Gastroretentive Dosage Forms

1

• Gastroretentive Dosage Forms

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Gastroretentive Dosage Forms

• Oral administration is the most convenient mode
  of drug delivery and is associated with superior
  patient compliance as compared to other modes of
  drug intake.
• However, oral administration has only limited use
  for important drugs, from various pharmacological
  categories, that have poor oral bioavailability
  due to incomplete absorption and/or degradation
  in the gastrointestinal (GI) tract.
• Some of these drugs are characterized by a narrow
  absorption window (NAW) at the upper part of the
  gastrointestinal tract. This is because the
  proximal part of the small intestine exhibits
  extended absorption properties (including larger
  gaps between the tight junctions, and dense
  active transporters).

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Gastroretentive Dosage Forms

• Despite the extensive absorption properties of
  the duodenum and jejunum, the extent of
  absorption at these sites is limited because the
  passage through this region is rapid.
• Enhancing the gastric residence time (GRT) of a
  NAW drug may significantly improve the net extent
  of its absorption.

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Gastroretentive Dosage Forms

• Extended release DDS possessing gastric retention
  properties may be potentially useful as the
  retention of oral dosage forms in the upper GIT
  causes prolonged contact time of drug with the GI
  mucosa, leading to
• Higher bioavailability, and hence therapeutic
  efficacy
• Reduced time intervals for drug administration
• Potentially reduced dose size and thus improved
  patient compliance

5
Gastroretentive Dosage Forms

• This issue was demonstrated in a seminal
  experiment by Levy (1976) that compared the
  bioavailability of riboflavin when taken with
  Coca Cola, light cola, or water. The GRT of
  riboflavin attained by the glucose together with
  phosphoric acid in the Coca Cola was considerably
  larger than that produced by phosphoric acid
  alone in the light cola, while the GRT following
  intake with water was the shortest. There was a
  direct correlation between the prolonged GRT and
  enhanced bioavailability.
• To further increase the GRT of drugs, a
  gastroretentive dosage form (GRDF) can be
  developed.
• It is quite complex to achieve extensive
  retention of the GRDF since the natural activity
  of the stomach is to evacuate its contents into
  the intestine.

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Gastroretentive Dosage Forms

• Drug Candidates for Gastric Retention
• Gastroretentive DDSs exhibiting controlled drug
  release are significantly important for drugs
  which are
• Acting locally in the stomach (e.g. antibiotics
  against Helicobacter Pylori, antacids and
  misoprostol)
• Absorbed incompletely due to a relatively narrow
  window of absorption in the GIT, such as
  cyclosporin, ciprofloxacin, furosemide, L-DOPA,
  p-aminobenzoic acid and riboflavin.
• Unstable in the intestinal or colonic environment
  such as captopril
• Exhibit low solubility at high pH values such as
  verapamil HCl, diazepam and chlordiazepoxide

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Gastroretentive Dosage Forms

• Drug Candidates for Gastric Retention
• Gastroretentive DDS, on the other hand, are not
  suitable for drugs
• That may cause gastric lesions, e.g.,
  non-steroidal anti-inflammatory agents
• Drug substances that are unstable in the strong
  acidic environment of the stomach.
• In addition, gastroretentive systems do not offer
  significant advantages over conventional dosage
  forms for drugs which are absorbed throughout the
  gastrointestinal tract.

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Approaches to Gastric Retention

• The most important parameters affecting gastric
  emptying and, hence, the gastric retention time
  of oral dosage forms include
• 1. Density, size and shape of the device.
• 2. Concomitant ingestion of food and its nature,
  caloric content and frequency of intake.
• 3. Simultaneous administration of drugs with
  impact on gastrointestinal transit time for
  example, drugs acting as anticholinergic agents
  (e.g. atropine, propantheline), opiates (e.g.
  codeine) and prokinetic agents (e.g.
  metoclopramide, cisapride).
• 4. Biological factors such as gender, posture,
  age, sleep, body mass index, physical activity
  and disease states (e.g. diabetes, Crohn's
  disease).

