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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Parmar et al.

World Journal of Pharmacy and Pharmaceutical Sciences

Volume 3, Issue 4, 418-444.

Review Article

ISSN 2278 – 4357

FLOATING DRUG DELIVERY SYSTEM: A NOVEL APPROACH TO PROLONG GASTRIC RETENTION Paresh D. Parmar*, Saikat Pande, Saumil H. Shah , Shailesh N. Sonara Department of Pharmaceutics and Pharmaceutical Technology, A. R. College of Pharmacy & G. H. Patel Institute of Pharmacy, V.V.Nagar, Anand-388120, Gujarat, India.

Article Received on 25 February 2014, Revised on 15 March 2014, Accepted on 06 April 2014

ABSTRACT Conventional oral dosage forms having low bioavailability problems due to their rapid gastric transition from stomach, in case of drugs which are less soluble at alkaline pH of intestine. Further drugs which produce their local action in stomach, get rapidly emptied do not get

*Correspondence for Author Paresh D. Parmar Department of Pharmaceutics

enough residence time in stomach. Hence, the frequency of dose administration in such cases is increased. To avoid these problems,

and Pharmaceutical

various efforts have been made to prolong the retention time of drug in

Technology, A. R. College of

stomach. Floating drug delivery system (FDDS) is one of the most

Pharmacy & G. H. Patel

important approaches in prolonging the retention time of drug in

Institute of Pharmacy,

stomach. FDDS is low-density systems that have sufficient buoyancy

V.V.Nagar, Anand, Gujarat, India.

to float over the gastric contents and remain buoyant in the stomach for a prolonged period of time without affecting the gastric emptying rate. While the system is floating on the gastric contents, the drug is

released slowly at the desired rate which results in a better control of the fluctuations in plasma drug concentration. Based on the mechanism of buoyancy, two types of technique employed for development of floating dosages form: effervescent and non-effervescent. This review given the detailed outline of floating drug delivery system with their advantages over the conventional drug delivery system and also include limitation. The purpose of this review is to compose the recent work going on this delivery system and provide valuable information related to formulation aspect to achieve prolong gastric retention and discussed the various challenges in it and measure to overcome them. Keywords: Floating drug delivery system, Gastric retention, Plasma drug concentration. INTRODUCTION Oral administration is the most convenient and preferred means of any drug delivery to the www.wjpps.com

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systematic circulation. Oral controlled release drug delivery have recently been of increasing interest in pharmaceutical field to achieve improved therapeutic advantages, such as ease of dosing administration, patient compliance and flexibility in formulation.[1] The de novo design of an oral controlled drug delivery system (DDS) should be primarily aimed at achieving more predictable and increased bioavailability of drugs. However, the development process is precluded by several physiological d i f f i c u lt i e s , such as an inability to restrain and localize the DDS within desired regions of the gastrointestinal (GI) tract and the highly variable nature of gastric empty-ing process. It can be anticipated that, depending upon the physiological state of the subject and the design of pharmaceutical formulation, the emptying process can last from a few minutes to 12 h. This variability, in turn, may lead to unpredictable bioavailability and times to achieve peak plasma levels, since the majority of drugs are preferentially absorbed in the upper part of the small intestine.

[2]

Furthermore,

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 gastric 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. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, flotation, sedimentation, expansion, modified shape systems that delay gastric emptying. Based on these approaches, classification of floating drug delivery systems (FDDS) has been described in detail.[3] BASIC PHYSIOLOGY OF THE GIT The stomach is anatomically divided into three parts: that occur fundus, body, and antrum (or pylorus). The proximal stomach, made up of the fundus and body regions, serves as a reservoir for ingested materials while the distal region (antrum) is the major site of mixing motions, acting as a pump to accomplish gastric emptying. Gastric emptying occurs during fasting as well as fed states. [4]

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Gastric emptying and problems 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.

Figure 1 : Anatomy of stomach [5] a. The short Gastric Residence Time [GRT] b. Variable (unpredictable) Gastric Emptying Time [GET] [6] 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. This is called the inter digestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases are : 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

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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. [6] This series of electrical events originates in the foregut and continues to the terminal ileum in the fasted state, repeating every 2–3 hr. Feeding sets off a continuous pattern of spike potentials and contractions called postprandial motility.[7]

Figure 2: Motility patterns of the GIT in the fasted state.[4] The particular phase during which a dosage form is administered influences the performance of perioral CRDDS and GRDDS. When CRDDS are administered in the fasted state, the MMC may be in any of its phases, which can significantly influence the total gastric residence time (GRT) and transit time in the GIT. This assumes even more significance for drugs that have an absorption window because it will affect the amount of time the dosage form spends in the region preceding and around the window. The less time spent in that region, the lower the degree of absorption. Therefore, the design of GRDDS should take into consideration the resistance of the dosage form to gastric emptying during Phase III of the MMC in the fasted state and also to continuous gastric emptying through the pyloric sphincter in the fed state. This means that GRDDS must be functional quickly after administration and able to resist the onslaught of physiological events for the required period of time.[4]

