Formulation And Evaluation of Metoprolol Succinate Poly Cap for the Treatment of Cardiovascular DiseaseCARDIOVASCULAR DISEASE

Abstract

The Indian Poly cap study (TIPS) conducted in India suggested taking a single capsule containing four drugs: a blood pressure lowering drug, statin, aspirin and diuretic could significantly cut the risk of heart disease among healthy people without side effects.A cheap four-in-one pill can guard against heart attacks and stroke, research suggests. The idea of a polypill is to try and treat multiple components of cardiovascular disease all at once, reducing the number of separate medications people have to take, and therefore increasing compliance. Therefore, the objective of this project to design novel approach for the treatment of cardiovascular diseases. Poly cap is a four in single pill containing Metoprolol succinate, Hydrochlorothiazide, Aspirin & simvastatin. The interaction studies of four chosen drugs were studied by using Fourier Transformer Infrared Spectroscopy (FTIR). The Poly cap was designed as two mini bilayer tablets in a capsule. The Quantitative detection of four individual drugs was determined by using UV_VIS spectrophotometer and optimized Poly cap was determined by using HPLC method, It was found that HPLC is sensitive, reproducible and valid for determination of “Poly cap”. The Novel Poly cap approach data reveled promising formula for improved relief patient complains during treatment or prevention of cardiovascular diseases.

Keywords

Poly cap, cardiovascular diseases, Metoprolol succinate, Hydrochlorothiazide, Aspirin, Simvastatin, TIPS

Introduction

Treatment of Cardiovascular diseases:

Heart disease treatments vary. It may need lifestyle changes, medications, surgery or other medical procedures as part of treatment. The goal in treating diseases of arteries (cardiovascular disease) is often to open narrowed arteries that cause symptoms. Depending on how severe the blockages in arteries are, treatment may include:

• ¹³Lifestyle changes. Whether heart disease is mild or severe, it's likely doctor will recommend lifestyle changes as part of treatment. Lifestyle changes include eating a low-fat and low-sodium diet, getting at least 30 minutes of moderate exercise on most days of the week, quitting smoking, and limiting how much alcohol drink.
• Medications. If lifestyle changes alone aren't enough, doctor may prescribe medications to control heart disease. These could include medications to lower blood pressure, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors or beta blockers; blood thinning medications, such as daily aspirin therapy; or cholesterol-lowering medications, such as statins or fibrates.
• Medical procedures or surgery. If medications aren't enough, it's possible doctor will recommend specific procedures or surgery to clear the blockages in heart. A common procedure is coronary angioplasty, which is performed by placing a catheter in an artery in arm or groin and threading a small balloon to blocked artery and inflating it to reopen the artery. A small metal coil called a stent is often placed in the artery during angioplasty. The stent helps keep the artery open.

Sometimes a more invasive procedure, coronary artery bypass surgery, is necessary. In this procedure, a vein from another part of body — usually leg — is used to bypass the blocked section of the artery.

2.6.1¹²Heart arrhythmia treatments

Depending on the seriousness of condition, doctor may simply recommend maneuvers or medications to correct your irregular heartbeat. It's also possible to need a medical device or surgery if the condition is more serious.

