DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
(See section 10 and rule 13)

PROVISIONAL SPECIFICATION

“A STABLE PHARMACEUTICAL COMPOSITION OF BUMETANIDE”

AMNEAL PHARMACEUTICALS PVT. LTD.
9th Floor, Iscon Elegance, Near Shapath - 5, Opp. Karnavati Club,
Prahaladnagar Crossroads, S.G. Highway,
Ahmedabad -380015, Gujarat, India

THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION:

A STABLE PHARMACEUTICAL COMPOSITION OF BUMETANIDE

FIELD OF THE INVENTION
The present invention relates to a stable solid pharmaceutical composition comprising bumetanide or a pharmaceutically acceptable salt thereof, process for preparing and method for using such composition.

BACKGROUND OF THE INVENTION
Bumetanide is a loop diuretic widely used to treat congestive heart failure and other oedematous conditions. Chemically, bumetanide is designated as 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid having the structural formula depicted in FIG. 1. An oral tablet formulation of bumetanide is commercially available under the trade name Bumex®.

FIG. 1
U.S. Patent Number 3,634,583 discloses pharmaceutical compositions containing as an active component bumetanide, or its pharmaceutically acceptable salt with organic or inorganic bases, together with solid or liquid pharmaceutical carriers and auxiliary agents. The disclosed compositions are useful in the treatment of edematous conditions.
Bumetanide may be prone to degradation which may result in formation of relatively high levels of impurities in the commercial product during storage. One such degradation impurity is 3-(butyl(nitroso)amino)-4-phenoxy-5-sulfamoylbenzoic acid (N-nitrosobumetanide) depicted in FIG. 2, which may form by a nitrosating reaction at the nitrogen of the N-butyl side chain of bumetanide.

FIG.2
N-nitroso compounds are known to be genotoxic and have carcinogenic potential in animals, including higher primates and humans. Several nitrosamine impurities, including N-nitrosodimethylamine (NDMA), have been classified as “probably carcinogenic to humans.” An investigation by the U.S. Food and Drug Administration (“USFDA”) found that nitrosamine impurities may increase the risk of cancer in patients, if they are exposed to above acceptable levels and over long periods of time. USFDA has also released a guidance document, “Control of Nitrosamine Impurities in Human Drugs,” recommending steps, including a comprehensive risk assessment strategy and other actions that manufacturers of active pharmaceutical ingredients (“API”) and drug products should take, to reduce or prevent the presence of such impurities in drug products.
Thus, there is a need for stable compositions of bumetanide which would present enhanced stability properties during storage, and in which the degradation to N-nitroso impurities is significantly controlled and reduced, in comparison to currently available compositions. The inventors of the present invention address the above problems and have discovered bumetanide compositions that have significantly lower initial quantities of such undesirable impurities immediately after manufacturing, and which are also stable under various stress conditions and yield relatively low amounts of N-nitroso impurities, such as N-nitrosobumetanide, on long term storage.

SUMMARY OF THE INVENTION
In one general aspect, the present invention relates to a stable solid pharmaceutical composition of bumetanide possessing enhanced storage stability properties at various temperature and humidity conditions. Accordingly, the invention provides a composition comprising or consisting essentially of bumetanide or pharmaceutically acceptable salt thereof, a stabilizer, and at least one pharmaceutically acceptable excipient, wherein the composition has reduced level of N-nitroso impurities.
In one embodiment, the stabilizer is selected from a group consisting of a sugar, a sugar alcohol, an organic acid, an inorganic acid, or mixtures thereof. In another embodiment, the stable solid pharmaceutical composition is a tablet.
The present invention also relates to a process for preparation of a stable solid pharmaceutical composition, wherein the process comprises the steps of (a) mixing bumetanide or pharmaceutically acceptable salt thereof, a stabilizer and at least one pharmaceutically acceptable excipient, and (b) converting the mixture into a pharmaceutical composition, wherein the composition has reduced level of N-nitroso impurities.
The present invention also provides a method for treating oedematous condition in a patient comprising administering to the patient a stable solid pharmaceutical composition comprising or consisting essentially of bumetanide or pharmaceutically acceptable salt thereof, a stabilizer, and at least one pharmaceutically acceptable excipient, wherein the composition has reduced level of N-nitroso impurities.

