Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Lipophilic drugs cross the barrier easily in either direction because of their membrane fluidity.Topical epinephrine (often in aphakic eyes) has been associated with cystoid macular edema. Topical brimonidine 0.2% has been demonstrated to provide vitreous concentrations of 185 nM, which is believed to be a significant enough posterior segment concentration to provide neuroprotection. Topical dorzolamide in rabbits achieved significant levels in the retina and choroid to provide inhibition of carbonic anhydrase. Clinically, topical dorzolamide has also demonstrated some beneficial effect in retinitis pigmentosa patients. Topical memantine HCl achieved high retinal bioavailability in rabbits similar to oral dosing.

Systemic agents such as digitalis, phenothiazines, quinine, methyl alcohol, and quinoline derivatives can cause retinal toxicity. Some drugs, such as sildenafil, may cause a temporary toxic effect (color vision disturbance) on the retina. Numerous studies of intraocular penetration after systemic administration of antibiotics such as the fluoroquinolones and linezolid have demonstrated inhibitory concentrations in the vitreous fluid. Some oral antifungal medications such as fluconazole and voriconazole have also produced significant levels in the posterior segment after systemic administration. A growing number of substances have been shown to be transported from the vitreous and retina into the blood plasma, including ions, drugs, and the prostaglandins associated with ocular inflammation.

The optic nerve is of interest here because some drugs are toxic to this tissue. The antibiotics chloramphenicol, ethambutol, streptomycin, and sulfonamides can cause optic neuritis. Vitamin A, especially in large doses, can result in papilledema. Digitalis can cause retrobulbar neuritis (see Chapter 35).

Blood Supply and Removal

of Drugs and Metabolites

The parenteral route of administration is effective only for drugs of low systemic toxicity that can be introduced into the eye at therapeutic concentrations. An important example of systemic dosing is the case of internal ocular infections, such as endophthalmitis, where a high concentration of antibiotic must be maintained. The systemic dose can also be augmented by topical drug applications to the eye.

Drugs that are unacceptable as systemic medications due to toxicity to certain organs, such as liver or kidney, can be especially useful for topical ocular dosing. Certain drugs are also well suited for topical use in the eye or for injection, because they are rapidly diluted by the bloodstream to levels that are nontoxic.

The bloodstream is responsible for removing drugs and drug metabolites from ocular tissues.The two circulatory pathways in the eye—the retinal vessels and the uveal vessels—are fairly different. The retinal vessels can remove many drugs, metabolites, and such agents as

prostaglandins from the vitreous humor and retina, apparently by active transport. Organic ions, such as the penicillins and cephalosporins, exhibit short half-lives in the vitreous fluid because they are removed by active transport through the retinal transport system and via the anterior route. On the other hand, drugs such as the aminoglycosides, which exit only through the anterior route, often exhibit longer vitreous half-lives.

The uveal vessels remove drugs by bulk transport from the iris and ciliary body.The direct outflow pathway from aqueous humor through trabecular meshwork and canal of Schlemm into the episcleral vessels is another major source of drug removal from the eye.

COMPARTMENT THEORY

AND DRUG KINETICS

The eye is a unique structure, because several of its fluids and tissues—tear film, cornea, aqueous humor, lens, and vitreous humor—are almost completely transparent. These components of the ocular system have no direct blood supply in the healthy state. Each can be considered a separate chamber or compartment. A compartment is defined here as a region of tissue or fluid through which a drug can diffuse and equilibrate with relative freedom. Each compartment is generally separated by a barrier from other compartments, so that flow between adjacent compartments requires more time than does diffusion within each compartment.

The tears are an example of a compartment with constant turnover, because the inflow of lacrimal fluid is constant and equal to the outflow through the puncta. Consider the fate of sodium fluorescein, a diagnostic tracer representative of a highly hydrophilic drug: Once instilled it mixes rapidly with the tears, and the tear flow carries away a portion per unit time, dependent on the drug concentration present.

Approximately 99% of fluorescein or of a hydrophilic drug exits the tears by lacrimal drainage, yet a very small amount penetrates the corneal epithelial barrier and enters the stroma. A barrier is a region of lower permeability or restricted diffusion that exists between compartments. If the epithelium is considered to be a barrier to drug penetration from the tears and the bulk of the cornea forms a compartment, a two-compartment model can be described. In the absence of an active transport mechanism, drugs diffuse across barriers according to the laws of thermodynamics, from a region of higher to one of lower concentration. Fick’s first law of diffusion states that the rate of diffusion across a barrier is proportional to the concentration gradient between the compartments on either side of the barrier.