• Vagal maneuvers. It include holding breath and straining, dunking face in ice water, or coughing. Doctor may be able to recommend other maneuvers to slow a fast heartbeat. These maneuvers affect the nervous system that controls heartbeat (vagal nerves), often causing heart rate to slow. Don't attempt any maneuvers without talking to doctor first.
• Medications. People who have a rapid heartbeat may respond well to anti-arrhythmic medications. Though they don't cure the problem, they can reduce episodes of heart beating rapidly or slow down the heart when an episode occurs. It's important to take any anti-arrhythmic medication exactly as directed by doctor in order to avoid complications.
• Medical procedures. Two common procedures to treat heart arrhythmias are cardioversion and ablation. In cardioversion, an electrical shock is used to reset heart to its regular rhythm. Usually this is done with paddles, placed on the chest, that can deliver an electrical shock in a monitored setting. You're given medication to sedate during the procedure, so there's no pain. In ablation, one or more catheters are threaded through blood vessels to your inner heart. They're positioned on areas of your heart identified by doctor as causing your arrhythmia. Electrodes at the catheter tips destroy (ablate) a small spot of heart tissue and create an electrical block along the pathway that's causing arrhythmia.
• Pacemakers or implantable cardioverter-defibrillators (ICDs). In some cases, your doctor may recommend having a pacemaker or ICD implanted to regulate your heartbeat. Pacemakers emit electrical impulses to quicken your heartbeat if it becomes too slow, and ICDs can correct a rapid or chaotic heartbeat using a similar type of electrical impulse as is used in cardioversion. The surgery to implant each device is relatively minor and usually requires only a few days of recovery.
• Surgery. For severe heart arrhythmias, or for those with an underlying cause such as a heart defect, surgery may be an option. Because the surgeries to correct heart arrhythmias are open-heart procedures that sometimes require several months for recovery, surgery is often a last-resort treatment option.

2.6.2¹²Heart defect treatments

Some heart defects are minor and don't require treatment, while others may require regular checkups, medications or even surgery. Depending on what heart defect the person have and how severe it is, treatment could include:

• Medications. Some mild congenital heart defects, especially those found later in childhood or adulthood, can be treated with medications that help the heart work more efficiently.
• Special procedures using catheters. Some people now have their congenital heart defects repaired using catheterization techniques, which allow the repair to be done without surgically opening the chest and heart. In procedures that can be done using catheterization, the doctor inserts a thin tube (catheter) into a leg vein and guides it to the heart with the help of X-ray images. Once the catheter is positioned at the site of the defect, tiny tools are threaded through the catheter to the heart to repair the defect.
• Open-heart surgery. In some cases, doctor may perform open-heart surgery to try to repair heart defect. These surgeries are major medical procedures and sometimes require a long recovery time. It's possible you'll need multiple surgeries over several years to treat the defect.
• Heart transplant. If a serious heart defect can't be repaired, a heart transplant may be an option.

2.6.3 Treatments for cardiomyopathy

Treatment for cardiomyopathy varies, depending on what type of cardiomyopathy person have and how serious it is. Treatments can include:

• Medications. Doctor may prescribe medications that can improve your heart's pumping ability, such as ACE inhibitors or angiotensin II receptor blockers. Beta blockers, which make heart beat more slowly and less forcefully, help reduce the strain.
• Medical devices. If the people have dilated cardiomyopathy, treatment may include a special pacemaker that coordinates the contractions between the left and right ventricles of heart, improving the heart's pumping ability. If people at risk of serious arrhythmias, an implantable cardioverter-defibrillator (ICD) may be an option. ICDs are small devices implanted in chest to continuously monitor heart rhythm and deliver electrical shocks when needed to control abnormal, rapid heartbeats. The devices can also work as pacemakers.
• Heart transplant. If people have severe cardiomyopathy and medications can't control symptoms, a heart transplant may be necessary.

2.6.4 Heart infection treatments

The first treatment for heart infections such as pericarditis, endocarditis or myocarditis is often medications, which may include:

• Antibiotics. If the person condition is caused by bacteria, doctor will prescribe antibiotics. Antibiotics are given by an intravenous (IV) line for two to six weeks, depending on how severe the infection is.
• Medications to regulate heartbeat. If the infection has affected heartbeat, doctor may prescribe medications such as angiotensin-converting enzyme inhibitors or beta blockers to help normalize heartbeat.

If the heart infection is severe and damages heart person may need surgery to repair the damaged portion of heart.