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Gastroretentive Dosage Forms

• The main approaches that have been examined for
  gastroretentive drug delivery include
• low density of the GRDF that causes buoyancy
  above gastric fluid
• high density which retains the dosage form (DF)
  in the body of the stomach that is anatomically
  lower than the pyloric sphincter
• concomitant administration of drugs or excipients
  which slow the motility of the gastrointestinal
  tract
• bioadhesion to gastric mucosa
• swelling to a large size which prevents emptying
  of the DF through the pyloric sphincter

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Approaches to Gastric Retention

• Controlled release (CR) dosage forms have been
  extensively used to improve therapy of many
  important medications. However, in the case of
  NAW drugs this pharmaceutical approach cannot be
  utilized since it requires sufficient colonic
  absorption of the drug (which is, by definition,
  not the case for NAW agents).
• On the other hand, incorporation of the drug in a
  controlled release gastroretentive dosage forms
  (CR-GRDF) can yield significant therapeutic
  advantages due to a variety of pharmacokinetic
  (PK) and pharmacodynamic (PD) factors.

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Pharmacokinetic Aspects

• Absorption windowvalidation that the drug is
  within the category of NAW agents
• Enhanced bioavailability
• Enhanced first pass biotransformation
• Improved bioavailability due to reduced
  P-glycoprotein (P-gp) activity in the duodenum
• Reduced frequency of dosing
• Targeted therapy for local ailments in the upper
  GI tract

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Absorption windowvalidation that the drug is
within the category of NAW agents

• Various experimental techniques permit us to
• Verify the absorption properties of the tested
  molecule
• To determine the mechanism of intestinal
  absorption
• To elucidate the permeability at different
  regions of the GI tract.
• In general, appropriate candidates for CR-GRDF
  are molecules that have poor colonic absorption
  but are characterized by better absorption
  properties at the upper parts of the GI tract.
• In the case of absorption by active transporters
  that are capacity limited, the efficacy of the
  transport activity may increase following
  sustained presentation of the drug to the
  transporting enzymes in comparison to non-CR mode
  of administration (fear of saturation)

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Enhanced bioavailability

• Once it has been ascertained that the compound in
  question is defined as NAW, the possibility of
  improving bioavailability by continuous
  administration of the compound to the specific
  site should be tested.
• For example certain bisphosphonates, including
  alendronate, are absorbed directly from the
  stomach. However, the magnitude of this pathway
  remains modest even in the case where the
  prolonged gastric retention of the bisphosphonate
  in rats is produced by experimental/surgical
  means.
• On the other hand, the bioavailability of
  riboflavin and levodopa CR-GRDF is significantly
  enhanced in comparison to administration of
  non-GRDF CR polymeric formulations.

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Enhanced bioavailability

• It may be concluded that several different
  processes, related to absorption and transit of
  the drug in the gastrointestinal tract, act
  concomitantly and influence the magnitude of drug
  absorption.

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Enhanced first pass biotransformation

• In a similar fashion to increased efficacy of
  active transporters exhibiting capacity limited
  activity, the pre-systemic metabolism of the
  tested compound may be considerably increased
  when the drug is presented to the metabolic
  enzymes (cytochrome P450, in particular CYP3A4)
  in a sustained manner, rather than by a bolus
  input.

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Improved bioavailability due to reduced
P-glycoprotein (P-gp) activity in the duodenum

• In apparent contrast to the higher density of
  CYP3A4 at the upper part of the intestine, P-gp
  mRNA levels increase longitudinally along the
  intestine such that the highest levels are
  located in the colon.
• Therefore, for drugs that are P-gp substrate and
  do not undergo oxidative metabolism, such as
  digoxin, CR-GRDF may elevate absorption compared
  to the immediate and CR dosage forms.

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Reduced frequency of dosing

• For drugs with relatively short biological
  half-life, sustained and slow input from CR-GRDF
  may result in a flip-flop pharmacokinetics and
  enable reduced dosing frequency.
• This feature is associated with improved patient
  compliance, and thereby improves therapy

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Targeted therapy for local ailments in the upper
GI tract

• The prolonged and sustained administration of the
  drug from the GRDF to the stomach may be
  advantageous for local therapy in the stomach and
  the small intestine.
• By this mode of administration, therapeutic drug
  concentrations may be attained locally while the
  systemic concentrations, following drug
  absorption and distribution, are minimal.

