39. M. Barza, A. Kane, and J. Baum. (1980). Oxacillin for bacterial endophthal- mitis: subconjunctival, intravenous, both or neither? Invest. Ophthalmol. Vis. Sci. 19:1348–1354. 40. W. M. Jay, R. K. Shockley, A. M. Aziz, M. Z. Aziz, and J. P. Rissing. (1984). Ocular pharmacokinetics of ceftriaxone following subconjunctival injection in rabbits. Arch. Ophthalmol. 102:430–432. 41. F. P. Furgiuele, J. P. Smith, and J. G. Baron. (1978). Tobramycin levels in human eyes. Am. J. Ophthalmol. 85:121–123. 42. D. M. Maurice, and S. Mishima. (1984). Ocular pharmacokinetics. In: Pharmacology of the Eye II. M. L. Sears, ed. New York: Springer-Verlag, p. 19. 43. M. Barza, A. Kane, and J. Baum. (1983). Pharmacokinetics of intravitreal carbenicillin, cefazolin, and gentamicin in rhesus monkeys. Invest. Ophthalmol. Vis. Sci. 24:1602–1606. 44. V. N. Reddy, B. Chakrapani, and C. P. Lim. (1977). Blood-vitreous barrier to amino acids. Exp. Eye Res. 25:543–545. 45. A. G. Schenk and G. A. Peyman. (1974). Lincomycin by direct intravitreal injection in the treatment of experimental bacterial endophthalmitis. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 190: 281–291. 46. S. C. Pflugfelder, E. Hernandez, S. J. Fliesler, J. Alvarez, M. E. Pflugfelder, and R. K. Forster. (1987). Intravitreal vancomycin. Retinal toxicity, clear- ance, and interaction with gentamicin. Arch. Ophthalmol. 105:831–837. 47. F. M. Ussery, 3rd, S. R. Gibson, R. H. Conklin, D. F. Piot, E. W. Stool, and A. J. Conklin. (1988). Intravitreal ganciclovir in the treatment of AIDS-asso- ciated cytomegalovirus retinitis. Ophthalmology, 95:640–648. 48. K. Henry, H. Cantrill, C. Fletcher, B. J. Chinnock, and H. H. Balfour, Jr. (1987). Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS. Am. J. Ophthalmol. 103:17–23. 49. G. A. Peyman, D. R. May, E. S. Ericson, and D. Apple. (1974) Intraocular injection of gentamicin. Toxic effects of clearance. Arch. Ophthalmol. 92:42– 47. 50. R. K. Shockley, W. M. Jay, T. R. Friberg, A. M. Aziz, J. P. Rissing, and M. Z. Aziz. (1984). Intravitreal ceftriaxone in a rabbit model. Dose- and time-depen- dent toxic effects and pharmacokinetic analysis. Arch. Ophthalmol. 102:1236– 1238. 51. A. G. Schenk, G. A. Peyman, and J. T. Paque. (1974). The intravitreal use of carbenicillin (Geopen) for treatment of pseudomonas endophthalmitis. Acta Ophthalmol. 52:707–717. 52. S. K. Gardner. (1987). Ocular drug penetration and pharmacokinetic princi- ples. In: Clinical Ophthalmic Pharmacology. D. W. Lamberts and D. E. Potter, eds. 53. T. S. Lesar and R. G. Fiscella. (1985). Antimicrobial drug delivery to the eye. Drug Intell. Clin. Pharm. 19:642–654. 54. J. D. Wright, F. D. Boudinot, and M. R. Ujhelyi. (1996). Measurement and analysis of unbound drug concentrations. Clin. Pharmacokinet. 30:445–462. Posterior Segment Microdialysis 277 Copyright © 2003 Marcel Dekker, Inc. 55. U. Ungerstedt. (1991). Microdialysis—principles and applications for studies in animals and man. J. Intern. Med. 230:365–373. 56. E. C. de Lange, M. Danhof, A. G. de Boer, and D. D. Breimer. (1997). Methodological considerations of intracerebral microdialysis in pharmacoki- netic studies on drug transport across the blood-brain barrier. Brain Res. Brain Res. Rev. 25:27–49. 57. R. Tao and S. Hjorth. (1992). Differences in the in vitro and in vivo 5-hydro- xytryptamine extraction performance among three common microdialysis membranes. J. Neurochem. 59:1778–1785. 