Gastro Retentive DELIVERY SYSTEMS

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Gastroretentive Dosage Forms


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Gastroretentive Dosage Forms Oral administration is the most convenient mode of drug

delivery and is associated with superior patientcompliance as compared to other modes of drug intake.

However, oral administration has only limited use forimportant drugs, from various pharmacological

categories, that have poor oral bioavailability due toincomplete absorption and/or degradation in thegastrointestinal (GI) tract.

Some of these drugs are characterized by a narrow

absorption window (NAW) at the upper part of thegastrointestinal tract. This is because the proximal partof the small intestine exhibits extended absorptionproperties (including larger gaps between the tight

junctions, and dense active transporters).


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Gastroretentive Dosage Forms Despite the extensive absorption properties of the

duodenum and jejunum, the extent of absorption atthese sites is limited because the passage through thisregion is rapid.

Enhancing the gastric residence time (GRT) of a NAW

drug may significantly improve the net extent of itsabsorption.


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Gastroretentive Dosage Forms This issue was demonstrated in a seminal experiment by Levy

(1976) that compared the bioavailability of riboflavin when taken withCoca Cola, light cola, or water. The GRT of riboflavin attained by theglucose together with phosphoric acid in the Coca Cola wasconsiderably larger than that produced by phosphoric acid alone inthe light cola, while the GRT following intake with water was theshortest. There was a direct correlation between the prolonged GRTand 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 sincethe natural activity of the stomach is to evacuate its contents into theintestine.


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Drug Candidates for Gastric Retention

Gastroretentive DDSs exhibiting controlled drug releaseare 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 ofabsorption in the GIT, such as cyclosporin, ciprofloxacin,

furosemide, L-DOPA, p-aminobenzoic acid and riboflavin.

Unstable in the intestinal or colonic environment such as

captopril

Exhibit low solubility at high pH values such as verapamil HCl,diazepam and chlordiazepoxide


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Drug Candidates for Gastric Retention

Gastroretentive DDS, on the other hand, are not suitablefor drugs:

That may cause gastric lesions, e.g., non-steroidal anti-

inflammatory agents

Drug substances that are unstable in the strong acidicenvironment of the stomach.

In addition, gastroretentive systems do not offer significant

advantages over conventional dosage forms for drugs which are

absorbed throughout the gastrointestinal tract.


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Approaches to Gastric Retention

The most important parameters affecting gastric

emptying and, hence, the gastric retention time of oral

dosage forms include:

1. Density, size and shape of the device.

2. Concomitant ingestion of food and its nature, caloric content

and frequency of intake.

3. Simultaneous administration of drugs with impact on

gastrointestinal transit time; for example, drugs acting as

anticholinergic agents (e.g. atropine, propantheline), opiates

(e.g. codeine) and prokinetic agents (e.g. metoclopramide,cisapride).

4. Biological factors such as gender, posture, age, sleep, body

mass index, physical activity and disease states (e.g. diabetes,

Crohn's disease).


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Gastroretentive Dosage Forms The main approaches that have been examined for

gastroretentive drug delivery include: low density of the GRDF that causes buoyancy above

gastric fluid

high density which retains the dosage form (DF) inthe body of the stomach that is anatomically lower

than the pyloric sphincter concomitant administration of drugs or excipients

which slow the motility of the gastrointestinal tract

bioadhesion to gastric mucosa

swelling to a large size which prevents emptying of

the DF through the pyloric sphincter


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Approaches to Gastric Retention

Controlled release (CR) dosage forms have been

extensively used to improve therapy of many importantmedications. However, in the case of NAW drugs thispharmaceutical approach cannot be utilized since itrequires sufficient colonic absorption of the drug (whichis, by definition, not the case for NAW agents).

On the other hand, incorporation of the drug in acontrolled release gastroretentive dosage forms (CR-GRDF) can yield significant therapeutic advantages dueto a variety of pharmacokinetic (PK) andpharmacodynamic (PD) factors.


