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Gastroretentive Drug Delivery Systems

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					                                                          Drug Delivery        ORAL




                                         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      Introduction                                                 nanoparticles, proteinoid microspheres and
in the Department of Pharmaceutics                                                                    pharmacosomes, etc. Compared with other
          of the National Institute of
      Pharmaceutical Education and       Oral delivery of drugs is by far the most preferable         applications, the frequency of dosing may be the
     Research (NIPER). His areas of      route of drug delivery due to the ease of                    same, but the gastroretentive dosage forms will
       research interest include novel
    drug delivery systems, especially
                                         administration, patient compliance and flexibility in        alter beneficially the absorption profile of the active
  osmotically controlled oral systems,   formulation, etc. From immediate release to site-            agent, thus enhancing its bioavailability. For
        bioadhesive formulations and     specific delivery, oral dosage forms have really             example, a significant increase in the bioavailability
      vaginal drug delivery systems.
     Professor Garg is involved with     progressed. However, it is a well-accepted fact that it is   of furosemide from a floating dosage form (42.9%)
  pharmaceutical project management      difficult to predict the real in vivo time of release with   has been reported, compared with commercially
         and with regulatory affairs.
                                         solid, oral controlled release dosage forms. Thus, drug      available tablets (Lasix ® (33.4%)) and enteric
Shringi Sharma is currently working
                                         absorption in the gastrointestinal (GI) tract may be very    products (29.5%).
  as Senior Research Fellow in the       short and highly variable in certain circumstances.
   Department of Pharmaceutics of                                                                     GRDFs greatly improve the pharmacotherapy of the
  NIPER. He completed his Masters
                  in pharmaceutics.      It is evident from the recent scientific and patent          stomach through local drug release, leading to high
                                         literature that an increased interest in novel dosage        drug concentrations at the gastric mucosa
                                         forms that are retained in the stomach for a                 (eradicating Helicobacter pylori from the submucosal
                                         prolonged and predictable period of time exists today        tissue of the stomach), making it possible to treat
                                         in academic and industrial research groups. One of           stomach and duodenal ulcers, gastritis and
                                         the most feasible approaches for achieving a                 oesophagitis, reduce the risk of gastric carcinoma and
                                         prolonged and predictable drug delivery profile in           administer non-systemic, controlled release antacid
                                         the GI tract is to control the gastric residence time        formulations (calcium carbonate).
                                         (GRT). Dosage forms with a prolonged GRT, i.e.
                                         gastroretentive dosage forms (GRDFs), will provide           GRDFs can be used as carriers for drugs with
                                         us with new and important therapeutic options.               so-called absorption windows. These substances,
                                                                                                      for example antiviral, antifungal and antibiotic
                                         The Multifarious Uses of GRDFs                               agents (sulphonamides, quinolones, penicillins,
                                                                                                      cephalosporins, aminoglycosides and tetracyclines,
                                         GRDFs extend significantly the period of time over           etc.), are taken up only from very specific sites of the
                                         which the drugs may be released. Thus, they not              GI mucosa. In addition, by continually supplying the
                                         only prolong dosing intervals, but also increase             drug to its most efficient site of absorption, the dosage
                                         patient compliance beyond the level of existing              forms allow for more effective oral use of peptide and
                                         controlled release dosage forms. This application is         protein drugs such as calcitonin, erythropoietin,
                                         especially effective in delivery of sparingly soluble        vasopressin, insulin, low-molecular-weight heparin,
                                         and insoluble drugs. It is known that, as the solubility     protease inhibitors and luteinising hormone-releasing
                                         of a drug decreases, the time available for drug             hormone analogues.
                                         dissolution becomes less adequate and thus the transit
                                         time becomes a significant factor affecting drug             Mechanistic Aspects of GRDFS
                                         absorption. To address this, oral administration of
                                         sparingly soluble drugs is carried out frequently,           Various attempts have been made to retain the
                                         often several times per day.                                 dosage form in the stomach as a way of increasing
                                                                                                      the retention time. These attempts include
                                         As a mechanism to override this problem, erodible,           introducing floating dosage forms (gas-generating
                                         gastroretentive dosage forms have been developed             systems and swelling or expanding systems),
                                         that provide continuous, controlled administration           mucoadhesive systems, high-density systems,
                                         of these drugs at the absorption site. In addition,          modified shape systems, gastric-emptying delaying
                                         these dosage forms are useful for delivering drugs           devices and co-administration of gastric-emptying
160                                      incorporated into vesicles such as liposomes,                delaying drugs. Among these, the floating dosage