From Fick’s law the rate of diffusion of a drug across a barrier is linearly dependent on the concentration difference between the compartments on either side of the barrier. As soon as the concentration of drug in the cornea equals that of the tears, drug no longer inwardly penetrates.

Therefore, corneal absorption depends on the integral tear film concentration (also known as the area under the curve) during the first 10 to 20 minutes after instillation of drug. Absorption is subject to modification by many factors, including other drugs, preservatives, infection, inflammation, or neuronal control, which can greatly affect drug bioavailability at the desired site of action.

The diffusion of drug from the cornea to the aqueous humor is similar to that from tears to cornea, except that for the corneal depot the aqueous humor receives the major proportion of drug. Both lateral diffusion across the limbus and diffusion back across the epithelium contribute relatively little to the total diffusion.

The bulk of the corneal drug depot eventually enters the aqueous humor, and the aqueous level rises to a maximum over approximately 3 hours. After this time the concentration of drug in the cornea and in the aqueous humor drops in parallel as the aqueous humor level decays logarithmically.

The compartment model just described can estimate the concentrations of drugs within various ocular tissues. A more complex compartment model that includes drug movement through the posterior aqueous, vitreous, and retina is shown in Figure 2-6. This model becomes useful when a drug is introduced directly into the vitreous or

systemic circulation or when the very slight amount of a topically applied drug reaching the lens, vitreous, or retina must be considered.

The molecular properties of drugs influence which tissues act as reservoirs for them and which act as barriers. Modeling parameters vary considerably for drugs with different penetration and partitioning properties. A lipophilic drug that is also water soluble penetrates the corneal epithelium more readily than does fluorescein, a more hydrophilic drug.

Active Transport and Diffusion Kinetics

Drug distribution usually depends on the rate of passive diffusion within and between compartments. It is governed by the barrier resistance between any two compartments where the distribution is unequal at a given time. In some cases, however, molecules accumulate against a concentration gradient on one side of a barrier. Either of two phenomena is responsible for such an observation: one, coupled pumping mechanisms in the cell may provide the energy necessary for active transport, or two, nonspecific binding due to ionic or other forces may cause an apparent accumulation of molecules against a concentration gradient.

The properties of passive drug release from a tissue or from an artificial device can vary under certain circumstances. One example is zero-order kinetics, a term used when the release of a drug is constant over time. Zeroorder kinetic conditions are satisfied when the concentration of a drug released over time is independent of concentration. Drugs usually obey zero-order kinetics when there is a rate-limiting barrier, as when a carrier system is saturated by an excess of drug. The Vitrasert, implanted into the vitreous cavity, is an example of drug dosing by zero-order kinetics.A reservoir of ganciclovir is released at a nearly constant rate from the device for several months for treatment of cytomegalovirus retinitis.

First-order kinetics is most commonly encountered in ocular drug movement. Here, the rate of movement is directly proportional to the concentration difference across the barrier, and the rate changes with time as the concentration differential across the barrier changes.The passive diffusion of molecules across a nonsaturated barrier generally adheres to first-order kinetics.

Prodrugs

When the metabolite of a drug is more active at the receptor site than is the parent form, the drug is often termed a prodrug.To be therapeutically useful a prodrug must metabolize predictably to the effective drug form before it reaches the receptor site.The greatest advantage of prodrugs is the potential to add groups that mask features of the drug molecule that prevent penetration or have other undesirable effects. Prodrug design can be a useful way of increasing penetration of a therapeutic agent through corneal or other barriers.

Dipivalyl epinephrine is the first successful example of the ophthalmic prodrug concept.A pair of pivalyl groups is attached to the two charged groups on epinephrine. The epithelial penetration is increased 10-fold by this diesterification because of the lipophilic nature of the modified prodrug. The pivalyl groups are removed by esterases in the cornea, leaving epinephrine to act at the receptor site.Thus, a topically applied dipivalyl derivative need only be one-tenth the concentration of epinephrine to achieve bioavailability equivalent to epinephrine. Systemic absorption of the drug is thereby greatly reduced. Dipivalyl epinephrine was widely used for IOP control in the treatment of glaucoma during the 1980s and early 1990s. Latanoprost and travoprost are also considered prodrugs in that the ester-linked group is cleaved off after penetrating the cornea with the free acid remaining in the aqueous humor.

