An Updated Overview: Floating (Gastroretensive) Drug Delivery System

 

Dadage Ketan K.*, Sakhare Ram S., Halle Pradeep D., Nabde Mahesh K. and Raut Deepika B.

Department of Pharmaceutics, Indira College of Pharmacy, Vishnupuri, Nanded, Maharashtra, India.

*Corresponding Author E-mail: kkdadage11@gmail.com

 

ABSTRACT:

Oral drug delivery system is most convenient and commonly used route of drug administration. More than 50% of drug available in market are meant for oral administration. The conventional drug therapy results in fluctuation of drug concentration, causing either toxic effect or no therapeutic effect. But now a day, recent technologies have been developed in research. Technological attempts have been made in the research and development of rate-controlled oral drug delivery systems to overcome physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), swelling and expanding systems, polymeric bio-adhesive systems, high-density systems, modified-shape systems and other delayed gastric emptying devices.

 

KEYWORDS: Floating Drug Delivery System, Gastroretensive Drug Delivery System, Novel Delivery System, single unit, multiple units.                 

 


INTRODUCTION:

Oral route has been the predominant route of drug delivery for most of the drug. During the last two decades, numerous oral delivery systems have been designed to act as drug reservoirs from which the active drug can be released over a defined period of time at a predetermined and controlled rate[1]. Oral controlled release (CR) dosage forms (DF) of many important medications with improve therapy have been extensively used [2]. 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. The extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa[3]. In the development of oral controlled drug delivery system, other main challenge is to modify the GI transit time. 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. Thus small transit time is an important parameter for drugs that are incompletely absorbed [4]. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, flotation, sedimentation, expansion modified shape systems or by the simultaneous administration of pharmacological agent that delay gastric emptying. This review focuses on the principal mechanism of floatation to achieve gastric retention.

 

FLOATING DRUG DELIVERY

FDDS have a bulk density less than gastric fluids and so 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 results in an increased GRT and a better control of fluctuations in plasma drug concentration. The floating sustained release dosage forms present most of the characteristics of hydrophilic matrices and are known as ‘hydro-dynamically balanced systems’ (‘HBS’) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gelled barrier at the outer surface.[5]

 

 

 

BASIC GASTROINTESTINAL TRACT PHYSIOLOGY [6]

Basically 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, the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions (Desai, 1984). 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 inter-digestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours (Vantrappen et al., 1979). This is called the inter-digestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington (Wilson and Washing-ton, 1989).

 

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.

 

Fig. 1: Motility pattern in GIT[6]

 

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 (Desai and Bolton, 1993). 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.

 

MECHANISM OF FLOATING SYSTEMS[5]

There are various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms (gas-generating systems and swelling or expanding systems, mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying drugs).

 

 (a)                                          (b)                                          (c)

Fig. 2: Different mechanisms of floating systems. [5]

 

Among these, the floating dosage forms have been most commonly used. Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so 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 (given in the Figure 2(a)), 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.               

 

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. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if F is on the higher positive side (Figure 2(b)). This apparatus helps in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intra-gastric buoyancy capability variations (Garg and Sharma, 2003).

                F = F buoyancy - F gravity = (Df - Ds) gv

 

Where, F= total vertical force, Df = fluid density, Ds = object density, v = volume and g = acceleration due to gravity

ADVANTAGES OF FDDS[7]

1. The Gastroretentive systems are advantageous for drugs absorbed through the stomach, e.g. ferrous salts, antacids.

2. 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.

3. FDDS improves patient compliance by decreasing dosing frequency.

4. 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.

5. The gastro retentive systems are advantageous for drugs meant for local action in the stomach. e.g. antacids.

6. Better therapeutic effect of short half-life drugs can be achieved.

7. Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration are avoided; a desirable plasma drug concentration is maintained by continuous drug release.

8. Enhanced absorption of drugs which solubilize only in stomach.

9. Gastric retention time is increased because of buoyancy.

10. Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multi particulate system.

11. Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.

 

DISADVANTAGES OF FDDS [8]

1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids.

2. One of the disadvantages of floating systems is that they require a sufficiently high level of fluids in the stomach, so that the drug dosages form float therein and work efficiently.