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Pharmacokinetic Aspects Absorption windowvalidation that the drug is within the

category of NAW agents Enhanced bioavailability

Enhanced first pass biotransformation

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

Reduced frequency of dosing Targeted therapy for local ailments in the upper GI tract


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Absorption windowvalidation that the drug

is within the category of NAW agents

Various experimental techniques permit us to: Verify the absorption properties of the testedmolecule

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 aremolecules that have poor colonic absorption but arecharacterized by better absorption properties at the

upper parts of the GI tract.

In the case of absorption by active transporters that arecapacity limited, the efficacy of the transport activity mayincrease following sustained presentation of the drug to

the transporting enzymes in comparison to non-CRmode of administration (fear of saturation)


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Enhanced bioavailability

Once it has been ascertained that the compound inquestion is defined as NAW, the possibility of improvingbioavailability by continuous administration of thecompound to the specific site should be tested.

For example: certain bisphosphonates, includingalendronate, are absorbed directly from the stomach.However, the magnitude of this pathway remains modesteven in the case where the prolonged gastric retention ofthe bisphosphonate in rats is produced by

experimental/surgical means.

On the other hand, the bioavailability of riboflavin andlevodopa CR-GRDF is significantly enhanced incomparison to administration of non-GRDF CR

polymeric formulations.


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Enhanced bioavailability

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


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Enhanced first pass biotransformation

In a similar fashion to increased efficacy of activetransporters exhibiting capacity limited activity, the pre-systemic metabolism of the tested compound may beconsiderably increased when the drug is presented tothe metabolic enzymes (cytochrome P450, in particular

CYP3A4) in a sustained manner, rather than by a bolusinput.


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Improved bioavailability due to reduced P-

glycoprotein (P-gp) activity in the duodenum

In apparent contrast to the higher density of CYP3A4 atthe upper part of the intestine, P-gp mRNA levelsincrease longitudinally along the intestine such that thehighest levels are located in the colon.

Therefore, for drugs that are P-gp substrate and do notundergo oxidative metabolism, such as digoxin, CR-GRDF may elevate absorption compared to theimmediate and CR dosage forms.


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Reduced frequency of dosing

For drugs with relatively short biological half-life,sustained and slow input from CR-GRDF may result in aflip-flop pharmacokinetics and enable reduced dosingfrequency.

This feature is associated with improved patientcompliance, and thereby improves therapy


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Targeted therapy for local ailments in the

upper GI tract

The prolonged and sustained administration of the drugfrom the GRDF to the stomach may be advantageous forlocal therapy in the stomach and the small intestine.

By this mode of administration, therapeutic drugconcentrations may be attained locally while thesystemic concentrations, following drug absorption anddistribution, are minimal.


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Pharmacodynamic aspects

Reduced fluctuations of drug concentration Improved selectivity in receptor activation

Reduced counter-activity of the body

Extended time over critical (effective) concentration

Minimized adverse activity at the colon


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Reduced fluctuations of drug concentration

Continuous input of the drug following CR-GRDFadministration produces blood drug concentrations withina narrower range compared to the immediate releasedosage forms.

Thus, fluctuations in drug effects are minimized andconcentration dependent adverse effects that areassociated with peak concentrations can be prevented.

This feature is of special importance for drugs with anarrow therapeutic index.


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Improved selectivity in receptor activation

Minimization of fluctuations in drug concentration alsomakes it possible to obtain certain selectivity in theelicited pharmacological effect of drugs that activatedifferent types of receptors at different concentrations.


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Reduced counter-activity of the body

In many cases, the pharmacological response whichintervenes with the natural physiologic processesprovokes a rebound activity of the body that minimizesdrug activity.

Slow input of the drug into the body was shown tominimize the counter activity leading to higher drugefficiency.


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Extended time over critical (effective)

concentration

For certain drugs that have non-concentration dependentpharmacodynamics, such as beta-lactam antibiotics, theclinical response is not associated with peakconcentration, but rather, with the duration of time over acritical therapeutic concentration.

The sustained mode of administration enables extensionof the time over a critical concentration and thusenhances the pharmacological effects and improves theclinical outcomes.