The future design and use of prodrugs hold much promise in ocular drug delivery, particularly where lipophilic prodrugs can be induced to penetrate the blood–vitreous barrier readily and then are metabolized to a form that is trapped in the vitreous compartment. Because of their selective permeability, drugs could reach an effective concentration in the eye by entrapment

within the vitreous compartment. A major problem with this approach is that the brain may sequester drug in the same manner as that evinced by the vitreous humor.This could be avoided by identifying a suitable enzyme that is present in vitreous humor and not in the brain.

Active Metabolites

Loteprednol etabonate is an active metabolite of a pred- nisolone-related compound that predictably and rapidly undergoes transformation by enzymes in the eye to an inactive form associated with fewer side effects. Loteprednol is a potent corticosteroid with less tendency to raise IOP than that of prednisolone.

PROPERTIES OF DRUG FORMULATIONS AFFECTING BIOAVAILABILITY

Biopharmaceuticals involves the development of optimum dosage forms for the delivery of a given drug. For example, preservatives that compromise the health of corneal epithelial cells have been eliminated from unitdose medications intended for patients with dry eye and for other sensitive individuals. Major advances are also taking place in the development of vehicles and specific formulations to enhance ocular bioavailability and to decrease systemic absorption of drugs.

Bioavailability

Bioavailability describes the amount of drug present at the desired receptor site. The dose level producing a response that is 50% of maximum is termed the ED50 (Figure 2-7). An effective dose level must be present for

Figure 2-7 Classic dose–response curve for a drug agonist A. The sigmoid curve defines the theoretic effect on a specific receptor for varying concentrations of the agonist. (pD2 = negative log of the molar concentration of agonist producing 50% of maximum receptor effect, the ED50.) (Reprinted with permission from Van Rossem JM, ed. Kinetics of drug action. Handbook of experimental pharmacology. Berlin: Springer, 1977: 47.)

28 CHAPTER 2 Ophthalmic Drug Formulations

a time sufficient to produce the desired action. The requirements for concentration and time to achieve ED50 differ widely, depending on the mechanism of action of the drug and the desired response.

Active Ingredients

Therapeutic and diagnostic drugs given topically or systemically can have major effects on uptake of other drugs as a result of their own actions on tissue permeability, blood flow, and fluid secretion. Preservatives, buffers, and vehicles also can have significant effects on drug absorption. Table 2-3 categorizes some topical medications and preservatives and their effects on the corneal epithelium, as evaluated by scanning electron microscopy.

Many drugs used to treat glaucoma decrease aqueous humor formation and thereby slow their own kinetics of removal and removal of other drugs by the aqueous route. In like manner, anti-inflammatory agents compensate for the increased permeability of the blood–aqueous barrier and help to bring it back within normal limits, thus altering the kinetics of drugs within the eye. Many similar examples of drug modification of pharmacokinetics can be found (e.g., the inhibition of tear flow by systemically administered anticholinergic agents).

Stability

No complex drug molecule is indefinitely stable in solution. The determination of drug stability is of major concern to the pharmaceutical industry. In the United States a manufacturer must demonstrate that at least 90% of the labeled concentration of a drug is present in the active form after storage at room temperature for the shelf life requested. In many cases a manufactured drug may contain 110% of the labeled amount of medication, so that 18% of the drug can degrade before the minimum acceptable level is reached. A shelf life of less than 18 months usually renders warehousing and distribution of a drug economically impractical, unless the drug is in very high demand. Once a sealed bottle is opened, the contents are subject to the risk of excessive oxidation from light exposure or heat and microbial contamination.