58. J. Landolt, H. Langemann, T. H. Lutz, and O. Gratzl. (1991). Non-linear recovery of cysteine and glutathione in microdialysis. In: H. Rollema, et al., eds. Meppel, Netherlands: Krips Repro, pp. 63–65. 59. J. Waga, I. Nilsson-Ehle, B. Ljungberg, A. Skarin, L. Stahle, and B. Ehinger. (1999). Microdialysis for pharmacokinetic studies of ceftazidime in rabbit vitreous. J. Ocul. Pharmacol. Ther. 15:455–463. 60. J. Waga. (2000). Ganciclovir delivery through an intravitreal microdialysis probe in rabbit. Acta Ophthalmol. Scand. 78:369–371. 61. A. Hamberger, C. H. Berthold, B. Karlsson, A. Lehmann, and B. Nystrom. (1983). Extracellular GABA, glutamate and glutamine in vivo perfusion dia- lysis of the rabbit hyppocampus. In: Glutamine, Glutamate and GABA in the Central Nervous System. New York: Alan R. Liss Inc., pp. 473–492. 62. M. Sandberg and S. Lindstrom. (1993). Amino acids in the dorsal lateral geniculate nucleus of the cat—collection in vivo. J. Neurosci. Methods. 9:64–74. 63. U. Tossman and U. Ungerstedt. (1986). Microdialysis in the study of extra- cellular levels of amino acids in the rat brain. Acta Physiol. Scand. 128:9–14. 64. A. Lehmann. (1989). Effects of microdialysis-perfusion with anisoosmotic media on extracellular amino acids in the rat hippocampus and skeletal mus- cle. J. Neurochem. 53:525–535. 65. J. M. Solis, A. S. Herranz, O. Herreras, J. Lerma, and R. Martin del Rio. (1988). Does taurine act as an osmoregulatory substance in the rat brain? Neurosci. Lett. 91:53–58. 66. J. V. Wade, J. P. Olson, F. E. Samson, S. R. Nelson, T. L. Pazdernik. (1988). A possible role for taurine in osmoregulation within the brain. J. Neurochem. 51:740–745. 67. S. A. Wages, W. H. Church, and J. B. Justice, Jr. (1986). Sampling considera- tions for on-line microbore liquid chromatography of brain dialysate. Anal. Chem. 58:1649–1656. 68. J. M. Delgado, J. Lerma, R. Martin del Rio, and J. M. Solis. (1984). Dialytrode technology and local profiles of amino acids in the awake cat brain. J. Neurochem. 42:1218–1228. 69. G. Amberg, and N. Lindefors. (1989). Intracerebral microdialysis: II. Mathematical studies of diffusion kinetics. J. Pharmacol. Methods 22:157–183. 70. T. Zetterstrom, L. Vernet, U. Ungerstedt, U. Tossman, B. Jonzon, and B. B. Fredholm. (1982). Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci. Lett. 29:111–115. 278 Macha and Mitra Copyright © 2003 Marcel Dekker, Inc. 71. I. Jacobson, M. Sandberg, and A. Hamberger (1985). Mass transfer in brain dialysis devices—a new method for the estimation of extracellular amino acids concentration. J. Neurosci. Methods 15:263–268. 72. P. Lonnroth, P. A. Jansson, and U. Smith. (1987). A microdialysis method allowing characterization of intercellular water space in humans. Am. J. Physiol. 253:E228–231. 73. D. Scheller and J. Kolb. (1991). The internal reference technique in micro- dialysis: a practical approach to monitoring dialysis efficiency and to calculat- ing tissue concentration from dialysate samples. J. Neurosci. Methods 40:31– 38. 74. H. Benveniste, A. J. Hansen, and N. S. Ottosen. (1989). Determination of brain interstitial concentrations by microdialysis. J. Neurochem. 52:1741– 1750. 75. G. Raviola. (1974). Effects of paracentesis on the blood-aqueous barrier: an electron microscope study on Macaca mulatta using horseradish peroxidase as a tracer. Invest. Ophthalmol. 13:828–858. 76. F. P. Killey, H. F. Edelhauser, and T. A. Aaberg. (1980). Intraocular fluid dynamics. Measurements following vitrectomy and intraocular sulfur hexa- fluoride administration. Arch. Ophthalmol 98:1448–1452. 