Title: Formulation of Cholesterol Lowering Agents with Fibrates and Additional Substances for Prevent/Treat Atherogenesis for better Vascular Endothelial Function
FIELD OF THE INVENTION:
This invention relates to the field of Pharmaceutical Technology. More particularly the invention principally relates to pharmaceutical composition of Cholesterol lowering Agents such as, Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, Pitavastatin, etc., with a nitric oxide releasing moiety OR chelated with Arginine. The subject matter of the Patent Application relates to the process of fixed dose formulation comprising a Cholesterol Reducers or their pharmaceutically acceptable hydrates, salts or esters in which the active materials are basically selected from among Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, Pitavastatin, etc., and reacted with a nitric oxide releasing moiety OR chelated with Arginine, in fixed dose combination with Fibrates (Fenofibrate), Vitamin-D or its analogues, such as Calcitriol and substances to control Hyperhomocysteinemia, such as Folic Acid, Methylcobalamin and Pyridoxine. The inclusion in the composition of nitric oxide releasing moiety OR chelated with Arginine enables to enhance the endothelial

protection and thereby, a better endothelial function. The composition containing Fibrates are indicated as adjunctive therapy to reduce LDL-C, Triglycerides and Apo-B, besides increasing HDL-C, thereby providing synergistic action of lipid control. The composition containing Vitamin-D or its analogues, Cholecalciferol provides vascular endothelial protection in a dose dependent manner by inhibition of processes that are important for intimal and medial artery calcification such as pro-inflammatory cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells (Curr Opin Lipidol. 2007 Feb;18(1):41-46)
The formulation under development is a Fixed Dose Combination with additional active pharmaceutical ingredients that can help in preventing/treating Hyperhomocystenemia. More particularly, the Fixed dose formulation contains Methylcobalamin (Vitamin B12), Folic Acid and Pyridoxine (Vitamin B6). It's a very well established scientific basis that all the three ingredients act synergistically to trigger the optimal metabolism of plasma homocysteine through 5-Methyltetrahydrofolate -homocysteine methyltamsferase pathway. Additionally, Pyridoxine contributes to homocysteine excretion by acting

through the trans-sulfuration pathway to cysteine. Besides, Pyridoxine also facilitates the cellular balance of Sodium and Potassium, which can be considered as another important benefit of this formulation in cardiac diseases.
The said formulation is being developed using novel technology of either tablet-in-tablet or bi-layered tablet or if necessary in a unique Sequential Drug Delivery System SDDS)
BACKGROUND OF THE INVENTION:
Majority of the Patients suffering from lifestyle diseases, particularly, Hyperlipidemia, Diabetes Mellitus, Hypertension, Syndrome-X and high risk groups like Individuals with Family History or Obesity or Smoking are all vulnerable to long-term effects of changes in vascular endothelium, and thereby pre¬disposing them to several angiopathic diseases, including IHD, Stroke and Peripheral Vascular Diseases
Cholesterol Reducers such as Statins have become the mainstay in preventing or treating Atherogenic conditions. However, treating with Statins alone may not provide comprehensive endothelial protection. Several recent studies have proved beyond doubt that Nitric Oxide plays a

predominant role in endothelial function, by being a natural vasodilator
Fibrates (Fenofibrate) are indicated as adjunctive therapy to
diet to reduce elevated LDL-C, Total-C, Triglycerides, and
Apo B, and to increase HDL-C in adult patients with primary
hypercholesterolemia or
mixed dyslipidemia (Fredrickson Types Ha and lib). Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate
Treatment of Hypertriglyceridemia
Fibrates (Fenofibrate) are also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention
Markedly elevated levels of serum triglycerides (e. g. > 2, 000 mg/dL) may increase the risk of developing pancreatitis. The effect of Fibrates (Fenofibrate) therapy on reducing this risk has not been adequately studied.
Patients with Atherogenic propensity are at increased risk due to Hyperhomocysteneimia. Preventing or treating Hyperhomocysteneimia cannot be achieved by Statins. Thus it is imperative to protect the patient against atherogenicity due to Hyperhomocysteneimia and proinflammatory cytokines.