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FACTORS AFFECTING ON GASTRIC RETENTION TIME [8] PHYSICOCHEMICAL FACTORS Size of dosage form: Dosage forms having diameter greater than the diameter of pyloric sphincter escape from gastric emptying and remain within gastric region. Shape of dosage form: Round or Ring shaped dosage form are considered better in shape. Density: Location of the particular gastro retentive dosage form in gastric region depends on density of the system. Those with low density tend to float on the gastric fluid surface while high density systems sink to the bottom of the stomach. BIOLOGICAL FACTORS Age : Geriatric patients show a longer gastric retention time, while the neonates and children have low gastric retention time, in comparison to a normal adult. Gender : Gastric retention time in male (3-4 hrs) is less than the female(4-6 hrs). Fed or Unfed state : Gastric motility is higher in fasting condition which depicts lesser GRT. Feed frequency : Higher the frequency of taking food, longer will be the GRT. Nature of meal : High amount of fatty acids and other indigestible polymers generally decreases the gastric retention time by altering gastric motility. Disease state : Gastro retentive time is altered during the various gastric diseases like Crohn’s disease etc. IDIOSYNCRATIC FACTORS Concomitant drug administration : Administration of certain drugs along with gastric motility enhancers (metoclopramide, cisapride) or depressants (atropine), greatly affect gastric retention time and hence absorption of stomach specific absorbing drugs. VARIOUS APPROACHES TO GASTRIC RETENTION [6,8] 1. High density (sinking) systems or non floating delivery 2. Low density systems or Floating delivery 3. Mucoadhesive/Bioadhesive Systems 4. Expandable Systems 5. Superporous Hydrogel Systems 6. Magnetic Systems. FLOATING DRUG DELIVERY SYSTEM (FDDS) Floating systems or Hydrodynamically controlled systems are low-density systems that have

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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 results in an increased GRT and a better control of the fluctuations in plasma drug concentration.[9] MECHANISM OF FLOATING SYSTEM [5,10] 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 (Figure 3 (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 thefloating 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 3(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 intragastric buoyancy Capability variations F = F buoyancy - F gravity = (Df - Ds) g * v Where, F= total vertical force, Df = fluid density, Ds = object density, v = volume and g = acceleration due to gravity.

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Figure 3 :Mechanism of floating systems, GF= Gastric fluid [10] APPROACHES TO DESIGN FLOTING DOSAGE FORMS The following approaches have been used for the design of floating dosage forms of single and multiple unit systems.[11] SINGLE-UNIT DOSAGE FORMS In low density approaches,[12] the globular shells apparently having lower density than that of gastric fluid can be usedas 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 shells [13]

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 ethyl cellulose or hydroxyl propyl 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 micro porous component that houses a drug reservoir. [14] 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,

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polyacrylamine, and poly alkyl cyano acrylate. 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.[15] 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. CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEM (FDDS)

[2,5,16-19]

Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in development of FDDS that are:  Effervescent System, and  Non- Effervescent System EFFERVESCENT FDDS These buoyant drug delivery systems utilize matrices prepared with swellable polymers such as Methocel® or polysaccharides, e.g., chitosan and effervescent components .Gas generating agents, carbonates (e.g. Sodium bicarbonate) and other organic acid (e.g. citric acid and tartaric acid) present in the formulation to produce carbon dioxide (CO2) gas due to acidity of gastric content and is entrapped in the gellified hydrocolloid, thus reducing the density of the system and making it float on the gastric fluid. An alternative is the incorporation of matrix containing portion of liquid, which produce gas that evaporate at body temperature. These effervescent systems further classified into two types:  Gas Generating Systems.  Volatile Liquid/Vacuum Containing Systems. I. GAS GENERATING SYSTEMS 1. Intragastric single layer floating tablets or Hydrodynamically balanced system (HBS) These are formulated by intimately mixing the CO2 generating agents and the drug within the matrix tablet (Figure 4). These have a bulk density lower than gastric fluids and therefore remain floating in the stomach unflattering the gastric emptying rate for a prolonged period. The drug is slowly released at a desired rate from the floating system and after the complete release the residual system is expelled from the stomach. This leads to an increase in the GRT and a better control over fluctuations in plasma drug concentration.

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Figure 4 : Intra-gastric floating tablet [17] 2. Intra gastric bilayer floating tablets These are also compressed tablet (Figure 5) and containing two layers. 

Immediate release layer and Sustained release layer

Figure 5 :Intra-gastric floating bilayer tablet [18] 3. Multiple unit type floating pills These systems consist of sustained release pills as ‘seeds’ surrounded by double layers (Figure 6(a) and (b)). The inner layer consists of effervescent agents while the outer layer is of swellable membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density. This lower density is due to generation and entrapment of CO2 within the system.

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Figure 6 : (a) A multiple-unit oral floating dosage system.[19] Figure 6 : (b) Stages of floating mechanism: (A) penetration of water (B) generation of CO2 and floating(C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (37 0C).[19] II. VOLATILE LIQUID/VACUUM CONTAINING SYSTEMS 1. Intragastric floating gastrointestinal drug delivery system This system can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a microporous compartment

Figure 7: Intragastric floating drug delivery device [17] 2. Inflatable gastrointestinal delivery systems In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug,

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impregnated polymeric matrix, then encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The drug continuously released from the reservoir into the gastric fluid (Figure 8).

