Title: Gastroretentive Dosage Forms
1- Gastroretentive Dosage Forms
2Gastroretentive 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).
3Gastroretentive 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.
4Gastroretentive 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
5Gastroretentive 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.
6Gastroretentive 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
7Gastroretentive 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.
8Approaches 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).
9Gastroretentive 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
10Approaches 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.
11Pharmacokinetic 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
12Absorption 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)
13Enhanced 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.
14Enhanced 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.
15Enhanced 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.
16Improved 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.
17Reduced 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
18Targeted 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.
19Pharmacodynamic 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
20Reduced 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.
21Improved 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.
22Reduced 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.
23Extended 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.
24Minimized 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.
25Rationale
- 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.
26Assessment 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.
27Assessment 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.
28Assessment 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.
29Assessment 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.
30Assessment 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.
31Assessment 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.
32Assessment 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.
33Assessment 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
34Assessment 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
35Assessment 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.
36Assessment 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.
37Formulation 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.
38Bioadhesive 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.
39Bioadhesive 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.
40Bioadhesive 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.
41Bioadhesive 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.
42Bioadhesive drug delivery systems
Carbopol General Formula
Carbopol 934 P is cross-linked with allyl sucrose
Polyglycerol
43Bioadhesive 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.
44Bioadhesive 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
45Bioadhesive 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.
46Size-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.
47Size-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.
48Size-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
49Size-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.
50(No Transcript)
51Size-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.
52Size-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.
53Size-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 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.
54Size-increasing drug delivery systems
55Size-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).
56Size-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.
57Size-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.
58Floating 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).
59Floating drug delivery systems
60High 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
61Evaluation 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.
62Evaluation 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
63Evaluation 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).
64Evaluation 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.
65Evaluation of novel CR-GRDF formulation of
levodopa in dogs
66Evaluation 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.
67Evaluation 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.
68Evaluation 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.
69Evaluation 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.
70Evaluation of novel CR-GRDF formulation of
levodopa in dogs
- Levodopa release rate showed an inverse
correlation to the ethylcelluloselevodopa
membrane thickness.
71Evaluation 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).
72Evaluation 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.
73Evaluation 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).
74Evaluation 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.
75Evaluation 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.
76Evaluation 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).
77Evaluation 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.