Case Study 1:

Case Study 1: Evaluation of Polyethylene Oxide Compacts as Gastroretentive Delivery Systems*

Background:

Objective: • Evaluate dissolution, swelling, in vitro and in vivo gastric retention properties of PVPPolyox compacts and their potential for delivering water soluble and insoluble compounds.

Experimental Methods: Preparation of compacts: • PVP K-90 (60%) and polyox WSR301 or polyox WSR303 or polyox coagulant (40%) compacts were prepared by direct compression, using a rotary tablet press under 1.5 ton force. • Compacts: Circular shaped / 6.5 mm in diameter and 0.9 mm in thickness / 65 mg weight.

Evaluation of Compacts: 1. Dissolution time: The time required for complete disappearance of compact matrix in simulated gastric fluid (SGF), maintained at 37 °C with 100 rpm agitation. Results: Compacts were non-disintegrating in nature and retained their physical integrity in simulated gastric fluid for about 6 hours.

2. Swelling: Increase in radial dimension of compacts when immersed in a known volume of simulated gastric fluid over 6 h’. Results: PVP-Polyox 301

0.93±0.06

PVP-Polyox 303

PVP-Polyox coagulant

0.85±0.05

0.86±0.03

Swelling nature of PVP-Polyox combination is suitable for gastroretentive formulations. It can retain the physical integrity of dosage unit and maintain its retentive properties for a prolonged period.

3. In vitro gastric retention: The time required for the compact to detach from stomach surface, under simulated conditions. Methodology: – Fixed 4 cm2 piece from the body region of porcine stomach on a solid platform. –

– The test polymeric compact was gently placed on the wet mucosal surface and allowed to contact for 1 minute. – It was then immersed into 250 ml of simulated gastric fluid at 60° position. –

– The entire set up was maintained at 37 °C and agitated at 100 rpm.

Results: PVP-Polyox 301

PVP-Polyox 303

PVP-Polyox coagulant

0.5 to 0.8 h

3.8 to 4.2 h

1.6 to 1.8 h

• Higher retention of PVP-Polyox 303: Higher molecular weight of polyox 303 / possibility of forming strong bonding with the mucosal surface. • Inclusion of 2% MB and PAA: Increased the swelling ratio (0.97±0.04 and 0.91±0.03, resp.). Reason: Faster dissolution of markers (compare to compact matrix) and rapid entry of gastric fluid into the polymer matrix.

4. In vivo Gastroretention: Test Product: PVP-Polyox 303 compacts / 2% of Methylene blue (MB) or phenylazoaniline (PAA) / coated with 3-4% of HPMC. Animals: Yorkshire cross swines (n=6 to 9) / 9-10 weeks old / 47 to 53 pounds / overnight fasted. Dosing: 75 mL of water / orogastric tubes. Post dosing observations: animals had free access to water and were observed for their normal behavior and/or any possible adverse effects throughout the study. Study Methodology: In MB compacts, three animals were sacrificed at the end of 1 and 3 hours. The GIT was isolated and visually examined for the location of compacts. A similar study was repeated with PAA compacts. Ethical approval: As per IACUC, University of the Pacific.

Results: PVP-polyox 303 compacts with MB After 1 h: Hydrated compacts, adhering to the gastric mucosa in the body region of stomach in all three animals.

– The force of adhesion of the swollen matrix withstood manual flushing with water. On manual removal, the matrix deformed.

• After 3 hours: Only a mild blue stain was observed in the body region of stomach in only one animal. In the remaining two animals, neither blue stain nor compact fragments could be located in stomach or intestine.

Results: PVP-polyox 303 compacts with PAA After 1 h: Hydrated compacts retained in the body region of stomach in all three animals.

–The force of adhesion of the hydrated compact matrix on the gastric mucosa was not as strong as those of methylene blue compacts. –The swollen mass of compact could be easily removed without deformation. As observed in vitro, PAA compacts showed lower swelling than MB compacts.

After 4 hours: Only a mild red stain of PAA was observed in the stomach of 2 animals; No fragments of compact could be located in any other part of GI tract; In the third animal, neither red stain nor compact fragments could be located in stomach or intestine.

Conclusion:

PVP and Polyox compacts showed swelling and retentive properties. Compare to liquids and disintegrating type products, these non disintegrating compacts which reside in the stomach for more than 1 hour are likely to enhance bioavailability of drugs that have preferential absorption in the upper GIT.