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Pharmacodynamic aspects

• Reduced fluctuations of drug concentration
• Improved selectivity in receptor activation
• Reduced counter-activity of the body
• Extended time over critical (effective)
  concentration
• Minimized adverse activity at the colon

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Reduced fluctuations of drug concentration

• Continuous input of the drug following CR-GRDF
  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.

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Improved selectivity in receptor activation

• Minimization of fluctuations in drug
  concentration also makes it possible to obtain
  certain selectivity in the elicited
  pharmacological effect of drugs that activate
  different types of receptors at different
  concentrations.

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Reduced counter-activity of the body

• In many cases, the pharmacological response which
  intervenes with the natural physiologic processes
  provokes a rebound activity of the body that
  minimizes drug activity.
• Slow input of the drug into the body was shown to
  minimize the counter activity leading to higher
  drug efficiency.

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Extended time over critical (effective)
concentration

• For certain drugs that have non-concentration
  dependent pharmacodynamics, such as beta-lactam
  antibiotics, the clinical response is not
  associated with peak concentration, but rather,
  with the duration of time over a critical
  therapeutic concentration.
• The sustained mode of administration enables
  extension of the time over a critical
  concentration and thus enhances the
  pharmacological effects and improves the clinical
  outcomes.

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Minimized adverse activity at the colon

• Retention of the drug in the GRDF at the stomach
  minimizes the amount of drug that reaches the
  colon.
• Thus, undesirable activities of the drug in colon
  may be prevented. This pharmacodynamic aspect
  provides the rationale for GRDF formulation for
  beta-lactam antibiotics that are absorbed only
  from the small intestine, and whose presence in
  the colon leads to development of microorganisms
  resistance.

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Rationale

• In most cases, due complexity of pharmacokinetic
  and pharmacodynamic parameters, in vivo studies
  are required to establish the optimal dosage form
  for a specific drug.
• For a certain drug, interplay of its
  pharmacokinetic and pharmacodynamic parameters
  will determine the effectiveness and benefits of
  the CR-GRDF compared to the other dosage forms.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Metformin is glucose-lowering agent that is
  widely used for management of type 2 diabetes.
• Metformin is absorbed mainly in the upper parts
  of the gastrointestinal tract and due to the fact
  that metformin molecule is ionized at physiologic
  pH, has tendency to adsorb to the intestinal
  epithelium thus affecting the drug absorption
  pattern and increasing the incidence of
  gastrointestinal adverse effects.
• In addition to these unique pharmacokinetic
  properties, the pharmacodynamics of metformin is
  rather complex and does not follow a direct
  relationship between plasma drug concentration
  and magnitude of effect.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Previous studies confirmed that the colonic
  absorption of metformin is poor and produced poor
  and inconsistent glucose-lowering effects.
• On the other hand, it was determined that most of
  the metformin absorption occurs in the upper
  parts of the gastrointestinal tract.
• This fact, together with the findings that major
  sites of metformin action are located in the
  gastrointestinal tract and the liver, provides a
  clear rationale for a sustained and prolonged
  release of this drug from a CR-GRDF into the
  stomach and duodenum, since absorption from these
  sites would result in continuous input of
  metformin to the sites of action.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Two controlled release matrix based tablet
  formulations with different rates of metformin
  release in vitro were used CR tablets I (matrix
  tablets) and CR tablets II (matrix tablets with
  ethylcellulose coating).
• The in vitro rate of drug release was assessed
  according to method stated in the USP
  Pharmacopoeia.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• To enable simultaneous PK and PD assessment in
  vivo, streptozotocin-diabetic rats (male,
  200250 g, n56) received different modes of
  metformin administration in a crossover design.
• The studied modes were CR tablets I or II at a
  dosage corresponding to 450 mg/kg metformin, or
  the same dose of the drug administered as a bolus
  oral solution or a constant rate intraduodenal
  infusion (duration of the infusion was 4 h).
• Serial blood samples were collected from the tail
  artery and assayed for glucose and metformin.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• The gastric retention of the tablets was assessed
  radiographically in a separate study applying
  radiopaque markers added to the tablet
  formulation.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• The preclinical model of the diabetic rat used in
  this work enabled simultaneous assessment of the
  PK and PD outcomes following administration of
  different dosage forms of metformin, and
  determination of the possible advantages of GRDF
  for this drug.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• The metformin blood concentrations versus time
  (PK data) and the glucose lowering effects (PD
  data) obtained for various modes of drug
  administration were determined.
• No significant differences in the bioavailability
  and the extent of the glucose-lowering effect
  were found following administration of the GRDF,
  bolus oral administration, or slow infusion of
  metformin to the duodenum.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Plasma metformin concentrations following
  administration of metformin (450 mg kg-1) as PO
  bolus, duodenal infusion, and gastroretentive CR
  tablets (CR I or CR II) to the streptozotocin-diab
  etic rats