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Minimized adverse activity at the colon

Retention of the drug in the GRDF at the stomach minimizes the

amount of drug that reaches the colon.

Thus, undesirable activities of the drug in colon may be prevented.This pharmacodynamic aspect provides the rationale for GRDFformulation for beta-lactam antibiotics that are absorbed only fromthe small intestine, and whose presence in the colon leads todevelopment of microorganisms resistance.


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Rationale

In most cases, due complexity of pharmacokinetic andpharmacodynamic parameters, in vivo studies arerequired to establish the optimal dosage form for aspecific drug.

For a certain drug, interplay of its pharmacokinetic andpharmacodynamic parameters will determine theeffectiveness and benefits of the CR-GRDF compared tothe other dosage forms.


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Assessment of PKPD rationale for CR-GRDF

formulations in a rat model: metformin as a model drug

Metformin is glucose-lowering agent that is widely usedfor management of type 2 diabetes.

Metformin is absorbed mainly in the upper parts of the

gastrointestinal tract and due to the fact that metforminmolecule is ionized at physiologic pH, has tendency toadsorb to the intestinal epithelium thus affecting the drugabsorption pattern and increasing the incidence ofgastrointestinal adverse effects.

In addition to these unique pharmacokinetic properties,the pharmacodynamics of metformin is rather complexand does not follow a direct relationship between plasmadrug concentration and magnitude of effect.


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Previous studies confirmed that the colonic absorption ofmetformin is poor and produced poor and inconsistentglucose-lowering effects.

On the other hand, it was determined that most of themetformin absorption occurs in the upper parts of thegastrointestinal tract.

This fact, together with the findings that major sites of

metformin action are located in the gastrointestinal tractand the liver, provides a clear rationale for a sustainedand prolonged release of this drug from a CR-GRDF intothe stomach and duodenum, since absorption from thesesites would result in continuous input of metformin to the

sites of action.


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Two controlled release matrix based tablet formulationswith different rates of metformin release in vitro wereused: CR tablets I (matrix tablets) and CR tablets II(matrix tablets with ethylcellulose coating).

The in vitro rate of drug release was assessed accordingto method stated in the USP Pharmacopoeia.

A t f PK PD ti l f CR GRDF


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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 acrossover design.

The studied modes were CR tablets I or II at a dosagecorresponding to 450 mg/kg metformin, or the samedose of the drug administered as a bolus oral solution ora constant rate intraduodenal infusion (duration of theinfusion was 4 h).

Serial blood samples were collected from the tail arteryand assayed for glucose and metformin.



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formulations in a rat model: metformin as a model drug The gastric retention of the tablets was assessed

radiographically in a separate study applying radiopaquemarkers added to the tablet formulation.



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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 PDoutcomes following administration of different dosageforms of metformin, and determination of the possibleadvantages of GRDF for this drug.



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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 weredetermined.

No significant differences in the bioavailability and theextent of the glucose-lowering effect were foundfollowing administration of the GRDF, bolus oraladministration, or slow infusion of metformin to theduodenum.



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Plasma metformin concentrations following administration ofmetformin (450 mg kg1) as PO bolus, duodenal infusion, andgastroretentive CR tablets (CR I or CR II) to the streptozotocin-

diabetic rats



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Glucose-lowering effects following administration of metformin(450 mg kg1) as PO bolus, duodenal infusion, and gastroretentiveCR tablets (CR I or CR II) to the streptozotocin-diabetic rats

Assessment of PK PD rationale for CR GRDF


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The underlying reason for these PK and PD outcomesfor the GRDF of metformin is apparently the high affinityof 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 intestinalwall in a sustained manner, producing a drug absorption

profile similar to that of the CR formulation.

As a result, the pharmaceutical manipulations thatmodify the release rate do not seem to improve theextent of metformin absorption and the magnitude of

glucose-lowering effect.

Assessment of PK PD rationale for CR GRDF


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Thus, due to this natural sustained release property,CR-GRDF of metformin does not seem to offer PK or PDadvantages over immediate release formulations. Thiswork demonstrates the need for a combined PK and PDassessment in vivo to determine whether a certain drugis a proper candidate for GRDF.