3. These systems also require the presence of food to delay their gastric emptying.

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.

5. 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.

6. Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery systems.

 

CLASSIFICATION OF FLOATINGDRUG DELIVERY SYSTEMBASED ON MECHANISM OF BUOYANCY [9]

A. Single Unit Floating Dosage Systems

                a) Non-effervescent Systems

                b) Effervescent Systems (Gas-generating Systems)

B. Multiple Unit Floating Dosage Systems

                a) Non-effervescent Systems

b) Effervescent Systems (Gas-generating Systems)

c) Hollow (Floating) Microspheres

C. Raft Forming Systems

 

A. Single Unit Floating Dosage Systems

Single unit dosage forms are easiest to develop but suffers from the risk of losing their effects too early due to their allornone emptying from the stomach and, thus they may cause high variability in bioavailability and local irritation due to large amount of drug delivered at a particular site of the gastro intestinal tract[10].

 

a) Non-effervescent Systems: One or more gel forming, highly swellable, cellulosic hydrocolloids (e.g. hydroxyl ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methyl cellulose [HPMC] and sodium carboxy methyl cellulose), polysaccharides, or matrix forming polymers (e.g., polycarbophil, polyacrylates, and polystyrene) are incorporated in high level (2075% w/w) to tablets or capsules[11,12].For the preparation of these types of systems, the drug and the gel forming hydrocolloid are mixed thoroughly. 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 gellike structure acts as a reservoir and allows sustained release of drug through the gelatinous mass.

 

b) Effervescent systems (Gas-generating Systems): These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, e.g. sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1.

 

B. Multiple Unit Floating Dosage Systems

Single unit formulations are associated with problems such as sticking together or being obstructed in gastrointestinal tract, which may have a potential danger of producing irritation. Multiple unit systems avoid the ‘allornone’ gastric emptying nature of single unit systems. It reduces the Intersubject variability in absorption and the probabilities for dose dumping is lower [13].

 

a) Non-effervescent Systems: A little or no much report was found in the literature on non-effervescent multiple unit systems, as compared to the effervescent systems. However, few workers have reported the possibility of developing such system containing indomethacin, using chitosan as the polymeric excipient. A multiple unit HBS containing indomethacin as a model drug prepared by extrusion process is reported. A mixture of drug, chitosan and acetic acid is extruded through a needle, and the extrudate is cut and dried. Chitosan hydrates float in the acidic media, and the required drug release could be obtained by modifying the drugpolymer ratio.

 

b) Effervescent Systems (Gas-generating Systems): A multiple unit system comprises of calcium alginate core and calcium alginate/PVA membrane, both separated by an air compartment was prepared. In presence of water, the PVA leaches-out and increases the membrane permeability, maintaining the integrity of the air compartment. Increase in molecular weight and concentration of PVA, resulted in enhancement of the floating properties of the system. Freezedrying technique is also reported for the preparation of floating calcium alginate beads. Sodium alginate solution is added drop wise into the aqueous solution of calcium chloride, causing the instant gelation of the droplet surface, due to the formation of calcium alginate. The obtained beads are freezedried resulting in a porous structure, which aid in floating.

 

The authors studied the behavior of radio labeled floating beads and compared with non-floating beads in human volunteers using gamma scintigraphy. Prolonged gastric residence time of more than 5.5 h was observed for floating beads. The non-floating beads had a shorter residence time with a mean onset emptying time of 1 hr. [14].

 

c) Hollow (Floating) Microspheres: A controlled release system designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microspheres. Techniques involved in their preparation include simple solvent evaporation, and solvent diffusion and evaporation. The drug release and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers, such as polycarbonate, Eudragit® S and cellulose acetate, are used in the preparation of hollow microspheres and the drug release can be modified by optimizing the amount of polymer and the polymerplasticizer-ration [15].

 

C. Raft Forming Systems:

The basic mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, where in each portion of the liquid swells forming a continuous layer called a raft. The raft floats because of the buoyancy created by the formation of CO2 and act as a barrier to prevent the reflux of gastric contents like HCl and enzymes into the esophagus. Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of to make the system less dense and float on the gastric fluids [16].

