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Journal of Current Pharmaceutical Research 2011; 5(1):7-18

JCPR 2011, 05:(1) 7-18 2010 Medipoeia Received: 11-12-2010 Revised: 15-3-2011 Accepted: 22-7-2011

Floating Drug Delievery System

Manoj Goyal1, Rajesh Prajapati1, Kapil Kumar Purohit2, S.C. Mehta3

ABSTRACT Management of illness through medication is entering a new era in which growing number of novel drug delivery systems are being employed and are available for therapeutic use. Oral sustained release gastro-retentive dosage forms (GRDFs) offer many advantages for drugs with absorption from upper parts of gastrointestinal tract and for those acting locally in the stomach, improving the bioavailability of the medication. Floating Drug Delivery Systems (FDDS) is one amongst the GRDFs used to achieve prolonged gastric residence time. The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. This review also summarizes the in vitro techniques, in vivo studies to evaluate the performance and application of floating systems, and applications of these systems. Keywords: floating drug delivery systems, single unit, multiple units, evaluation in-vitro and in-vivo, characterization, patents.

Manoj Goyal1, Rajesh Prajapati1 Department of Pharmaceutics, Institute of Professional Studies College of Pharmacy Gwalior Kapil Kumar Purohit2 Department of Pharmaceutics, Nagaji Institute of pharmaceutical sciences Gwalior Prof. S.C. Mehta3 Department of Medicinal Chemistry GRMC Medical College Gwalior

1. INTRODUCTION Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation etc. Oral sustained drug delivery formulations show some limitations connected with the gastric emptying time. Variable and too rapid gastrointestinal transit could result in incomplete drug release from the device into the absorption window leading to diminished efficacy of the administered dose. It is evident from the recent research and patent literature that an increased interest in novel dosage forms that are retained in the stomach for a prolonged and predictable period of time exists today. 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. One of such difficulties is the ability to confine the dosage form in the desired area of the gastrointestinal tract. To overcome this physiological problem, several drug delivery systems with prolonged gastric retention time have been investigated. Attempts are being made to develop a controlled drug delivery system that can provide therapeutically effective plasma drug concentration levels for longer durations, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug concentration at steady state by delivering drug in a controlled and reproducible manner (Hirtz J. et al. 1985). 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 of drugs that are less soluble in high pH environment. Gastric retention to provide new therapeutic possibilities and substantial benefits from patients. The controlled gastric retention of solid dosage forms may be achieved by the mechanism of muco adhesion (Ponchel G et al., 1998, Lenaerts VM et al.,1990) floatation, sedimentation, expansion, modified shape systems or by the administration of pharmacological agents (Groning et al.,1984,1989) that delaying gastric emptying. Based on these approaches, floating drug delivery systems seems to be the promising delivery systems for control release of drugs.

Correspondence: Prof. S.C. Mehta3 Department of medicinal chemistry Grmc medical college gwalior, india. Email:

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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 actions13. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the two states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. 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.(Wilson CG et al.,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. 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 rate16. 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. 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. Stomach doesnt 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 such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chrons disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down. (Singh BN et al.,2000) 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. 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 Andre18 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 (>1 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. (Mojaverian P et al., 1985) Several formulation parameters can affect the gastric residence time. 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.20 Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma reported that tetrahedron- and ringshaped 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. The density of a dosage form

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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. Timmermans et al studied the effect of buoyancy, posture, and nature of meals on the gastric emptying process in vivo using gamma scintigraphy. To perform these studies, floating and nonfloating 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. 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 gastro-duodenal 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 ( Figure 1 ). 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. A comparison was made to study the affect of fed and non fed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach. 4. DRUG CANDIDATES SUITABLE FOR FLOATING DRUG DELIVERY Drugs which have site-specific absorption in the stomach or upper parts of the small intestine (furosemide, riboflavine-5phosphate), drugs required to exert local therapeutic action in the stomach (antacids, anti-H.pylori agents, misoprostol), drugs unstable in the lower part of Gastro-intestinal tract (captopril), drugs insoluble in intestinal fluids (quinidine, diazepam), drugs with variable bioavailability (satolol HCl). (Baichwal and Kawashima Y et al.,1992) 5. APPROACHES TO DELIVERY SYSTEM DESIGN FLOATING DRUG

