FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
A NOVEL PHARMACEUTICAL COMBINATION FOR AMILORIDE AND TORSEMIDE AND PROCESS FOR MANUFACTURING THE SAME."
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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A NOVEL PHARMACEUTICAL COMBINATION FOR AMILOR1DE AND
TORSEMIDE AND PROCESS FOR MANUFACTURING THE SAME,
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates generally to a novel combination of diuretics among which one drug is selected from the class of loop diuretics and the other diuretic is selected from the class of potassium sparing type of diuretic. This invention also relates to the process for preparation for the same.
2. Description of the Related Art
Blood pressure is very common problem and mainly is influenced by how much water is in your body and salt intake. Diuretics reduce water and sodium in your body, and for decades have been the chief method for treating high blood pressure. They are still considered the first choice by many experts, especially for treating the elderly patients. Diuretics have been recommended as the first line agents in treatment of Hypertension as per recent JNC VII guidelines. JNC stands for "Joint National Committee for Hypertension". This is based at USA and the guidelines on hypertension are updated in their meetings which last happened in their last JNC VII meet.
The words "heart failure" sound alarming, but they do not mean that your heart has suddenly stopped working. Instead, heart failure means your heart is not pumping as well as it should to deliver oxygen-rich blood to your body's cells.
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Congestive heart failure (CHF) happens when the heart's weak pumping action causes a buildup of fluid called congestion in your lungs and other body tissues.
CHF usually develops slowly. You may go for years without symptoms, and the symptoms tend to get worse with time. This slow onset and progression of CHF is caused by your heart's own efforts to deal with its gradual weakening. Your heart tries to make up for this weakening by enlarging and by forcing itself to pump faster to move more blood through your body.
Diuretics, commonly known as "water pills," help your body get rid of unneeded water and salt through the urine. Getting rid of excess fluid makes it easier for your heart to pump.
Diuretics are categorized as Thiazide-like (Hydrochlorthiazide, Chlorthalidone), loop (Frusemide, Torsemide) or potassium-sparing (Spironolactone). Thiazide diuretics cause moderate increases in water excretion and are appropriate for long-term use. Loop diuretics are more powerful and are especially useful in emergencies. Potassium-sparing diuretics help your body retain the mineral potassium and are often prescribed in conjunction with the other two types of diuretics.
Thus this invention discloses a novel combination of diuretics in which one diuretic is a powerful diuretic (loop diuretic) and the other is mild (potassium sparing) . The use of combination of diuretics results into a synergestic effects and reduces the risk of off set side effects to help maintain a normal potassium level in the body and. Thus minimizes the risk of kidney or liver damage which is likely to happened especially when the powerful diuretics like loop diuretics are used alone for a prolong period of time.
Thus the combination of diuretics help in reducing the high blood pressure, substantially reduces the risk of stroke and heart attack. The combination of diuretics also reduces the swelling and water built up caused by heart failure. It also reduces kidney/liver problems to some extend by reducing the amount of fluid build-up associated with cirrhosis (disease of the liver). This combination drug therapy also helps in curing Glaucoma by reducing the pressure in the eye associated with this disease
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This combination is also used to treat high blood pressure (hypertension). High blood pressure adds to the work load of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.
Diuretics help to reduce the amount of water in the body by acting on the kidneys to increase the flow of urine. This also helps to lower blood pressure.
Also, diuretics remove fluid from the body by making people urinate more . This can cause dehydration if too high dose is taken. Adverse effects on kidney function, serum sodium, and serum calcium levels may be seen. They can affect sexual potency in men . However, these medications are safe and well tolerated by the vast majority of patients taking them.
Torsemide, chemically known as l-isopropyl-3-[(4-/w-toluidino-3-pyridyl) sulfonylurea, may be represented by the structure of Formula I.


H3C

Torsemide is in a class of drugs called loop diuretics (water pills). It decreases the amount of fluid in the body by increasing the amount of salt and water lost in the urine. Torsemide is used to treat swelling in the body caused by congestive heart failure, liver disease, or kidney disease
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Amiloride chemically known as 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide monohydrochloride.

