A Comprehensive Review On Floating Tablets

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Patidar H.C.

Patidar H.C

Abstract

In recent years scientific and technological advancements have been made in the research and development of controlled release oral drug delivery systems by overcoming physiological adversities like short gastric residence times and unpredictable gastric emptying times. Floating tablets are the systems which are retained in the stomach for a longer period of time and thereby improve the bioavailability of drugs. Floating tablets were prepared using directly compression technique using polymers like HPMC K4M and HPMCK100M for their gel-forming properties.

Introduction

The oral route is considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factors such as gastric emptying process, gastrointestinal transit time of dosage form, drug release from the dosage form and site of absorption of drugs. Most of the oral dosage forms possess several physiological limitations such as variable gastrointestinal transit, because of variable gastric emptying  leading to non-uniform absorption profiles, incomplete drug release and shorter residence time of the dosage form in the stomach. This leads to incomplete absorption of drugs having absorption window especially in the upper part of the small intestine, as once the drug passes down the absorption site, the remaining quantity goes unabsorbed. The gastric emptying of dosage forms in humans is affected by several factors because of which wide inter- and intra-subject variations are observed. Since many drugs are well absorbed in the upper part of the gastrointestinal tract, such high variability may lead to non-uniform absorption and makes the bioavailability unpredictable. Hence a beneficial delivery system would be one which possesses the ability to control and prolong the gastric emptying time and can deliver drugs in higher concentrations to the absorption site (i.e. upper part of the small intestine).

The identification of new diseases and the resistance shown towards the existing drugs called for the introduction of new therapeutic molecules. In response, a large number of chemical entities have been introduced, of which some have absorption all over the gastrointestinal tract (GIT), some have absorption windows (i.e. absorption sites, especially the upper part of the small intestine) and some drugs have poor solubility in intestinal media. The drugs belonging to the second and third categories, and the drugs which are required for local action in the stomach, require a specialized delivery system. All the above requirements can be met and effective delivery of the drugs to the absorption window, for local action and for the treatment of gastric disorders such as gastro-esophageal reflux, can be achieved by floating drug delivery systems (FDDS).

To date, a number of FDDS involving various technologies, carrying their own advantages and limitations were developed such as, single and multiple unit hydro dynamically balanced systems (HBS), single and multiple unit gas generating systems, hollow microspheres and raft forming systems.

The hydrodynamic balanced system (HBS) also called Floating drug delivery system (FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time of the dosage form within the GIT. It is a formulation of a drug with gel forming hydrocolloids meant to remain buoyant in the stomach contents. Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions. The retentive characteristics of the dosage form are not significant for the drugs that:

ØAre insoluble in intestinal fluids

ØAct locally

ØExhibit site-specific absorption.

The formulation of the dosage form must comply with three major criteria for HBS.

ØIt must have sufficient structure to form a cohesive gel barrier.

ØIt must maintain an overall specific gravity less than that of gastric content.

ØIt should dissolve slowly enough to serve as a “Reservoir” for the delivery system.

Floating systems are one of the important categories of drug delivery systems with gastric retentive behavior. Drugs that could take advantage of gastric retention include:  furosemide, cyclosporine, allopurinol ciprofloxacin and metformin. Drugs whose solubility is less in the higher pH of the small intestine than the stomach (e.g. chlordiazepoxide and cinnarizine, the drugs prone for degradation in the intestinal pH (e.g. captopril), and the drugs for local action in the stomach (e.g. misoprostol) can be delivered in the form of dosage forms with gastric retention. Antibiotics, catecholamines, sedative, analgesics, anticonvulsants, muscle relaxants, antihypertensive and vitamins can be administered in HBS dosage form.

Drugs reported to be used in the formulation of floating dosage forms are:

Floating microspheres (aspirin, griseofulvin, p-nitroaniline, ibuprofen, terfinadine and tranilast), floating granules (diclofenac sodium, indomethacin and prednisolone), films (cinnarizine), floating capsules (chlordiazepoxide hydrogen chloride,diazepam, furosemide, misoprostol, L-Dopa, benserazide, ursodeoxycholic acid and pepstatin) andfloating tablets and pills  (acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, para aminobenzoic acid, piretamide, theophylline and verapimil hydrochloride, etc.).

Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.

Advantages

  1. The principle of HBS can be used for any particular medicament or class of medicament.
  2. The HBS formulations are not restricted to medicaments, which are principally absorbed from the stomach. Since it has been found that these are equally efficacious with medicaments which are absorbed from the intestine e.g. Chlorpheniramine maleate.
  3. The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids.
  4. The efficacy of the medicaments administered utilizing the sustained release principle of HBS has been found to be independent of the site of absorption of the particular medicaments.
  5. Administration of a prolonged release floating dosage form tablet or capsule will result in dissolution of the drug in gastric fluid. After emptying of the stomach contents, the dissolve drug available for absorption in the small intestine. It is therefore expected that a drug will be fully absorbed from the floating dosage form if it remains in solution form even at alkaline pH of the intestine.
  6. When there is vigorous intestinal movement and a short transit time as might occur in certain type of diarrhoea, poor absorption is expected under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.
  7. Gastric retention will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.
  8. Many drugs categorized as once-a-day delivery have been demonstrated to have suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended release development challenging. Therefore, a system designed for longer gastric retention will extend the time within which drug absorption can occur in the small intestine.
  9. Certain types of drugs can benefit from using gastro retentive devices. These include:

• Drugs acting locally in the stomach;

• Drugs those are primarily absorbed in the stomach;

• Drugs those are poorly soluble at an alkaline pH;

• Drugs with a narrow window of absorption;

• Drugs absorbed rapidly from the GI tract; and

• Drugs those degrade in the colon.

Disadvantages

  1. There are certain situations where gastric retention is not desirable. Aspirin and non-steroidal anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted.
  2. Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment should not be formulated in gastroretentive systems.
  3. Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric retention system.

Approaches

Several approaches have been attempted in the preparation of gastro-retentive drug delivery systems. These include floating systems, swell able and expandable systems, high density systems, bioadhesive systems, altered shape systems, gel forming solution or suspension systems and sachet systems. Various approaches have been followed to encourage gastric retention of an oral dosage form. Floating systems have low bulk density so that they can float on the gastric juice in the stomach. The problem arises when the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to float on. Floating systems can be based on the following:   

  1. Hydrodynamically balanced systems (HBS) – incorporated buoyant materials enable the device to float;
  2. Effervescent systems – gas-generating materials such as sodium bicarbonates or other carbonate salts are incorporated. These materials react with gastric acid and produce carbon dioxide, which entraps in the colloidal matrix and allows them to float;
  3. Low-density systems -- have a density lower than that of the gastric fluid so they are buoyant;
  4. Bioadhesive or mucoadhesive systems – these systems permit a given drug delivery system (DDS) to be incorporated with bio/mucoadhesive agents, enabling the device to adhere to the stomach (or other GI) walls, thus resisting gastric emptying. However, the mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.
  5. High-density Systems - sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on diameter of the pellets, although many conflicting reports stating otherwise also abound in literature.

Methods

  1. Using gel forming hydrocolloids such as hydrophilic gums, gelatin, alginates, cellulose derivatives, etc.
  2. Using low density enteric materials such as methacrylic polymer, cellulose acetate phthalate.
  3. By reducing particle size and filling it in a capsule.
  4. By forming carbon dioxide gas and subsequent entrapment of it in the gel network.
  5. By preparing hollow micro-balloons of drug using acrylic polymer and filled in capsules.
  6. By incorporation of inflatable chamber which contained in a liquid e.g. solvent that gasifies at body temperature to cause the chambers to inflate in the stomach.

Fig: 1 is showing the floating drug delivery in stomach and fig: 2 demonstrate the mechanism of floating drug delivery systems.