overcome the difficulty experienced by some persons of gagging or choking after swallowing medicinal pills. The author suggested that such difficulty could be overcome by providing pill having a density of less than 1.0g/cm3, so that pill will float on water surface. Since then several approaches have been used to develop an ideal floating drug delivery system.(Nakagawa M et al.,2006) 5.2 Approaches to Design Single and Multiple Unit Dosage Form The following approaches have been used for the design of floating dosage forms of single and multiple unit systems. 5.2.1 Single Unit Dosage Form: In low density approaches, the globular shells apparently having lower density than that of gastric fluid can be used as a carrier like popcorn, poprice, polystrol for the drug for its controlled release. The polymer of choice can be either Ethyl cellulose or HPMC. Depending on type of release 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 in to a micro porous component that houses as a reservoir having apertures present at top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. Hydro Dynamically Balanced System : These systems are designed to prolong the stay of the dosage forms in the gastric intestinal tract and aid in enhancing the absorption. Drugs having a better solubility in acidic environment and also having specific site of absorption in the upper part of small intestine is achieved by these HBS systems. To retain in stomach for a prolonged period of time the dosage form must have bulk density of less than 1 and has to maintain its structural integrity and release drug constantly from the dosage form. Among all the advantages single-unit formulations are associated with some limitations/problems such as sticking together or being obstructed in the GIT which may lead to potential danger of producing irritation. (Dorozynski P et al.,2007) 5.2.2 Multiple Unit Dosage Form: Multiparticulate dosage forms are gaining much favor over single-unit dosage forms. The potential benefits include increased bioavailability; predictable, reproducible and generally short gastric residence time, no risk of dose dumping; reduced risk of local irritation, and the flexibility to blend pellets with different compositions or release patterns. Because of their smaller particle size these systems are capable of passing through the GI tract easily, leading to less inter- and intra-subject variability.29 However, potential drug loading of a Multiparticulate system is lower because of the proportionally higher need for excipients (e.g., sugar cores). Most Multiparticulate Pulsatile delivery systems

5.1 Practical Approaches in Designing FDDS The concept of FDDS was first described in the literature as early as 1968, when Davis (1968) disclosed a method to

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are reservoir devices coated with a reputable polymeric layer. Upon water ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure build-up within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas producing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. Water soluble drugs are mainly released by diffusion; while for water insoluble drug, the release is dependent on dissolution of drug. (Wu W et al.,1997)

triple layered tablets may be prepared, which contains swellable gas generating layer, sustainable approach was utilized in the development of floating or pulsatile drug delivery system based on the coated effervescent core. The dosage form had two layers, first layer consisted of drug, cellulose acetate or HPMC as a sustained release core and second layer consisted of effervescent agents, PEG 4000 (4% based on the weight of the second layer) and lactose or microcrystalline cellulose as filler. Sodium bicarbonate and citric acid were used as an effervescent agent in a ratio of 1:0 in the concentration of 30-50 % of the w/w of the core. The carbon dioxide is generated upon contact with the medium and gets entrapped in the polymeric matrix, which provides buoyancy to the dosage form. It was observed that addition of 10-20% w/w of HPMC significantly retarded drug release compared to the dosage form without HPMC. Programmable drug delivery systems for oral administration were developed. It was a new prototype model device (3 cm long and 0.9 cm internal diameter) made to comprise of a cylindrical shell in the form of oral capsule. Drug was placed in a cylindrical disc made up of slowly eroding polymer and compressed to zero porosity, a flexible rubber disc, compressible acid resistant spring and a special acid impervious non-permeable rubber ballooning system containing bicarbonate granules. The device in the form of non-digestible oral capsule containing drug in a slowly eroding matrix was designed to utilize on automatically operated geometric obstruction that keeps the device floating in the stomach and prevents the system from passing through remainder of GIT. The different grades of HPMC were used to develop the eroding matrix. They concluded that duration of action was dependent on erosion rate of the incorporated polymer and the in vitro release of drug from developed device could be maintained up to 20 days. (Li S et al., 2001)