While treating patients with history of Ischemic Diseases or potential to develop the same, focusing only on Hyperlipidemia or Dyslipidemia may not provide the complete protection against atherogenicity and the related diseases. The main objective of our approach is to provide a holistic approach to vascular protection than addressing only the cholesterol related vascular risk
Thus the novelty in the present formulation is the unique approach of protecting the vascular endothelium through several pathways, more importantly in a manner that can either work synergistically or complement each other
The relevant prior art methods, which teach adaptation of diverse delivery systems for sustained release of the active, are as follows.
United States Patent 7166638
Abstract:
Statin nitroderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for treating and/or preventing several diseases, in particular coronary syndromes, neurodegenerative disorders as well as for reducing cholesterol levels.
Nitroso Compounds or Nitric Oxide Releasing Compounds with Nitric Oxide Scavengers of Statins

1. Patent number: EP1669091
Publication date: 2006-06-14
Inventor: Kunz Lawrence L (US)
Applicant: Boston Scient Ltd (BB)
Title : Therapeutic inhibitor of vascular
smooth muscle cells
This invention comprises of an intravascular stent comprising a sustained release dosage form comprising a cytostatic amount of a therapeutic agent that inhibits vascular smooth muscle cell activity without killing the target cells, wherein the therapeutic agent is selected from at least one of modified toxins, methotrexate, adriamycin, radionuclides, peptidic or mimetic inhibitors, protein kinase inhibitors, staurosporin, subfragments of heparin, triazolopytimidine, lovastatin, prostglandins E1 or 12, cytoskeletal inhibitors, colchicine, vinblastin, cytochalasins, taxol, triochothecenes, modified diphteria and ricin toxins, or Pseudomonas exotoxin, suramin, nitric oxide releasing compounds, nitroglycerin, roridin A, sphingosine, somastatin, or N-ethylmaleimide.
2. Patent number: US2002052394
Publication date: 2002-05-02
Inventor: Mason R Preston (US)
Applicant:
Title: Synergistic effect of amlodipine
and atorvastatin on cholesterol crystal formation inhibition and aortic endothelial cell nitric oxide release
This invention deals with the combination of the antihypertensive calcium channel blocker amlodipine

and lipid-lowering agent atorvastatin that inhibits free cholesterol crystallization in atherosclerotic-like membranes. In addition, the invention also claims that treatment with a combination of amlodipine and atorvastatin results in a synergistic effect on the release of NO from rabbit aorta endothelial cells.
3. Patent number: US2003195256
Publication date: 2003-10-16
Inventor: Singh Inderjit (US)
Applicant: Muse Foundation For Res Dev
(US)
Title: Inhibitors of nitric oxide
synthase
The current invention discloses novel methods for the inhibition of inducible nitric oxide synthesis (iNOS) and the production of NO. Methods of inhibiting the induction of proinflammatory cytokines are also described. Methods of treating various disease states, such as X-linked adrenoleukodystrophy, multiple sclerosis, Alzheimer's and septic shock using inhibitors of iNOS and cytokine induction are disclosed. The inhibitors include the exemplary compounds lovastatin, a sodium salt of phenylacetic acid (NaPA), FPT inhibitor II, N-acetyl cysteine (NAC), and cAMP.
4. Patent number: US2005009888
Publication date: 2005-01 -13
Inventor: Mason R Preston (US)
Applicant:

Title: Synergistic effect of amlodipine
and atorvastatin on cholesterol crystal formation inhibition and aortic endothelial cell nitric oxide release
This invention deals with the combination of the antihypertensive calcium channel blocker amlodipine and lipid-lowering agent atorvastatin inhibits free cholesterol crystallization in atherosclerotic-like membranes. In addition, it is claimed that treatment with a combination of amlodipine and atorvastatin results in a synergistic effect on the release of NO from aorta endothelial cells.
5. Patent number: US2005119270
Publication date: 2005-06-02
Inventor: Mason R P (US)
Applicant:
Title: Synergistic effect of amlodipine
and atorvastatin on aortic endothelial cell nitric oxide release
This invention comprises of the combination of amlodipine and atorvastatin act to synergistically synthesize NO production. Moreover, the addition of a tertiary compound to this invention is claimed to complement this combination of amlodipine and atorvastatin in NO production.
6. Patent number: WO2004091626
Publication date: 2004-10-28

