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Gastroretentive Dosage Forms
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).
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.
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
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.
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
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 antiinflammatory 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.
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).
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
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 (CRGRDF) can yield significant therapeutic advantages due
to a variety of pharmacokinetic (PK) and
pharmacodynamic (PD) factors.
Pharmacokinetic Aspects
• Absorption window—validation 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
Absorption window—validation 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)
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.
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.
Enhanced first pass biotransformation
• In a similar fashion to increased efficacy of active
transporters exhibiting capacity limited activity, the presystemic 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.
Improved bioavailability due to reduced Pglycoprotein (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, CRGRDF may elevate absorption compared to the
immediate and CR dosage forms.
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
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.
Pharmacodynamic aspects
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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
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.
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.
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.
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.
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 microorganism’s resistance.
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.
Assessment of PK–PD 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.
Assessment of PK–PD 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.
Assessment of PK–PD 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.
Assessment of PK–PD 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, 200–250 g, n=5–6)
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.
Assessment of PK–PD 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.
Assessment of PK–PD 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.
Assessment of PK–PD 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.
Assessment of PK–PD 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 streptozotocindiabetic rats
Assessment of PK–PD 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
Assessment of PK–PD 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.
Assessment of PK–PD 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.
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.
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.
Bioadhesive drug delivery
systems
• Bioadhesive polymers are usually macromolecular,
hydrophilic gelling substances with numerous hydrogenbond 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.
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.
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.
Bioadhesive drug delivery systems
Carbopol General
Formula
Carbopol 934 P is
cross-linked with allyl
sucrose
Polyglycerol
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.
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
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.
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.
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.
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
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.
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.
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.
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 riboflavincontaining collagen solution. 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.
Size-increasing drug delivery systems
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).
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 (n=6). DF, dosage form; GRDF, gastroretentive dosage
form.
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.
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).
Floating drug delivery systems
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 1.5–2.4 g/cm3
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 Parkinson’s 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.
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
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
• The CR-GRDFs were comprised of an inner layer
composed of a polymer–drug 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 cm×2.5 cm.
• Several types of the CR-GRDFs were prepared with
different thickness and amount of levodopa compounded
(CR-GRDF A–C).
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.
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
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.
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.
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.
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.
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
• Levodopa release rate showed an inverse correlation to
the ethylcellulose–levodopa membrane thickness.
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
• Effect of the mode of levodopa administration on the plasma
concentrations in beagle dogs (n=6, mean+S.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).
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 (>500 ng ml) for more than 9 h after drug
administration.
• This outcome is considerably different from the shortlasting elevation of levodopa concentrations produced by
the non-gastroretentive oral modes of administration.
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 (n=6):
(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).
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
• As seen, the absorption from CR-GRDF A and CRGRDF 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.
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
• MDTs following administration of CR-GRDF A, CRGRDF B and CR-GRDF C were 2.69±0.3, 1.2±0.07 and
4.17±0.33 h, respectively.
• A correlation between the percent levodopa released (invitro) and the percent levodopa absorbed can be made.
• It can be seen that this relationship is similar for all the
CR-GRDF types.
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).
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 size=5 cm×2.1 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.