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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 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

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)

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
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 microorganisms 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 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.

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.

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.

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, n=56) 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 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.

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.

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.

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 kg1) as PO bolus, duodenal infusion, and gastroretentive CR tablets (CR I or CR II) to the streptozotocindiabetic rats

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 kg1) as PO bolus, duodenal infusion, and gastroretentive CR tablets (CR I or CR II) to the streptozotocin-diabetic rats

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.

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.

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). Grning et al (Grning 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/cm), 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

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.

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 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).

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 ethylcelluloselevodopa 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 2.690.3, 1.20.07 and 4.170.33 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 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.