 

FACTORS AFFECTING GASTRIC RESIDENCE TIME OF FDDS

1) Formulation factors

a) Size of tablets

b) Density of tablets

c) Shape of tablets

d) Viscosity grade of polymer

2) Idiosyncratic factors

a) Gender

b) Age

c) Posture

i) Upright position

ii) Supine position

d) Concomitant intake of drugs

e) Feeding regimen

 

1) Formulation factors

a) Size of tablets

Retention of floating dosage forms in stomach depends on the size of tablets. Small tablets are emptied from the stomach during the digestive phase, but large ones are expelled during the house keeping waves [17]. Floating and non-floating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and 9.9 mm (large units), were formulated and analyzed for their different properties. It was found that floating dosage units remained buoyant regardless of their sizes on the gastric contents throughout their residence in the gastrointestinal tract, while the non-floating 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 non-floating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase [18].

 

b) Density of tablets

Density is the main factor affecting the gastric residence time of dosage form. A buoyant dosage form having a density 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. A density of less than 1.0g/ml i.e. less than that of gastric contents has been reported. However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy capabilities [19].

 

c) Shape of tablets

The shape of dosage form is one of the factors that affect its gastric residence time. Six shapes (ring tetrahedron, cloverleaf, string, pellet, and disk) were screened in vivo for their gastric retention potential. The tetrahedron (each leg 2cm long) rings (3.6 cm in diameter) exhibited nearly 100% retention at 24 hr [20].

 

d) Viscosity grade of polymer

Drug release and floating properties of FDDS are greatly affected by viscosity of polymers and their interaction. Low viscosity polymers (e.g., HPMC K100 LV) were found to be more beneficial than high viscosity polymers (e.g., HPMC K4M) in improving floating properties. In addition, a decrease in the release rate was observed with an increase in polymer viscosity [21].

 

 

 

2) Idiosyncratic factors

a) Gender

Women have slower gastric emptying time than do men. Mean ambulatory GRT in meals (3.4±0.4 hours) is less compared with their age and racematched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface [22].

 

b) Age

Low gastric emptying time is observed in elderly than do in younger subjects. Intra-subject and inter-subject variations also are observed in gastric and intestinal transit time. Elderly people, especially those over 70 years have a significantly longer GRT [23].

 

c) Posture

i) Upright position

An upright position protects floating forms against postprandial emptying because the floating form remains above the gastric contents irrespective of its size [23]. Floating dosage forms show prolonged and more reproducible GRTs while the conventional dosage form sink to the lower part of the distal stomach from where they are expelled through the pylorus by antral peristaltic movements [24].

 

ii) Supine position

This position offers no reliable protection against early and erratic emptying. In supine subjects large dosage forms (both conventional and floating) experience prolonged retention. The gastric retention of floating forms appear to remain buoyant anywhere between the lesser and greater curvature of the stomach. On moving distally, these units may be swept away by the peristaltic movements that propel the gastric contents towards the pylorus, leading to significant reduction in GRT compared with upright subjects [25].

 

d) Concomitant intake of drugs

Drugs such as prokinetic agents (e.g., metoclopramide and cisapride), anti Cholinergics (e.g., atropine or propan- theline), opiates (e.g., codeine) may affect the performance of FDDS. The co-administration of GImotility decreasing drugs can increase gastric emptying time [25].

 

e) Feeding regimen

Gastric residence time increases in the presence of food, leading to increased drug dissolution of the dosage form at the most favorable site of absorption. A GRT of 410 hr has been reported after a meal of fats and proteins [26].

 

APPROACHES TO DESIGN FLOATING DOSAGE FORMS:

The following approach has been used for the design of floating dosage forms of single and multiple unit systems.

 

Single-Unit Dosage Forms:

In Low-density approach, 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 obtained by using a fluid-filled system that floats in the stomach. In coated shells popcorn, pop rice, and polystyrol has been exploited as drug carriers. A sugar polymeric material such as methacrylic polymer and cellulose acetate phthalate has been used to undercoat these shells. These were further coated with a drug-polymer mixture. The polymer of choice can be either ethyl cellulose 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 [27].