                                                                                                                    BUSINESS BRIEFING: PHARMATECH 2003
                           Drug Delivery       ORAL




       Figure 1: The Mechanism of Floating Systems

                                                                  Fgravity

                    Swelling system                                          RW +ve                          Gas-generating
                                                                                                                 system




                   Imbibition of GF                                            GF                    CO2 released             GF
                                                                                                  provides F buoyancy
                                                        RW -ve
                                                                 Fbuoyancy

                           a                                          b                                                 c
      GF = Gastric fluid

       forms have been used most commonly. However,                          GRT of the unit can be expected to be very
       most of these approaches are influenced by a                          short. However, in the fed state, MMC is delayed
       number of factors that affect their efficacy as a                     and GRT is considerably longer;
       gastroretentive system:1–3
                                                                          • nature of meal – feeding of indigestible polymers
       • density – GRT is a function of dosage form                         or fatty acid salts can change the motility pattern
         buoyancy that is dependent on the density;                         of the stomach to a fed state, thus decreasing the
                                                                            gastric emptying rate and prolonging drug release;
       • size – dosage form units with a diameter of more
         than 7.5mm are reported to have an increased                     • caloric content – GRT can be increased by four
         GRT compared with those with a diameter of                         to 10 hours with a meal that is high in proteins
         9.9mm;                                                             and fats;

       • shape of dosage form – tetrahedron and ring-                     • frequency of feed – the GRT can increase by over
         shaped devices with a flexural modulus of 48                       400 minutes when successive meals are given
         and 22.5 kilopounds per square inch (KSI) are                      compared with a single meal due to the low
         reported to have better GRT ≈ 90% to 100%                          frequency of MMC;
         retention at 24 hours compared with other
         shapes;                                                          • gender – mean ambulatory GRT in males (3.4±0.6
                                                                            hours) is less compared with their age and race-
       • single or multiple unit formulation – multiple unit                matched female counterparts (4.6±1.2 hours),
         formulations show a more predictable release                       regardless of the weight, height and body surface);
         profile and insignificant impairing of performance
         due to failure of units, allow co-administration of              • age – elderly people, especially those over 70,
         units with different release profiles or containing                have a significantly longer GRT;
         incompatible substances and permit a larger
         margin of safety against dosage form failure                     • posture – GRT can vary between supine and
         compared with single unit dosage forms;                            upright ambulatory states of the patient;

       • fed or unfed state – under fasting conditions, the               • concomitant drug administration – anticholinergics
         GI motility is characterised by periods of strong                  like atropine and propantheline, opiates like
         motor activity or the migrating myoelectric                        codeine and prokinetic agents like metoclopramide
         complex (MMC) that occurs every 1.5 to 2 hours.                    and cisapride; and
         The MMC sweeps undigested material from the
         stomach and, if the timing of administration of the              • biological factors – diabetes and Crohn’s disease,
         formulation coincides with that of the MMC, the                    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
162       of an indigestible solid: pharmaceutical considerations”, Pharm. Res., 10 (1988), pp. 639–644.


                                                                                      BUSINESS BRIEFING: PHARMATECH 2003
                       Drug Delivery        ORAL