Figure 1. Intragastric residence positions of floating and nonfloating units. 6. CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEM : Floating drug delivery systems are classified depending up on the two formulations variables Effervescent and Noneffervescent systems. 6.1 Effervescent Floating Drug Delivery System : These are matrix type systems prepared with the help of swellable polymers such as hydroxypropyl methyl-cellulose or polysaccharides and chitosan and various effervescent components like sodium bicarbonate, calcium carbonate, citric acid or tartaric acid. These dosage forms are developed in such a way that, when they come in contact with gastric juice in the stomach, Carbon dioxide is liberated and is trapped in the swollen hydrocolloids. This provides buoyancy to the dosage form. The liberated carbon dioxide may intimately get mixed within the tablet matrix in case of single layered tablet. The multiparticulate floating reservoir types of delivery systems may contain double or triple layers. The

Mechanism of Effervescent systems Diagrammatic sketch of the device representing its operation mechanism (A, B, C, D.) (A) Intact device; (B) device at the beginning of drug release; (C) device with half drug-polymer compact eroded; and (D) device after complete drugpolymer erosion and evacuation of entrapped carbon dioxide. Sodium alginate beads consisting of gas forming agent were made up of HPMC and sodium alginate (9:1w/w) with

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gas generating agent in the concentration 0:1 to 1:1(gas forming agent/alginate w/w). The resultant solution was dropped in to 1% (w/v) calcium chloride solution containing 10% (v/v) acetic acid. The suspended beads were stirred with a magnetic stirrer for 10 minutes. The prepared beads were evaluated for the effect of carbon dioxide producing agent on size, floating properties, porosity, morphology and mechanical strength of beads. It was observed that amount of gas forming agent had a significant effect on size, floating ability, porosity, morphology, release rate and mechanical strength. Calcium carbonate formed smaller but stronger beads as compared to sodium bicarbonate. Calcium carbonate was found to be less effective gas generating agent than sodium bicarbonate. But it forms superior quality floating beads with significantly extended drug release. Multiple unit type of floating pills composed of inner effervescent layer containing sodium bicarbonate and tartaric acid and outer swellable polymeric membrane made up of polyvinyl acetate and purified shellac. The inner layer was further divided into two sub layers to avoid physical contact between sodium bicarbonate and tartaric acid. When the pill was immersed in buffer solution at 37 C, it settled down at the bottom, buffer solution entered in to the effervescent layer through the outer swellable membrane. Carbon dioxide was generated due to reaction between sodium bicarbonate and tartaric acid and formed swollen pills (like balloons) with a density much lesser than 1.0 g/ml. The system was found to float completely within 10 minutes and had a good floating ability independent of pH, viscosity of the medium and drug release in a sustained manner.

approaches in the development of such floating dosage forms involves thorough mixing of drug and gel forming hydrocolloids. After oral administration, the dosage form comes in contact with gastric fluids and gets swollen, form a gelatinous barrier at the surface. The swollen dosage form maintains a relative integrity of shapes and bulk density less than 1.0. The air entrapped within the swollen polymer matrix imparts buoyancy to the dosage forms. Hydrodynamically balanced capsules containing mixture of drug and hydrocolloids. Upon contact with gastric fluid, the capsule shell dissolved in gastric fluid followed by swelling of mixtures, formation of a gelatinous barrier and maintains bulk density less than 1.0, which remained buoyant on the gastric fluid for an extended period of time. (Erni W et al., 1987) Intragastric Floating Drug Delivery Device : The system composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. The peripheral walls of the reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with walls of the stomach