DETAILED DESCRIPTION
The present invention relates to a stable solid pharmaceutical composition of bumetanide or a pharmaceutically acceptable salt thereof. The compositions include a stabilizer to reduce degradation and provide significantly lower levels of specified impurities, particularly N-nitroso impurities.
The term "about" described herein is intended to compensate for variability allowed for in the pharmaceutical industry and practice and includes an acceptable error range for the value. Alternatively, the term may allow for up to 5, 10, 15 or 20% variation from the stated value.
The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable for human pharmaceutical use. The term "pharmaceutically acceptable salt" means salts that are pharmaceutically acceptable, as defined above, that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Such salts also include salts formed with inorganic or organic bases. Bumetanide or pharmaceutically acceptable salt thereof may be present in amount ranging from about 0.1 mg to about 10 mg, preferably from about 0.25 mg to about 5 mg, in the composition.
The term "stable" as described herein refers to low levels of N-nitroso impurities in a pharmaceutical composition when exposed to specified temperature and humidity conditions for specified amount of time. Accordingly, the invention provides a composition containing less than 0.1% w/w of N-nitroso impurities when the composition is stored at a temperature of 25 °C and at 60% relative humidity. In another embodiment is provided a composition containing less than 0.1% w/w of N-nitroso impurities when the composition is stored at a temperature of 45 °C and at 75% relative humidity. In a preferred embodiment, the compositions as described herein contains less than 0.05% w/w or less than 0.02% w/w or less than 0.01% w/w of N-nitroso impurities, including N-nitrosobumetanide, measured as total weight of the composition.
The amount of impurities can also be expressed as parts per million (ppm) of the total weight of the composition. Accordingly, the present invention describes compositions containing less than 1000 ppm, or less than 500 ppm, or less than 200 ppm or less than 100 ppm of N-nitroso impurities, including N-nitrosobumetanide, when the composition is stored at specified temperature and humidity conditions.
The compositions as described herein exhibits enhanced storage stability and low levels of N-nitroso impurities for a shelf-life of a period of 24 months, or a period of 18 months, or period of 12 months, or 6 months, or a period of 3 months, or a period of one month, when stored at specified temperature and humidity conditions.
The stable compositions as described herein include a stabilizer selected from a group consisting of a sugar, a sugar alcohol, an organic acid, an inorganic acid, or mixtures thereof.
The sugar may be selected from a group consisting of a monosaccharide, a disaccharide, an oligosaccharide or polysaccharide. Preferably, the sugar includes, but are not limited to lactose, sucrose, maltose, and the like. The sugar may be present in an amount ranging from 10% to 99% by weight of the composition.
The sugar alcohol as described herein may be selected from mannitol, sorbitol, xylitol, and the like. The sugar alcohol may be present in an amount ranging from 10% to 99% by weight of the composition.
The stabilizer as described herein may be selected from organic acids such as citric acid, lactic acid, tartaric acid, malic acid, formic acid, acetic acid, and the like. The stabilizer may be selected from an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, and the like. The organic or inorganic acid may be present in an amount ranging from about 1% to 10% by weight of the composition.
According to another embodiment of the present invention, the stable pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient selected from diluent, binder, disintegrant, lubricant, glidant, and coating agent.
The diluent as described herein are selected from the group consisting of microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, lactose mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose, maltodextrin, dextrates, dextrin, and mixtures thereof. The diluent may present in an amount ranging from about 1% to 99% by weight of the composition, preferably from about 10% to 70% by weight of composition.
The binder as described herein are selected from the group consisting of a starch, natural and synthetic gum, cellulose derivative, gelatin, povidone, copovidone, polyethylene glycol, waxes, sodium alginate, alcohols, water, and mixtures thereof. Preferred binder include starch such as maize starch, pregelatinized starch, and the like. The binders may present in an amount ranging from about 1% to 20% by weight of composition, preferably from about 3% to 15 % by weight of composition, and more preferably from about 5 to 10% by weight of composition.
The disintegrant as described herein is selected from the group consisting of a crospovidone, sodium starch glycolate, crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), low substituted hydroxypropyl cellulose, and mixtures thereof. Preferable disintegrants include crospovidone and sodium starch glycolate. The disintegrant may present in an amount ranging from about 1% to 30% by weight of composition, preferably from about 1% to 25% by weight of composition, and more preferably from about 5% to 20% by weight of composition.
The lubricant as descried herein is selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, stearic acid, zinc stearate, and sodium stearyl fumarate and a combination thereof. Preferred lubricant includes magnesium stearate and sodium stearyl fumarate. The lubricant may be present in amount ranging from about 0.1% to 10% by weight of composition, preferably from about 0.5 to 5%, and more preferably from about 1% to 2% by weight of composition.
The glidant as described herein is selected from the group consisting of a starch, talc, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, colloidal silicon dioxide, and mixtures thereof. The glidant may be present in an amount ranging from about 0.1% to 20% by weight, preferably from about 0.5% to about 5%by weight of the composition.
In accordance with the invention, the term “solid” composition as described herein includes a tablet, capsule, granules or powder.
According to one embodiment, there is provided a process for preparation of stable solid pharmaceutical composition, wherein the process comprises the steps of (a) mixing bumetanide or pharmaceutically acceptable salt thereof, a stabilizer and at least one pharmaceutically acceptable excipient, and (b) converting the mixture into a pharmaceutical composition, wherein the composition has reduced level of N-nitroso impurities. In a preferred embodiment, the stable pharmaceutical composition is an oral tablet prepared by conventional techniques such direct compression or granulation, such as wet or dry granulation. Accordingly, there is provided a process for the preparation of a stable tablet comprising the steps of (a) mixing bumetanide or a pharmaceutically acceptable salt thereof, a stabilizer, and at least one pharmaceutically acceptable excipient, (b) compressing the mixture into a tablet, and (c) optionally coating the tablet. In another embodiment, the stable tablet as described herein can be prepared by (a) mixing bumetanide or a pharmaceutically acceptable salt thereof, a stabilizer, and at least one pharmaceutically acceptable excipient, (b) granulating the mixture with an aqueous or non-aqueous solvent, optionally containing a binder, (c) compressing the mixture into a tablet, and (d) optionally coating the tablet. Coating may be performed by applying a coating agent, with or without other pharmaceutically acceptable excipient, as a solution/suspension using conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.