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Glucose-lowering effects following administration
  of metformin (450 mg kg-1) as PO bolus, duodenal
  infusion, and gastroretentive CR tablets (CR I or
  CR II) to the streptozotocin-diabetic rats

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• The underlying reason for these PK and PD
  outcomes for the GRDF of metformin is apparently
  the high affinity of the drug to the negatively
  charged intestinal wall.
• Due to the basic properties of the biguanide
  molecule (positive charge), it adsorbs to the
  intestinal wall, producing a natural sustained
  release system.
• The adsorbed metformin is released from the
  intestinal wall in a sustained manner, producing
  a drug absorption profile similar to that of the
  CR formulation.
• As a result, the pharmaceutical manipulations
  that modify the release rate do not seem to
  improve the extent of metformin absorption and
  the magnitude of glucose-lowering effect.

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Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug

• Thus, due to this natural sustained release
  property, CR-GRDF of metformin does not seem to
  offer PK or PD advantages over immediate release
  formulations. This work demonstrates the need for
  a combined PK and PD assessment in vivo to
  determine whether a certain drug is a proper
  candidate for GRDF.

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Formulation Technologies

• The main approaches to prolonging the gastric
  residence time of pharmaceutical dosage forms
  include
• bioadhesive delivery systems, which adhere to
  mucosal surfaces
• devices that rapidly increase in size once they
  are in the stomach to retard the passage through
  the pylorus
• density-controlled delivery systems, which float
  on or settles in gastric fluids.

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Bioadhesive drug delivery systems

• It involves the use of bioadhesive polymers that
  can adhere to the epithelial surface of the GIT.
• A bioadhesive can be defined as a substance with
  the ability to interact with biological materials
  and is capable of being retained on the
  biological substrate for a period of time.

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Bioadhesive drug delivery systems

• Bioadhesive polymers are usually macromolecular,
  hydrophilic gelling substances with numerous
  hydrogen-bond forming groups (carboxyl, hydroxyl,
  amide and sulfate groups)
• crosslinked polyacrylic acids, sodium
  carboxymethyl cellulose (CMC), sodium alginate
  and carrageenan.
• Anionic polymers have been found to have better
  binding capacity than neutral or cationic
  polymers.

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Bioadhesive drug delivery systems

• The proposed mechanism of bioadhesion is the
  formation of hydrogen and electrostatic bonding
  at the mucus-polymer boundary.
• Rapid hydration in contact with the
  muco-epithelial surface appears to favor adhesion.

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Bioadhesive drug delivery systems

• microspheres consisting of a drug and Carbopol
  934P dispersed within a waxy matrix of
  polyglycerol esters of fatty acids were proposed
  as muco-adhesive delivery system.
• These systems were found to adhere to the stomach
  mucosa in rats and to prolong the drug's
  gastrointestinal residence time after oral
  administration.

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Bioadhesive drug delivery systems
Carbopol General Formula
Carbopol 934 P is cross-linked with allyl sucrose
Polyglycerol
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Bioadhesive drug delivery systems

• The adherence can be attributed to the hydration
  and swelling of Carbopol in the microspheres upon
  contact with water.
• Importantly, parts of the macromolecules remain
  within the microspheres, whereas the rest is
  anchored within the mucus layer.
• When furosemide was administered to rats, and
  riboflavin to human volunteers, with the use of
  microspheres, enhanced levels in plasma were
  observed compared with the administration of
  furosemide or riboflavin suspensions.