Drugs formulated in an acid solution are sometimes more stable than those at neutral or alkaline pH, particularly when the drug is a weak base. Often, such a drug must be stored at an acid pH to increase protonation and to prevent rapid degradation. Polypeptides, such as growth factors, which are now of interest in ophthalmic formulations, may require alkaline storage. In the eye the normal pH is approximately 7.4. Tear pH can remain altered for more than 30 minutes after addition of a strongly buffered solution.A change of tear pH can cause such irritation and stimulation of lacrimation that drug penetration is decreased.The use of a low concentration of buffer in the drug vehicle can allow the natural ocular

buffering system to reestablish normal tear film pH rapidly after drug instillation.

Certain drug formulations are not stable in solution. An extreme stability problem is posed by acetylcholine, a drug very useful in rapidly and reversibly constricting the pupil in some surgical procedures, such as cataract extraction.This agent degrades within minutes in solution. Therefore, a system for packaging has been developed using a sterile aqueous solution in one compartment and lyophilized (freeze-dried) drug in the other. A plunger displaces a stopper between chambers, allowing mixing just before use.

Osmolarity

The combination of active drug, preservative, and vehicle usually results in a hypotonic formulation (< 290 mOsm). Simple or complex salts, buffering agents, or certain sugars are often added to adjust osmolarity of the solution to the desired value.An osmolarity of 290 mOsm is equivalent to 0.9% saline, and this is the value sought for most ophthalmic and intravenous medications.The ocular tear film has a wide tolerance for variation in osmotic pressure. However, increasing tonicity above that of the tears causes immediate dilution by osmotic water movement from the eyelids and eye. Hypotonic solutions are sometimes used to treat dry eye conditions and to reduce tear osmolarity from abnormally high values.

Preservatives

The formulation of ocular medications has included antimicrobial preservatives since the historic problem of fluorescein contamination in the 1940s. Pseudomonas, a soil bacterium that can cause corneal ulceration, uses the fluorescein molecule as an energy source for metabolism. Many years ago this bacterium caused serious consequences for practitioners who kept unpreserved solutions of fluorescein in the office to assist in the diagnosis of corneal abrasions. As a result of several tragic infections, two actions have been taken by manufacturers. First, fluorescein is now most commonly supplied as a dried preparation on filter paper, which prevents the growth of pathogens. Second, as a precautionary measure, most ophthalmic solutions designed for nonsurgical, multiple use after opening now contain preservatives. One example, moxifloxacin 0.5%, is considered “selfpreserving” and contains no preservative, although it is in a multidose container. However, preservatives used at high concentrations can irritate and damage the ocular surface.

Various types of preservatives are currently available for commercial use. One group, the surfactants, is ionically charged molecules that disrupt the plasma membrane and is usually bactericidal. Another group of chemical toxins includes mercury and iodine and their derivatives, as well as alcohols. These compounds block

Preparations causing no epithelial damage

Drugs

Surface epithelial microvilli normal in size, shape, and distribution; no denuded cells; cell junctions intact; plasma membranes not wrinkled; usual number of epithelial “holes”

30 CHAPTER 2 Ophthalmic Drug Formulations

the normal metabolic processes of the cell. They are considered bacteriostatic if they only inhibit growth or bactericidal if they destroy the ability of bacteria to reproduce. In contrast to antibiotics, which selectively destroy or immobilize a specific group of organisms, the preservatives act nonselectively against all cells. Another group, the oxidative preservatives, can penetrate cell membranes or walls and interfere with essential cellular function. Hydrogen peroxide and a stabilized oxychlorocomplex (Purite) are examples of these newer preservative systems.

Benzalkonium Chloride and Other Surfactants

The quaternary surfactants benzalkonium chloride (BAC) and benzethonium chloride are preferred by many manufacturers because of their stability, excellent antimicrobial properties in acid formulation, and long shelf life. They exhibit toxic effects on both the tear film and the corneal epithelium and have long been known to increase drug penetration. The toxicity of these compounds may be increased by the degree of acidity of the formulation.

A single drop of 0.01% BAC can break the superficial lipid layer of the tear film into numerous oil droplets because it can interface with the lipid monolayer of the tear surface and disrupt it by detergent action. BAC reduces the breakup time of the tear film by one-half. Repeated blinking does not restore the lipid layer for some time.The inclusion of BAC in artificial tear formulations is questionable. It neither protects the corneal epithelium nor promotes a stable oily tear surface.