77. L. L. Knudsen, T. Olsen, and F. Nielsen-Kudsk (1988). Anterior chamber fluorescein kinetics compared with vitreous kinetics in normal subjects. Acta Ophthalmol. Scand. 76:561–567. 78. J. Wagar and B. Ehinger. (2000). NGF administered by microdialysis into rabbit vitreous. Acta Ophthalmol. Scand. 78:154–155. Posterior Segment Microdialysis 279 Copyright © 2003 Marcel Dekker, Inc. 9 Ocular Penetration Enhancers Thomas Wai-Yip Lee and Joseph R. Robinson School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A. I. INTRODUCTION Drug delivery to the eye is not an easy assignment. The cornea, being a very important compon ent in the visual pathway, is well protected by a number of very effective defense mechanisms, e.g., blinking, high tear secretion rate flushing its surface, induced lacrimation and tear protein production in response to foreign substances, etc. These protective mechanisms provide a challenge for pharmaceutical scientists to design drug delivery systems that can deliver therapeutic agents in sufficient concentrations to target sites. After topical instillation of an eye drop, the drug is subject to a num- ber of very efficient elimination mechanisms such as drainage, binding to proteins, normal tear turnover, induced tear production, and nonproductive absorption via the conjunctiva. Typically, drug absorption is virt ually com- plete in 90 seconds due to the rapid removal of drug from the precorneal area. To make matters worse, the cornea is poorly permeable to both hydro- philic and hydrophobic compounds. As a result, only approximately 10% or less of the topically applied dose can be absorbed into the anterior segment of the eye. Basically, the two major barriers encountered in ocular drug delivery are (a) short residence time in the precorneal area and (b) poor permeability of the cornea. Various efforts have been made to prolong the drug solution residence time via vehicle modification (1,2), bioadhesives (3), inserts (4), etc. Another approach to improve ocular bioavailability, which is less well understood, is penetration enhancement. Penetration enhancement can be achieved via pro- 281 Copyright © 2003 Marcel Dekker, Inc. drugs,penetrationenhancers,etc.Prodrugswillbecoveredelsewhereinthis book.Themainfocusofthischapterwillbeontheuseofpenetrationenhan- cerstoimproveoculardrugdelivery.Fundamentalaspectsofocularpenetra- tionenhancerswillbecovered,andrecentadvanceswillbepresentedaswell. II.KINETICBASISOFTHENEEDFORPENETRATION ENHANCEMENT ThesimplestmodelforocularpharmacokineticsisshowninFigure1(5).It iswellknownthatformostdrugsthetrueabsorptionrateconstantismuch smallerthantheeliminationrateconstant.Thiswillnormallygiverisetoa flip-flopmodel.However,whentheparalleleliminationpathwayisintro- duced(Fig.2)(5),theapparentabsorptionrateconstantisdefinedas: Apparent k abs ¼ k abs þ k loss;pp Thus, the model is not a flip-flop model and drug concentration can be described as C ¼ðFD=V d Þ½k=ðk À KÞðe ÀKt À e Àkt Þð1Þ where F is the fraction of dose absorbed, D is the dose, k and K are absorption and elimination rate constants, respectively, and V d is the appar- ent volume of distribution. Obviously, K ¼ k elim , k ¼ k abs þ k loss;pp : For many drugs, k loss; pp is of the order of 0.5–0.7 min À1 , being several orders of magnitude larger than k abs , which is typically of the order of 0.001 min À1 . As a result, the peak