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11. Floating Drug Delivery System a Significant Tool for Stomach Specific Release of Cardiovascular Drugs

Kaushik Avinash*, Dwivedi Abha, Kothari Praween, Govil Abhinav
School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur-302017
Corresponding Author: Kaushik Avinash Y Department of pharmaceutics School of Pharmaceutical Sciences, Jaipur National University, Jaipur - 302017. Email ID: lavi1191@gmail.com
Received: 06 November 2012 Accepted: 11 November 2012
Citation: Kaushik Avinash*, Dwivedi Abha, Kothari Praween, Govil Abhinav “Floating Drug Delivery System a Significant Tool for Stomach Specific Release of Cardiovascular Drugs” Int. J. Drug Dev. & Res., October-December 2012, 4(4): 116-129.
Copyright: © This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
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Abstract

Floating drug delivery system is a recent advancement in pharmaceutical technology which has also several advantages over the conventional drug delivery systems. Those advantages of floating system can be used in the treatment of world’s most affective diseases like cardiovascular diseases. Cardiovascular diseases are group of diseases which are many of the time fetal for the patients due to problems associated with the oral conventional tablets. These problems can be overcome by this delivery system. With an increasing understanding of polymer behavior and the role of the biological factors, it is suggested that future research work on the way of floating drug delivery system should be aimed to control accurately the drug input rate into the gastrointestinal tract for the optimization of the pharmacokinetic and toxicological profiles of cardiovascular agents. This review gives an overview of cardiovascular disease, floating drug delivery system & role of floating drug delivery system in treatment of heart patient.

Key words

Floating, NDDS, cardiac disease, controlled system

Introduction

Floating drug delivery system is a class of gastroretentive drug delivery system & use of floating drug delivery for treatment of cardiovascular diseases is recent trend. Cardiovascular Diseases are those diseases which are related with the heart physiology & functions. Diseases like Congestive heart disease, Cardiac arrhythmia, Ischemic heart diseases, Hypertension come under cardiovascular disease category which are the major diseases by which maximum populations are suffer all over the world. Causes of these diseases are Tobacco consumption, Elevated LDL, Low HDL, High blood pressure, Elevated glucose, Physical inactivity, Obesity, Diet, Low socioeconomic status, Elevated prothrombotic factors: fibrinogen, PAI-1, Markers of infection or inflammation, Elevated homocysteine, Elevated lipoprotein, Psychological factors (depression, anger proneness, hostility, stress, acute life-events).[1]

Cardiovascular Diseases

Congestive Heart Failure is a condition in which the heart no longer functions effectively as a pump. Depending upon the cause, heart failure may be classified as low output failure or high output failure. Low output failure is said to occur when the pumping efficiency of the heart becomes reduced by factors that impair cardiac function. High output failure occurs when the cardiac output of the heart remains significantly elevated for a long period.[2]
Cardiac Arrhythmia is a change in the rhythm of heartbeat. When the heart beats too fast, it's called tachycardia. When it beats too slowly, it's called bradycardia. An arrhythmia can also mean that heart beats irregularly.[3]
Ischemic Heart Disease classified mainly into Angina pectoris & Myocardial infarction. Angina pectoris is a disease in which oxygen supply to the heart is decreased in comparison to demand in myocardial. It may classical, prinzmental and unstable angina.[4] Myocardial infarction is also called heart attack is characterized by necrosis of a portion of the heart muscles.[5]
Hypertension is the most common cardiovascular disease. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Even mild hypertension (blood pressure 140/90 mmHg) increases the risk of eventual end organ damage. Starting at 115/75 mmHg cardiovascular disease risk doubles with each increment of 20/10 mmHg throughout the blood pressure range.[6]
Congenital Heart Defects are problems with the heart's structure that are present at birth. These defects can involve: The interior walls of the heart, the valves inside the heart, the arteries and veins that carry blood to the heart or the body. Congenital heart defects change the normal flow of blood through the heart. There are many types of congenital heart defects. They range from simple defects with no symptoms to complex defects with severe, lifethreatening symptoms.[7]
There are some other diseases like coronary heart disease (heart attacks); cerebrovascular disease (stroke); peripheral artery disease; rheumatic heart disease and congenital heart disease (since birth) are also included in this category.[8]