 

Fluid-filled floating chamber type of dosage forms includes incorporation of a gas-filled floatation chamber into a micro porous component that houses a drug reservoir. 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 were 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 swallow able 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. Hydro-dynamically balanced systems (HBS) were 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 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 [28]. Single unit dosage forms are easiest to develop but suffers from the risk of losing their effects too early due to their all or none emptying from the stomach and, thus they may cause high variability in bioavailability and local irritation due to large amount of drug delivered at a particular site of the gastro intestinal tract [29].

 

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 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. 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 in the recent patent literature. These dosage forms excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded [30]. Single unit formulations are associated with problems such as sticking together or obstructed in gastrointestinal tract, which may have a potential danger of producing irritation. Multiple unit systems avoid the ‘all or none’ gastric emptying nature of single unit systems. It reduces the inter-subject variability in absorption and the probabilities for dose dumping is lower [29].

 

Selection criteria of drugs for Gastro-retention

Delivery of the Drugs in continuous and controlled manner have a lower level of side effects and provide their effects without the need for repeated dosing 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, from where absorption occurs and contact time is limited.

 

Appropriate candidate for controlled release gastro-retentive dosage forms are molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of the GIT.

1. Narrow absorption window in GI tract, e.g., riboflavin and levodopa [31].

2. Drugs that disturb normal colonic microbes e.g. antibiotics against Helicobacter pylori [31].

3. Drugs those are unstable in the intestinal or colonic environment e.g. captopril, ranitidine HCl, metronidazole.

4. Drugs that act locally in the stomach, e.g., antacids and misoprostol [32].

5. Primarily absorbed from stomach and upper part of GIT, e.g., calcium supplements, chlordiazepoxide and cinnarazine [32].

 

Drugs used in FDDS [33]

List of Drugs along with Floatable Drug Delivery Systems:

 

Table 1: Drugs Generally Used in FDDS

Sr.

No.

DOSAGE FORM

DRUGS

1.

Microspheres

Aspirin, Cholestyramine, Dipyridamol, Griseofulvin, Ibuprofen, Ketoprofen[34], Nicardipine, Nifedipine, p-nitroanilline, Piroxicam, Tranilast[35], Terfinadine[36], Theophylline, Verapamil,

2.

Granules

Diclofenac sodium, Indomethacin, Prednisolone

3.

Films

Cinnarizine[37], Albendazole

4.

Powders

Several basic drugs

5.

Capsules

Chlordiazepoxide HCl, Diazepam, Furosemide, L-Dopa, benserazide, Misoprostol, Nicardipine, Propranolol HCl, Ursodeoxycholic acid

6.

Tablets/pills

Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Captopril, Chlorpheniramine, Cinnarizine, Ciprofloxacin, Diltiazem, Fluorouracil, Furosemide, Isosorbide mononitrate, Metformin Hydrochloride, Nimodipine, Isosorbidedinitrate, Isosorbidemononitrate[38], p-aminobenzoic acid pentoxyfilline,  Piretanide[39], Prednisolone, Quinidine gluconate, Riboflavin-5’-phosphate, Sotalol[40], Theophylline, Verapamil HCl

 

SELECTION OF POLYMERES [41, 42, 43]

A. GAS GENERATING AGENTS

Alkalinizing agents and acidulent

Sodium bicarbonate, Calcium carbonates, Citric acid, Tartaric acid, Adipic acid

 

Rational behind the selection

Effervescent compound generally use for this purpose. Sodium bicarbonate, calcium carbonate with citric acid and tartaric acid. When these compounds come in contact with the acidic gastric contents, carbon dioxide is liberated and gets entrapped in swelled hydrocolloids, which provide buoyancy to the dosage forms. Sodium bicarbonate induced CO2 generation in the presence of dissolution medium (0.1 N HCL). The gas generated trapped and protected with in the gel, formed by the hydration of polymer, thus decreasing the density of the tablet as the density of the tablet falls below 1, the tablet become buoyant.

 

Acidulent is used; since the pH of the stomach is elevated under fed condition (~3.5). Acidulent (Citric acid, Tartaric acid, Adipic acid) was incorporate in the formulation to provide an acidic medium for sodium bicarbonate.