Intragastric floating drug delivery device Novel levodopa gastro retentive dosage form based on unfolding polymeric membranes, that combines extended dimensions with high rigidity. It was folded into a large size gelatin capsules. In vitro studies showed that unfolded form reached within 15 minutes after administration and it was confirmed in vivo in beagle dogs. The unfolded form was maintained for at least 2 hours. It was concluded that this dosage form could improve therapy of different narrow absorption window drugs. However, there are possibilities of the polymeric films to get stuck in the esophagus causing extreme discomfort to the patient or drug related injuries and repeated administration of rigid dosage form may result in gastric obstruction. (Etyan Klausner A et al., 2003) 7. LIST OF DRUGS EXPLORED FLOATING DOSAGE FORMS FOR VARIOUS

Floating pills a) The penetration of water into effervescent layer leads to a CO2 generation and makes the system to float (b) Mechanism of floatation. 6.2 Non Effervescent Floating Drug Delivery System : The non-effervescent FDDS works on the mechanism of polymer swelling, bioadhesion of the polymer to mucosal layer of GI tract. The most commonly used excipients for the preparations of non-effervescent FDDS are gel forming or swellable type hydrocolloids, polysaccharides and matrix forming polymers like polymethacrylates, polycarbonates, polyacrylates, polystyrenes and bioadhesion polymers like chitosan and carbopols. One of the

7.1 Microspheres Tablets /Pills: Chlorpheniramine maleate, Aspirin, griseofulvin, Acetaminophen, p-nitroaniline, Acetylsalicylic acid, Ibuprofen, Amoxycillin trihydrate, Terfenadine, Ampicillin, Tranilast,Atenolol, Theophylline, Captopril, Isosorbide di nitrate, Sotalol, Isosorbide mononitrate.

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7.2 Films: P-Aminobenzoic acid, Prednisolone, Quinidine gluconate.



8.5 Release rate retardants (5%-60%): eg. Dicalcium phosphate, talc, magnesium stearate. 8.6 Buoyancy increasing agents (upto80%) : eg. Ethyl cellulose. 8.7 Low density material : Polypropylene foam powder (Accurel MP 1000). 9. ADVANTAGES OF FDDS:

7.3 Granules: Cinnarizine, Diclofenac sodium , Diltiazem, Indomethacin ,Fluorouracil ,Prednisolone , Isosorbide mononitrate ,Isosorbide dinitrate. 7.4 Powders: Riboflavin,phosphate, Sotalol, Theophylline. 7.5 Capsules: Verapamil HCl, Chlordiazepoxide HCl, Diazepam, Furosemide, L-,opa and benserazide Misoprostol, Propranolol HCl, Ursodeoxycholic acid, Nicardipine MARKETED PRODUCTS OF FDDS : S. No. 1 2 3 4 Products Active Ingredients

Madopar Valrelease Topalkan Almagate flatcoat Liquid gavison

Levodopa and benserzide Diazepam Aluminum magnesium Antacid Antacid

1. Floating dosage forms such as tablets or capsules will remains in the solution for prolonged time even at the alkaline pH of the intestine. 2. FDDS are advantageous for drugs meant for local action in the stomach eg: Antacids 3. FDDS dosage forms are advantageous in case of vigorous intestinal movement and in diarrhea to keep the drug in floating condition in stomach to get a relatively better response. 4. Acidic substance like aspirin causes irritation on the stomach wall when come in contact with it hence; HBS/FDDS formulations may be useful for the administration of aspirin and other similar drugs. 5. The FDDS are advantageous for drugs absorbed through the stomach eg: Ferrous salts, Antacids. 10. DISADVANTAGES OF FDDS:

Alginic acid and sodium bicarbonate

8. POLYMERS AND OTHER INGREDIENTS USED IN PREPARATIONS OF FLOATING DRUGS: 8.1 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, 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. 8.2 Inert fatty materials (5%-75%) : Edible, inert fatty materials 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. 8.3 Effervescent agents : Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbonate, CG (Citroglycine). 8.4 Release rate accelerants (5%-60%) : eg. lactose, mannitol

