FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
[See section 10]
"A NOVEL METHOD OF PRESENTATION OF DOSAGE FORMS FOR SECONDARY PREVENTION OF CORONARY ARTERY DISEASE"

(a) IPCA LABORATORIES LTD.

(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:

A novel method of presentation of dosage forms for secondary prevention of coronary artery disease
Technical field
[0001] The present invention relates to a combipack for secondary
prevention of coronary artery disease, the combipack comprising one or more of the following: a) a statin and aspirin, b) a statin, aspirin and a beta blocker, c) a statin, aspirin, beta blocker and ACE inhibitor and d) a statin, aspirin, beta blocker and angiotensin II antagonist in therapeutically effective dosage quantities; More particularly the invention relates to a combipack of a) Simvastatin or Atorvastatin with Aspirin, b) Simvastatin or Atorvastatin with Aspirin and Metoprolol, c) Simvastatin or Atorvastatin with Aspirin, Metoprolol and Ramipril or d) Simvastatin or Atorvastatin with Aspirin, Metoprolol and Losartan in a daily dosage form.
Background and Prior Art
[0002] Cardiovascular mortality and disability is expected to rise
exponentially in developing countries. India too is facing an epidemic of cardiovascular disease. Several studies have revealed that Indians have a higher rate of coronary heart disease (CHD) than people of European origin. The prevalence rate of coronary heart disease in our county is almost 80 to 120 per 1000 population. Moreover it is anticipated that the mortality attributable to cardiovascular disease (CVD) in India will rise by 103 per cent in men and by 90 per cent in women during the period 1985 to 2015. To compound the problem further, coronary artery disease (CAD) among Indians, tends to occur early in life, is more severe and extensive and follows a malignant course.
[0003] High blood pressure accounts for about 50 per cent of
cardiovascular disease worldwide and elevated cholesterol levels for around one

third. In all, some 9 million deaths and more than 75 million lost healthy life years annually due to unfavourable levels of blood pressure or cholesterol. These conditions are much more prominent in developing countries than was earlier understood and contribute significantly to their disease burden. There is increasingly clear evidence that cholesterol and blood pressure measurements that are considered average are in feet too high for good health and that the vast majority of people would benefit from lower levels as the risks are continuous.
[0004] Patients with high normal blood pressure are 1.5 times to 2.5 times
more likely to have a cardiovascular event or to die within 10 years, compared to those with optimal blood pressure. A small reduction in average systolic blood pressure can result in considerable drop in deaths from stroke, heart diseases and overall mortality. Thus a tighter control on blood pressure is required.
[0005] Three oral agents have been shown in randomized controlled trials
to decrease cardiovascular morbidity and mortality - Beta blockers, aspirin and angiotensin coverting enzyme (ACE) inhibitors or angiotensin II (AIT) receptor blockers. These drugs are now recommended and used by virtually all cardiologists and internists as they are necessary for the management of acute and chronic ischemic syndromes, manifestations of ischemic heart diseases (IHD).
[0006] In the recent past, the statins have been added to the list of proven
agents. Its role in IHD is well established.
[0007] The approximate life-saving potentials of these agents are:
Beta blockers - 33 % (they enhance the salutary effects of ACE inhibitors)
Aspirin - 23%
ACE inhibitors - 20%
Statins - 30%

[0008] Researchers have called for an increased use of cardiac treatments
such as aspirin, heparin, beta blockers and statins to prevent unnecessary mortality and morbidity.
[0009] According to a recent article by WHO (World Health
Organisation), low-cost combination drug treatment given daily to people at elevated risk of heart attack and stroke can provide the most immediate improvements in cardiovascular health. Such a regime, alongside other simple national and individual interventions, could reduce death rates and disability from heart disease and strokes by more than 50 per cent.
[0010] A combination of statin, low dose antihypertensive and aspirin
could be used much more widely in the industrialised world and is increasingly affordable in the developing world, which will bear the brunt of the growing cardiovascular disease according to WHO. If no action is taken, 25 per cent more healthy life years will be lost to cardiovascular disease globally by 2020.
[0011 ] As per NICE-MI guidelines, 2001
• In patients with prior MI without heart failure
start with a beta blocker and aspirin add statins and ACE inhibitor
• In patients with prior MI with heart failure
start with an ACE inhibitor add a beta blocker and aspirin
[0012] Beta adrenergic receptor antagonist agents remain a cornerstone in
the therapy of all stages of ischemic heart disease. It is s standard therapy for effort angina, mixed effort and rest angina and unstable angina. Beta blockers decrease mortality in acute phase myocardial infarction in the postinfarct period.