 

B. Viscolyzing agent

Sodium alginate, Carbopol 934

 

Rational behind the selection

They used to increase the viscosity in the system. Carbopol is being used in the controlled release solid dosage formulations since last four decades. The numbers of manufacturers commercializing controlled release tablets using Carbomers are increasing considerably in recent period of development. Tablet formulations using Carbopol polymers have demonstrated zero-order and near zero-order release kinetics. These polymers are effective at low concentrations (less than 10%). Still they show extremely rapid and efficient swelling characteristics in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The Carbopol polymers produce tablets of excellent hardness and low friability. These polymers can be successfully formulated into a variety of different tablet forms, including the traditional swallowable tablets, chewable tablets, buccal tablets, sublingual tablets, effervescent tablets, and suppositories; providing controlled-release properties as well as good binding characteristics. Carbomers show larger dissolution times at lower concentrations than other excipients. Because of these factors Carbopol polymers have greater extent in formulating dosage forms. Because Carbopol polymers swell rapidly in water and absorb great quantities, to avoid the use of flammable solvents, roller compaction is being used as the method to prepare a new form of Carbopol polymer 71G NF. Carbopol polymer 71G NF is a useful and versatile controlled-release additive for tablet formulations in direct compression.

Drug Dissolution Mechanism from Carbopol Polymers

In the dry state, the drug is trapped in a glassy core. As the external surface of the tablet is hydrated, it also forms a gelatinous layer upon hydration; however, this gel layer is significantly different structurally from the traditional matrix tablet. The hydrogel are not entangled chains of polymer, but discrete microgels made up of many polymer particles, in which the drug is dispersed. The crosslink network enables the entrapment of drugs in the hydrogel domains. Since these hydrogels are not water soluble, they do not dissolve, and erosion in the manner of linear polymers does not occur. Rather, when the hydrogel is fully hydrated, osmotic pressure from within works to break up the structure, essentially by sloughing off discrete pieces of the hydrogel. It is postulated that as the concentration of the drug becomes high within the gel matrix and its thermodynamic activity or chemical potential increases, the gel layer around the tablet core actually acts almost like a rate controlling membrane, resulting in linear release of the drug. Because of this structure, drug dissolution rates are affected by subtle differences in rates of hydration and swelling of the individual polymer hydrogels, which are dependent on the molecular structure of the polymers, including crosslink density, chain entanglement, and crystallinity of the polymer matrix. The magnitude and rate of swelling is also dependent on the pH of the dissolution medium. The channels which form between the polymer hydrogels are influenced by the concentration of the polymer, as well as the degree of swelling. Increasing the amount of polymer will decrease the size of the channels, as does an increase in swelling degree. All of these factors must be taken into account to describe the mechanism for release control in tablets formulated with Carbopol polymers.

 

C. Swelling agent/Gel forming polymer

Hydroxypropylmethylcellulose (HPMC)

 

Rational behind the selection

Hypermellose powder is stable material, although it is hygroscopic after drying. Solution is stable at pH 3-11. Increasing temperature reduces the viscosity of solutions. Hypermellose undergoes a reversible sol-gel transformation upon heating and cooling, respectively. The gel point 50-90°C, depending upon grade and concentration of material. Grades which are generally used in floating tablet are, which are highly viscous in nature like HPMC K 100, HPMC K 4, and HPMC K 15.

 

D. Disintegrating agent

Povidone, Polyplasdone XL and XL-10

 

Rational behind the selection

PVP belongs to a class of compounds known as superdisintegrantes. When they comes in contact with the fluid media they provide the swelling properties to the system they used as highly active explosive agent and as an accelerating agent for disintegration of solid medications. In tableting, povidone solutions are used as binder in the wet granulation processes.

Polymers and other ingredients used in preparations of floating drugs

1. Polymers: The following polymers used in preparations of floating drugs -

HPMC K4 M, Calcium alginate, Eudragit S100, Eudragit RL, Propylene foam, Eudragit RS, ethyl cellulose, poly methyl methacrylate, Methocel K4M, Polyethylene oxide, β Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate, PVA, Polycarbo-nate, Sodium alginate, HPC-L, CP 934P, HPC, Eudragit S, HPMC, Metolose S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4 M and Carbopol.