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Amiloride tablets and oral solution contain the active ingredient amiloride, which is a type of medicine called a potassium-sparing diuretic. (Diuretics are sometimes referred to as 'water tablets').
Diuretics work by causing the kidneys to increase the amount of salts such as sodium that are filtered out of the blood and into the urine. When these salts are filtered out of the blood by the kidneys, water is also drawn alongside. As diuretics increase the removal of salts from the blood, they also cause more water to be drawn out of the blood and into the urine.
Removing water from the blood decreases the volume of fluid circulating through the blood vessels. This subsequently decreases the pressure within the blood vessels. Diuretics are therefore used to lower high blood pressure.
As diuretics remove fluid from the body, they are also used to treat conditions where excess fluid has been retained in the body (oedema). In heart failure for example, fluid can accumulate in the lungs, causing shortness of breath. Diuretics are used to help the body remove this excess fluid and therefore relieve the symptoms of heart failure. The decreased pressure in the blood vessels caused by the diuretic also decreases the effort required by the heart to pump blood around the body, which is useful in heart failure where the pumping mechanism of the heart is less effective.
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The loss of fluid caused by diuretics is also used to remove excess fluid that can accumulate in people with cirrhosis of the liver. This fluid may accumulate in the abdomen (ascites) or in the legs (oedema).
Amiloride has a weak diuretic effect when used on its own; hence it is usually used in combination with other diuretics. Most other diuretics cause the amount of potassium in the blood to drop. Amiloride doesn't have this effect, as it is a 'potassium-sparing' diuretic. It is usually added to diuretic treatment to prevent excessive amounts of potassium from being lost.
Various combinations like Amiloride and Hydrochlorothiazide, Spironolactone and Hydrochlorothiazide, Triamterene and Hydrochlorothiazide, furosemide (40 mg) + amiloride (5 mg), furosemide (20mg) + spironolactone (50mg), furosemide (50mg) + spironolactone (20mg) are available in the market, But Torsemide is found tobe more superior to Furosemide, Torsemide appears to be superior than Furosemide on the following pharmacokinetic parameters like Torsemide has a bioavailability of 80 - 90% which is greater than Furosemide which is only 64% bioavailable thus allowing better absorption. Torsemide has a longer half-life (3-6 hours) as compared to Furosemide (1/2 - 2 hours) thus accounting for longer action. Torsemide can be given once a day as compared to Furosemide which may be given once/twice a day thus allowing for a convenient dosing. 10-20 mg of Torsemide has demonstrated equivalent diuresis to that of 40 mg of Furosemide thus indicating that it is more potent than Furosemide. Torsemide has shown a superior efficacy than Furosemide in cirrhotic patients with uncomplicated ascites. Torsemide induced a significantly greater diuretic response than Furosemide at 24 hours thus indicating that it is safe for long term treatment of cirrhotic patients with ascites .Torsemide in Congestive Heart Failure study demonstrated that Torsemide has a lower mortality of 2.2% as compared to Furosemide / other diuretic groups which showed a mortality of 4.5% in congestive cardiac failure patients. TORIC study showed that abnormally low serum potassium levels were observed in fewer Torsemide (12.9%) than Furosemide / other diuretics (37.2%). This indicates that it is safer
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than furosemide' For excretion of water and sodium, Torsemide was significantly more active than Furosemide (2576 ml and 270 mEq as compared to 2034 ml & 240 mEq). Also Furosemide caused significantly greater kaliuresis than compared to Torsemide (73.7 mEq as compared to 47.6 mEq).[ Torsemide Micromedex Healthcare Series 2004],[ Cohn JN. The Management of chronic heart failure. NEJM 1996;335 (7):490-98.]
Similraly Amiloride is superior to spironolactone, another potassium sparing diuretic in terms pharmacokinetic parameters and safety .Amiloride has a peak action at 3-4 hours as compared to 6-8 hours of spironolactone. Thus it is faster acting than spironolactone. Amiloride has longer duration of action (24 hours) as compared to 16-24 hours of spironolactone. Amiloride is more bioavailable (30 - 90%) as compared to spironolactone (73%). Amiloride is longer acting with a half life of 6-9 hours as compared to 1.3 - 1.4 hours of spironolactone^ From safety issue point of view, Spironolactone binds to androgenic receptors and cause estrogenic sexual side effects which are not seen with Amiloride. Thus Amiloride is better tolerated than spironolactone
So, the purpose of this invention is to introduce a new combination of Torsemide and Amiloride in the market as a diuretic in the treatment of Congestive Cardiac Failure. So the rational behind having this combination is Torsemide acts at the loop of Henle and Amiloride at the distal nephron. Thus the action of the two diuretics compliment each other by giving synergestic effects. The pharmacokinetic profiles of Torsemide and Amiloride are complimentary with a once daily dosing schedule. Torsemide being a loop diuretic causes Kaliuresis thus can cause hypokalemia. Amiloride on the other hand prevents potassium loss. Thus, serum levels of potassium are balanced. Amiloride thus counteracts the potassium loss caused by Torsemide.[ Jessup M et al. Medical progress: Heart failure, NEJM 2003;348:2007-18.]
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Thus the benefits of a combination of Torsemide and Amiloride may prove advantageous and synergestic than either agent alone in the management of congestive cardiac failure.
This combination is found tobe clinically more effective due to the synergestic effects than the existing products alone or in combinations in the market.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, is to provide a combination of product in which one ingredient is selected for the group of loop diuretics , and the second active ingredient is selected from the group of' potassium-sparing' diuretic.
Yet another aspect of the invention is to provide a process for making this combination product that also results into a stable pharmaceutical composition.
Yet another aspect of the invention is the loop diuretic is selected from the group of bumetanide,ethacrynic acid, forosemide,torsemide etc.
Further aspect of the invention is to provide a potassium sparing diuretics is selected from the group of amilorode,Eplerenone,spironolactone,Triamterene etc.
Another aspect of the invention is Amiloride Hydrochloride is granulated separately by wet granulation or by dry granulation process, but most preferably by dry granulation by slugging.
Further aspect of the invention is Forsemide is granulated using wet granulation or by using dry granulation technique, but most preferably by wet granulation.
A pharmaceutical formulation of the invention is in the form of a bilayered tablet and both the drugs used in the invention are instant released.
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Yet another aspect of the invention is the said tablet can be prepared in the form of single layered tablet as well,
Further aspect of the invention is the tablet composition containing Torsemine as one active ingredient and Amiloride as another active ingredient is found to be stable composition.
Yet another aspect of the invention is the composition is made in such a way that it is cost effective and the process of manufacture is conventional.
DEFINITIONS
The term "treating" or "treatment" of a state, disorder or condition as used herein means (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
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The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local ,oral or by systemic administration of the active ingredient to the host.
As used herein, the term "binders" in Torsemide layer is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
As used herein, the term "diluent" in Torsemide layer is intended to mean substances that acts as a filler in the formulation .Microcrystalline starch, Lactose monohydrate, dicalcium phosphate, starch etc. can be used as diluents in this composition, or combinations thereof and other material known to those of ordinary skill in the art.
The term "disintegrant as used herein intended to mean a substance that helps in breaking the tablet into granules in stipulated period of time. Crosscarmellose sodium, sodium starch glycolate, pregelatinized starch, crosspovidone, Eudragit EPO can be used as disintegrants in this composition or combinations thereof and other material known to those of ordinary skill in the art.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses a combination diuretic product of Torsemide and Amiloride in the form of a bilayred tablet and the process of manufacturing a stable pharmaceutical formulations for the same.
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The tablet is prepared as a bilayred tablet . The Torsemide layer is prepared by dry granulation or by wet granulation technique. Most preferably Torsemide granules are prepared by wet granulation.
Also, the Amiloride layer may be prepared by dry or wet granulation, but most preferably by dry granulation .Colorent is added to distinguish the two layers prominently.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of this invention.
EXAMPLE 1.