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Bioadhesive drug delivery systems

• Extended gastric residence times of the
  positively charged ion-exchange resin
  cholestyraminedue to adhering to and coating of
  the gastric mucosa.
• On the other hand, the oppositely charged
  exchange resin Amberlite IRP-69 did not possess
  the same characteristics

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Bioadhesive drug delivery systems

• The major challenge for bioadhesive drug delivery
  systems is the high turnover rate of the gastric
  mucus and the resulting limited retention times.
• Furthermore, it is difficult to target
  specifically the gastric mucus with bioadhesive
  polymers.
• Most bioadhesive polymers (Polycarbophil,
  Carbopol and chitosan) will stick to various
  other surfaces that they come into contact with.
  In addition, the possibility of oesophageal
  binding might present a challenge regarding
  safety aspects.

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Size-increasing drug delivery systems

• Another approach to retaining a pharmaceutical
  dosage form in the stomach is by increasing its
  size above the diameter of the pylorus .
• However, owing to significant inter-individual
  variations, the cut-off size cannot be determined
  exactly.
• Roughly, the dosage forms should be larger than
  13 mm, but even bigger units have been found to
  be emptied from the stomach.

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Size-increasing drug delivery systems

• In order to facilitate swallowing, it is highly
  desirable to design dosage forms with an
  initially small size that once in the stomach
  significantly increase in size.
• The expanded state should be achieved rapidly in
  order to prevent premature emptying through the
  pylorus.
• Conversely, the systems should also guarantee
  their clearance from the stomach after
  predetermined time intervals to avoid
  accumulation upon multiple administrations.
• In addition, the dosage form should have no
  effect on gastric motility or emptying process.

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Size-increasing drug delivery systems

• The increase in the systems size can be based on
  several principles, including
• Expansion due to swellable excipients in the
  stomach.
• The expansion of this type of DDS is generally
  due to the presence of specific hydrogel formers,
  which after swallowing drastically increase in
  size upon contact with aqueous media.
• unfolding and/ or shape modification (to complex
  geometric shapes) in the stomach.
• These are non disintegrating geometric shapes
  moulded from silastic elastomer or extruded from
  polyethylene blends, which extend the gastric
  residence time depending on size, shape and
  flexural modulus of the drug delivery device

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Size-increasing drug delivery systems

• Deshpande et al. (Deshpande et al., 1997a
  Deshpande et al., 1997b) developed a
  controlled-release gastric retention system
  composed of
• a swellable core, which consisted of the drug,
  chlorphenamine maleate or riboflavin 5'
  phosphate, and the expanding agents crosslinked
  polyvinyl pyrrolidone (PVP), Carbopol 934P and
  calcium carbonate.
• The tablet core was coated with a permeable
  coating, consisting of blends of Eudragit RL 30
  D and NE 30 D in different ratios.
• The tablets swelled to 2- 4 times their original
  volume, while releasing the drug in a controlled
  manner.
• The optimal ratio of Eudragit RL 30 D NE 30 D
  was found to be 70 30, which was optimum for
  sufficient elasticity to withstand the pressure
  of expansion during the initial swelling phase,
  and allowing the breakdown of the tablet
  following release of the drug.

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51
Size-increasing drug delivery systems

• Enzyme-digestible hydrogels, consisting of
  poly(vinyl pyrrolidone) cross-linked with
  albumin, were described as gastroretentive dosage
  form.
• These specially designed hydrogels swell to a
  significant extent, which is a function of the
  albumin content and degree of albumin alkylation.
  The polymers are degraded in the presence of
  pepsin either via bulk or surface erosion.
• With increasing albumin alkylation, pepsin
  digestion is diminished and bulk erosion becomes
  predominant.

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Size-increasing drug delivery systems

• In dogs, the gastric residence time exceeded
  24 h, even under fasted conditions. Such an
  enzyme-digestible swelling hydrogel formulation
  was used to deliver riboflavin to the upper small
  intestine of these animals. Importantly, the drug
  could be detected for up to 54 h after
  administration in the blood, indicating gastric
  retention of the hydrogel in the stomach.

