Floatin Drug Delivery System

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Gastroretentive Drug Deliver y Systems a report by

S a n j a y G a r g and S h r i n g i S h a r m a Associate Professor and Senior Research Fellow, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)

Sanjay Garg is Associate Professor in the Department of Pharmaceutics of the National Institute of Pharmaceutical Education and Research (NIPER). His areas of research interest include novel drug delivery systems, especially osmotically controlled oral systems, bioadhesive formulations and vaginal drug delivery systems. Professor Garg is involved with pharmaceutical project management and with regulatory affairs. Shringi Sharma is currently working as Senior Research Fellow in the Department of Pharmaceutics of NIPER. He completed his Masters in pharmaceutics.

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. From immediate release to sitespecific delivery, oral dosage forms have really progressed. However, it is a well-accepted fact that it is difficult to predict the real in vivo time of release with solid, oral controlled release dosage forms. Thus, drug absorption in the gastrointestinal (GI) tract may be very short and highly variable in certain circumstances. It is evident from the recent scientific 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 in academic and industrial research groups. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT). Dosage forms with a prolonged GRT, i.e. gastroretentive dosage forms (GRDFs), will provide us with new and important therapeutic options. The Multifarious Uses of GRDFs

GRDFs extend significantly the period of time over which the drugs may be released. Thus, they not only prolong dosing intervals, but also increase patient compliance beyond the level of existing controlled release dosage forms. This application is especially effective in delivery of sparingly soluble and insoluble drugs. It is known that, as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. To address this, oral administration of sparingly soluble drugs is carried out frequently, often several times per day.

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As a mechanism to override this problem, erodible, gastroretentive dosage forms have been developed that provide continuous, controlled administration of these drugs at the absorption site. In addition, these dosage forms are useful for delivering drugs incorporated into vesicles such as liposomes,

nanoparticles, proteinoid microspheres and pharmacosomes, etc. Compared with other applications, the frequency of dosing may be the same, but the gastroretentive dosage forms will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability. For example, a significant increase in the bioavailability of furosemide from a floating dosage form (42.9%) has been reported, compared with commercially available tablets (Lasix ® (33.4%)) and enteric products (29.5%). GRDFs greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa (eradicating Helicobacter pylori from the submucosal tissue of the stomach), making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis, reduce the risk of gastric carcinoma and administer non-systemic, controlled release antacid formulations (calcium carbonate). GRDFs can be used as carriers for drugs with so-called absorption windows. These substances, for example antiviral, antifungal and antibiotic agents (sulphonamides, quinolones, penicillins, cephalosporins, aminoglycosides and tetracyclines, etc.), are taken up only from very specific sites of the GI mucosa. In addition, by continually supplying the drug to its most efficient site of absorption, the dosage forms allow for more effective oral use of peptide and protein drugs such as calcitonin, erythropoietin, vasopressin, insulin, low-molecular-weight heparin, protease inhibitors and luteinising hormone-releasing hormone analogues. Mechanistic Aspects of GRDFS

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. Among these, the floating dosage BUSINESS BRIEFING: PHARMATECH 2003

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Figure 1: The Mechanism of Floating Systems

Fgravity Swelling system

RW +ve

Imbibition of GF

GF

Gas-generating system

CO2 released provides F buoyancy

GF

RW -ve Fbuoyancy a

b

c

GF = Gastric fluid

forms have been used most commonly. However, most of these approaches are influenced by a number of factors that affect their efficacy as a gastroretentive system:1–3 • density – GRT is a function of dosage form buoyancy that is dependent on the density; • size – dosage form units with a diameter of more than 7.5mm are reported to have an increased GRT compared with those with a diameter of 9.9mm; • shape of dosage form – tetrahedron and ringshaped devices with a flexural modulus of 48 and 22.5 kilopounds per square inch (KSI) are reported to have better GRT ≈ 90% to 100% retention at 24 hours compared with other shapes; • single or multiple unit formulation – multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms; • fed or unfed state – under fasting conditions, the GI motility is characterised by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the

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GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer; • nature of meal – feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release; • caloric content – GRT can be increased by four to 10 hours with a meal that is high in proteins and fats; • frequency of feed – the GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC; • gender – mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and racematched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface); • age – elderly people, especially those over 70, have a significantly longer GRT; • posture – GRT can vary between supine and upright ambulatory states of the patient; • concomitant drug administration – anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; and • biological factors – diabetes and Crohn’s disease, etc.

1. B M Singh and K H Kim, “Floating drug delivery systems: an approach to controlled drug delivery via gastric retention”, J. Control. Rel., 63 (2000), pp. 235–259. 2. J Timmermans and A J Moes, “Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules: new data for reconsidering the controversy”, J. Pharm. Sci., 83 (1994), pp. 18–24. 3. P Mojaverian, P H Vlasses, P E Kellner and M L Rocci, Jr., “Effects of gender, posture, and age on gastric residence time of an indigestible solid: pharmaceutical considerations”, Pharm. Res., 10 (1988), pp. 639–644.