STEP NO. NAME OF INGREDIENTS %0. A. MG /TAB %OF FORMULA
Torsemide Layer
I Torsemide 2.00 10.31 2.79
Lactose Monohydrate - 94.69 25.59
Povidone (K-30) — 5.00 1.35
Purified Water
MicrocrystallineCellulose(Avicel PH l0l) — 82.40 22.27
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Croscarmellose Sodium - 5.60 1.51
Magnesium Stearate ~ 2.00 0.54
Sub-Total 200.00 54.05
Amiloride Layer
II Amiloride Hydrochloride 2.00 5.83 1.58
Dibasic Calcium Phospate, anhydrous (DC) — 52.27 14.13
Lactose (DC) — 85.00 22.97
Yellow Oxide of Iron ~ 0.20 : 0.05
Starch ~ 25.00 6.76
Magnesium Stearate ~ 1.00 0.27

Magnesium Stearate — 0.70 0.19
Sub-Total 170.00 45.95
Total 370.00 100.00
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MANUFACTURING PROCESS:
I Torsemide Granulation;
i Sifting & Mixing:
Sift the active drug & other RM through 60 #.
Torsemide
Lactose
Dry mix for 10 mins.
ii Binding solution :
Purified water.
Povidone K 30.
Stir well to dissolve completely.
iii Wet mixing: for 10-15 mins.
iv Wet sifting:
sift through 10# sieve.
v Drying:
Tray Dryer
Temprature 40-45°C Drying time 30 minutes.
vi Diminution :
Final granules pass through 16 # sieve.
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v Lubrication :
Collect the fines through 40# then mix the lubricants Avicel PH l0l
Croscarmellose sodium
Magnessium Stearate.
II Amiloride Hydrochloride Granulation:
i Sifting & Mixing:
Sift the active drug & other RM through 60 #.
Amiloride Hydrochloride.
Dibasic calcium phosphate.
Lactose (directly compressible).
Yellow oxides of iron
Starch,
Dry mix for l0 mins.
Magnessium Stearate.
Mix for 3 mins.
ii Slugging
iii Deslugging through 10# sieve.
iv Diminution :
Final granules pass through 16 # sieve.
v Lubrication :
Collect the fines through 40# then mix the lubricants
Magnesium Stearate.
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MANUFACTURING PROCESS FLOW CHART

Equipment used

Process

Critical parameter

In-process test

TORSEMIDE GRANULATION

Vibratory Sifter Sifting of Drug,
and excipients.

Dry mixing
RMG at slow speed for 15minutes



RMG at slow speed for 2 to 3 minutes & 0.5 to 1 minute at fast speed Binder addition&Granulation
RPM and Time



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FBD for about 10 to 25 minutes at 60°C

Drying

LOD should not be more than 2.0%
w/w

LOD
should not be more than 2.0%w/w

Vibratory sifter and multimill

Sifting and
sizing through 16 # sieve

Vibratory Sifter

Sifting Lubricants

of

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.
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Moreover, those skilled in the art will envision other modifications within the scope spirit of the claims appended hereto.
Dated this Ninth ( 9th )day of March 2006

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