Inventor: Garrett I Ross (US); Mundy
Gregory R (US); Gutierrez Gloria (US)
Applicant: Osteoscreen Inc (US); Garrett I
Ross (US); Mundy Gregory R (US); Gutierrez Gloria (US)
Title: Bone Growth Stimulation With
No/Statin And Other No Modulating Combinations
This invention deals with methods and compositions relating to the promotion of bone formation and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation. It specifically claims a method of enhancing bone formation by administering at least two components selected from at least one statin-like compound, at least one nitric oxide generating system, and at least one phosphodiesterase inhibitor. Also disclosed is a pharmaceutical composition comprising said at least two components.
Other References:
Hobbs, et al. "Achievement of English National Service Framework Lipid-lowering Goals: Pooled Data from Recent Comparative Treatment Trials of Statins at Starting Doses" J. Clin. Pract., vol. 59, 10 (2005), 1171-1177.
Omori, et al. "Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy

normocholesterolaemic subjects," British J. Clin. Pharmacol., vol. 54, 395, 399 (2002). Shishehbor, et al., "Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways" Circulation. 2003; 108: 426-431. Laufs, et al. "Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice Editorial Comment" Stroke, 2000: 32: 2442-2449.
Semeraro et al., "Direct Induction of Tissue Factor Synthesis by Endotoxin In Human Macrophages From Diverse Anatomical Sites," Immunology 50 529-535, 1983.
Vezza et al., "Prostaglandin E2 Potentiates Platelet Aggregation by Priming Protein Kinase C," Blood 82 2704-2713, 1993.
Rossiello et al., "Fibrin Down-regulates LPS- and PMA-induced Tissue Factor Expression by Blood Momonuclear Cells," Thromb Haemost 84 453-459, 2000.
Momi et al., "Prevention of Pulmonary Thromboembolism by NCX 4016, a Nitric Oxide-Releasing Asprin," European Journal of Pharmacology 397 177-185,2000.
Emanueli et al., "Local Delivery of Human Tissue Kallikrein Gene Accelerates Spontaneous Angiogenesis in Mouse Model of Hindlimb Ischemia," Circulation 2/9 125-132,2001.
Wanstall et al., "Vascular Smooth Muscle Relaxation Mediated by Nitric Oxide Donors: A Comparison with Acetylcholine, Nitric Oxide and Nitroxyl Ion," British Journal of Pharmacology 134 463-472, 2001. Bonetti et al., "Statin Effects Beyond Lipid Lowering— Are They Clinically Relevant?," European Heart Journal 24 225-248, 2003.
Ongini et al., Nitric Oxide (NO)-Releasing Statin Derivatives, A Class of Drugs Showing Enhanced Antoproliferative And Antiinflammatory Properties, PNAS 101 8497-8502, 2004.
Bonazzi et al., "New Nitric Oxide (NO)-releasing Statin Derivatives With Enhanced Anti-Inflammatory Properties," AHA Scientific Sessions 9-12, 2003.

Dever et al., "Effects of No-Pravastatin on Leukocyte
Adhesion and Reactive Oxygen Species Generation in
Control and Apoe Knockout Mice," AHA Scientific
Sessions 9-12, 2003.
Rossiello et al., "Nitropravastatin (NCX6550) Exerts an
Antiplatelet/ Antithrombotic Activity and Inhabits Tissue
Factor Expression," AHA Scientific Sessions 9-12,
2003.
Emanueli et al., "The Nitric Oxide (NO)-Releasing
Pravastatin Derivative, NCX 6550, Potentiates
Reparative Angiogenesis In A Mouse Model Of
Peripheral Ischemia," BPS, 2003.
Guzzetta et al., "Nitric Oxide (NO)-Releasing Statins: A
New Class of Drugs Combining NO and Statin
Properties," BPS, 2003.
Momi et al., "Antiplatelet and Antithrombotic Activity of
NCX 6550, A Nitrick Oxide (NO)-Releasing Derivative
of Pravastatin," BPS, 2003.
Guzzetta et al., "Novel Nitric Oxide (NO)-releasing
Derivatives of Statins Modulate Cellular NO
Homeostasis Acting on eNOS and iNOS Expressions,"
9th International Conference on Alzheimer's Disease
and Related Disorders, 2004.
GAPS IN THE PRIOR ART(S)
It may be observed that most or all of the prior arts and references lay emphasis on the role of nitroso compounds in synergy with Statins. However, none of the said inventions in the prior art provide the additional protection with Fibrates or do they address the Atherogenesis due to Hyperhomocysteneimia. Besides, the potential role of Vitamin - D (or its analogues) in cardio protection has been completely missed out