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Types of System Floating Drug Delivery Systems1

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 (see Figure 1a), 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 (RW) has been reported in the literature.4 The RW 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 RW is on the higher positive side (see Figure 1b). This apparatus helps in optimising FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations. RW or F = F buoyancy - F gravity = (Df - Ds) gV, where RW = total vertical force, Df = fluid density, Ds = object density, V = volume and g = acceleration due to gravity. The FDDS can be divided into gas-generating and non-effervescent systems. Gas-generating Systems

These buoyant systems utilise matrices prepared with swellable polymers like methocel, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethylcellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach (see Figure 1c). Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a 164

mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology, etc. Non-effervescent Systems

This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. These systems may be referred to as the ‘plug-type systems’ since they have a tendency to remain lodged near the pyloric sphincter. One of the formulation methods of such dosage forms involves the mixing of drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms (see Figure 1a). Other approaches reported in the literature are hydrodynamically balanced systems developed by Sheth and Tossounian, which contain a mixture of drug and hydrocolloids, sustained release capsules containing cellulose derivatives like starch and a higher fatty alcohol or fatty acid glyceride, bilayer compressed capsules, multilayered flexible sheet-like medicament devices, hollow microspheres of acrylic resins, polystyrene floatable shells, single and multiple unit devices with floatation chambers and microporous compartments and buoyant controlled release powder formulations, etc. Recent developments include use of superporous hydrogels that expand dramatically (hundreds of times their dehydrated form within a matter of seconds) when immersed in water. Oral drug delivery formulations made from the gels would swell rapidly in the stomach, causing medications to move more slowly from the stomach to the intestines and be absorbed more efficiently by the body. Drugs reported to be used in the formulation of floating dosage forms are floating microspheres (aspirin, griseofulvin, p-nitroaniline, ibuprofen, terfinadine and tranilast), floating granules (diclofenac sodium, indomethacin and prednisolone), films (cinnarizine), floating capsules (chlordiazepoxide hydrogen chloride, diazepam, furosemide, misoprostol, L-Dopa, benserazide, ursodeoxycholic acid and pepstatin) and floating tablets and pills (acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, para-

4. J Timmermans and A J Moes, “How well do floating dosage forms float?”, Int. J. Pharm., 62 (1990), pp. 207–216.

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aminobenzoic acid, piretamide, theophylline and verapimil hydrochloride, etc.). Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol®, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates. Some of the marketed formulations are listed as follows: • Valrelease® – floating capsule of diazepam; • Madopar® – benserazide and L-Dopa combination formulation; • Liquid Gaviscon® – floating liquid alginate preparations; • Topalkan® – aluminium – magnesium antacid preparation; and • Almagate Flot-Coat® – antacid preparation.

mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on diameter of the pellets, although many conflicting reports stating otherwise also abound in literature. Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by up to 1.5–2.4g/cm-3. However, no successful highdensity system has made it to the market. Large Single-unit Dosage Forms

Bioadhesive Systems

Bioadhesive drug delivery systems (BDDS) are used to localise a delivery device within the lumen to enhance the drug absorption in a site-specific manner. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach. A microbalance-based system is reported for measuring the forces of interaction between the GI mucosa and the individual polymers, and the Cahn Dynamic Contact Angle Analyzer has been used to study the adherence.5 Gastric mucoadhesion does not tend to be strong enough to impart to dosage forms the ability to resist the strong propulsion forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seems to limit the potential of mucoadhesion as a gastroretentive force. Some of the most promising excipients that have been used commonly in these systems include polycarbophil, carbopol, lectins, chitosan, CMC and gliadin, etc. Some investigators have tried out a synergistic approach between floating and bioadhesion systems. Other approaches reported include use of a novel adhesive material derived from the fimbriae (especially Type 1) of bacteria or synthetic analogues combined with a drug to provide for attachment to the gut, thereby prolonging the transit time, a composition comprising an active ingredient and a material that acts as a viscogenic agent (for example curdlan and/or a low-substituted hydroxypropylcellulose), etc. High-density Systems

Sedimentation has been employed as a retention

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These dosage forms are larger than the pyloric opening and so are retained in the stomach. There are some drawbacks associated with this approach. Permanent retention of rigid large-sized single-unit forms can cause bowel obstruction, intestinal adhesion and gastroplasty. Co-administration of Gastric-emptying Delaying Drugs

This concept of simultaneous administration of a drug to delay gastric emptying together with a therapeutic drug has not received the favour of clinicians and regulatory agencies because of the questionable benefit-to-risk ratio associated with these devices. Evaluation of Gastroretentive Dosage Forms

Evaluation for gastroretention is carried out by means of X-ray and/or gamma scintigraphic monitoring of the dosage form transit in the GI tract. The modern technique of gamma scintigraphy now makes it possible to follow the transit behaviour of dosage forms in human volunteers in a non-invasive manner. Conclusion

Finally, while the control of drug release profiles has been a major aim of pharmaceutical research and development in the past two decades, the control of GI transit profiles could be the focus of the next two decades and might result in the availability of new products with new therapeutic possibilities and substantial benefits for patients. Soon, the so-called ‘once-a-day’ formulations may be replaced by novel gastroretentive products with release and absorption phases of approximately 24 hours. ■

5. D E Chickering, J S Jacob and E Mathowitz, “Bioadhesive microspheres II: Characterisation and evaluation of bioadhesion involving hard, bioerodible polymers and soft tissue”, Reactive Polymers, 25 (1995), pp. 189–206.

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