      Types of System                                              mixture of sodium alginate and sodium bicarbonate,
                                                                   multiple unit floating pills that generate carbon dioxide
      Floating Drug Delivery Systems1                              when ingested, floating minicapsules with a core of
                                                                   sodium bicarbonate, lactose and polyvinyl pyrrolidone
      Floating drug delivery systems (FDDS) have a bulk            coated with hydroxypropyl methylcellulose (HPMC),
      density less than gastric fluids and so remain buoyant in    and floating systems based on ion exchange resin
      the stomach without affecting the gastric emptying rate      technology, etc.
      for a prolonged period of time. While the system is
      floating on the gastric contents (see Figure 1a), the drug   Non-effervescent Systems
      is released slowly at the desired rate from the system.
      After release of drug, the residual system is emptied        This type of system, after swallowing, swells
      from the stomach. This results in an increased GRT           unrestrained via imbibition of gastric fluid to an
      and a better control of the fluctuations in plasma drug      extent that it prevents their exit from the stomach.
      concentration. However, besides a minimal gastric            These systems may be referred to as the ‘plug-type
      content needed to allow the proper achievement of the        systems’ since they have a tendency to remain lodged
      buoyancy retention principle, a minimal level of             near the pyloric sphincter. One of the formulation
      floating force (F) is also required to keep the dosage       methods of such dosage forms involves the mixing of
      form reliably buoyant on the surface of the meal. To         drug with a gel, which swells in contact with gastric
      measure the floating force kinetics, a novel apparatus       fluid after oral administration and maintains a relative
      for determination of resultant weight (RW) has been          integrity of shape and a bulk density of less than one
      reported in the literature.4 The RW apparatus operates       within the outer gelatinous barrier. The air trapped
      by measuring continuously the force equivalent to F (as      by the swollen polymer confers buoyancy to these
      a function of time) that is required to maintain the         dosage forms (see Figure 1a).
      submerged object. The object floats better if RW is on
      the higher positive side (see Figure 1b). This apparatus     Other approaches reported in the literature are
      helps in optimising FDDS with respect to stability and       hydrodynamically balanced systems developed by
      durability of floating forces produced in order to           Sheth and Tossounian, which contain a mixture of
      prevent the drawbacks of unforeseeable intragastric          drug and hydrocolloids, sustained release capsules
      buoyancy capability variations.                              containing cellulose derivatives like starch and a
                                                                   higher fatty alcohol or fatty acid glyceride, bilayer
                 RW or F = F buoyancy - F gravity                  compressed capsules, multilayered flexible sheet-like
                         = (Df - Ds) gV,                           medicament devices, hollow microspheres of acrylic
                                                                   resins, polystyrene floatable shells, single and multiple
      where RW = total vertical force, Df = fluid density,         unit devices with floatation chambers and
      Ds = object density, V = volume and g =                      microporous compartments and buoyant controlled
      acceleration due to gravity.                                 release powder formulations, etc.

      The FDDS can be divided into gas-generating and              Recent developments include use of superporous
      non-effervescent systems.                                    hydrogels that expand dramatically (hundreds of
                                                                   times their dehydrated form within a matter of
      Gas-generating Systems                                       seconds) when immersed in water. Oral drug
                                                                   delivery formulations made from the gels would
      These buoyant systems utilise matrices prepared with         swell rapidly in the stomach, causing medications to
      swellable polymers like methocel, polysaccharides like       move more slowly from the stomach to the intestines
      chitosan, effervescent components like sodium                and be absorbed more efficiently by the body.
      bicarbonate, citric acid and tartaric acid or chambers
      containing a liquid that gasifies at body temperature.       Drugs reported to be used in the formulation of
      The optimal stoichiometric ratio of citric acid and          floating dosage forms are floating microspheres (aspirin,
      sodium bicarbonate for gas generation is reported to be      griseofulvin, p-nitroaniline, ibuprofen, terfinadine and
      0.76:1. The common approach for preparing these              tranilast), floating granules (diclofenac sodium,
      systems involves resin beads loaded with bicarbonate         indomethacin and prednisolone), films (cinnarizine),
      and coated with ethylcellulose. The coating, which is        floating capsules (chlordiazepoxide hydrogen chloride,
      insoluble but permeable, allows permeation of water.         diazepam, furosemide, misoprostol, L-Dopa,
      Thus, carbon dioxide is released, causing the beads to       benserazide, ursodeoxycholic acid and pepstatin) and
      float in the stomach (see Figure 1c). Other approaches       floating tablets and pills (acetaminophen, acetylsalicylic
      and materials that have been reported are highly             acid, ampicillin, amoxycillin trihydrate, atenolol,
      swellable hydrocolloids and light mineral oils, a            diltiazem, fluorouracil, isosorbide mononitrate, para-