Diagram of Floating Drug Delivery System

Mechanism of Floating Drug Delivery System

Factors Affecting

  1. Density – gastric retention time (GRT) is a function of dosage form buoyancy that is dependent on the density;
  2. Size – dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared with those with a diameter of 9.9 mm;
  3. Shape of dosage form – tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes;
  4. Single or multiple unit formulation – multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms;
  5. 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 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 longe
  6. 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;
  7. Caloric content – GRT can be increased by four to 10 hours with a meal that is high in proteins and fats;
  8. Frequency of feed – the GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC;
  9. Gender – mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface);
  10. Age – elderly people, especially those over 70, have a significantly longer GRT;
  11. Posture – GRT can vary between supine and upright ambulatory states of the patient;
  12. Concomitant drug administration – anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time.
  13. Biological factors – diabetes and Crohn’s disease, etc.

Limitations

ØThe major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bioadhesive polymers that easily adhere to the mucosal lining of the stomach

ØFloating system is not feasible for those drugs that have solubility or stability problem in gastric fluids.

ØThe dosage form should be administered with a minimum of glass full of water (200-250 ml).

ØThe drugs, which are absorbed throughout gastro-intestinal tract, which under go first-pass metabolism (nifedipine, propranolol etc.), are not desirable candidate.

ØSome drugs present in the floating system causes irritation to gastric mucosa.

Marketed Products

Some of the marketed formulations are listed as follows:

Table → Marketed Products of GRDDS

Brand name

Delivery system

Drug (dose)

Company name

Valrelease®

Floating capsule

Diazepam (15mg)

Hoffmann-LaRoche, USA

Madopar® HBS

(Prolopa® HBS)

Floating, CR capsule

Benserazide (25mg) and L-Dopa (100mg)

Roche Products, USA

Liquid Gaviscon®

Effervescent Floating liquid  alginate preparations

Al hydroxide (95 mg), Mg Carbonate (358 mg)

GlaxoSmithkline, India

Topalkan®

Floating liquid  alginate preparation

Al – Mg  antacid

Pierre Fabre Drug, France

Almagate Flot coat®

Floating dosage form

Al – Mg  antacid

-----------

Conviron®

Colloidal gel forming FDDS

Ferrous sulphate

Ranbaxy, India

Cytotech®

Bilayer floating capsule

Misoprostol (100µg/200µg)

Pharmacia, USA

Cifran OD®

Gas-generating floating form

Ciprofloxacin (1gm)

Ranbaxy, India

Applications

ØRecent study indicated that the administration of diltiazem floating tablet twice a day might be more effective compared to normal tablets in controlling the blood pressure of hypertensive patient.

ØMadopar® HBS- containing L-dopa and benserazide- here drug was released and absorbed over a period of 6-8 hour and maintain substantial plasma concentration for parkinson’s patients.

ØCytotech® -- containing misoprostol, a synthetic prostaglandin- E1 analog, for prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDS).

ØAs it provides high concentration of drug within gastric mucosa, it is used to eradicate pylori (A causative organism for chronic gastritis and peptic ulcers).

Ø5-Fluorouracil has been successfully evaluated in patients with stomach neoplasm.

ØDeveloping HBS dosage form for tacrine provides a better delivery system and reduces its GI side effects in alzheimer’s patients.

ØTreatment of gastric and duodenal cancers.

ØAlza corporation has developed a gastroretentive platform for the OROS® system, which showed prolong residence time in a dog model as the product remain in the canine stomach at 12 hrs. post dose and was frequently present at 24 hrs.

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About Authors:

Patidar H.C.

Patidar H.C
Bansal College of Pharmacy, Bhopal, M.P.-India

Dwivedi S

Dwivedi S
Chordia Institute of Pharmacy, Indore, M.P.-India

Dwivedi A

Dwivedi A
NRI Institute of Pharmaceutical Sciences, Bhopal, M.P.-India

Kapadia R

Kapadia R
People’s Institute of Pharmacy and Research Center, Bhopal, M.P.-India

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