[0013] Aspirin has rightly gained widespread use in the management of
unstable angina and acute MI and in the prevention of nonfatal and fetal MI during the years following infarction. Also salutary effects have been demonstrated in patients with stable angina, cerebral TIAs and in the prevention of occlusion of CABGs.
[0014] Although dyslipimedia, diabetes, smoking and hypertension are
major risk factors for cardiovascular disease, they do not fully account for the risk. Epidemologic and experimental data suggest that activation of the renin-aldosterone system has an important role in increasing the risk of cardiovascular events. ACE inhibitors block the activation of the renin-angiotensin system and could retard the progression of both heart failure and atherosclerosis. ACE inhibitors may thus have a role in preventing myocardial infarction in a broad range of patients.
[0015] In the HOPE study (The Heart Outcome Prevention Evaluation
Study), ramipril significantly reduced the risk of death, myocardial infarction and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.
[0016] The management of hyperlipidemia has been revolutionized with
the expanded use of statins. These agents are proven effective in reducing LDL cholesterol to goal levels, mortality in patients with IHD, the incidence of MI in patients with IHD, the degree of obstructive atheroma in coronary arteries and the risk of stroke.
[0017] Adding simvastatin to existing treatments safely produces
substantial additional benefits for a wide range of high-risk patients, irrespective

of their initial cholesterol concentrations. This has been demonstrated by the large MRC/BHF Heart Protection Study.
[0018] The MRC/BHF Heart Protection Study concluded that 5 years of
simvastatin would prevent about 70-100 people per 1000 from suffering at least one of the major vascular events (and longer treatment should produce further benefits).
[0019] Patients of CAD are taking the above drugs separately. A
combipack of the four drugs may therefore find an important place in the management of CAD patients.
[0020] Approximately 30 per cent of patients do not tolerate ACE
inhibitor because of cough. In such patients, angiotensin receptor blockers (ARB) are a good option. ACE inhibitor can be replaced by ARB such as losartan.
[0021] Despite cogent evidence from well designed clinical trials that
aspirin, beta blockers, ACE inhibitors, lipid lowering drugs reduce morbidity and mortality, these therapies remain underutilized. A treatment gap exists as evidenced by the results of several clinical trials and reports on utilization of therapy.
[0022] Underutilization of drug therapy may stem from misperceptions
regarding drug safety profiles and dosages necessary to achieve optimal benefits or from concerns about adverse effects. A combipack of drugs such as statin, aspirin, beta blocker and ACE inhibitor would promote patient compliance and also can be optimally priced to reduce cost of therapy.
[0023] When two or more drugs are prescribed for management of any
critical health problems or disease there is likelihood of patients not complying

with the dosage regimen fully. Often, the patient may run out of one or more drugs and may only consume what is available on hand. Self-medication, overmedication or patients' own judgment on which drug is to be taken or not, also is a problem often encountered. Another critical factor in rural areas or far-flung states, district or villages is non-availability of one or more dosage forms or brands in the chemist shops or medical stores.
[0024] For a patient suffering from coronary artery disease, these are very
serious matters of concern and hence a combipack of two or more of the minimum essential medicines prescribed by the doctor, made available together in a single unit pack for consumption at a time offers total patient convenience and patient compliance.
[0025] U.S. Patent 6087305 to Kober et al describes compositions made
available advantageously in two parts, as a 'double pack' or combipack for a herbicidal crop protection.
[0026] US Patent Application 0020103181 by Himadri Sen et al deals
with a composition wherein the controlled release part in a hydrophilic matrix and immediate release probenacid part are compressed separately into tablets and are packed in a way to be administered simultaneously.
[0027] Although there are 'combipacks' reported or available in the
market, there have till now been no combipacks developed and offered for secondary prevention of coronary artery disease, which is a critical medical condition, where the individual drugs have to be administered simultaneously daily. The present invention fulfils such a need and provides a rational combination of individual dosage forms available together to a patient for total compliance.

[0028] Thus the present invention will satisfy the following requirements:
Adheres to the recommendations of WHO/NICE
It will make the physicians aware about benefits of the 4 drugs commonly used in IHD.
Improve patient's compliance Cost of therapy can be reduced.
Summary of Invention
[0029] The present invention relates to a combipack for secondary
prevention of coronary artery disease comprising one or more of the following combinations of individual drugs: a) a statin and aspirin, b) a statin, aspirin and beta blocker, c) a statin, aspirin, beta blocker and ACE inhibitor and d) a statin, aspirin, beta blocker and angiotensin II antagonist in therapeutically effective daily dosage form.
[0030] Objectives of the Invention
1. An objective of the present invention is to provide more complete therapy of ischemic heart disease patients.
2. An other objective of the present invention is to reduce the cost of therapy
3. A further objective of the present invention is to improve patient compliance by offering the drug in a combipack format.
4. An additional objective is that the present invention complies with the WHO/NICE recommendations.