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Formulation Technologies

The main approaches to prolonging the gastric residence

time of pharmaceutical dosage forms include:

bioadhesive delivery systems, which adhere to mucosal

surfaces;

devices that rapidly increase in size once they are in thestomach to retard the passage through the pylorus;

density-controlled delivery systems, which float on or settles in

gastric fluids.


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Bioadhesive drug delivery

systems It involves the use of bioadhesive polymers that can

adhere to the epithelial surface of the GIT.

A bioadhesive can be defined as a substance with the

ability to interact with biological materials and is capable

of being retained on the biological substrate for a period

of time.


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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.

Bi dh i d d li


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systems The proposed mechanism of bioadhesion is the

formation of hydrogenand electrostatic bonding at the

mucus-polymer boundary.

Rapid hydration in contact with the muco-epithelialsurface appears to favor adhesion.


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Bioadhesive drug delivery systems microspheres consisting of a drug and Carbopol 934P

dispersed within a waxy matrix of polyglycerol esters offatty acids were proposed as muco-adhesive deliverysystem.

These systems were found to adhere to the stomach

mucosa in rats and to prolong the drug's gastrointestinalresidence time after oral administration.


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Bioadhesive drug delivery systems

Carbopol General

FormulaCarbopol 934 P is

cross-linked with allyl

sucrose

Polyglycerol


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Bioadhesive drug delivery systems The adherence can be attributed to the hydration and

swelling of Carbopol in the microspheres upon contactwith water.

Importantly, parts of the macromolecules remain withinthe microspheres, whereas the rest is anchored within

the mucus layer.

When furosemide was administered to rats, andriboflavin to human volunteers, with the use ofmicrospheres, enhanced levels in plasma were observed

compared with the administration of furosemide orriboflavin suspensions.


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Bioadhesive drug delivery systems Extended gastric residence times of the positively

charged ion-exchange resin cholestyraminedue toadhering to and coating of the gastric mucosa.

On the other hand, the oppositely charged exchangeresin Amberlite IRP-69 did not possess the same

characteristics


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Bioadhesive drug delivery systems

The major challenge for bioadhesive drug deliverysystems is the high turnover rate of the gastric mucusand the resulting limited retention times.

Furthermore, it is difficult to target specifically the gastric

mucus with bioadhesive polymers.

Most bioadhesive polymers (Polycarbophil, Carbopoland chitosan) will stick to various other surfaces thatthey come into contact with. In addition, the possibility of

oesophageal binding might present a challengeregarding safety aspects.


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Size-increasing drug delivery systems

Another approach to retaining a pharmaceutical dosageform in the stomach is by increasing its size above thediameter 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 emptiedfrom the stomach.


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In order to facilitate swallowing, it is highly desirable todesign 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 theirclearance from the stomach after predetermined timeintervals to avoid accumulation upon multiple

administrations.

In addition, the dosage form should have no effect ongastric motility or emptying process.


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The increase in the systems size can be based onseveral principles, including: Expansion due to swellable excipients in the stomach.

The expansion of this type of DDS is generally due to the presence ofspecific hydrogel formers, which after swallowing; drastically increase in sizeupon contact with aqueous media.

unfolding and/ or shape modification (to complex geometricshapes) in the stomach.

These are non disintegrating geometric shapes moulded from silasticelastomer or extruded from polyethylene blends, which extend the gastricresidence time depending on size, shape and flexural modulus of the drugdelivery device


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Size-increasing drug delivery systems Deshpande et al. (Deshpande et al., 1997a; Deshpande et al.,

1997b) developed a controlled-release gastric retention systemcomposed of:

a swellable core, which consisted of the drug, chlorphenamine maleate orriboflavin 5 phosphate, and the expanding agents crosslinked polyvinylpyrrolidone (PVP), Carbopol 934P and calcium carbonate.

The tablet core was coated with a permeable coating, consisting of blends ofEudragit RL 30 D and NE 30 D in different ratios.