Cardiovascular Therapy

Hypertension is the major heart disease. It is treated with many of the drug. Those drugs are acting through the different mechanism which are described here category wise:
a. Diuretics such as; Thiazides (Hydrochlorthiazides), Loop acting (Furosemide, Terosemide), Potassium sparing drugs (Spironolactone, Triamterene)
b. Antiadrenergic Agents such as; Centrally acting (Clonidine, Methyldopa), Acting on autonomic ganglia (Trimethaphan), Acting on nerve ending (Guanithidine, Guanadrel), &- Receptor acting (Prazosin, Terazosin), )- Receptor acting (Atenolol, Propranolol), &/) Receptor acting (Labetalol, Carvediol)
c. Vasodilators such as; Hydralazine, Minoxidil, Diazoxide, Nitroprusside
d. Angiotensin Related Drug such as; ACE inhibitors (Captopril, Benazepril, Enalapril), Angiotensin antagonists (Nifedipine, Felodipine, Nicardipine)[9]
Congestive heart failure is treated by different drugs. Cardiac glycosides are mainly digoxin & digitoxin used which has the unique characteristic of increasing contractility (positive inotropy) while decreasing heart rate (negative chronotropy). This pharmacological profile results from indirect as well as direct effects of digitalis glycosides on the heart. It works directly on the heart through an action on the sodium - potassium (Na+–K+) ATPase.[10] Other anti hypertensive drugs can be used for the treatment of this disease.
Cardiac arrhythmia is also mainly treated with all those type drugs which are used for above cardiac diseases. They are classified in following manner:
a. Class IA drugs such as Quinidine, Procainamide
b. Class IB drugs such as Lidocaine, Phenytoin, Tocainide
c. Class IC drugs such as Flecainide, Propafenone
d. Class II drugs such as Propranolol, Metoprolol, Atenolol, Timolol, Sotalol
e. Class III drugs such as Amiodarone, Bretylium, Dofetalide
f. Class IV drugs such as Ibutilide, Dofetilide, Verapamil[11]
Angina is the most common disease in all the cardiac disease which can also treated by the medicines like Nitroglycerin is a sublingual (under the tongue) medication relieves angina symptoms by expanding blood vessels and decreasing the muscle's need for oxygen. This allows more blood to flow through the coronary arteries.[12] Treatment for the congenital heart defect can include medicines, surgery and other medical procedures like cardiac catheterization and heart transplants. The treatment depends on the type and severity of the defect and a child's age, size and general health.[13]

Gastrointestinal tract physiology

The stomach is anatomically divided into three parts: fundus, body, and pylorus. The proximal stomach, made up of the fundus and body regions, serves as a reservoir for ingested materials while pylorus, the distal region is the major site of mixing motions, acting as a pump to accomplish gastric emptying. The process of gastric emptying occurs both during fasted and fed states but the pattern of motility differs markedly in the two states. In the fasted state, it is characterized by an interdigestive series of electrical events which cycle both through the stomach and small intestine every 2–3 h. This activity is called the interdigestive myoelectric cycle or migrating myoelectric complex (MMC), which is often divided into four consecutive phases. As described by Wilson and Washington, phase I is a quiescent period lasting from 40 to 60 min with rare contractions. Phase II is a period of similar duration consisting of intermittent action potentials and contractions that gradually increase in intensity and frequency as the phase progresses. Phase III is a short period of intense, large regular contractions lasting from 4 to 6 min. It is this phase, which gives the cycle the term ‘housekeeper’ wave, since it serves to sweep undigested materials out of the stomach and down the small intestine. As phase III of one cycle reaches the end of the small intestine, phase III of the next cycle begins in the duodenum. Phase IV is a transitional phase occurs between phase III and phase I of two consecutive cycles. In the fed state, the gastric emptying rate is slowed since the onset of MMC is delayed. In other words, feeding results in a lag time prior to the onset of gastric emptying.[15]