OBJECT OF THE INVENTION:
With the intention of solving the above said therapeutic and pharmaceutical gaps the inventor has set out the following objectives for the present invention. The main objective of the present new invention is to provide a pharmaceutical composition that provides Cholesterol reducers with Nitric Oxide Releasing Moiety or chelated with Arginine.
Another objective of the present invention is to provide Fibrates (Fenofibrate) to reduce LDL-C, Triglycerides and Apo-B, besides enhancing HDL-C and thereby provide the synergy to Statins
Another objective of the present invention is to provide a pharmaceutical composition that strengthen the arteries and help reduce elevated blood pressure, by providing Vitamin -D or its analogues, Cholecalciferol
A further objective of the present invention is to provide a pharmaceutical composition that protects against Hyperhomocysteneimia by providing the Fixed Dose combination of Methylcobalamin, Folic Acid and Pyridoxine
Another objective of the present invention is to provide a pharmaceutical composition that provides a unique release

pattern of either tablet-in-tablet or bi-layered tablet or in a special Sequential Drug Delivery System.
Yet another objective of the present invention is to provide a pharmaceutical preparation that provides a Fixed dose combination of Cholesterol Reducers, Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, Pitavastatin, etc., with a nitric oxide releasing moiety OR chelated with Arginine, and additionally, Fibrates, Vitamin - D or its analogues, Methylcobalamin, Pyridoxine and Folic Acid
SUMMARY:
In view of the above circumstances, the composition of the present invention is in the form of a matrix tablet comprising the active ingredient, w-hydrophilic polymers, water-soluble and/or water dispersible diluents, pharmaceutically acceptable tablet excipients, and antibiotic adjuvant if any, for controlling the release of active ingredients. According to the present invention, the active ingredient is a Cholesterol Reducer, or its pharmaceutically acceptable hydrates, salts or esters in a standard therapeutic dose, depending on the Statin chosen

According to the present invention the Nitric Oxide Moiety or chelated compound is developed using special proprietary process to release Nitric Oxide in vascular endothelium
According to the present invention the addition of Fibrates (Fenofibrate) provide the synergistic action of lipid control in patients with Hypercholesterolemia
According to the present invention, the pharmaceutical composition contains Vitamin - D or its analogues to strengthen the arteries and help reduce elevated blood pressure
According to the present invention, the pharmaceutical composition contains substances to prevent or treat Hyperhomocysteneimia, namely Methylcobalamin (up to 1500 meg), Pyridoxine (up to 100 mg) and Folic acid (up to 5 mg)
DETAILED DESCRIPTION OF THE INVENTION WITH REFERENCE TO METHODS:
The pharmaceutical composition of the present invention may be prepared by procedures well known to formulation chemists. The method of manufacturing can affect the

release characteristics of the composition. The method is as follows:
1. This invention relates to pharmaceutical formulations, in particular to novel formulations for the treatment of atherogenic conditions.
2. Cholesterol Reducers, Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, Pitavastatin, etc., in fixed dose combination with Fibrates are provided in the respective therapeutic doses and contain the following inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion., tribasic calcium phosphate NF, crospovidone NF, triacetin NF, yellow ferric oxide, and red ferric oxide NF.
3. Nitric Oxide Moiety or the Chelation with Arginine is a special proprietary process

4. Methylcobalamin, Folic Acid and Pyridoxine are provide in the usual therapeutic doses with the intent to prevent or treat Hyperhomocysteneimia. The inactive ingredients could be from the following: Dibasic Calcium Phosphate Dihydrate, Microcrystalline Cellulose, Opadry II Beige 40L174427 (Titanium Dioxide, Polydextrose, Hypromellose 3cP, Hypromellose 6cP, Triacetin, Hypromellose 50cP, Polyethylene Glycol 8000, FD&C Yellow # 6-Lake, FD&C Blue # 2-Lake, FD&C Red #40-Lake), Crospovidone, Croscarmellose Sodium, Magnesium Stearate (Vegetable Source), Opadry II Clear #Y-19-7483 (Hypromellose 6cP, Maltodextrin, Hypromellose 3cP, PEG 400, Hypromellose 50cP)
5. Vitamin - D or Cholecalciferol is given in usual therapeutic dose with inactive ingredients as follows: microcrystalline cellulose, lactose anhydrous, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate, butylated hydroxytoluene, modified food starch, and sodium aluminum silicate.