The tablets swelled to 2- 4 times their original volume, whilereleasing the drug in a controlled manner.

The optimal ratio of Eudragit RL 30 D: NE 30 D was found to be70: 30, which was optimum for sufficient elasticity to withstand thepressure of expansion during the initial swelling phase, and allowingthe breakdown of the tablet following release of the drug.


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Size-increasing drug delivery systems Enzyme-digestible hydrogels, consisting of poly(vinyl

pyrrolidone) cross-linked with albumin, were describedas gastroretentive dosage form.

These specially designed hydrogels swell to a significantextent, which is a function of the albumin content anddegree of albumin alkylation. The polymers aredegraded in the presence of pepsin either via bulk orsurface erosion.

With increasing albumin alkylation, pepsin digestion isdiminished and bulk erosion becomes predominant.


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Size-increasing drug delivery systems In dogs, the gastric residence time exceeded 24 h, even

under fasted conditions. Such an enzyme-digestibleswelling hydrogel formulation was used to deliverriboflavin to the upper small intestine of these animals.Importantly, the drug could be detected for up to 54 hafter administration in the blood, indicating gastric

retention of the hydrogel in the stomach.


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Size-increasing drug delivery systems Omidian et al. (Omidian et al., 2005; Omidian et al., 2006)

developed superporous hydrogel hybrids, which are prepared bycrosslinking a water-soluble or water-dispersible polymer to theformed superporous hydrogel.

Examples for hybrid agents are polysaccharides, such as sodiumalginate, pectin, chitosan or synthetic water-soluble hydrophilic

polymers, e.g. poly(vinyl alcohol).

Grning et al (Grning et al., 2007; Groning et al., 2006) developedgastroretentive dosage forms prepared from compressed collagensponges.

The sponges were manufactured by freeze-drying a riboflavin-containing collagen solution. The precompressed collagen wastransported into a tablet machine for tablet compression.

Following contact with aqueous fluids, the collagen spongeexpanded to a large size. Both systems released the drug in a

controlled manner.


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


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Effects of the mode of administration of 100 mg riboflavin-5-phosphate on theresulting (a)mean riboflavin plasma concentration and (b)cumulative amount ofriboflavin absorbed in dogs (n=6). DF, dosage form; GRDF, gastroretentive dosageform.


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Size-increasing drug delivery systems In general, size-increasing drug delivery systems

potentially present the hazard of permanent retention inthe stomach and could lead to life-threatening effectsupon multiple administration.

To avoid this risk, the systems should consist of

biodegradable materials or have the ability to lose theirintegrity after a desired time period. However, thesystems also need to be sufficiently resistant in order towithstand the powerful mechanical contractions withinthe stomach.

A major advantage of size-increasing systems is theindependence of their performance on the filling state ofthe stomach.


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Floating drug delivery systems Drug delivery systems that float immediately upon

contact with gastric fluids present promising approachesfor increasing the bioavailability of drugs with absorptionwindows 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 decreaseswith time) first settle down in the stomach and, thus,undergo the risk of premature emptying.

Inherent low density can, for example, be provided bythe 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).


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Floating drug delivery systems


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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 thegastric juice (~1.004 g/cm), the device settles down tothe bottom of the stomach, and remains located below

the pylorus.

This could be accomplished by including a heavy inertmaterial such as zinc oxide, titanium dioxide, ironpowder 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


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Evaluation of novel CR-GRDF formulation of

levodopa in dogs

Levodopa, a NAW drug that is absorbed solely via aspecific transporter in the small intestine, is used for thetreatment of Parkinsons disease.

Sustained levodopa blood concentrations followingcontinuous levodopa administration or administration ofCR dosage forms provide a clear clinical advantagecompared to conventional oral dosage forms in terms ofimproved pharmacological efficacy and reduced

wearing off effect at the end of dose interval.



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levodopa in dogs

Based on the pharmacokinetic and pharmacodynamicproperties of levodopa it is expected that a CR-GRDFwould optimize the therapy for this drug.