 

2. Inert fatty materials (5%-75%):  Edible, inert fatty material having a specific gravity of less than one can be used to decrease the hydrophilic property of formulation and hence increase buoyancy. E.g. Beeswax, fatty acids, long chain fatty alcohols, Gelucires 39/01 and 43/01.

 

3. Effervescent agents:  Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbonate, CG (Citroglycine).

 

4. Release rate accelerants (5%-60%):  eg. lactose, mannitol.

 

5. Release rate retardants (5%-60%):  eg. Dicalcium phosphate, talc, magnesium stearate.

 

6. Buoyancy increasing agents (upto80%):  eg. Ethyl cellulose.

 

7. Low density material:  Polypropylene foam powder (Accurel MP 1000).

 

EVALUATION TECHNIQUES

In-vitro evaluation of floating tablets

Evaluation was performed to assess the physicochemical properties and release characteristics of the developed formulations.

 

I. Pre-compression parameters

a) Angle of Repose (Shoufeng L et al. 2001)

The frictional forces in a loose powder or granules can be measured by angle of repose. This is the maximum angle possible between the surface of a pile of powder or granules and the horizontal plane. Shown in fig,

 

Fig. 3: - Angle of repose

The granules were allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of granules formed.

                tan σ= h/r

                σ = tan-1 (h/r)

Where, σ = angle of repose, h = height of the heap, r = radius of the heap

 

The relationship between Angle of repose and powder flow is as follows in table,

 

 

Angle of repose

Powder flow

< 25

Excellent

25-30

Good

30-40

Passable

> 40

Very poor

 

b) Compressibility Index

The flow ability of powder can be evaluated by comparing the bulk density (ρo) and tapped density (ρt) of powder and the rate at which it packed down. Compressibility index was calculated by,

                Compressibility index (%) = ρt otx 100

 

Where, ρo = Bulk density g/ml002E

ρt= Tapped density g/ml.

 

II. Post-compression parameters

a) Shape of Tablets

Compressed tablets were examined under the magnifying lens for the shape of the tablet.

 

b) Tablet Dimensions

Thickness and diameter were measured using a calibrated varniear caliper. Three tablets of each formulation were picked randomly and thickness was measured individually.

 

c) Hardness (Hilton AK et al.1992)

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It was expressed in kg/cm2. Three tablets were randomly picked and hardness of the tablets was determined.

 

d) Friability test (Shoufeng L et al.2001)

The friability of tablets was determined by using Roche Friabilator. It was expressed in percentage (%). Ten tablets were initially weighed (Winitial) and transferred into friabilator. The friabilator was operated at 25rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (Wfinal). The % friability was then calculated by,

% of Friability = 100 (1-W0/W)

% Friability of tablets less than 1% was considered acceptable.

 

 

 

e) Tablet Density (Ozdemir N et al.2000)

Tablet density was an important parameter for floating tablets. The tablet would floats only when its density was less than that of gastric fluid (1.004). The density was determined using following relationship.

V = r2 h d = m/v

Where,   v = volume of tablet (cc)

r = radius of tablet (cm)

h = crown thickness of tablet (g/cc)

m= mass of tablet

 

f) Weight Variation Test (Shoufeng L et al.. 2001)

Ten tablets were selected randomly from each batch and weighed individually to check for weight variation. A little variation was allowed in the weight of a tablet by U.S. Pharmacopoeia. The following percentage deviation in weight variation was allowed show in table,

 

 

Average weight of a tablet

Percent deviation

130 mg or less

10

>130mg and <324mg

7.5

324 mg or more

5

 

 

g) Buoyancy / Floating Test

The time between introduction of dosage form and its buoyancy on the simulated gastric fluid and the time during which the dosage form remain buoyant were measured. The time taken for dosage form to emerge on surface of medium called Floating Lag Time (FLT) or Buoyancy Lag Time (BLT) and total duration of time by which dosage form remain buoyant is called Total Floating Time (TFT).