Detailed Description
[0031] The composition of the present invention is in the form of
combipack, comprising either of the following: a) a statin and aspirin, b) a statin, aspirin and beta blocker, c) a statin, aspirin, beta blocker and ACE inhibitor, d) a statin, aspirin, beta blocker and angiotensin II antagonist.
[0032] According to the present invention, statin can be either simvastatin
or atorvastatin. Metoprolol, Ramipril and Losartan is used as beta blocker, ACE inhibitor and angiotensin II antagonist respectively.
[033] The present invention also concerns a method of treating ischemic
heart disease with or without associated conditions.
[034] Simvastatin:
Simvastatin is a lipid lowering agent that is derived synthetically from a
fermentation product of Aspergillus terreus. After oral ingestion, Simvastatin,
which is an active lactone, is hydrolysed to the corresponding beta-hydroxy acid,
a potent inhibitor of HMG-CoA reductase.
Tablets of Simvastatin for oral administration contains, 10mg of Simvastatin and
the following inactive ingredients; Cellulose, Hydroxypropylmethyl Cellulose,
Iron Oxide, Lactose, Magnesium Stearate, Starch, Talc, Titanium Dioxide and
other ingredients, butylated Hydroxy Toluene and Ascorbic acid are added as
preservatives.
10 mg tablets are peach in colour, oval, biconvex and filmcoated without
breakline.
[035] Atorvastatin:
Atorvastatin is a synthetic lipid lowering agent. It is an inhibitor of HMG-CoA reductase.

Atorvastatin tablets for oral administration contain: 10 mg of Atorvastatin and the following inactive ingredients; Calcium Carbonate, Sodium Starch Glycollate, Magnesium Stearate, Microcrystalline Cellulose, Lactose Monohydrate, Hydroxypropyl methyl Cellulose, Polyethylene Glycol, Talc, Titanium Dioxide, Isopropyl Alcohol and Methylene Chloride. Atorvastatin tablets are white, elliptical, film coated, plain on both sides.
[036] Aspirin:
Each tablet contains: Acetaminophen 250mg, and inactive ingredients; Benzoic
acid, Carnauba Wax, Hydroxypropylmethyl Cellulose, Microcrystalline Cellulose,
Mineral Oil, Polysorbate-20, Povidone, Propylene Glycol, Propyl Gallate,
Simethicone Emulsion, Sorbiton Monolaureate, Stearic acid and Titanium
Dioxide.
[037] Metoprolol Succinate extended release:
Metoprolol Succinate ER tablets contain 23.75, 57.5, 95 and 190 mg of
Metoprolol Succinate equivalent to 25,50, 100 and 200mg of Metoprolol Tartrate
USP respectively.Inactive ingredients include Carbomers, Cellulose compounds,
Povidone, Polyethylene Glycol, Titanium Dioxide, Talc, Magnesium Stearate.
Metoprolol Succinate is a beta selective adrenoreceptor blocking agent for oral
administration, available as extended release tablets. XL has been formulated to
provide a controlled and predictable release of Metoprolol for once daily
administration.
Tablets are white, biconvex and film coated.
[038] Losartan Potassium:
Losartan Potassium is the first of the new class of antihypertensives. It is an
angiotensin II receptor antagonist.
Losartan is available as tablets for oral administration containing 25mg of
Losartan Potassium and the following inactive ingredients; Microcrystalline
Cellulose, Maize Starch, Magnesium Stearate, Colloidal Silicone Dioxide,

Sodium Starch Grycollate, Colour-Lake of Ponceau-4R, Talc Opadry OY 55030 Red, Isopropyl Alcohol and Methylene Chloride. Losartan 25mg tablets contain 2.12mg potassium.
[039] Ramipril:
Ramipril is an antihypertensive drug. Ramiprilat, the diacid metabolite of
Ramipril, is a non-sulfhydryl ACE inhibitor.
Ramipril capsules are hard shelled capsules for oral administration, containing
1.25 to 2.5mg of Ramipril. The inactive ingredients present are pregel starch
gelatin and titanium dioxide. The 2.5mg capsule shell contains D&C yellow #10
and FD&C red #40.
Ramipril capsules are supllied as orange/white hard gelatin capsules.
COMBIPACK Simvastatin + Aspirin

Dated this 5 day of
february 2003

DR. GOPAKUMAR G. NAIR
Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES
Nair Baug, Akurli Road KandivU (East), Mumbai - 400 101

To
The Controller of Patents The Patent Office,
At Mumbai.