tim e, which is controlled by k loss;pp and k abs ,is similar (20–40 min) for a wide range of compounds since k loss;pp , which is mainly due to drainage, induced lacrimination, etc., predominates over k abs in controlling the peak time. In order to improve the bioavailability ðF ¼ k abs =½k abs þ k loss;pp Þ sig- nificantly, it is essential to increase k abs by one or two order of magnitudes or reduce k loss;pp to a similar extent. Several approaches have attempted to reduce the magnitude of k loss;pp . However, it has its limit. Keister et al. (6) showed that reducing the dose volume from 25 mL to zero brings only a fourfold improvement in bioavail- ability for a poorly permeable compound. However, it is practically impos- 282 Lee and Robinson Figure 1 A one-compartment model for ocular absorption. Copyright © 2003 Marcel Dekker, Inc. diffusion,andcarrier-mediatedtransport.Incontrast,thelatterrepresents diffusiveandconvectivetransportoccurringthroughintercellularspaces andtightjunctions.Duetoitsaqueousnature,hydrophilicsoluteswould preferablyadopttheparacellularpathway.However,therearethreeforms ofjunctionalcomplexesthatformbetweencellswhichhindertransportof hydrophilicmolecules,namely,tightjunctions(zonulaoccludens),inter- mediatejunctions(beltdesmosomeorzonulaadherens),andspotdesmo- somes(maculaadherens)(Fig.3)(9).Amongthem,thetightjunctionisthe uppermostandtightest,anditgivesthegreatestresistanceforhydrophilic moleculestogobetweencells.Thebarrierpropertyofthetightjunctioncan bereflectedbythetransepithelialelectricalresistance(TEER).Thehigher theTEER,thetighterthejunctionsthatgiveahigherresistancefortrans- portofmolecules.Generally,epitheliawithresistancesintherangeof10– 100cm 2 areconsideredleaky,whereasthosewithresistancerangingfrom 300to10,000cm 2 are‘‘tight.’’Thecorneaisgenerallyclassifiedasa moderatelytightormoderatelyleakytissue(400–1000cm 2 ).Acompar- isonoftheelectrophysiologyandpermeabilityofthecorneawithother tissuesisshowninTable2and3,respectively(10). Thecorneaalsoshowspermselectivity(11).Ithasanisoelectricpoint (pI)of3.2.AtpHsabovethepI,itcarriesanegativechargeandisselective topositivelychargedmolecules.Ontheotherhand,atpHsbelowthepI,it 284LeeandRobinson Table1ExpectedMechanismsofCornealPenetration Drug type Apparent rate-limiting membrane Mechanisms Water soluble Epithelium Low o/w partition into epithelium Slow diffusion through epithelium High partition rate + rapid diffusion through stroma/ endothelium Via leaky channels Solute movement may be intercellular and/or transcellular Water and oil soluble Epithelium-stroma Both mechanisms operate Oil soluble Stroma High o/w partition into epithelium Rapid diffusion through epithelium Ionizable Epithelium + stroma or leaky channel Mechanism not solely dependent upon partition coefficient Source: Adapted from Ref. 8. Copyright © 2003 Marcel Dekker, Inc. Ocular Penetration Enhancers 287 Figure 4 A simplified diagram of histology of the cornea. (Modified from Ref. 8.) The innermost layer is the endothelium. Although the endothelium is lipo- philic, it is leaky and does not give any significant resistance to the transport of molecules. It is believed that the epithelium provides the major resistance for hydrophilic/charged molecules and gives minimal resistance to small lipophilic molecules. However, after passing across the epithelium, further movement of these lipophilic molecules is limited by the matrix, which is hydrophilic in nature. As a result, in order