 

h) Swelling Study

The swelling behavior of a dosage form was measured by studying its weight gain or water untake the dimensional changes could be measured in terms of the increase in tablet diameter and/or thickness over time. Water uptake was measured in terms of percent weight gain, as given by the equation,

                WU = (Wt – W0) x 100

                                W0

Wt = Weight of dosage form at time t.

W0= Initial weight of dosage form

 

j) In-vitro drug release studies

The test for buoyancy and in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37oC. In practice, floating time is determined by using the USP dissolution apparatus containing 900ml of 0.1 HCl as a testing medium maintained at 37oC. The time required to float the HBS dosage form is noted as floating (or floatation) time.

 

CHARACTERIZATION PARAMETERS:

1. Size and shape evaluation: The particle size and shape plays a major role in determining solubility rate of the drugs and thus potentially its bioavailability. The particle size of the formulation was determined using Sieve analysis, Air elutriation analysis, Photo analysis, Optical microscope, Electro résistance counting methods (Coulter counter), Sedimentation techniques, Laser diffraction methods, ultrasound attenuation spectroscopy, Air Pollution Emissions Measurements etc. (Vedha hari b.n.et al 2010).

 

2. Floating properties: Effect of formulation variables on the floating properties of gastric floating drug delivery system was determined by using continuous floating monitoring system and statistical experimental design (Choi BY et al.2002).

 

3. Surface topography: The surface topography and structures were determined using scanning electron microscope (SEM, JEOL JSM– 6701 F, Japan) operated with an acceleration voltage of 10k.v, Contact angle meter, Atomic force microscopy (AFM), Contact profiliometer. (Ichikawam et al.1991)

 

4. Determination of moisture content: The water content per se is seldom of interest. Rather, it shows whether a product intended for trade and production has standard properties such as,

a)       Storability

b)       Agglomeration in the case of powders

c)       Microbiological stability

d)       Flow properties, viscosity

e)       Dry substance content

f)        Concentration or purity

g)       Commercial grade (compliance with quality agreements)

 

Thus moisture content of the prepared formulations was determined by Karl fisher titration, vacuum drying, Thermo gravimetric methods, Air oven method, Moisture Meters, Freeze drying as well as by physical methods.(Etyan Klausner A et al.2003)

 

5. Swelling studies: Swelling studies were performed to calculate molecular parameters of swollen polymers. Swelling studies was determined by using Dissolution apparatus, optical microscopy and other sophisticated techniques which include H1NMRimaging, Confocal laser scanning microscopy (CLSM), Cryogenic scanning electron microscopy (Cryo-SEM), Light scattering imaging (LSI) etc. The swelling studies by using Dissolution apparatus (USP dissolution apparatus (usp-24) labindia disso 2000) was calculated as per the following formula (Ferdous Khan et al.2008)

 

Swelling ratio = Weight of wet formulation / Weight of formulations

 

 

6. Determination of the drug content: Percentage drug content provides how much amount of the drug that was present in the formulation. It should not exceed the limits acquired by the standard monographs. Drug content was determined by using HPLC, HPTLC methods, near infrared spectroscopy (NIRS), Microtitrimetric methods, Inductively Coupled Plasma Atomic Emission Spectrometer (ICPAES) and also by using spectroscopy techniques. (Yuvarej Singh Tanwar et al.2007)

 

 

7. Percentage entrapment efficiency: Percentage entrapment efficiency was reliable for quantifying the phase distribution of drug in the prepared formulations. Entrapment efficiency was determined by using three methods such as Micro dialysis method, Ultra centrifugation, and pressure Ultra filtration. (Sunil kumar Bajpai et al.2007)

 

8. In-vitro release studies: In vitro release studies (USP dissolution apparatus (usp-24) lab India disso 2000) were performed to provide the amount of the drug that is released at a definite time period. Release studies were performed by using Franz diffusion cell system and synthetic membrane as well as different types of dissolution apparatus. (Shweta Arora et al.2005)

 

9. Powder X-ray differaction: X-ray powder diffraction (Philips analytical, model-pw1710) is the predominant tool for the study of polycrystalline materials and is eminently suited for the routine characterization of pharmaceutical solids. Samples were irradiated with α radiation and analyzed between 2 ºC and 60 ºC .The voltage and current used were 30KV and 30mA respectively.(Girish S.Sonar et al.2007)

