Académique Documents
Professionnel Documents
Culture Documents
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 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.
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.
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
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.
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.
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.
Anionic polymers have been found to have better binding capacity than neutral or cationic polymers.
Carbopol General Formula Carbopol 934 P is cross-linked with allyl sucrose Polyglycerol
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
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.
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).
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.
Several types of the CR-GRDFs were prepared with different thickness and amount of levodopa compounded (CR-GRDF AC).
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.
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).
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).
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).