to pass across the whole cornea, the molecule has to have a balance between its lipophilic and hydrophilic character. Other transport mechanisms such as carrier-mediated transport, endo- cytosis, etc. may also be involved in transcellular transport but they are poorly understood. IV. MECHANISMS OF OCULAR PENETRATION ENHANCERS A detailed mechanistic description of penetration enhancement is beyond the scope of this chapter and can be found elsewhere (13). Our main focus is on ocular penetration enhancement (14). Ideally, penetration enhancers should have the following characteristics (15): 1. The absorbing-enhancing action should be immediate and uni- directional, and the duration should be specific and predictable. 2. There is immediate recovery of the tissue after removing the absorption enhancers. 3. There is no systemic and local effect associated with the enhancers. Copyright © 2003 Marcel Dekker, Inc. 4.Theenhancersshouldbephysicallyandchemicallycompatible withawiderangeofdrugsandexcipients. However,currentlyavailablepenetrationenhancersarefarfromsatisfying theaboverequirements.NonehaveyetbeenapprovedbytheFDApresum- ablybecauseofsafetyconcerns.Inordertodesignanefficientandsafe penetrationenhancer,itisnecessarytohaveathoroughunderstandingof themechanismsofpenetrationenhancement.Basically,penetrationenhan- cersworkbyoneormoreofthefollowingmechanisms(13): 1.Alteringmembranestructureandenhancingtranscellulartrans- portbyextractingmembranecomponentsand/orincreasing fluidity. 2.Enhancingparacellulartransport: Chelatingcalciumionsleadstoopeningoftightjunctions; Inducinghighosmoticpressurethattransientlyopenstight junctions; Introducingagentstodisruptthestructureoftightjunctions. 3.Alteringmucusstructureandrheologysothatthisdiffusionbar- rierisweakened 4.Modifyingthephysicalpropertiesofthedrug-enhancerentity 5.Inhibitingenzymeactivity AsummaryofocularpenetrationenhancersisshowninTable4(14). Typically, ocular penetration enhancement falls into two categories: para- cellular and transcellular. A. Enhanced Paracellular Transport As mentioned earlier, tight junctions are the major determinant of paracel- lular transport. In other words, tight junctions are the primary targets for a penetration enhancer to act on in order to improve paracellular transport. The most well-known penetration enhancer to improve paracellular trans- port is EDTA, which is a calcium chelator commonly used as a preservative. It is well known that proper functioning of tight junctions depends on calcium ions. In the absence of calcium ions, there is a widening of tight junctions, resulting in an increase in paracellula r permeability (8). EDTA can remove divalent ions by its chelating action. Therefore, there is no surprise that it has a permeabilizing effect on biological membranes (16). However, its action on the cornea is believed to be much more complicated. Rojanasakul et al. (17) showed that severe membrane damage is evident in corneas treated with EDTA, bile salts, and surfactants. This disruption of plasma membrane structures by EDTA is somewhat unexpected since it is believed that EDTA only interferes with the ability of calcium to maintain 288 Lee and Robinson Copyright © 2003 Marcel Dekker, Inc. 290 Lee and Robinson Enhancers Concentration Drugs Animal Effect 10 mM 6-Carboxyfluorescein Rabbit Enhanced penetrated amount 7.2 times 2–10 mM FD-4 Rabbit Enhanced penetrated amount slightly Taurodeoxycholic acid 0.05% Atenolol, Timolol, Levobunolol, Betaxolol