The present invention further provides a method of for treating oedematous condition in a patient, such as treatment of edema associated with congestive heart failure, hepatic and renal disease, comprising administering to the patient a stable solid pharmaceutical composition as described above.

The following examples illustrate the invention but should not be construed as limiting the scope of the invention.

EXAMPLE 1: Bumetanide Tablet Containing Lactose as Stabilizer

Ingredients Weight (in Mg)
Bumetanide 2.0
Lactose 116.8
Magnesium stearate 1.2
Tablet Weight 120.0

Bumetanide was dry mixed with lactose; magnesium stearate was added as a lubricant and the mixture was compressed to produce a tablet. Each tablet contained 2 Mg bumetanide.

EXAMPLE 2: Bumetanide Tablet Containing Mannitol as Stabilizer

Ingredients Weight (in Mg)
Bumetanide 2.0
Mannitol 116.8
Magnesium stearate 1.2
Tablet Weight 120.0

Bumetanide was dry mixed with mannitol; magnesium stearate was added as a lubricant and the mixture was compressed to produce a tablet. Each tablet contained 2 Mg bumetanide.

EXAMPLE 3: Bumetanide Tablet Containing (Lactose and?) Citric Acid as Stabilizer
Ingredients Weight (in Mg)
Bumetanide USP 2.0
Lactose 142.3
Microcrystalline Cellulose 124.5
Pregelatinized Starch 34.0
Citric Acid 10.0
Maize Starch 17.0
Talc 6.8
Magnesium Stearate 3.4
Tablet Weight 340.00

Bumetanide was dry mixed with lactose, microcrystalline cellulose and pregelatinized starch. Citric acid was dissolved in isopropyl alcohol and the above dry mixture was granulated with the solution containing citric acid. The granules were dried and mixed with Maize Starch (disintegrant), talc (glidant) and magnesium stearate (lubricant), and the final blend obtained was compressed to produce a tablet. Each tablet contained 2 Mg Bumetanide.