2.6.5 Valvular heart disease treatments

Although treatments for valvular heart disease can vary depending on what valve is affected and how severe condition is, treatment options generally include:

• Medications. It's possible valvular heart disease, if mild, can be managed with medications. Commonly prescribed medications for valvular heart disease include medications to open blood vessels (vasodilators), medications to lower cholesterol (statins), medications that reduce water retention (diuretics), and blood-thinning medications (anticoagulants).
• Balloon valvuloplasty. This procedure is sometimes used as a treatment for valve stenosis. During this procedure, doctor threads a small tube through a vein in leg and up to your heart. An uninflated balloon is placed through the opening of the narrowed pulmonary valve. Doctor then inflates the balloon, opening up the narrowed pulmonary valve and increasing the area available for blood flow.
• Valve repair or replacement. If the person condition is severe, person may need surgery to correct it doctor may be able to repair the valve. If the valve can't be repaired, it may be replaced with a valve that's made of synthetic materials.

2.7 ¹⁶Prevention of cardiovascular diseases:

Certain types of heart disease, such as heart defects, can't be prevented. However, you can help prevent many other types of heart disease by making the same lifestyle changes that can improve your heart disease, such as:

• Quit smoking
• Control other health conditions, such as high blood pressure, high cholesterol and diabetes
• Exercise at least 30 minutes a day on most days of the week
• Eat a diet that's low in salt and saturated fat
• Maintain a healthy weight
• Reduce and manage stress
• Practice good hygiene     

MATERIALS AND METHODS

METOPROLOL  succinate recived from Natco pharma hydrochlorothiazide, aspirin simvastatin recived from Arabindo pharma. Excipient included pupk30,starch ,sodium hydroxide,potassium hydrogen ortho phosphate ,hydrochloric acid ,mg stearate, talc ,mcc,isopropyl alcohol,hpmc  ,xantham gum pmck100h.obtained from repuated pharma suppliers

Instruments

1.Electronic balance = Shimadzu, A×200, Japan1.

2. uv visible spectrophotometer =Elico

3. HPLC = SHIMADZU Corporation, LC-2010 C HT liquid chromatography

4. Tablet dissolution test apparatus = VEGO Disso 2000

5. Tablet disintegratingtest apparatus= Labindia Disso 2000

6. P^H meter = Systronic; µ P^H system 361

Methods

3Preformulation studies:

The following preformulation studies were performed or Metoprolol succinate, hydrochlorothiazide, Aspirin & Simvastatin.

1. Solubility
2. Determination of pH
3. Density
4. Carr’sIndex(I)
5.  Hausner’s Ratio
6. Angle of repose
7. Particle size analysis using stage micrometer.

4.3.1.Solubility

A known quantity of solute was dispersed in the solvent and based on following table the solubility was determined.

Determination of pH

A  2%      w\v solution of glucosamine sulphate, 1%w\v solution of chondroitin sulphate was prepared using water as a solvent and 2%w/v of Boswelliawaspreparedusingmethanol.ThepHmeterwaspreviouslycalibrated with standard buffer solution.The glass electrodes of the Ph meter were immersed in the prepared solution and the pH of the corresponding solutions was recorded.

4.3.3. Density

• Bulk Density (Db):

Itistheratiooftotalmassofpowdertothebulkvolumeofpowder.Itwas measuredby pouringtheweighedpowderintoameasuringcylinderandthe volume was noted. It is expressed in gm/ml and is given by

Db=M/Vb

WhereM= is the mass of powder.

Vb=is the bulk volume of the powder.

• Tapped Density (Dt):

Itistheratiooftotalmassofpowdertothetappedvolumeofpowder.The tapped volume wasmeasuredbytappingthepowdertoconstantvolume.Itis expressed in gm/ml and is given by

Dt=M/Vt

M= is the mass of powder.

Vt=isthetapped volume of the powder.

RESULT Thepresentresearchworkisanattemptmadetoprepareandevaluatethe Poly cap for treatment ofCardiovascular diseases.A novel approach to improve therapeutic efficacy and to improve patient compliances and to reduce the cost, one pill per one day best therapeutic action for cardiovascular diseases. For this purpose different therapeutic action and to target one objective selected as Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin and to sustained the drugs the polymers selected as Guar gum, Xantham gum, HPMC k100, HPMCk15 and for immediate release of action of poorly soluble drugs the polymer selected as Crosspovidone, CCS,SSG. To fulfil my object amoung different techniques I were selected Poly cap technology. Based on the above investigation report following results were obtained.