Problems associated with the absorption from oral route

There are many of the factors which affect the absorption of oral dosage form like Bioavailability Problem, Extended Dosage Regimen, First Pass Metabolism, Gastric Emptying Time, Effect of PH on Drugs, Absorption Windows, and Enzymatic Degradation in Gastrointestinal Tract.[16-22]

Approaches to overcome the problem related with oral dosage forms

The pharmaceutical approach involves modification of formulation, manufacturing process or the physicochemical properties of the drug without changing the chemical structure.
The pharmacokinetic approach causes alteration by modifying its chemical structure. This approach is further divided into two categories- Development of new chemical entity with desirable features and Prodrug design.
The biological approach whereby the route of drug administration may be changed such as from oral to perenteral route.[23]
Pharmaceutical approaches are mainly used for overcoming the problem related with other oral drug delivery system. Recently Sustained Release & Control Release Drug Delivery System is preferred.

Sustained & Controlled Release Drug Delivery System

Sustained release system is slow release system in which the drug is slowly release from the dosage form but not predictable. Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time. Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of gastrointestinal tract.[24,25] Those are the advancements made in other drug delivery systems in order to increase the clinical efficacy and patient compliance. Controlled drug delivery systems are of many types.
Recently the gastroretention is a major approach to overcoming the problem related with other oral drug delivery system.

Gastroretentive Drug Delivery Systems

Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.[26]

Need For Gastroretentive Drug Delivery System

Various drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have a lower level of side effects and provide their therapeutic effects without the need for repeated dosages or with a low dosage frequency. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited. Under normal or average conditions, for example, material passes through the small intestine in as little as 1-3 hours. Gastroretentive systems useful for drugs acting locally in the stomach (Antacids and drugs for H. Pylori viz., Misoprostol), Drugs that are primarily absorbed in the stomach (Amoxicillin), Drugs that is poorly soluble at alkaline pH (Furosemide, Diazepam, Verapamil), Drugs having narrow absorption window (Cyclosporine, Methotrexate, Levodopa), Drugs which are absorbed rapidly from the GI tract (Metonidazole, tetracycline), Drugs that degrade in the colon (Ranitidine, Metformin HCl), Drugs that disturb normal colonic microbes (antibiotics against Helicobacter pylori).[27,28]

Factors Controlling Gastroretention of Dosage Forms

The stomach anatomy and physiology contain parameters to be considered in the development of gastroretentive dosage forms. To pass through the pyloric valve in to the small intestine, the particle size should be in the range of 1 to 2 mm.[29] The most important parameters controlling the gastric retention time (GRT) of oral dosage forms include : density, size and shape of the dosage form, food intake and its nature, caloric content and frequency of intake, posture, gender, age, sex, sleep, body mass index, physical activity and diseased states of the individual (e.g. chronic disease, diabetes etc.) and administration of drugs with impact on gastrointestinal transit time for example drugs acting as anticholinergic agents (e.g. atropine, propantheline), Opiates (e.g. codeine) and prokinetic agents (e.g. metclopramide, cisapride).[30] The molecular weight and lipophilicity of the drug depending on its ionization state are also important parameters.[31]

Types of gastroretentive system

a. High Density System : Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture.[32]
b. Modified Shape Systems/ Unfolding Systems: These are the dosage forms, which after swallowing, swell to an extent that prevent their exit from the pylorus. As a result, the dosage form is retained for a longer period of time.[33]
c. Mucoadhesive Systems : Bioadhesive drug delivery systems are used as a delivery device within the human to enhance drug absorption in a site-specific manner. In this approach, bio adhesive polymers are used and they can adhere to the epithelial surface in the stomach. Thus, they improve the prolongation of gastricretention.[34] Materials commonly used for bioadhesion are poly acrylic acid, chitosan, cholestyramine, sodium alginate, hydroxypropyl methylcellulose (HPMC), sucralfate, tragacanth, dextrin, polyethylene glycol (PEG) and polylactic acids etc. Even though some of these polymers are effective at producing bioadhesive, it is very difficult to maintain it effectively because of the rapid turnover of mucus in the gastrointestinal tract (GIT).[35]
d. Floating Drug Delivery System: Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time.