EXAMPLE 4: Bumetanide Tablet Containing Mannitol and Citric acid as Stabilizer
Ingredients Weight (in Mg)
Bumetanide 2.0
Mannitol 113.2
Citric Acid 3.6
Magnesium stearate 1.2
Tablet Weight 120.0

Bumetanide was dry mixed with mannitol and citric acid; magnesium stearate was added as a lubricant and the mixture was compressed to produce a tablet. Each tablet contained 2 Mg Bumetanide.

EXAMPLE 5: Bumetanide Tablet containing Mannitol and Ascorbic acid as Stabilizer
Ingredients Weight (in Mg)
Bumetanide USP 2.000
Mannitol 113.200
Ascorbic Acid 3.600
Magnesium stearate 1.200
Tablet weight 120.00

Bumetanide was dry mixed with mannitol and ascorbic acid; magnesium stearate was added as a lubricant and the mixture was compressed to produce a tablet. Each tablet contained 2 Mg Bumetanide.

COMPARATIVE EXAMPLE 1: Bumetanide Tablet Containing No Stabilizer

Ingredients mg/tab
Bumetanide USP 2.0
Lactose 144.0
Microcrystalline Cellulose 132.8
Pregelatinized Starch 34.0
Maize Starch 17.0
Talc 6.8
Magnesium Stearate 3.4
Tablet Weight 340.0

Bumetanide was dry mixed with lactose, microcrystalline cellulose and Pregelatnized starch. The dry mixture obtained above was granulated by addition of isopropyl alcohol. The granules were dried, mixed with maize starch (disintegrant), talc (glidant) and magnesium stearate (lubricant), and the final blend obtained was compressed to produce a tablet. Each tablet contained 2 Mg Bumetanide.

EXAMPLE 6: Results obtained from Stability Testing of Examples 1-5 and Comparative Example 1 for the presence of N-Nitrosobumetanide.

Tablets prepared according to Examples 1-5 and Comparative Example 1 were stored under two accelerated storage conditions, at 40 °C and 75% relative humidity (RH) and at 25 °C and 60% RH. Samples were withdrawn at the end of 6 months and tested for N-nitrosobumetanide impurity content. A validated HPLC method was used for analysis of the samples. The stability results obtained are set forth in Table 1.

TABLE 1: Comparison of N-nitrosobumetanide impurity levels expressed in Parts Per Million (PPM)

Trial details Initial (ppm) 6 Month 40/75 (ppm) 6 Month 25/60 (ppm)
Comparative Example 1 573.28 - -
Example 1 2.4 8.0 8.1
Example 2 1.7 7.8 8.0
Example 3 27.6 35.3 49.6
Example 4 1.3 4.1 10.8
Example 5 1.15 1.40 1.80

,CLAIMS:We claim:
1. A stable pharmaceutical composition of bumetanide comprising stabilizer and at least one pharmaceutically acceptable excipient.
2. The stable composition of claim 1, wherein the stabilizer is selected from the group consisting of sugar, sugar alcohol, organic acid, or mixtures thereof.
3. The composition of claim 2, wherein the stabilizer is lactose.
4. The composition of claim 2, wherein stabilizer is mannitol.
5. The composition of claim 2, wherein stabilizer is mannitol and citric acid.
6. The composition of claim 2, wherein stabilizer is mannitol and ascorbic acid.
7. The composition of claim 1, wherein the composition is prepared by direct compression.
8. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluent, binder, disintegrant, lubricant and glidant.
9. A stable pharmaceutical composition of bumetanide comprising mannitol and ascorbic acid as stabilizer, wherein the composition contains N-nitrosobumetanide impurity level of less than 2 ppm upon 6 months storage at 25 0C and 60% relative humidity.
10. A stable pharmaceutical composition of bumetanide comprising mannitol and comprising ascorbic acid as stabilizer, wherein the composition contains N-nitrosobumetanide impurity level of less than 2 ppm upon 6 months storage at 40 0C and 75% relative humidity.