6.1preformulation Studies:

6.1.1Identification of Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin:

• Solubility:

InIdentification of API itwasfoundthatMetoprolol succinate wassolubleinwater, Hydrochlorothiazide was sparingly soluble in water, Aspirin was slightly soluble in water and Simvastatin was practically insoluble in water.

• Melting Point:

ItwasalsofoundMelting point of Metoprolol succinate was 136⁰C, Aspirin was 135

⁰C, Hydrochlorothiazide was 274⁰C and Simvastatin 131⁰C.

• Wavelength:

Itwasfoundwavelength by using UV-VIS spectrophotometer of Metoprolol succinate was 274nm, Hydrochlorothiazide was 273 nm, Aspirin was 265 nm and Simvastatin was 238 nm.

The above parameters were given in the above table 17&18.

6.1.2 Characterisation of Micromeritic parameters of Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin:

Characterisation of Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin was conducted by different parameters and the reports were shown in the above table 14.

6.1.3Angle of Repose:

FurtherstudiesonangleofreposeshowedthatMetoprolol succinate, Aspirin, Hydrochlorothiazide and Simvastatin as 35^o, 36⁰, 38⁰ and 40⁰values the final results was  indicated  poor  flow property of the API.

6.1.4Density:

• Metoprolol succinate showed bulk density  value 0.286gm/cc and tapped density value 0.321gm/cc, true density value 0.416gm/cc.
• Aspirin showedbulk density value 0.342gm/cc and tapped density value 0.616gm/cc and true density value 0.981gm/cc.
• Hydrochlorothiazide showed bulk density value 0.288gm/cc and tapped density value 0.325gm/cc, true density value 0.401gm/cc.
• Simvastatin showedbulk density value 0.291gm/cc and tapped density value 0.326gm/cc and true density value 0.353gm/cc.

6.1.5Carr’s Index:

ThevalueofCarr’sIndexforMetoprolol succinate, Aspirin, Hydrochlorothiazide and Simvastatinwas as follows 24, 28, 25 and 22indicatedthatthese four drugsshowedverymuchpoor flow characteristics.

6.1.6 Compressability Index:

ThevalueofCompressabilityIndexforMetoprolol succinate, Aspirin,  Hydrochlorothiazide, andSimvastatinwas 27.15,24.7,23.9 and 24.5indicatedthatthesedrugsshowedverymuchpoor flow characteristics.

ThevalueofHausner’s ratioforMetoprolol succinate, Aspirin , Hydrochlorothiazide and Simvastatinwas 1.34,1.43,1.52 and 1.35 indicatedthatthesedrugsshowedverymuchpoor flow characteristics.

From the above studies these results indicated  should not follow the specified limits of IP standards and based on results i was found poor flow. So need to improve the flow of the powder

6.1.7 Particle Size:

TheparticlesizeanalysisdatashowedthataveragediameterforMetoprolol succinate is 12µm, Hydrochlorothiazide 7 µm, Aspirin 40 µmand for Simvastatinwas 8µm respectively. the above results Aspirin powder particle size is not uniform to overcome of this the powder is passed through sieve No.44. These micromeritic parameters were shown in the above table 19

6.2 Drug & Excipient Compatibility Stability Studies:

6.2.1 FT-IR studies:

Fromthe FT-IR spectra, it was concluded that similar characteristic peaks with minordifferenceforthedrugandtheirformulation.Hence,itappearsthattherewas no chemical interaction between the drugs and excipients used. The IR Spectra of Metoprolol succinate with guar gum, Xanthan gum & HPMC K100 were shown in fig.1, 6, 7 & 8. The following peaks were observed in Metoprolol Succinate as well as Metoprolol succinate with excipients. The IR Spectra of Hydrochlorothiazide with SSg, Crospovidone, CCS were shown in fig.3, 10, 11 & 12.The following peaks were observed in hydrochlorothiazide as well as Hydrochlorothiazide with excipients. The IR Spectra of Aspirin with HPMC K15 were shown in fig.2 &9. The following peaks were observed in Aspirin as well as Aspirin with excipients. The IR Spectra of Simvastatin with SSG, Crosspovidone, CCS were shown in fig. 4, 13, 14 &15. The following peaks were observed in Simvastatin as well as Simvastatin with excipients. The IR Spectra of Aspirin and Simvastatin with excipients were shown in fig.17. The IR Spectra of Metoprolol succinate and Hydrochlorothiazide with excipients were shown in fig.16. The IR Spectra of Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin with excipients were shown in fig.5 & 18.The following peaks were observed in Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin as well as Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin with excipients.