1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids. 2. Drugs such as Nifedipine, which is well absorbed along the entire GI tract and which undergo significant first-pass metabolism, may not be suitable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailability. Also there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa. 3. 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. 4. These systems also require the presence of food to delay their gastric emptying. 11. EVALUATION OF FLOATING DOSAGE FORMS 11.1 For Single Unit Dosage Forms (ex: tablets). (Baumgartner S et al.,2000 And Rosa M. et al.,1994) (i) Floating lag time: It is the time taken by the tablet to emerge onto the surface of dissolution medium and is expressed in seconds or minutes. (ii) Invitro drug release and duration of floating: This is determined by using USP II apparatus (paddle) stirring at a speed of 50 or 100 rpm at 37 0.2 c in simulated gastric fluid (pH 1.2 without pepsin). Aliquots of the samples are collected and analysed for the drug content. The time (hrs) for which the tablets remain

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buoyant on the surface of the dissolution medium is the duration of floating and is visually observed. (iii) In vivo evaluation for gastro-retention: This is carried out by means of X-ray or Gammascintigraphic monitoring of the dosage form transition in the GIT. The tablets are also evaluated for hardness, weight variation, etc. 11.2 For Multiple Unit Dosage Forms (ex: microspheres) Apart from the In vitro release, duration of floating and in vivo gastro-retention tests, the multiple unit dosage forms are also evaluated for (i) Morphological and dimensional analysis with the aid of scanning electron microscopy (SEM). The size can also be measured using an optical microscope. (ii) % yield of microspheres: This is calculated from Weight of microspheres obtained 100 / total weight of drug and polymer (iii) Entrapment efficiency: The drug is extracted by a suitable method, analysed and is calculated from Practical amount of drug present 100 / Theoretical drug content (iv) In vitro floating ability (Buoyancy %): A known quantity of microspheres are spread over the surface of a USP (Type II) dissolution apparatus filled with 900 ml of 0.1 N HCl containing 0.002% v/v Tween 80 and agitated at 100 rpm for 12 hours. After 12 hours, the floating and settled layers are seperated, dried in a dessicator and weighed. The buoyancy is calculated from the following formula. Buoyancy (%) = Wf / ( Wf + Ws) * 100 Where, Wf and Ws are the weights of floating and settled microspheres respectively. (v) Drug-excipient (DE) interactions: This is done using FTIR. Appearance of a new peak, and/or disappearance of original drug or excipient peak indicates the DE interaction. Apart from the above mentioned evaluation parameters, granules (ex: Gelucire 43/01) are also evaluated for the effect of ageing with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy. 12. CHARACTERIZATION PARAMETERS: 12.1 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 rsistance counting methods (Coulter

counter), Sedimentation techniques, Laser diffraction methods, ultrasound attenuation spectroscopy, Air Pollution Emissions Measurements etc. 12.2 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. 12.3 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. 12.3 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 1. Storability 2. Agglomeration in the case of powders 3. Microbiological stability 4. Flow properties, viscosity 5. Dry substance content 6. Concentration or purity 7. 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. 12.4 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 12.5 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

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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. 12.7 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. 12.8 In-vitro Release Studies: In vitro release studies (USP dissolution apparatus (usp24) 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. 12.9 Powder X-ray Differaction: X-ray powder diffraction (Philips analytical, modelpw1710) is the predominant tool for the study of poly-crystalline materials and is eminently suited for the routine characterization of pharmaceutical solids. Samples were irradiated with radiation and analyzed between 2 C and 60 C .The voltage and current used were 30KV and 30mA respectively. 12.10 Fourier Transform Infrared Analysis: Fourier transform infrared spectroscopy (FT-IR, Shimadzu, 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 drugloaded 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. 12.11 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 10C/min; over a temperature range of 25 C 65C. Inert atmosphere was maintained by purging nitrogen gas at the flow rate of 50ml/min.

