Chronopharmacokinetic considerations in the design of ocular drug delivery systems

Thursday, Sep 24, 1992 Des Iles Borromees CORNEA

AND

CONNECTIVE

X ICER Abstracts

CODE: C-IO

SEPTEMBER

24ffHURSDAY

TISSUE

HOTELROOM:

CHRONOPHARMAC OKINEX’IC COWSIDERATIONS IN THE DESIGN DCUIAR DRUG DELIVERY SYSTEMS Vincent H.L. Lee, University of Southern California, School of Pharmacy, Los Angeles, CA 90033 U.S.A.

DES ILES BORROMEES

CHAIRPERSONS:

MIGUEL F. REFOJO 1. CARLOS PASTOR

The

ocular sustained release drug delivery zero order release characteristics implicitly that ocular pharmacokinetic processes are invariant with time. For this reason, constant drug concentrations at the target site are usually expected from the constant drug release rate which has been preprogrammed into the delivery system. This expectation cannot be fulfilled, however, if there are timedependent changes in any of the relevant pharnacokinetic processes. There is now evidence that the ocular absorption of topically applied timolol is influenced the time of drop instillation. In the pigmented by rabbit, absorption of topically applied timolol into the eye at 1200 hr was about two times better than at 600, 1800 or 2400 hr. These dosing time-dependent changes in the time course of ocular timolol concentrations, particularly between 0600 and 1200 hr, may be attributed to circadian changes in precorneal drug loss and cornea1 drug penetration rather than to circadian changes in drug elimination from the target tissue/fluid. The above findings suggest that circadian changes in ocular pharmacokinetic processes is a factor that should be considered in the design of sustained drug release systems for timolol. (Supported by NIH grants EY3816 and EY7389 and by the Gavin S. Herbert Professorship.)

(USA) (SPAIN)

systems

PRESENTATION

11:oo

Introducmry M.F. Refojo

Remarks (USA) e11c

ti Desien of Ocular V.H.L. Lee (USA)

Conslderauons Drue Deliverv

Svm

1l:lS

Phase Chance Qcula Drue J.R. iobinson

II:35

mesive Delivery M.F. Saermne

1152

Microsoheres Controlled T . Moritera

12:09

lnlraocular Tolerance and Pharmacoklnetlcs gf Polvanhidrides Loaded with 5-FIuor~ J.C. Paslor, M.I. Lopez, J.I. Alonso, A. Pampliega and A. Alberola (Spain)

and Bioadhesive Delivery (USA) Effects

in

Sustained

Svstems

in

Ocular

(Italy)

of Biodegradable Polymers Drue Delivery and Y. Ogura (Japan)

for

PHASE

Acid (RAI from Microsoheres of &&.zradahle Polymers m an m Model gf Proliferative Vitreor~v iPV_B1 G.G. Giordano and M.F. Refojo (USA) Polvmer Based Swained for Anlineoolastics and Qohlhalmolo~ T.J. Smilh and P. Ashlon

Delivers Anlivirals

of

CHANGE

DELIVERY Robinson. School of N. Charter

12:26

12:43

design with assumes

OF

AND

BIOADHESIVE

J. R. Pharmacy, University St., Madison, WI

SYSTEMS of 53706

IN

OCULAR

DRUG

Wisconsin-Madison, U.S.A.

425

Very extensive and rapid loss of drug from a topically applied solution leads to low ocular bioavailability for most drugs. Attempts to improve this situation through the use of water soluble or insoluble ocular inserts must contend with the unfavorable patient acceptance typically It would apassociated with this drug delivery system. oear then that a liauid deliverv svstem. of relatively iow viscosity, would be the prefgrrea typ; of ocular do& One approach to satisfy these requirentants is age form. phase-change polymer solutions. In this case, such trigger mechanisms as temperature! pH, ionic strength, and specific ions cause a dramatic increase in viscosity. The viscous drop/solid mass, must be deformable to avoid a foreion bodv sensation. A sianificant drawback to maw of these systems is their relagively high water content leading to rapid diffusion of water soluble drugs out of the vehicle. -An alternative to phase-change polymers is to emolov oolvmer solutions in which the Dolvmer attach&,-
SYstems in

(USA)

543

3 MUCOADHESIVE

EFFECTS IN SUSTAINED

OCULAR

DELlVERY

Dept. of Pharmaceutical TechnoIogy/Biopharmaceutics, University of Piss, Via Bonanno 6, I-56100 Pisa, (Italy) The so-called bio-adhesive approach to improve the bioavailability of ophthalmic drugs consists of the realisation of polymeric vehicles whose prolonged retention on the eye depends on interactions with precomeamucus~ The particular, loose structure of the thin mucin layer coating the cornea1 epithelium, and the well-known restraints imposed by the site of application, dictate severe limitations in the choice of a potentially muco-adhesive ocular delivery system. In particular, liquid (or very moderately viscous) muco-adhesive preparations might be &efer&le, because bf a greater ease of adminisiration and dosing, and of lesser interference with vision. Recent investigations carried out in the laborarory of the author and of his associates have pointed to some polyanionic natural or synthetic polymers as interesting bioadhesive carriers for ophthalmic drugs. These polymers (e.g., glycosaminoglycans, mucopolysaccharides, polygalacturonic acid, etc.) can form salts (or polyanionic complexes) with selected basic drugs such as pilocarpine, cyclopentolate, betablockers, etc. Topical administration of solutions of the salts (sometimes disolayinp. very low viscosity) has been shown ro produce: a) an inc~ea~ed~pha~macological response, corresponding tb a prolongedoulse deliverv. b) increased aoueous humour levels. and c) a reduction bf systemic

&or&ion

of the d&x.

The advantages and limitations of this approach are discussed, ootential develoaments. leadina to oohthalmic formulations showing an improved o&r-to-systemic ~bsorptibn, are outlined. and

S.162