6.2.2 Microbial testing of polymers:

6.2.2.1 Metoprolol succinate with polymers:

Guar gum, Xanthan gum and HPMC k100 individually and combined with Metoprolol succinate were tested for the presence of microbial organism by inoculating them aseptically into a previously sterilized nutrient broth separately and incubated at 37^oC.As microorganisms were not observed after the completion of the incubation period shown in Figure 19, 23, 24 & 25. Hence it was confirmed that the gums were not contaminated with microbial flora.

6.2.2.2 Aspirin with polymers:

HPMC k15 and its combination with Aspirin were tested for the presence of microbial organism by inoculating them aseptically into a previously sterilized nutrient broth separately and incubated at 37^oC.As microorganisms were not observed after the completion of the incubation period shown in Figure 21 & 26. Hence it was confirmed that the polymer was not contaminated with microbial flora.

6.2.2.3Hydrochlorothiazide with polymers:

Crosspovidone , Crosscarmellose individually and combined with Hydrochlorothiazide were tested for the presence of microbial organism by inoculating them aseptically into a previously sterilized nutrient broth separately and incubated at 37^oC.As microorganisms were not observed after the completion of the incubation period shown in Figure 22, 31 & 32. Hence it was confirmed that the superdisintigrents were not contaminated with microbial flora.

6.2.2.4 Simvastatin with polymers:

Crosspovidone , Crosscarmellose, SSG individually and combined with Simvastatin were tested for the presence of microbial organism by inoculating them aseptically into a previously sterilized nutrient broth separately and incubated at 37^oC.As microorganisms were not observed after the completion of the incubation period shown in Figure 20, 28, 29 & 30. Hence it was confirmed that the superdisintigrents were not contaminated with microbial flora. Metoprolol succinate, Hydrochlorothiazide, Aspirin & Simvastatin were tested for the presence of microbial organism by inoculating them aseptically into a previously sterilized nutrient broth separately and incubated at 37^oC.As microorganisms were not observed after the completion of the incubation period shown in Figure 23. Hence it was confirmed that the superdisintigrents were not contaminated with microbial flora. micro organism growth was not observed after 24 hrs of incubation period of drug and polymers.

6.3 Analytical Method:

Metoprolol succinate, Aspirin, Hydrochlorothiazide and Simvastatinwasestimatedusing UV/VIS Spectrophotometer and HPLCmethod. Itwasfoundthat under UV/VIS Spectrophotometer Standardabsorbance  of  the peak of Metoprolol succinatewas 0.252 for 60 µg/ml of standard weight and for Aspirinitwasfoundthatstandardabsorbance ofthepeakwas0.151for60 µg/mlof standard weight and for Hydrochlorothiazideitwasfoundthatstandardabsorbance ofthepeakwas0.333for6 µg/mlof standard weight and for Simvastatinitwasfoundthatstandardabsorbance ofthepeakwas0.246for6 µg/mlof standard weight . And in HPLC itwasfoundthat Standardarea of the peak of Metoprolol succinatewas 1523448 for 56.8ppm of standard weight, for Aspirin was 4112321 for 84.40ppm standard weight, for Hydrochlorothiazide was 1652932 for 14.3ppm standard weight and for Simvastatinitwasfoundthatstandardarea ofthepeakwas 821792for 13ppm of standard weight.