FLOATING DRUG DELIVERY SYSTEM

Floating drug delivery system is also known as hydrodynamically balanced system (HBS). While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration.[36]

Advantages of FDDS

Floating dosage systems form important technological drug delivery systems with gastric retentive behavior and offer several advantages in drug delivery. These advantages include:
1) Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.
2) Controlled delivery of drugs.
3) Delivery of drugs for local action in the stomach.
4) Minimizing the mucosal irritation due to drugs, by drug releasing slowly at controlled rate.
5) Treatment of gastrointestinal disorders such as gastro-esophageal reflux.
6) Simple and conventional equipment for manufacture.
7) Ease of administration and better patient compliance.
8) Site-specific drug delivery.[37]

Limitations of FDDS

1) Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted.
2) Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery systems.
3) High variability in gastric emptying time due to its all or non-emptying process.
4) Gastric emptying of floating forms in supine subjects may occur at random and becomes highly dependent on the diameter and size. Therefore patients should not be dosed with floating forms just before going to bed.[38]

Factors affecting the floating and floating time

a. Density: Floating is a function of dosage form buoyancy that is dependent on the density. Density o f t h e dosage form should be less than the gastric contents (1.004gm/ml).
b. Shape of dosage form: Dosage form unit with a diameter of more than 7.5 mm are reported to have an increased GRT competed to with those with a diameter of 9.9 mm. Tetrahedron and ring shaped devices with flexural modules of 48 and 22.5 kilo pounds per square inch (ksi) are reported to have better floating, 90% to 100% retention at 24 hours compared with other shapes.
c. Concomitant drug administration: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time.
d. Fed or unfed state: Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (mmc) that occurs in every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.
e. Nature of meal: Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
f. Caloric content and feeding frequency: Floating can be increased by four to 10 hours with a meal that is high in proteins and fats. The floating can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of mmc.
g. Age: Elderly people, especially those over 70, have a significantly longer; floating. Disease condition such as diabetes and crohn’s disease etc also affect drug delivery.
h. Gender: Mean ambulatory GRT in males (3.4 0.6 hours) is less compared with their age and race-matched female counter parts(4.6 1.2 hours), regardless of the weight, height and body surface.
i. Posture: Floating can vary between supine and upright ambulatory states of the patient.[39,40]

Approaches to design floating drug delivery system

Practical approaches in designing FDDS
The concept of FDDS was first described in the literature as early as 1968, when Davis (1968) disclosed a method to overcome the difficulty experienced by some persons of gagging or choking after swallowing medicinal pills. The author suggested that such difficulty could be overcome by providing pill having a density of less than 1.0g/cm3, so that pill will float on water surface. Since then several approaches have been used to develop an ideal floating drug delivery system.[41]
Approaches to design single and multiple unit dosage form
The following approaches have been used for the design of floating dosage forms of single and multiple unit systems.
a. Single Unit Dosage Form
In low density approaches, the globular shells apparently having lower density than that of gastric fluid can be used as a carrier like popcorn, poprice, polystrol for the drug for its controlled release. The polymer of choice can be either Ethyl cellulose or HPMC depending on type of release desired. Finally the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration. Fluid filled floating chamber type of dosage forms includes incorporation of a gas filled floatation chamber in to a micro porous component that houses as a reservoir having apertures present at top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. Hydro Dynamically Balanced Systems are designed to prolong the stay of the dosage forms in the gastric intestinal tract and aid in enhancing the absorption. Drugs having a better solubility in acidic environment and also having specific site of absorption in the upper part of small intestine is achieved by these HBS systems. To retain in stomach for a prolonged period of time the dosage form must have bulk density of less than ‘1’ and has to maintain its structural integrity and release drug constantly from the dosage form. Among all the advantages single-unit formulations are associated with some limitations/problems such as sticking together or being obstructed in the GIT which may lead to potential danger of producing irritation.[42]
b. Multiple Unit Dosage Form
Multiparticulate dosage forms are gaining much favor over single-unit dosage forms. The potential benefits include increased bioavailability; predictable, reproducible and generally short gastric residence time, no risk of dose dumping; reduced risk of local irritation, and the flexibility to blend pellets with different compositions or release patterns. Because of their smaller particle size these systems are capable of passing through the GI tract easily, leading to less inter- and intra-subject variability. However, potential drug loading of a Multiparticulate system is lower because of the proportionally higher need for excipients (e.g., sugar cores). Most Multiparticulate Pulsatile delivery systems are reservoir devices coated with a reputable polymeric layer. Upon water ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure build-up within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas producing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. Water soluble drugs are mainly released by diffusion; while for water insoluble drug, the release is dependent on dissolution of drug.[43]