Patients who receive anti-inflammatory agents are at particularly high risk of experiencing tear film breakup and corneal erosion because of the presence of BAC as a preservative.The repeated application of these drops can further compromise an eye in which the tear film or cornea may already be damaged. It may be necessary in superficial inflammation or corneal erosion to eliminate all medications; this alone may allow healing. In many cases of superficial inflammation, a lubricating eyedrop without preservatives may be the best course of treatment.

Histopathologic effects on both the conjunctiva and trabecular meshwork have been demonstrated with BACcontaining antiglaucoma medications. Long-term treatment of patients with antiglaucoma drugs is at least partially responsible for toxic inflammatory effects (or both) on the ocular surface. BAC is reported to produce a dose-dependent arrest of cell growth and death, causing necrosis at higher concentrations and apoptosis at concentrations as low as 0.0001%.

Chlorhexidine

Chlorhexidine is a diguanide that is useful as an antimicrobial agent in the same range of concentrations occupied by BAC, yet it is used at lower concentrations in marketed formulations. It does not alter corneal permeability to the same degree as does BAC for perhaps two

major reasons. First, the structure of chlorhexidine is such that it has two positive charges separated by a long carbon backbone, and it cannot intercalate into a lipid layer in the same manner as does BAC. Second, proteins neutralize the toxicity of chlorhexidine, and this may occur in the tear film.

Mercurials

Of the mercurial preservatives, thimerosal is less subject to degradation into toxic mercury than either phenylmercuric acetate or phenylmercuric nitrate. Thimerosal is most effective in weakly acidic solutions. Some patients, however, develop a contact sensitivity and must discontinue use after several weeks or months of exposure. Because thimerosal affects internal cell respiration and must be present at high continuous concentrations to have biologic effects, its dilution by the tear film prevents short-term epithelial toxicity on single application. It has no known effects on tear film stability. A concentration of 1% thimerosal is required to equal the effects on corneal oxygen consumption of 0.025% BAC.

Chlorobutanol

Chlorobutanol is less effective than BAC as an antimicrobial and tends to disappear from bottles during prolonged storage. No allergic reactions are apparently associated with prolonged use. Scanning electron microscopy of rabbit corneal epithelial cells also indicates that twicedaily administration of a chlorobutanol-preserved artificial tear results in only modest exfoliation of corneal epithelial cells. Chlorobutanol is not a highly effective preservative when used alone and therefore is often combined with ethylenediaminetetraacetic acid (EDTA) in ophthalmic drug formulations.

Stabilized Oxychloro-Complex and Sodium Perborate

Stabilized oxychloro-complex (Purite, Allergan, Irvine, CA) and sodium perborate (CIBA Vision) are relatively new oxidative preservative systems. Both Purite (present in Refresh Tears) and sodium perborate (in GenTeal) are found in artificial tear products. Purite dissipates into water and sodium chloride on exposure to light. Sodium perborate is converted to hydrogen peroxide and then oxygen and water once in the eye. Hydrogen peroxide itself is used as an effective contact lens disinfectant.

The oxidative preservatives, in contrast to the chemical preservatives, can be neutralized by mammalian cells and do not accumulate. These preservative systems thus provide effective activity against microorganisms while producing very low toxicity. Both compounds offer significant advantages over traditional preservatives and may produce less cellular toxicity.

Miscellaneous Preservatives

The preservatives methylparaben and propylparaben are used in artificial tears and nonmedicated ointments.They can cause allergic reactions and are unstable at high pH.

Disodium EDTA is a special type of molecule known as a chelating agent. EDTA can preferentially bind and sequester divalent cations in the increasing order: Ca2+, Mg2+, Zn2+, Pb2+. Its role in preservation is to assist the action of thimerosal, BAC, and other agents. By itself, EDTA does not have a highly toxic effect on cells, even in culture. Contact dermatitis is known to occur from EDTA.

When instilled topically in the eye, mercurial and alcoholic preservatives are rapidly diluted below the toxic threshold by tears. However, surfactant preservatives rapidly bind by intercalating into the plasma membrane and can increase corneal permeability before dilution can occur. The changed barrier property of the cornea can allow large hydrophilic molecules to penetrate the cornea far more readily.

SofZia is a new preservative system composed of boric acid, propylene glycol, sorbitol, and zinc chloride. Incorporated into Travatan Z, a prostaglandin for treatment of glaucoma, it is considered an extension of the manufacturer’s borate/polyol preservative systems. SofZia has successfully met challenges from many ocular pathogens including Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus niger.