6.4 Preparation of tablets:

6.4.1 Preparation of Metoprolol succinate tablets:

The formulations M-1, M-2, -M-3, and M-4 contains Guar gum as a polymer in 1:1, 1:1.5, 1:2 and 1:3 (Drug: Guar gum). Guar gum is used as a polymer in this formulation to sustain drug release, and to target the site. Guar gum is targeted to colon. PVP k30 was used as a binding agent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for sustain release. The formula was reported in the table7. 

The formulations M-5, M-6, M-7and M-8prepared with Xanthan gum as polymer in 1:1, 1:1.5, 1:2 and 1:3 (drug: Xanthan gum) . Xanthan gum is used as a polymer in this formulation to sustain the drug release and to target the colon. PVP k30 was used as a binding agent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for sustain release. The formula was reported in the table 8.

Similarly, the formulation M-9, M-10,M-11 and M-12 prepared with HPMCk100 in the ratios of 1:1, 1:1.5,1:2 and 1:3(Drug : HPMC k100) HPMC k100 is used as a synthetic polymer in this formulation to sustain the drug release. PVP k30 was used as a binding agent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for sustain release. The formula was reported in the table 9.

From above all the studies, the sustain release and efficiency was increased with an increase in concentration of the polymer. Guar gum, Xanthan gum and HPMC k100 were used in this investigation. Among these three polymers Guar gum (M-4) was found to be best for the sustain release of Metoprolol succinate.

6.4.2 Preparation of Aspirin tablets:

The formulations A-1, A-2, A-3,A-4,A-5 and A-4 contains HPMC k15 as a polymer in 10%,20%,30%,40%,50% and 60%. HPMC k15 is used as a polymer in this formulation to sustain the drug release and to target the duodenum. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentrations of polymer were used for formulation. The formula was reported in the table 10.

From above all the studies, the sustain release and efficiency was increased with an increase in concentration of the polymer. Different concentrations HPMC k15 were used in this investigation. Among these polymers concentration (A-6) was found to be best for the sustain release of Aspirin.

6.4.3 Preparation of Hydrochlorothiazide tablets:

The formulations H-1, H-2 and H-3contains Crosspovidone as a supper disintigrent in 2%, 4% and 6% (Crosspovidone). Crosspovidone was used as a Super disintigrent in this formulation to enhance drug release. Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table11. 

Similarly, The formulations H-4, H-5 and H-6contains Crosscarmellose as a supper disintigrent in 2%, 4% and 6% (Crosscarmellose). Crosscarmellose was used as a Super disintigrent in this formulation to enhance drug release. Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table 12.

Similarly The formulations H-7, H-8 and H-9 contains SSG as a supper disintigrent in 2%, 4% and 6% (SSG). SSG was used as a Super disintigrent in this formulation to enhance drug release. Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is 1:1 Isopropyl alcohol & water. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table13. 

From above all the studies, the Immediate release and efficiency was increased with an increase in concentration of the super disintigrent. Crosspovidone, Crosscarmellose and SSG were used in this investigation. Among these three distintgrents Crosspovidone (6%) was found to be best for the Immediate release of Hydrochlorothiazide.

6.4.4 Preparation of Simvastatin tablets:

The formulations S-1, S-2 and S-3contains Crosspovidone as a supper disintigrent in 2%, 4% and 6% (Crosspovidone). Crosspovidone was used as a Super disintigrent in this formulation to enhance drug release. BHA is used as an antioxidising agent because simvastatin having oxidation property to minimise the oxidation property we add anti oxidants.  Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is Isopropyl alcohol. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table 14

Similarly, The formulations S-4, S-5 and S-6contains Crosscarmellose as a supper disintigrent in 2%, 4% and 6% (Crosscarmellose). Crosscarmellose was used as a Super disintigrent in this formulation to enhance drug release. BHA is used as an antioxidising agent because simvastatin having oxidation property to minimise the oxidation property we add anti oxidants.  Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is Isopropyl alcohol. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table 15.

Similarly, The formulations S-7, S-8 and S-9contains SSG as a supper disintigrent in 2%, 4% and 6% (SSG). SSG was used as a Super disintigrent in this formulation to enhance drug release. BHA is used as an antioxidising agent because simvastatin having oxidation property to minimise the oxidation property we add anti oxidants.  Lactose and MCC are used as a diluents. Starch was used as a binder and disintigrent. Binding solution used in this formulation is Isopropyl alcohol. The different concentration ratio of polymer was prepared for immediate release. The formula was reported in the table 16.