Types of Floating Drug Delivery System

Floating drug delivery systems can be divided in to non-effervescent and gas-generating system.
Non-effervescent systems : This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excipients used most commonly in these systems include hydroxypropyl methyl cellulose (HPMC), polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.[44] This system can be further divided into four sub-types:
a. Colloidal gel barrier system such a system contains drug with gel-forming hydrocolloids meant to remain buoyant on the stomach content. This prolongs GRT and maximizes the amount of drug that reaches its absorption sites in the solution form for ready absorption. This system incorporates high level of one or more gel-forming highly soluble cellulose type hydrocolloid, e.g. hydroxypropyl cellulose, hydoxy ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), polysaccharides and matrixforming polymer such as polycarbophil, polyacrylateand polystyrene. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface.[45]
b. Microporous compartment system, this technology is based on the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric surface with the undissolved drug. In the stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric content. Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption.[46]
c. Alginate beads, in which Multi-unit floating dosage forms have been developed from freezedried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate. The beads are then separated, snap-frozen in liquid nitrogen, and freeze-dried at -40 ºC for 24 hours, leading to the formation of a porous system, which can maintain a floating force for over 12 hours. These floating beads gave a prolonged residence time which is more than 5.5 hours.[47]
d. Raft Forming Systems have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and disorders. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of CO2. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids, described an antacid raft forming floating system. The system contains a gel forming agent (e.g. alginic acid), sodium bicarbonate and acid neutralizer, which forms a foaming sodium alginate gel (raft) when in contact with gastric fluids. The raft thus formed floats on the gastric fluids and prevents the reflux of the gastric contents (i.e. gastric acid) into the esophagus by acting as a barrier between the stomach and esophagus.[48]
Gas-generating (effervescent) systems: These buoyant systems utilize matrices prepared with swell able polymers such as methocel, polysaccharides (e.g., chitosan), effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid). The system is so prepared that upon arrival in the stomach; carbon dioxide is released, causing the formulation to float in the stomach. Other approaches and materials that have been reported are a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology.[49]
Hollow microspheres / Microballons loaded with drug in their outer polymer shelf were prepared by a novel emulsion solvent diffusion method. The ethanol/dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40ºC. The gas phase is generated in the dispersed polymer droplet by the evaporation of dichloromethane formed and internal cavity in the microsphere of the polymer with drug. The microballoon floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 hours.[50]

Conclusion

This review gives an overview of concepts used to design pharmaceutical dosages form with prolonged gastric retention time. Number of commercial products and patents issued in this field are the evidence of it. The FDDS become an additional advantage for cardiovascular drugs that are absorbed primarily in the upper part of GI tract, i.e., the stomach, duodenum, and jejunum. Gastro-retentive floating drug delivery systems have emerged as an efficient means of enhancing the bioavailability and controlled delivery of many drugs. The increasing sophistication of delivery technology will ensure the development of increase number of gastroretentive drug delivery to optimize the delivery of molecules that exhibit absorption window, low bioavailability and extensive first pass metabolism. It seems that to formulate an efficient FDDS for cardiovascular disease needs an ideal approach with industrial applicability and feasibility.
 

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