 

10. Fourier transform infrared analysis: Fourier transform infrared spectroscopy (FTIR, Shi-madzu, and Model-RT-IR-8300) is a technique mostly used to identify organic, polymeric, and some inorganic materials as well as for functional group determination. Fourier Transform Infrared Analysis (FT-IR) measurements of pure drug, polymer and drug loaded polymer formulations were obtained on FTIR. The pellets were prepared on KBr-press under hydraulic pressure of 150kg/cm2; the spectra were scanned over the wave number range of 3600 to 400 cm-1 at the ambient temperature. (Girish S.Sonar et al.2007).

 

11. Differential Scanning Calorimetry (DSC): DSC (Shimadzu, Model-DSC-60/DSC-50/ Metler Toldeo) are used to characterize water of hydration of pharmaceuticals .Thermo grams of formulated preparations were obtained using DSC instrument equipped with an intercooler. Indium/Zinc standards were used to calibrate the DSC temperature and enthalpy scale. The sample preparations were hermitically sealed in an aluminum pan and heated at a constant rate of 10°C/min; over a temperature range of 25° C – 65°C. Inert atmosphere was maintained by purging nitrogen gas at the flow rate of 50ml/min. (Girish S.Sonar et al.2007).

APPLICATION OF FLOATING DRUG DELIEVERY SYSTEM

1. Enhanced Bioavailability: The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption. (Cook JD et al.1990)

 

2. Sustained drug delivery: Oral CR formulations are encountered with problems such as gastric residence time in the GIT. These problems can be overcome with the HBS systems which can remain in the stomach for long periods and have a bulk density <1 as a result of which they can float on the gastric contents. These systems are relatively larger in size and passing from the pyloric opening is prohibited. (Moursy NM et al.2003)

 

3. Site specific drug delivery systems: These systems are particularly advantageous for drugs that are specifically absorbed from the stomach or the proximal part of the small intestine .The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency. Eg: Furosemide and Riboflavin. (Menon A et al.1994).

 

4. Absorption enhancement: Drugs which are having poor bioavailability because of site specific absorption from the upper part of the GIT are potential candidates to be formulated as floating drug delivery systems, there by maximizing their absorption. (Rouge N et al.1998).

 

5. Minimized adverse activity at the colon: Retention of the drug in the HBS systems at the stomach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This Pharmacodynamic aspect provides the rationale for GRDF formulation for beta-lactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance.

 

6. Reduced fluctuations of drug concentration: Continuous input of the drug following CRGRDF administration produces blood drug concentrations within a narrower range compared to the immediate release dosage forms. Thus, fluctuations in drug effects are minimized and concentration dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index. (Yie Chein et al.1992)

 

PATENT ON FDDS

Table 2: Patents on FDDS

Sr. No.

Type of formulation

Patent no.

Reference

1.

Gastro retentive dosage form

U.S-7, 413,752

44

2.

Multiple unit floating dosage form

European patent (EP) 10697

45

3.

Bilayer tablet

EP-002445

46

4.

Floating Tablet

U.S-66, 352279

47

5.

Microspheres

U.S-6207197

48

6.

3-layer tablet

U.S-5780057

49

7.

Foams (or) hollow bodies

U.S-5626876

50

8.

Floating tablet

U.S-5169639

51

9.

Granule

U.S-4844905

52

10.

Floating capsules

U.S-4814178, 79

53

11.

Floating device

U.S-4055178

54

12.

Floating capsule

U.S-4126672

55

13.

Empty globular shells

U.S-3976164

56

 

CONCLUSION:

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. 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 delivery to optimize the delivery of molecules that exhibit absorption window, low bioavailability and extensive first pass metabolism. FDDS promises to be a potential approach for gastric retention. Although there are number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.

 

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Received on 27.09.2012          Modified on 20.10.2012

Accepted on 11.11.2012         © RJPT All right reserved

Research J. Pharm. and Tech. 5(12): Dec. 2012; Page 1467-1477