From above all the studies, the Immediate release and efficiency was increased with an increase in concentration of the super disintigrent. Crosspovidone, Crosscarmellose and SSG were used in this investigation. Among these three distintgrents Crosspovidone (6%) was found to be best for the Immediate release of Hydrochlorothiazidet and discussion

CONCLUSION

1. The present work was carried to design and development of Poly Cap for the treatment of cardiovascular diseases.
2. The previous studies literature was reveled monotherapy is not effective for cardiovascular diseases. It requires more than one drug good treatment. So it was selected Aspirin, Simvastatin, Metoprolol succinate, Hydrochlorothiazide.
3. Poly Cap combines 75mg Aspirin, 10mg simvastatin, 50mg Metoprolol succinate, 12.5mg Hydrochlorothiazide in a capsule.
4. To fulfill our object I was selected two mini bilayer tablets  fixed  in a capsule the technology is called Poly cap technology.
5. Metoprolol succinate granules prepared with Guar gum, Xanthan gum, and HPMC K 100 in different ratios, among all these formulations M-4 (drug : guar gum1:3) shows sustain release for 16hrs. The ability of the used gums to sustain the release is as follows  Guar gum > HPMC k 100 > Xanthan gum
6. Aspirin granules prepared with HPMC k15 in different ratios, among all these formulations A-6 (60%HPMC k15)shows the maximum amount of the drug released in duodenum up to 24hrs.
7. Hydrochlorothiazide granules prepared with Crosspovidone, Crosscarmellose, SSG in different ratios, among all these formulations H-3 (6%crosspovidone) shows 98% of drug release with in 20min.
8.  Simvastatin granules prepared with Crosspovidone, Crosscarmellose, SSG in different ratios, among all these formulations S-3 (6%crosspovidone) shows immediate release with in 20min.
9. The study shows the release of Metoprolol succinate 16hr, Hydrochlorothiazide 20 min, Aspirin 24hrs, Simvastatin 20 min.
10. The Poly Cap study shows 10% of Aspirin and 40% of Simvastatin   was degraded in gastric fluids.
11. A cheap four-in-one pill can guard against heart attacks and stroke.
12. The Poly Cap is one of the best dosage form to treat cardiovascular diseases. Because it was reported the combination of these four drugs reduce mortality by 83% in high risk patients with Heart diseases, Hypertension, Diabetes, Obesity.

REFERENCES

1. Bridget B. Kelly; Institute of Medicine; Fuster, Valentin (2010). Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health. Washington, D.C: National Academies Press. ISBN 0-309-14774-3.
2. Heart Disease overview in WebMD health center is an online review article.WWW.Google.com
3. "WHO Disease and injury country estimates". World Health Organization. 2009. http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html. Retrieved Nov. 11, 2009.
4. "Understand Your Risk of Heart Attack". American Heart Association”. http://www.heart.org/HEARTORG/Conditions/HeartAttack/UnderstandYourRiskofHeartAttack/Understand-Your-Risk-of-Heart-Attack_UCM_002040_Article.jsp
5. Donald.Crizzo, fundamental of Anotomy and Physiology.
6. T.S Ranganthan, A Text book of Human Anotomy.
7. Boos CJ, Lip GY Targeting the renin-angiotensin-aldosterone system in atrial fibrillation: from pathophysiology to clinical trials.J Hum Hypertens.2005;19:855-9.
8. Lindholt JS, Fasting H, Henneberg EW, Ostergaard L A review of Chlamydia pneumoniae and atherosclerosis.Eur J Vasc Endovasc Surg.1999;17:283-9.
9. Micha, R; Mozaffarian, D (2010 Oct). "Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence
10. Mendis, S.; Puska, P.; Norrving, B.(editors) (2011), Global Atlas on cardiovascular disease prevention and control, ISBN 978-92-4-156437-3.