INTRODUCTION:

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa.¹Thus small intestinal transit time is an important parameter for drugs that are incompletely absorbed.

Gastroretensive 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.

The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion,² flotation,³ sedimentation,⁴ expansion modified shape systems⁵ or by the simultaneous administration of pharmacological agent^6,7 that delay gastric emptying. This review focuses on the principal mechanism of floatation to achieve gastric retention.

FLOATING DRUG DELIVERY SYSTEM:

Floating systems or Hydrodynamically controlled systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. 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 result sin an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal (Fig 1). Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hollow microspheres. Table 1 enlists examples of various drugs formulated as different forms of FDDS.

Approaches To Design Floating Dosage Forms:

The following approaches have been used for the design of floating dosage forms of single and multiple unit systems.⁸

Single-Unit Dosage Forms:

In low density approaches,³ the globular shells apparently having lower density than that of gastric fluid can be used as a carrier for drug for its controlled release. A buoyant dosage form can also be obtained by using a fluid-filled system that floats in the stomach. In coated shells⁹ popcorn, poprice, and polystyrol have been exploited as drug carriers. Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to undercoat these shells. These are further coated with a drug-polymer mixture. The polymer of choice can be either ethylcellulose or hydroxypropyl cellulose depending on the type of released 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 into a microporous component that houses a drug reservoir.¹⁰ Aperture or opening are present along the top and bottom walls through which the gastrointestinal fluid enters to dissolve the drug. The other two walls in contact with the fluid are sealed so that the undissolved drug remains therein. The fluid present could be air, under partial vacuum or any other suitable gas, liquid, or solid having an appropriate specific gravity and an inert behavior. The device is of swallowable size, remains afloat within the stomach for a prolong time, and after the complete release the shell disintegrates, passes off to the intestine, and is eliminated. Hydrodynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastro intestinal tract and aid in enhancing the absorption. Such systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine. To remain in the stomach for a prolong period of time the dosage form must have a bulk density of less than 1. It should stay in the stomach, maintain its structural integrity, and release drug constantly from the dosage form. Single unit formulations are associated with problems such as sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation.

Multiple-Unit Dosage Forms

The purpose of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multiple-unit floatable dosage forms have been designed. Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine, and poly alkyl cyanoacrylate. Spherical polymeric microsponges also referred to as “microballoons” have been prepared. Microspheres have a characteristic internal hollow structure and show an excellent in vitro floatability.¹¹ In Carbon dioxide- generating multiple-unit oral formulations several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to18 mm in their expanded state is exceeded (Fig 2 A).

Classification of Floating Drug Delivery¹²:

Floating drug delivery systems are classified depending on the use of two formulation variables: effervescent and non-effervescent systems.

Effervescent Floating Dosage Forms:

These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, C0₂ is liberate and gas entrapped in swollen hydrocolloids which provides buoyancy to the dosage forms (Fig. 2 B).

Non-effervescent Floating Dosage Forms:

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass.

Evaluation of floating drug delivery systems¹³:

Various parameters that need to be evaluated in gastro-retensive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In the case of multiparticulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, mechanical properties and X-ray diffraction studies are also performed.

TABLE 1: List of Drugs Formulated as Single and Multiple Unit Forms of Floating Drug Delivery Systems

Tablets	Cholrpheniramine maleate, Theophylline, Furosemide, Ciprofloxacin, Captopril, Acetylsalicylic acid, Nimodipine, Amoxycillin trihydrate, Verapamil HCI, Isosorbide di nitrate, Sotalol, Isosorbide mononitrate, Aceraminophen, Ampicillin, Cinnarazine, Dilitiazem, Florouracil, Piretanide, Prednisolone, Riboflavin- 5`Phosphate.
Capsules	Nicardipine, L-Dopa and benserazide, chlordizepoxide HCI, Furosemide, Misoprostal, Diazepam, Propranlol, Urodeoxycholic acid.
Microspheres	Verapamil, Aspirin, Griseofulvin, and p-nitroanilline, Ketoprofen, Tranilast, Iboprufen, Terfenadine.
Granules	Indomethacin, Diclofenac sodium, Prednisolone.
Films	Drug delivery device. Cinnarizine
Powders	Several basic drugs.

Advantages of Floating drug delivery system^14,15:

1. The gastroretensive systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids.

2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.

3. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine.

4. The gastroretensive systems are advantageous for drugs meant for local action in the stomach. e.g. antacids.

5. When there is a vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, 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.

Disadvantages of floating drug delivery system:

1. Floating system is not feasible for those drugs that have solubility or stability problem in G.I. tract.

2. These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently-coat, water.

3. The drugs that are significantly absorbed through out gastrointestinal tract, which undergo significant first pass metabolism, are only desirable candidate.

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

Application of Floating Drug Delivery Systems

Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.

1. Sustained Drug Delivery:

HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of <1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited.

Eg. Sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo. The formulation compared with commercially available MICARD capsules using rabbits. Plasma concentration time curves showed a longer duration for administration (16 hours) in the sustained release floating capsules as compared with conventional MICARD capsules (8 hours).¹⁶

2. Site-Specific Drug Delivery:

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide.

Eg. Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.¹⁷

3. Absorption Enhancement:

Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.

Eg. A significantly increase in the bioavailability of floating dosage forms(42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX-long product (29.5%).¹⁷

CONCLUSION:

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 gastro-retentive drug deliveryto optimize the delivery of molecules that exhibit absorption window, low bioavailability and extensive first pass metabolism.

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Floating drug delivery systems to increase gastric retention of drugs: A Review

AV Mayavanshi* and SS Gajjar

KEYWORDS: Floating drug delivery systems, its classification and application.

Approaches To Design Floating Dosage Forms:

Disadvantages of floating drug delivery system:

Application of Floating Drug Delivery Systems