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Size-increasing drug delivery systems

• Omidian et al. (Omidian et al., 2005 Omidian et
  al., 2006) developed superporous hydrogel
  hybrids, which are prepared by crosslinking a
  water-soluble or water-dispersible polymer to the
  formed superporous hydrogel.
• Examples for hybrid agents are polysaccharides,
  such as sodium alginate, pectin, chitosan or
  synthetic water-soluble hydrophilic polymers,
  e.g. poly(vinyl alcohol).
• Gröning et al (Gröning et al., 2007 Groning et
  al., 2006) developed gastroretentive dosage forms
  prepared from compressed collagen sponges.
• The sponges were manufactured by freeze-drying a
  riboflavin-containing collagen dispersion. The
  precompressed collagen was transported into a
  tablet machine for tablet compression.
• Following contact with aqueous fluids, the
  collagen sponge expanded to a large size. Both
  systems released the drug in a controlled manner.

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Size-increasing drug delivery systems
55
Size-increasing drug delivery systems

• Schematic presentation of the gastroretentive
  drug delivery system multilayer polymeric films
  consisting of (a)shielding (outer) layers (b)
  rigid (frame) strips (c) polymer-drug matrix
  and (d) anti-adhering layers (microcrystalline
  cellulose).

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Size-increasing drug delivery systems

• Effects of the mode of administration of 100 mg
  riboflavin-5-phosphate on the resulting (a) mean
  riboflavin plasma concentration and (b)
  cumulative amount of riboflavin absorbed in dogs
  (n6). DF, dosage form GRDF, gastroretentive
  dosage form.

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Size-increasing drug delivery systems

• In general, size-increasing drug delivery systems
  potentially present the hazard of permanent
  retention in the stomach and could lead to
  life-threatening effects upon multiple
  administration.
• To avoid this risk, the systems should consist of
  biodegradable materials or have the ability to
  lose their integrity after a desired time
  period. However, the systems also need to be
  sufficiently resistant in order to withstand the
  powerful mechanical contractions within the
  stomach.
• A major advantage of size-increasing systems is
  the independence of their performance on the
  filling state of the stomach.

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Floating drug delivery systems

• Drug delivery systems that float immediately upon
  contact with gastric fluids present promising
  approaches for increasing the bioavailability of
  drugs with absorption windows in the upper small
  intestine.
• However, immediate floating can only be achieved
  if the density of the device is low at the very
  beginning.
• Devices with an initially high density (which
  decreases with time) first settle down in the
  stomach and, thus, undergo the risk of premature
  emptying.
• Inherent low density can, for example, be
  provided by the entrapment of air (e.g. hollow
  chambers) or by the (additional) incorporation of
  low-density materials (e.g. fatty substances or
  oils, or foam powder).

59
Floating drug delivery systems
60
High density drug delivery systems

• These devices use their weight as a retention
  mechanism.
• When the density of the system is larger than
  that of the gastric juice (1.004 g/cm³), the
  device settles down to the bottom of the stomach,
  and remains located below the pylorus.
• This could be accomplished by including a heavy
  inert material such as zinc oxide, titanium
  dioxide, iron powder or barium sulphate into the
  drug containing core pellets or coating drug
  containing pellets with it.
• These materials increase density by up to 1.52.4
  g/cm3

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Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Levodopa, a NAW drug that is absorbed solely via
  a specific transporter in the small intestine, is
  used for the treatment of Parkinsons disease.
• Sustained levodopa blood concentrations following
  continuous levodopa administration or
  administration of CR dosage forms provide a clear
  clinical advantage compared to conventional oral
  dosage forms in terms of improved pharmacological
  efficacy and reduced wearing off effect at the
  end of dose interval.

62
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Based on the pharmacokinetic and pharmacodynamic
  properties of levodopa it is expected that a
  CR-GRDF would optimize the therapy for this drug.
  
• After oral administration, such a CR-GRDF would
  be retained in the stomach and would release the
  drug there in a controlled and sustained manner,
  providing continuous supply of the drug to its
  absorption sites in the small intestine, and
  yielding a sustained and prolonged levodopa input
  to the systemic blood circulation

63
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• The CR-GRDFs were comprised of an inner layer
  composed of a polymerdrug matrix framed with
  rigid polymeric strips covered on both sides by
  two outer (shielding) layers.
• The CR-GRDFs were folded before insertion into
  gelatin capsules (000). The dimensions, prior to
  folding, of the CR-GRDF (and of the shielding
  layers) were 5 cm2.5 cm.
• Several types of the CR-GRDFs were prepared with
  different thickness and amount of levodopa
  compounded (CR-GRDF AC).

