Introduction of Floating Tablet

By: Pharma Tips | Views: 12798 | Date: 08-May-2011

The design of floating drug delivery Systems (FDDS) should be primarily aimed to achieve more predictable and increased bioavailability. Now-a-days most of the pharmaceutical scientist is involved in developing the ideal FDDS. This ideal system should have advantage of single dose for the whole duration of treatment and it should deliver the active drug directly at the specific site. Scientists have succeeded to develop a system and it encourages the scientists to develop control release tablet.

1.    Introduction
                 The design of floating drug delivery Systems (FDDS) should be primarily aimed to achieve more predictable and increased bioavailability. Now-a-days most of the pharmaceutical scientist is involved in developing the ideal FDDS. This ideal system should have advantage of single dose for the whole duration of treatment and it should deliver the active drug directly at the specific site. Scientists have succeeded to develop a system and it encourages the scientists to develop control release tablet. Control release implies the predictability and reproducibility to control the drug release, drug concentration in target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose.
               Under certain circumstances prolonging the gastric retention of a delivery system is desirable for achieving greater therapeutic benefit of the drug substances. For example, drugs that are absorbed in the proximal part of the gastrointestinal tract, and the drugs that are less soluble or are degraded by the alkaline pH may benefit from the prolong gastric retention. In addition, for local and sustained drug delivery to the stomach and the proximal small intestine to treat certain conditions, prolonging gastric retention of the therapeutic moiety may offer numerous advantages including improved bioavailability, therapeutic efficacy and possible reduction of the dose size. Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the 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. Thus, small intestinal transit time is an important parameter for drugs that are incompletely absorbed. Basic human physiology with the details of gastric emptying, motility patterns, and physiological and formulation variables affecting the cosmic emptying are summarized.
                       Gastro retentive 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.

2.    Basic Gastrointestinal Tract Physiology
Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.

Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The place, which cycle both through stomach and intestine every 2 to 3 hours.14 This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.

1.    Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.
2.    Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.
3.    Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.
4.    Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.
After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.

Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate

3.    Factors Affecting Gastric Retention
        Gastric residence time of an oral dosage form is affected by several factors. 
o    Size-To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm. The ph of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Nature of meal-stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach; hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state. The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time.

Biological factors- Biological factors such as age, body mass index (bmi), gender, posture, and diseased states (diabetes, chron’s disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down.

Sex-Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.

Volume of liquids -The resting volume of the stomach is 25 to 50 ml. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids.
o    Fed state-Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves. Timmermans and Andre studied the effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves. It has been demonstrated using radio labeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (91 mm) indigestible objects from stomach was dependent upon interdigestive migrating myoelectric complex. When liquid and digestible solids are present in the stomach, it contracts ~3 to 4 times per minute leading to the movement of the contents through partially opened pylorus. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Studies have shown that the gastric residence time (GRT) can be significantly increased under the fed conditions since the MMC is delayed.

o    Formulation parameter-Several formulation parameters can affect the gastric residence time.
o    Single or multiple unit formulation-More reliable gastric emptying patterns are observed for multiparticulate formulations as compared with single unit formulations, which suffer from “all or none concept.” As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food compared with single unit formulation.

Size and shape- size and shape of dosage unit also affect the gastric emptying. Garg and Sharma reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm.

Density-The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. Density of the dosage form should be less than the gastric contents (1.004gm/ml).

Floating and nonfloating dosage units -On comparison of floating and nonfloating dosage units, it was concluded that regardless of their sizes the floating dosage units remained buoyant on the gastric contents throughout their residence in the gastrointestinal tract, while the nonfloating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastroduodenal junction were protected from the peristaltic waves during digestive phase while the nonfloating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase. It was also observed that of the floating and nonfloating units, the floating units were had a longer gastric residence time for small and medium units while no significant difference was seen between the 2 types of large unit dosage forms. When subjects were kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention.

Nature of Meal -Feeding of indigestible polymers of fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging the drug release.

4.    Approaches to Design Floating Dosage Forms
The following approaches have been used for the design of floating dosage forms (tablets) of single- and multiple-unit systems.

A) Single-Unit Dosage Forms
In Low-density approach4 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 shells24 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 release desired. Finally, the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.

Fluid- filled floating chamber25 type of dosage forms includes incorporation of a gas-filled floatation chamber into a microporous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract 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 prolonged 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 prolonged 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. HBS of chlordiazeopoxide hydrochloride26 had comparable blood level time profile as of three 10-mg commercial capsules. HBS can either be formulated as a floating tablet or capsule. Many polymers and polymer combinations with wet granulation as a manufacturing technique have been explored to yield floatable tablets.

Various types of tablets (bilayered and matrix) have been shown to have floatable characteristics. Some of the polymers used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, crosspovidone, sodium carboxymethyl cellulose, and ethyl cellulose.Self-correcting floatable asymmetric configuration drug delivery system23employs a disproportionate 3-layer matrix technology to control drug release.
The 3-layer principle has been improved by development of an asymmetric configuration drug delivery system in order to modulate the release extent and achieve zero-order release kinetics by initially maintaining a constant area at the diffusing front with subsequent dissolution/erosion toward the completion of the release process. The system was designed in such a manner that it floated to prolong gastric residence time in vivo, resulting in longer total transit time within the gastrointestinal tract environment with maximum absorptive capacity and consequently greater bioavailability. This particular characteristic would be applicable to drugs that have pH-dependent solubility, a narrow window of absorption, and are absorbed by active transport from either the proximal or distal portion of the small intestine.
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.

B) 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 polyalkylcyanoacrylate. 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.27 In Carbon dioxide–generating multiple-unit oral formulations28 several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described in the recent patent literature. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded.

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