Vehicles

An ophthalmic vehicle is an agent other than the active drug or preservative added to a formulation to provide proper tonicity, buffering, and viscosity to complement drug action (Box 2-1). The use of one or more high- molecular-weight polymers increases the viscosity of the formulation, delaying washout from the tear film and increasing bioavailability of drugs. Polyionic molecules can bind at the corneal surface and increase drug retention and can stabilize the tear film. Petrolatum or oil-based ointments provide even longer retention of drugs at the corneal surface and provide a temporary lipid depot. In artificial tears the vehicles themselves may be the therapeutically active ingredients that moisturize and lubricate the cornea and conjunctiva and augment the tear film, preventing desiccation of epithelial cells.

The therapeutic index of drugs, particularly those that are systemically absorbed, can be maximized in many ways, including modifying the vehicle used for drug delivery. The β-blockers are an example of such a group. Increased viscosity and controlled-depot drug release are vehicular strategies that can contribute to increased specificity of these drugs. Increasing the pH to a more neutral pH has also allowed for increased bioavailability.

Brimonidine Purite 0.15% and 0.1% are formulated at a more neutral pH, thereby providing increased bioavailability inside the aqueous fluid compared with brimonidine 0.2% while maintaining equivalent ability to lower IOP. Timolol maleate 0.5% formulated in potassium sorbate 0.47% provides for a more lipophilic or less polarized form of timolol. The less polarized form produces

humor concentrations, allowing for once daily dosing. The monomer unit structure of the vehicle and its

molecular weight and viscosity control the behavior of the vehicle. In the manufacture and purification of polymers, a range of molecular sizes is usually present in the final product.

Box 2-1 Examples of Excipients Used in

Ophthalmic Formulations

Viscous agents

Methylcellulose

Polyvinyl alcohol

Polyvinylpyrrolidone (povidone)

Propylene glycol

Polyethylene glycol

Polysorbate

Dextran

Gelatin

Carbomers (various; e.g., 934P, 940)

Antioxidants

Sodium sulfites

Ethylenediaminetetraacetic acid

Wetting agents and solubilizing agents

Benzalkonium chloride Benzethonium chloride Cetylpyridinium chloride Docusate sodium Octoxynol and Nonoxynol Polysorbate

Poloxamer

Sodium lauryl sulfate Sorbitan

Tyloxapol

Buffers

Acetic, boric, and hydrochloric acids

Potassium and sodium bicarbonate

Potassium and sodium borate

Potassium and sodium phosphate

Potassium and sodium citrate

Tonicity agents

Buffers

Dextrans

Dextrose

Glycerin

Propylene glycol

Potassium and sodium chloride

Adapted from Bartlett JD, et al., eds. Ophthalmic drug facts. St. Louis, MO: Wolters Kluwer Health, 2007; and Ali Y, et al. Adv Drug Deliv Rev 2006.

32 CHAPTER 2 Ophthalmic Drug Formulations

Molecular viscosity, which is measured in centistokes, is a nonlinear function of molecular weight and of concentration. Thus, a 2% solution of polymer in water usually does not have twice the viscosity of a 1% solution. Each batch of a commercial polymer therefore must be measured for viscosity at the appropriate concentration. The addition of salts can affect the final viscosity of some polymers. Divalent anions and cations can have a major effect on the conformation of polymers in solution, occasionally causing incompatibilities when formulations are mixed together in the eye.

Polyvinylpyrrolidone

Polyvinylpyrrolidone (PVP, U.S. Pharmacopeia [USP] name, povidone) is the homopolymer of N-vinyl-2-pyrroli- done, which was used as a blood plasma substitute during World War II. Although PVP is considered to be a nonionic polymer, it has specific binding and detoxification properties that are of great interest in health care. For example, it complexes iodine, reducing its toxicity 10-fold while still allowing bactericidal action to occur. This occurs through the formation of iodide ions by reducing agents in the polymer, which then complex with molecular iodine to give tri-iodide ions. PVP can also complex with mercury, nicotine, cyanide, and other toxic materials to reduce their damaging effects.