6. The formulation may be formulated for administration by oral or enteric route (if situation warrants). As specified in Claims, the Fixed dose formulation would be formulated as tablet-in-tablet or bil—layered tablet or as a special Sequential Drug Delivery System
7. The enteral formulation may be formulated as granules or powder with the objective of administering in patients having difficulty in swallowing
8. A formulation according to the invention may be in unit dosage form, for example unit dosage form for oral or enteral administration, which latter will primarily include administration by injection or infusion, especially intra muscular and intravenous administration.
9. The above-mentioned formulations may contain 0.1-90% by weight, preferably from 10-60% by weight of the active materials, depending on the method of administration.
AMBIT OF THE INVENTION:

Cholesterol Lowering Agents with Fibrates and Additional Substances to prevent/treat Atherogenesis for better Vascular Endothelial Function have wide-ranging therapeutic applications as follows:
1. DYSLIPIDEMIA
2. HYPERCHOLESTEROLEMIA
3. DIABETES MELLITUS WITH CVD
4. ISCHEMIC HEART DISEASES
5. STROKE
6. PATIENTS WITH CEREBRAL ISCHEMIA
7. SYNDROME-X
DISCLOSURE OF INVENTION:
The lipid modifying activity of Cholesterol Reducers, particularly Statins is unparalleled. However, Total Vascular protection should not limit to just correcting the lipid profile. The therapeutic approach must encompass a larger canvas or rather holistic approach of preventing all the possible and potential causes of Atherogenesis in patients who already have altered lipid profile, wherein, Cholesterol Reducers are warranted. Our Novel approach is to tackle the Atherogenicity and Hypercholesterolemia through a multi-

pronged strategy, besides providing greater protection to the vascular endothelium
In order to achieve the above-mentioned objective(s), we have invented novel formulations that can prevent and treat problems like Dyslipidemia, Atherogenicity, and Endothelial Dysfunction and thereby achieve the objective of better quality of life in patients with Vascular Diseases
The compositions of the invented formulations are as follows
• Formulation containing Fenofibrate 130 mg combined with Atorvastatin 10 to 80 mg having nitric oxide releasing moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg
• Formulation containing Fenofibrate 130 mg combined with Lovavastatin 5 to 40 mg having nitric oxide releasing moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg
• Formulation containing Fenofibrate 130 mg combined with Simvastatin 5 to 40 mg having nitric oxide releasing

moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg
• Formulation containing Fenofibrate 130 mg combined with Rosuvastatin 5 to 40 mg having nitric oxide releasing moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg
• Formulation containing Fenofibrate 130 mg combined with Pitavastatin 5 to 40 mg having nitric oxide releasing moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg
• Formulation containing Fenofibrate 130 mg combined with Pravavastatin 5 to 40 mg having nitric oxide releasing moiety or chelated with Arginine, in fixed dose combination with Vitamin D (200 - 400 I.U), Methylcobalamin 1500 meg, Pyridoxine 25 to 100 mg and Folic Acid 1 to 5 mg

Thus the invention has been an attempt to offer a solution to attain better quality of life in patients with Vascular Diseases due to Hypercholesterolemia, Atherogenesis and Endothelial Dysfunction
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth

I claim:
1. A Pharmaceutical composition of Cholesterol Reducing Agents such as Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, Pitavastatin, etc., with a nitric oxide releasing moiety OR the above-mentioned compounds chelated with Arginine, to provide additional endothelial protection
2. A Pharmaceutical composition to enhance the lipid control as claimed in claim 1, wherein Fibrates (Fenofibrate) are provided to reduce LDL-C, Apo-B and Triglycerides, besides enhancing HDL-C
3. A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claim 1, wherein Vitamin D is provided in fixed dose combination with the above-mentioned formulation
4. A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claim 1 and claim

2, wherein Methylcobalamin is provided in fixed dose combination with the above-mentioned formulation, as per claim 1 and claim 2
5. A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claim 1, claim 2 and claim 3, wherein Folic Acid is provided in fixed dose combination with the above-mentioned formulation, as per claim 1, claim 2 and claim 3
6. A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claim 1, claim 2, claim 3 and claim 4, wherein Pyridoxine is provided in fixed dose combination with the above-mentioned formulation, as per claim 1, claim 2, claim 3, claim 4 and claim 5
7. A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claims 1 to 5, , wherein the fixed dose combination of the formulation

may be given as a single conventional tablet or as a bilayered tablet or as tablet-in-tablet, depending upon the compatibility of the said ingredients
A Pharmaceutical composition to enhance the antiatherogenic activity as claimed in claims 1 to 5, wherein formulations may contain 0.1-90% by weight, preferably from 10-60% by weight of the active ingredients, depending on the method of administration.