Figure 8 : Gastro-inflatable drug delivery device [19] 3. Intragastric osmotically controlled drug delivery system It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In the stomach, the capsule quickly disintegrates to release the intragastirc osmotically controlled drug delivery device. The inflatable support inside forms a deformable hollow polymeric bag that contains a liquid that gasifies at body temperature to inflate the bag. The osmotic pressure controlled drug delivery devices consist of two components; drug reservoir compartment and an osmotically active compartment

Figure 9 : Intra-gastric osmotic controlled drug delivery system [17] NON EFFERVESCENT FDDS The Non effervescent FDDS is based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GIT. The most commonly used excipients in non-effervescent FDDS are gel

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forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymer such as chitosan and carbopol. In one approach, gel forming hydrocolloid swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and the bulk density of less than unity within gastric environment. The various types of this system are as: 1. Single layer floating tablets They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms. 2. Bilayer floating tablets A bilayer tablet contain two layer one immediate release layer which release initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach. 3. Alginate beads Multi unit floating dosage forms were developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hrs. 4. Hollow microspheres Hollow microspheres (microballoons), loaded with drug in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated aqueous solution of PVA that was thermally controlled at 400C. The microballoons floated continuously over the surface of acidic dissolution media containing surfactant for more than 12 hours in vitro.

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Figure 10 : Formulation of hollow microspheres [20] IN-VIVO AND IN-VITRO EVALUATION PARAMETERS OF STOMACH SPECIFIC FLOATING DRUG DELIVERY SYSTEM Different studies reported in the literature indicate that pharmaceutical dosage forms exhibiting gastric residence in vitro floating behaviour show prolonged gastric residence in vivo. PRECOMPRESSION PARAMETERS 1. Bulk density It is a ratio of mass of powder to bulk volume. The bulk density depends on particle size distribution, shape and cohesiveness of particles. Bulk density = M/Vo Where, M = mass of the powder, Vo = bulk volume of the powder 2. Tapped density Ten gram of powder was introduced into a clean, dry 100 ml measuring cylinder. The cylinder was then tapped 100 times from a constant height and the tapped volume was read. It is expressed in gm/ml and is given by Tapped density = M/Vt Where, M = mass of the powder, Vt = final tapping volume of the powder 3. Compressibility index (Carr’s index) Compressibility index is used as an important parameter to determine the flow behavior of

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the powder. It is indirectly related to the relative flow property rate, cohesiveness and particle size. It is Simple, fast and popular method for predicting flow characteristics. Carr’s index can be represented Carr’s index (%) = Tapped density – Bulk density * 100 Tapped density 4. Hausner'sratio : It is the ratio of tapped density to bulk density. It is given by Hausner ratio = Tapped density / Bulk density Table no.1 Powder flow Characteristics in relation to Carr’s index & Hausner’s ratio Compressibility Index (%) 38

Flow Characteristics Excellent Good Fair Passable Poor Very Poor Extremely Poor

Hausner’s ratio 1.00-1.11 1.12-1.18 1.19-1.25 1.26-1.34 1.35-1.45 1.46-1.59 >1.60

5. Angle of Repose It is defined as the maximum angle possible between the surface of the pile of the powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed with its tip at a given height ‘h, above a flat horizontal surface to which a graph paper was placed. Powder was carefully poured through a funnel till the apex of the conical pile just touches the tip of the funnel. The angle of repose was then calculated using following equation Angle of repose (θ)= tan-1(h/r) Where, h=height of the pile, r=radius of the pile, θ=angle of repose. Table no.2 Powder flow characteristics in relation to Angle of repose Sr.No 1 2 3 4

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Angle of Repose 40

Powder Flow Characteristics Excellent Good Passable Very Poor

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6. Drug-excipient (DE) interactions :[22,23] This is done using FTIR. Appearance of a new peak, and/or disappearance of original drug or excipient peak indicate the DE interaction. Apart from the above mentioned evaluation parameters, for the effect of ageing with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy. POST COMPRESSION PARAMETERS Thickness,

Hardness,

Friability,

Assay and

Content Uniformity (Tablets)

:

These are the tests can be performed as per the procedures mentioned in the official monographs. Tablet density [24] Tablet density is an important parameter for floating tablets. The tablet would floats only when its density is less than that of gastric fluid (1.004). The density is determined using following relationship. V = r2 h d = m/v v = volume of tablet (cc), r = radius of tablet (cm) h = crown thickness of tablet (g/cc) and m= mass of tablet Weight variation To study weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. Table no.3 Tablet weights and the deviation permissible

Sr.No 1 2 3

Average weight of Tablet (As per USP) 130 mg or Less > 130 mg or < 324 mg 324 mg or More

Percentage Deviation ±10 ± 7.5 ±5

Average weight of Tablet (As per IP) 80 mg or less >80mg and