The pharmacokinetics of PVP is well understood as a result of this agent’s experimental use to determine the properties of pores in biological membranes. PVP molecules can readily penetrate hydrophilic pores in membranes if they are small enough, and they are also taken up by pinocytotic vesicles. Apparently, PVP is not detectably bound to membrane surfaces and hence does not provide long-lasting viscosity enhancement beyond the normal residence time in the tears.

PVP has very low systemic toxicity, shows no immune rejection characteristics, and is easily excreted by the kidneys at molecular weights up to 100,000 Da.The pKa of the conjugate acid (PVP . H+) is between 0 and 1, and the viscosity of PVP does not change until near pH 1, when it doubles.Therefore the ionic character of the PVP chain should not be appreciable at pharmaceutical or physiologic pH values. However, with ionic cosolutes, anions are bound much more readily than are cations by PVP.

Polyvinyl Alcohol

Introduced into ophthalmic practice in 1942, polyvinyl alcohol (PVA) is a water-soluble viscosity enhancer with both hydrophilic and hydrophobic sites. A common concentration used in ophthalmic preparations is 1.4%. PVA is useful in the treatment of corneal epithelial erosion and dry eye syndromes because it is nonirritating to the eye and actually appears to facilitate healing of abraded epithelium. It is used also to increase the residence time of drugs in the tears, aiding ocular absorption.

Hydroxypropyl Methylcellulose

Like PVA, the viscosity enhancer hydroxypropyl methylcellulose is available in a variety of molecular weights and in formulations with different group substitutions. It has been shown to prolong tear film wetting time and to increase the ability of fluorescein and dexamethasone to penetrate the cornea. Hydroxypropyl methylcellulose 0.5% has been shown to exhibit twice the ocular retention time of 1.4% PVA.

Carboxymethylcellulose

Carboxymethylcellulose is a vehicle whose properties in solution resemble another cellulose ether, hydroxymethylcellulose. However, the carboxylic and hydroxylic groups provide anionic charge, which may be valuable in promoting mucoadhesion and increasing tear retention time.Tensiometric testing has shown that carboxymethylcellulose has a greater adhesion to mucins than do other viscous vehicles currently used in ocular formulations (Table 2-4). Greater efficacy was demonstrated of unpreserved artificial tears containing carboxymethylcellulose over a preserved formulation of hydroxypropyl methylcellulose. Direct comparison of the two agents is similar, whereas the unpreserved formulation has yet to be demonstrated.

Table 2-4

Mucoadhesive Performance of Several Polymers

From Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev 2006.

Sodium Hyaluronate

High-molecular-weight polymers, including mucin, collagen, and sodium hyaluronate (SH), have a viscosity that rises more rapidly than would be expected from increased concentration alone. When these substances are exposed to shear (e.g., with the motion of blinking), the viscosity decreases as the molecules orient themselves along the shear forces.This non-Newtonian property is termed shear thinning. An advantage of shear-thinning polymers is that they have a high viscosity in the open eye, stabilizing the tear film. When blinking occurs, such polymers thin, preventing the feeling of irritation that would occur with a high-viscosity newtonian fluid.

Several studies have demonstrated that SH remains in contact with the cornea for a longer time than does isotonic saline. Gamma scintigraphy has also shown that a solution of 0.25% has a longer residence time in the precorneal area of humans than does phosphate buffer solution. In addition, when 0.25% SH is combined with certain agents, it can enhance their ocular bioavailability. Compared with phosphate buffer solution, 0.25% SH significantly increases tear concentrations of topically applied gentamicin sulfate at 5 and 10 minutes after instillation. More studies are necessary to establish the safety of SH and its ability to maintain efficient drug levels in the precorneal area.

Gel-Forming Systems

A newer development in ocular drug delivery systems is the use of large molecules that exhibit reversible phase transitions whereby an aqueous drop delivered to the eye reversibly gels on contact with the precorneal tear film. Such changes in viscous properties can be induced by alterations in temperature, pH, and electrolyte composition. Gelrite, a polysaccharide low-acetyl gellan gum, forms clear gels in the presence of monoor divalent

cations typically found in tear fluid. Gelrite enhances corneal penetration and prolongs the action of topically applied ocular drugs (Figure 2-8). Comparison of timolol in the gel formulation (Timoptic-XE) to a standard solution has shown that a single daily dose of the gel is as effective in lowering IOP in patients with open-angle glaucoma as is twice-daily instillation of the solution.

