 1 is then compressed to obtain Nitisinone tablets.

Example 16- 21:

Ingredients mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet
Example 16 17 18 19 20 21
Nitisinone 10.00 10.00 5.00 5.00 2.00 2.00
Maleic Acid 36.28 36.28 37.92 37.92 38.93 38.93
Glutamic Acid 36.26 36.26 37.94 37.94 38.93 38.93
Aspartic Acid 36.26 36.26 37.94 37.94 38.94 38.94
Sodium Stearyl Fumrate 1.20 1.20 - 1.20 -
Glycerol Dibehenate - 1.20 - 1.20 - 1.20

Total weight of Core Tablet 120.00 120.00 120.00 120.00 120.00 120.00

Procedure:

1. Nitisinone, aspartic acid, glutamic acid and maleic acid are blended in a blender followed by lubrication with sodium stearyl fumarate or glycerol dibehenate.

2. The lubricated blend of step 1 is then compressed to obtain Nitisinone tablets.

Example 22-24

Nitisinone Tablets 10 mg 5 mg 2 mg
Sr. No. Ingredients Qty.
mg/Tab Qty.
mg/Tab Qty.
mg/Tab
1 Microcrystalline Cellulose 75.00 to 100 80.00 to 105 85.00 to 108
2 Maleic Acid 0.5 to 6.00 0.5 to 6.00 0.5 to 6.00
3 Sodium Stearyl Fumarate 2.5 to 4.00 2.5 to 4.00 2.5 to 4.00

Procedure:

1. Dispense all the raw materials such as Nitisinone, Microcrystalline Cellulose, Maleic Acid, Stearyl Fumarate.
2. Mix Nitisinone and Microcrystalline Cellulose in geometrical order and sift through #40 mesh fitted to vibro sifter and collect in double poly-lined containers.
3. Co-sift the above step and Maleic acid through #40 mesh fitted to vibro sifter and collect in double poly-lined containers.
4. Load the Co-sifted blend of Step-5.3 in suitable capacity of blender and mix for 20 minutes at 10 RPM.
5. Sift quantity of Sodium Stearyl Fumarate through 60# mesh and add it to step-5.4 blend, lubricate for 3 minutes at 10 RPM.
6. Unload the lubricated blend in double poly-lined containers.
7. Compress lubricated blend to form the Nitisinone pharmaceutical composition of 10mg, 5mg and 2mg in accordance with the present invention.

Further, since lactose and Mannitol or their derivatives are note used in the present Nitisinone formulation that’s why the formulation is free of Lactose and Mannitol.

While the 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 with the scope of the present invention.

We claim:

1. A stable pharmaceutical composition comprising: Nitisinone pharmaceutically accepted salt thereof; one or more pharmaceutically acceptable excipients; and a stabiliser selected from the group consisting of fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof, wherein the pharmaceutical composition is composition is free of lactose, and mannitol.

2. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, lubricants, or mixtures thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein the diluent includes microcrystalline cellulose, acid modifier includes maleic acid and lubricant includes Sodium Stearyl fumarate.

4. The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprising Nitisinone, microcrystalline cellulose, maleic acid and Sodium Stearyl fumarate.

5. The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprising Nitisinone in the range of 1-10%w/w, microcrystalline cellulose in the range of 80-95% w/w, maleic acid in the range of 0.5-6.00 %w/w and Sodium Stearyl fumarate in the range of 0.5-4.0% w/w.

6. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is stable for a period of six months.

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition does not have more than 0.2% of acid impurity and 0.6% of total impurity when stored at 40oC/75% RH for a period of six months.

,CLAIMS:We claim:

1. A stable pharmaceutical composition comprising: Nitisinone pharmaceutically accepted salt thereof; one or more pharmaceutically acceptable excipients; and a stabiliser selected from the group consisting of fumaric acid, maleic acid, aspartic acid, glutamic acid and mixtures thereof, wherein the pharmaceutical composition is composition is free of lactose, and mannitol.

2. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, lubricants, or mixtures thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein the diluent includes microcrystalline cellulose, acid modifier includes maleic acid and lubricant includes Sodium Stearyl fumarate.

4. The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprising Nitisinone, microcrystalline cellulose, maleic acid and Sodium Stearyl fumarate.

5. The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprising Nitisinone in the range of 1-10%w/w, microcrystalline cellulose in the range of 80-95% w/w, maleic acid in the range of 0.5-6.00 %w/w and Sodium Stearyl fumarate in the range of 0.5-4.0% w/w.

6. The stable pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is stable for a period of six months.

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition does not have more than 0.2% of acid impurity and 0.6% of total impurity when stored at 40oC/75% RH for a period of six months.