After oral administration, such a CR-GRDF would beretained in the stomach and would release the drugthere in a controlled and sustained manner, providingcontinuous supply of the drug to its absorption sites inthe small intestine, and yielding a sustained and

prolonged levodopa input to the systemic bloodcirculation



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levodopa in dogs

The CR-GRDFs were comprised of an inner layercomposed of a polymerdrug matrix framed with rigidpolymeric strips covered on both sides by two outer(shielding) layers.

The CR-GRDFs were folded before insertion into gelatincapsules (000). The dimensions, prior to folding, of theCR-GRDF (and of the shielding layers) were5 cm2.5cm.

Several types of the CR-GRDFs were prepared withdifferent thickness and amount of levodopa compounded(CR-GRDF AC).



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levodopa in dogs

Novel unfolding CR-GRDFs of levodopa that werecharacterized by extended geometrical dimensions with

enhanced rigidity were developed.



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levodopa in dogs



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levodopa in dogs

The in vitro release rate of levodopa from the DFs intosimulated gastric fluid was conducted according to the

method described in the USP Pharmacopoeia.



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levodopa in dogs

The absorption of levodopa following intragastricadministration of the GRDFs was studied in Beagle dogsin a crossover design in comparison to the CR dosageform and drug solution.

Serial blood samples were collected, plasma wasobtained and assayed for levodopa.

The anatomical location of the CR-GRDFs in thegastrointestinal tract was accomplished radiographically

by incorporating the radiopaque threads in the dosageform.

The unfolding of the GRDFs was studied applyinggastroscopic equipment.



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levodopa in dogs

The results of the in vitro drug release test showed thatthe CR-GRDFs released levodopa in a controlledmanner. Levodopa release rate showed an inversecorrelation to the ethylcellulose membrane thickness,and different types of the GRDFs were characterized by

different release rates.



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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 ornon-gastroretentive CR-particles.



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levodopa in dogs

Levodopa release rate showed an inversecorrelation tothe ethylcelluloselevodopa membranethickness.



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levodopa in dogs

Effect of the mode of levodopa administration on the plasmaconcentrations in beagle dogs (n=6, mean+S.E.M.): (a) differenttypes of controlled release (CR) gastroretentive dosage forms(GRDFs); (b) CR-GRDF C in comparison to the two control modesof administration (oral solution and CR-particles).



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levodopa in dogs

As can be seen, while CR-GRDF A produced too low aconcentration and CR-GRDF B had a short absorptionphase, CR-GRDF C produced elevated levodopaconcentrations (>500 ng ml) for more than 9 h after drugadministration.

This outcome is considerably different from the short-lasting elevation of levodopa concentrations produced bythe non-gastroretentive oral modes of administration.



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levodopa in dogs

Effect of the mode of levodopa administration on the meancumulative amount of drug absorbed over time in beagle dogs (n=6):(a) different types of controlled release (CR) gastroretentive dosageforms (GRDFs); (b) CR-GRDF C in comparison to the two control

modes of administration (oral solution and CR-particles).



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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-particlesadministration, the absorption process lasted for about 2

and 3 h, respectively.

The apparent rates of absorption for CR-particles andCR-GRDF C during the first few hours were slower thanthe absorption rate obtained following administration of

the drug as an oral solution.



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levodopa in dogs

MDTs following administration of CR-GRDF A, CR-GRDF B and CR-GRDF C were 2.690.3, 1.20.07 and4.170.33 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 theCR-GRDF types.



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levodopa in dogs

In-vitro in-vivo correlation presented as mean percent levodopaabsorbed versus mean percent levodopa released of variouscontrolled release (CR) gastroretentive dosage forms (GRDFs).



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levodopa in dogs

Results of this investigation confirm that a combination ofextended physical dimensions with compounding rigidconstituents enhances the gastroretentivity of DFs invivo.

Multilayer polymeric GRDFs with size=5 cm2.1cm thatwere characterized by high rigidity retained in the humanstomach for more than 5 h.

On the other hand, the formulation with extended

dimensions but lacking high rigidity did not retain in thestomach like the equivalent size GRDFs.

Gastro Retentive DELIVERY SYSTEMS

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