13. APPLICATION OF FLOATING DRUG DELIEVERY SYSTEM : 13.1 Enhanced Bioavailability: The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of nonGRDF 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) 13.2 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. 13.3 Site Specific Drug Delievery 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) 13.4 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) 13.5 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 betalactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganisms resistance. 13.6 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.68

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Among the drugs currently in clinical use are several narrow absorption window drugs that may benefit from compounding into a FDDS. Replacing parentarl administartion of drugs to oral pharmacotherapy would substantially improve treatment. It is anticipated that FDDS may enhance this possibility. Moreover, it is expected that the FDDS approach may be used for many patentially active agents with narrow absorption window, whose development has been halted due to lack of appropriate pharmaceutical FDDS technologies. Combination therapy to treat H.Pylori infection in a single FDDS need to be developed. Further investigation may concentrate on the following concept: Identification of a minimal cut-off size above that DFs retained in the human stomach for prolonged period of time. This would permit a more specific control to be achieved in gestroretentivity. Design of array of FDDS, each having a narrow GRT for use according to the clinical need e.g. dosage and state of disease. This may be achieved by compounding polymeric metrices with various boidegradation prpoerties. Study of the effect of various geometric shape, in a more excessive manner than previous studies, extended dimensions with high rigidity, on gestroretentivity. Design of novel polymers according to clinical and phamaceutical need. 15. 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 gastroretentive 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. 16. REFERENCES Hirtz J. The git absorption of drugs in man: a review of currentconcepts and methods of investigation. Br J Clin Pharmacol. 1985;19:77S-83S. Ponchel G, Irache JM. Specific and non-specific bioadhesive particulate system for oral delivery to the gastrointestinal tract. Adv Drug Del Rev. 1998;34:191219.PubMed DOI: 10.1016/S0169-409X(98)00040-4 Lenaerts VM, Gurny R. Gastrointestinal TractPhysiological variables affecting the performance of oral sustained

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PATENTS ON FDDS S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 Type of formulation Gastro retentive dosage form Multiple unit floating dosage form Bilayer tablet Floating Tablet Microspheres 3-layer tablet Foams (or) hollow bodies Floating tablet Granule Floating capsules Tiny pills Floating capsule Floating device Patent no. U.S-7,413,752 European patent (EP)10697 EP-002445 U.S-66,352279 U.S-6207197 U.S-5780057 U.S-5626876 U.S-5169639 U.S-4844905 U.S-4814178,-79 U.S-4434153 U.S-4126672 U.S-4055178 Ref. Devane et al., 2008 Vanderbist et al., 2007 Lohray et al., 2004 Kolter et al., 2003 Illum et al., 2001 Conte et al., 1998 Muller et al., 1997 Baichwal et al., 1992 Ichikawa et al., 1989 Sheth et al., 1989 Urguhart et al., 1984 Sheth et al., 1978 Harrigan et al., 1977

LIST OF DRUGS FORMULATED AS SINGLE AND MULTIPLE UNIT FORMS OF FLOATING DRUG DELIVERY SYSTEMS. (Soppimath KS et al., 2001) Tablets Chlorpheniramine maleate Theophylline Furosemide Ciprofolxacin Pentoxyfillin Captopril Acetylsalicylic acid Nimodipine Amoxycillin trihydrate Verapamil HCl Isosorbide di nitrate Sotalol Atenolol Isosorbide mono nitrate Acetaminophen Ampicillin Cinnarazine Diltiazem Florouracil Piretanide Prednisolone Riboflavin- 5 Phosphate Capsules Nicardipine L- Dopa and benserazide hlordiazepoxide HCl Furosemide Misoprostal Diazepam Propranlol Urodeoxycholic acid Microspheres Verapamil Aspirin, griseofulvin, p-nitroaniline Ketoprofen Tranilast Iboprufen Terfenadine Granules Indomathacin Diclofenac sodium Prednisolone Films Drug delivery device Cinnarizine