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


                                                                                BUSINESS BRIEFING: PHARMATECH 2003
                       Drug Delivery         ORAL




      aminobenzoic acid, piretamide, theophylline and               mechanism for pellets that are small enough to be
      verapimil hydrochloride, etc.). Excipients used most          retained in the rugae or folds of the stomach body near
      commonly in these systems include HPMC,                       the pyloric region, which is the part of the organ with
      polyacrylate polymers, polyvinyl acetate, Carbopol®,          the lowest position in an upright posture. Dense
      agar, sodium alginate, calcium chloride, polyethylene         pellets (approximately 3g/cm3) trapped in rugae also
      oxide and polycarbonates. Some of the marketed                tend to withstand the peristaltic movements of the
      formulations are listed as follows:                           stomach wall. With pellets, the GI transit time can be
                                                                    extended from an average of 5.8–25 hours, depending
      • Valrelease® – floating capsule of diazepam;                 more on density than on diameter of the pellets,
      • Madopar® – benserazide and L-Dopa                           although many conflicting reports stating otherwise
        combination formulation;                                    also abound in literature. Commonly used excipients
      • Liquid Gaviscon® – floating liquid alginate                 are barium sulphate, zinc oxide, titanium dioxide and
        preparations;                                               iron powder, etc. These materials increase density by
      • Topalkan® – aluminium – magnesium antacid                   up to 1.5–2.4g/cm-3. However, no successful high-
        preparation; and                                            density system has made it to the market.
      • Almagate Flot-Coat® – antacid preparation.
                                                                    Large Single-unit Dosage Forms
      Bioadhesive Systems
                                                                    These dosage forms are larger than the pyloric
      Bioadhesive drug delivery systems (BDDS) are used to          opening and so are retained in the stomach. There
      localise a delivery device within the lumen to enhance        are some drawbacks associated with this approach.
      the drug absorption in a site-specific manner. This           Permanent retention of rigid large-sized single-unit
      approach involves the use of bioadhesive polymers,            forms can cause bowel obstruction, intestinal
      which can adhere to the epithelial surface in the             adhesion and gastroplasty.
      stomach. A microbalance-based system is reported for
      measuring the forces of interaction between the GI            Co-administration of Gastric-emptying
      mucosa and the individual polymers, and the Cahn              Delaying Drugs
      Dynamic Contact Angle Analyzer has been used to
      study the adherence.5                                         This concept of simultaneous administration of a drug
                                                                    to delay gastric emptying together with a therapeutic
      Gastric mucoadhesion does not tend to be strong               drug has not received the favour of clinicians and
      enough to impart to dosage forms the ability to resist        regulatory agencies because of the questionable
      the strong propulsion forces of the stomach wall. The         benefit-to-risk ratio associated with these devices.
      continuous production of mucous by the gastric
      mucosa to replace the mucous that is lost through             Evaluation of Gastroretentive Dosage
      peristaltic contractions and the dilution of the              Forms
      stomach content also seems to limit the potential of
      mucoadhesion as a gastroretentive force.                      Evaluation for gastroretention is carried out by means
                                                                    of X-ray and/or gamma scintigraphic monitoring of
      Some of the most promising excipients that have               the dosage form transit in the GI tract. The modern
      been used commonly in these systems include                   technique of gamma scintigraphy now makes it
      polycarbophil, carbopol, lectins, chitosan, CMC and           possible to follow the transit behaviour of dosage
      gliadin, etc. Some investigators have tried out a             forms in human volunteers in a non-invasive manner.
      synergistic approach between floating and bioadhesion
      systems. Other approaches reported include use of a           Conclusion
      novel adhesive material derived from the fimbriae
      (especially Type 1) of bacteria or synthetic analogues        Finally, while the control of drug release profiles has
      combined with a drug to provide for attachment to the         been a major aim of pharmaceutical research and
      gut, thereby prolonging the transit time, a composition       development in the past two decades, the control of
      comprising an active ingredient and a material that acts      GI transit profiles could be the focus of the next two
      as a viscogenic agent (for example curdlan and/or a           decades and might result in the availability of new
      low-substituted hydroxypropylcellulose), etc.                 products with new therapeutic possibilities and
                                                                    substantial benefits for patients. Soon, the so-called
      High-density Systems                                          ‘once-a-day’ formulations may be replaced by novel
                                                                    gastroretentive products with release and absorption
      Sedimentation has been employed as a retention                phases of approximately 24 hours. ■

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


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