Rabbit Enhanced Papp 5.8 times for atenolol and 1.6 times for timolol 0.075–0.1% Timolol Rabbit Enhanced Papp 5.2–5.5 times 10 mM 6-Carboxyfluorescein Rabbit Enhanced penetrated amount 593 times 2–10 mM FD-4 Rabbit Enhanced penetrated amount 30.9–61.5 times Urodeoxycholic acid 0.05% Atenolol, Timolol, Levobunolol, Betaxolol Rabbit Enhanced Papp 2.1 times for timolol and 1.6 times for betaxolol 0.075–0.1% Timolol Rabbit Enhanced Papp 8.3–11.0 times Tauroursodeoxycholic acid 0.05% Atenolol, Timolol, Levobunol, Betaxolol Rabbit Enhanced Papp 3.0 times for atenolol and 1.5 times for betaxolol 0.075–0.1% Timolol Rabbit Enhanced Papp 3.3 times at 0.1% Fatty acids Capric acid 0.5% Atenolol, Carteolol, Tilisolol, Timolol, Befunolol Rabbit Enhanced Papp 20.3 times for atenolol, 8.9 times for carteolol, 5.1 times for tilisolol, and 3.0 times for timolol Table 4 Continued Copyright © 2003 Marcel Dekker, Inc. Ocular Penetration Enhancers 291 Enhancers Concentration Drugs Animal Effect Preservatives Benzalkonium chloride 0.01% Prostaglandin F 2a , Pilocarpine, Dexamethasone Pig Enhanced Papp 7.2 times for prostaglandin F 2a , 1.7 times for pilocarpine, and 3.3 times for dexamethasone 0.01% Tilisolol, FD-4, FD- 10 Rabbit Enhanced Papp 3.5 times for tilisolol, 28.8 times for FD-4, and 37.1 times for FD- 10 0.02% Atenolol, Timolol, Levobunolol, Betaxolol Rabbit Enhanced Papp 5.2 times for atenolol, 2.7 times for timolol, and 1.3 times for betaxolol 0.05% FD-4, FD-10 Rabbit Enhanced Papp 43.6 times for FDA and 60.6 times for FD-10 0.005-0.02% Fluorescein Rabbit Increased permeability 4–2.5 times 0.02% 0.01–0.03% Carbachol Rabbit Enhanced miotic response about 20 times 0.025% Titmolol Rabbit Enhanced the ocular absorption about 80% and the systemic absorption about 40% Chlorhexidine digluconate 0.01% Pilocarpine, Dexamethasone Pig Enhanced Papp 1.5 times for dexamethasone 0.0025–0.05% Fluorescein Rabbit, Human Enhanced permeability significantly over at 0.005% Benzyl alcohol 0.5% Tilisolol, FD-4, FD- 10 Rabbit Enhanced Papp 2.6 times for FDA and 8.1 times for FD-10 Chlorbutanol 0.5% Pilocarpine, Dexamethasone Pig Enhanced Papp 1.8 times for pilocarpine and 4.7 times for dexamethasone Copyright © 2003 Marcel Dekker, Inc. [...]... 50 Yen, W.-C., and Lee, V H L Role of Na+ in the asymmetric paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg across rabbit colonic segments and Caco-2 cell monolayers J Pharmacol Exp Ther J Contr Rel 36: 25 37, 2 75: 114–119, 19 95 Copyright © 2003 Marcel Dekker, Inc Ocular Penetration Enhancers 307 51 Saha, P., Yang, J., and Lee, V H L Existence of a P-glycoprotein drug. .. 1998 52 Zimmer, A., and Kreuter, J Microcapsules and nanoparticles used in ocular delivery systems Adv Drug Delivery Rev 16:61–73, 19 95 53 Calvo, P., Alonson, M J., Vila-Jato, J L., and Robinson, J R Improved ocular bioavailability of indomethacin by novel ocular drug carriers J Pharm Pharmacol 48:1147–1 152 , 1996 54 Yang, X., and Robinson, J R Bioadhesion in mucosal drug delivery In: Biomaterials for Drug. .. the permeability coefficient of hGH across the cornea of a rabbit by 10-fold (46) Further study is ongoing in our laboratory to confirm the efficacy and toxicity of these carriers as delivery agents/carriers for ocular drug delivery B Pz-Peptide Pz-peptide (4-phenylazobenzoxycarbonyl-Pro-Leu-Gly-Pro-D-Arg) is a hydrophilic collagenase-labile pentapeptide with a molecular weight of 777 daltons, which is... Structure-function