64
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Novel unfolding CR-GRDFs of levodopa that were
  characterized by extended geometrical dimensions
  with enhanced rigidity were developed.

65
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
66
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• The in vitro release rate of levodopa from the
  DFs into simulated gastric fluid was conducted
  according to the method described in the USP
  Pharmacopoeia.

67
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• The absorption of levodopa following intragastric
  administration of the GRDFs was studied in Beagle
  dogs in a crossover design in comparison to the
  CR dosage form and drug solution.
• Serial blood samples were collected, plasma was
  obtained and assayed for levodopa.
• The anatomical location of the CR-GRDFs in the
  gastrointestinal tract was accomplished
  radiographically by incorporating the radiopaque
  threads in the dosage form.
• The unfolding of the GRDFs was studied applying
  gastroscopic equipment.

68
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• The results of the in vitro drug release test
  showed that the CR-GRDFs released levodopa in a
  controlled manner. Levodopa release rate showed
  an inverse correlation to the ethylcellulose
  membrane thickness, and different types of the
  GRDFs were characterized by different release
  rates.

69
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• The in-vitro release kinetics of levodopa into
  acidic buffer (pH 1.2) from controlled release
  (CR) gastroretentive dosage forms (GRDFs) with
  different thicknesses of the drug-loaded
  polymeric matrix or non-gastroretentive
  CR-particles.

70
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Levodopa release rate showed an inverse
  correlation to the ethylcelluloselevodopa
  membrane thickness.

71
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Effect of the mode of levodopa administration on
  the plasma concentrations in beagle dogs (n6,
  meanS.E.M.) (a) different types of controlled
  release (CR) gastroretentive dosage forms
  (GRDFs) (b) CR-GRDF C in comparison to the two
  control modes of administration (oral solution
  and CR-particles).

72
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• As can be seen, while CR-GRDF A produced too low
  a concentration and CR-GRDF B had a short
  absorption phase, CR-GRDF C produced elevated
  levodopa concentrations (gt500 ng ml) for more
  than 9 h after drug administration.
• This outcome is considerably different from the
  short-lasting elevation of levodopa
  concentrations produced by the non-gastroretentive
  oral modes of administration.

73
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Effect of the mode of levodopa administration on
  the mean cumulative amount of drug absorbed over
  time in beagle dogs (n6) (a) different types of
  controlled release (CR) gastroretentive dosage
  forms (GRDFs) (b) CR-GRDF C in comparison to the
  two control modes of administration (oral
  solution and CR-particles).

74
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• As seen, the absorption from CR-GRDF A and
  CR-GRDF B terminated in less than 6 h.
• In the cases of oral solution and CR-particles
  administration, the absorption process lasted for
  about 2 and 3 h, respectively.
• The apparent rates of absorption for CR-particles
  and CR-GRDF C during the first few hours were
  slower than the absorption rate obtained
  following administration of the drug as an oral
  solution.

75
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• MDTs following administration of CR-GRDF A,
  CR-GRDF B and CR-GRDF C were 2.690.3, 1.20.07
  and 4.170.33 h, respectively.
• A correlation between the percent levodopa
  released (in-vitro) and the percent levodopa
  absorbed can be made.
• It can be seen that this relationship is similar
  for all the CR-GRDF types.

76
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• In-vitro in-vivo correlation presented as mean
  percent levodopa absorbed versus mean percent
  levodopa released of various controlled release
  (CR) gastroretentive dosage forms (GRDFs).

77
Evaluation of novel CR-GRDF formulation of
levodopa in dogs

• Results of this investigation confirm that a
  combination of extended physical dimensions with
  compounding rigid constituents enhances the
  gastroretentivity of DFs in vivo.
• Multilayer polymeric GRDFs with size5 cm2.1 cm
  that were characterized by high rigidity retained
  in the human stomach for more than 5 h.
• On the other hand, the formulation with extended
  dimensions but lacking high rigidity did not
  retain in the stomach like the equivalent size
  GRDFs.