relationship among Quillaja saponins serving as excipients for nasal and ocular delivery of insulin J Pharm Sci 85: 518 52 4, 1996 38 Morgan, R V Delivery of systemic regular insulin via the ocular route in cats J Ocular Pharmacol 11 :56 5 57 3, 19 95 39 Morgan, R V., and Huntzicker, M A Delivery of systemic regular insulin via the ocular route in dogs J Ocular Pharmacol 12 :51 5 52 6, 1996... Derivatives Chitosan (poly[b-( 1-4 )-2 -amino-2-deoxy-D-glucopyranose]) (58 ) is a hydrophilic, biocompatible, biodegradable polymer of low toxicity It is widely used as a pharmaceutical excipient for direct compression of tablets, controlled release rate of drugs from a dosage form, enhanced dissolution, etc (58 ) It also shows strong mucoadhesive properties (59 ) Chitosan was evaluated as a delivery system to increase... 2-Phenylethanol 0 .5% Tilisolol, FD-4, FD10 Rabbit Enhanced Papp 2.7 times for tilisolol, 5. 6 times for FD-4, and 4.8 times for FD-10 Paraben 0.04% Tilisolol, FD-4, FD10 Rabbit Enhanced Papp 1.9 times for FD-10 Propyl paraben 0.02% Dexamethasone Pig Enhanced Papp 1 .5 times Chelating Agents EDTA 0 .5% Atenolol, Timolol, Levobunolol, Betaxolol Atenolol, Carteolol, Tilisolol, Timolol, Befunolol FD-4, FD-10... 25 77 times Enhanced Papp 16 .5 times for atenolol, 11.0 times for timolol, 1.3 times for levobunolol, 2.0 times for betaxolol Enhanced Papp 2.1 times at 0.01%, 3.3 times at 0.0 15% , and 8.3 times at 0.0 25% 0.1–0 .5% 0.01–0.0 25% Rabbit 293 Copyright © 2003 Marcel Dekker, Inc 294 Table 4 Continued Enhancers Concentration Drugs Animal 0 .5% Atenolol, Carteolol, Tilisolol, Befunolol Rabbit 0 .5% FD-4, FD-10... (Polymeric Penetration Enhancers) 1 Colloidal Systems Colloidal systems have been extensively studied as carriers for ocular drug delivery (52 ) The mechanism of enhancement is generally believed to be related to prolonged residence time in the cul-de-sac However, enhanced penetration may also be one of the explanations for improved ocular delivery Poly-e-caprolactone nanoparticles, nanocapsules, and submicron... times for befunolol Enhanced Papp 15. 5 times for FDA and 39.0 times for FD-10 Enhanced Papp 31 times for atenolol and 1.9 times for timolol at 0 .5% 0 .5% 0 .5% 0.1–0 .5% Drugs Animal Rabbit Rabbit Effect 0. 05% Others Azone Copyright © 2003 Marcel Dekker, Inc Atenlool, Timolol, Levobunolol, Betaxolol Timolol Rabbit Enhanced ocular and systemic absorption significantly 0.0 25 1.0% Cimetidine Rabbit Enhanced... Missel, P J., Lang, J C., and Hager, D F Limits on optimizing ocular drug delivery J Pharm Sci 80 :50 53 , 1990 7 Harris, D., and Robinson, J R Bioadhesive polymers in peptide drug delivery Biomaterials 11: 652 – 658 , 1990 8 Grass, G M Mechanisms of Corneal Drug Penetration Ph.D thesis, School of Pharmacy, University of Wisconsin–Madison, 19 85 9 Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, . enzyme inhibi tory effect. 4. Chitosan and Derivatives Chitosan (poly[b-( 1-4 )-2 -amino-2-deoxy- D-glucopyranose]) (58 ) is a hydro- philic, biocompatible, biodegradabl e polymer of low toxicity. It. 2.7 times for befunolol 0 .5% FD-4, FD-10 Rabbit Enhanced Papp 100 times for FD-4 and 114 times for FD-10. FD-4: FITC-dextran (average molecular weight 4400); FD-10: FITC-dextran (average molecular. Animal Effect 2-Phenylethanol 0 .5% Tilisolol, FD-4, FD- 10 Rabbit Enhanced Papp 2.7 times for tilisolol, 5. 6 times for FD-4, and 4.8 times for FD-10 Paraben 0.04% Tilisolol, FD-4, FD- 10 Rabbit