A heteropolysaccharide (xanthan gum) vehicle also produces longer ocular surface contact time and has been incorporated into a once-daily timolol gel formulation (Falcon gel-forming). Twenty-one minutes after instillation, 12% of a reference solution, 25% of the xanthan gum solution, and 39% of Gelrite solution remain on the ocular surface (see Figure 2-8).

Polyionic Vehicles

Advances in chemical synthesis and in an understanding of the tear film of the eye have resulted in the development of compounds with two or more regions that vary in both their lipophilic nature and binding. The first of these to be tested in the eye was poloxamer 407, a block polymer vehicle with a hydrophobic nucleus of polyoxypropylene, and hydrophilic end groups of polyoxyethylene. One advantage of poloxamers is their ability to produce an artificial microenvironment in the tear film, which can greatly enhance the bioavailability of lipophilic drugs such as steroids.

Polyacrylic Acids

Several of the polyacrylic acids are used as vehicles for various ophthalmic products.The polyacrylic acids, such as the carbopol gels, display pseudoplastic properties, demonstrating a decrease in viscosity with increasing shear rate, blinking, and ocular movement.These properties allow for greater patient acceptance. The carbopol gels also demonstrate good mucoadhesive and wetting

Time (min)

Ref. sol.

HEC 0.325%

Xanthan gum 0.3%

Gelrite R 0.6%

34 CHAPTER 2 Ophthalmic Drug Formulations

properties on the surface of the eye. Ophthalmic products containing carbopol gels include Pilopine gel (carbopol 940), Vexol (carbomer 934P), Betoptic S (carbomer 934P), and Azopt (carbomer 974P).

Cation Exchange Resin (Amberlite)

Emulsions are biphasic lipid–water or water–lipid combinations that can dissolve and deliver both hydrophilic and lipophilic compounds. A binding agent, such as the polyacrylic acid polymer carbopol 934P, is added to the mixture to enhance physical stability and ease of resuspendability of the product. This system has been used with the topical antiglaucoma drug betaxolol. Betaxolol is first combined with a cation exchange resin to which it binds. This binding reduces the amount of free drug in solution and enhances ocular comfort after topical application.The drug-resin particles are then incorporated into a vehicle containing the carbopol 934P, which increases viscosity of the formulation and prolongs ocular contact time of the drug. The ocular bioavailability of 0.25% betaxolol suspension (Betoptic-S) is equivalent to that of 0.5% betaxolol solution.

Ointments

Ointments are commonly used for topical application of drugs to the eye.These vehicles are primarily mixtures of white petrolatum and liquid mineral oil with or without a water-miscible agent, such as lanolin.The mineral oil is added to the petrolatum to allow the vehicle to melt at body temperature, and the lanolin is added to the nonemulsive ointment base to absorb water. This allows for water and water-soluble drugs to be retained in the delivery system. Commercial ophthalmic ointments are derivatives of a hydrocarbon mixture of 60% petrolatum USP and 40% mineral oil USP, forming a molecular complex that is semisolid but melts at body temperature. In general, ointments are well tolerated by the ocular tissues, and when antibiotics are incorporated they are usually more stable in ointment than in solution.

The primary clinical purpose for an ointment vehicle is to increase the ocular contact time of the applied drugs.The ocular contact time is approximately twice as long in the blinking eye and four times longer in the nonblinking (patched) eye as compared with a saline vehicle. Ointments are retained longer in the conjunctival sac because the large molecules of the ointment are not easily removed into the lacrimal drainage system by blinking. A nonpolar oil is a component of tears, and this is another factor in the prolonged retention. Because ointments are nonpolar oil bases, they are readily absorbed by the precorneal and conjunctival tear films. Ointments are used to increase drug absorption for nighttime therapy or for conditions in which antibiotics are delivered to a patched eye, such as corneal abrasions, because they markedly increase contact time. They are also useful in treating children because they do not wash out readily with tearing. Ointments have several disadvantages,

however, including transient blurred vision, difficult administration, and potential for minor corneal trauma.

Colloidal Systems

Various colloidal systems have been studied for use as potential ophthalmic delivery systems, including liposomes and nanoparticles. Liposomes are bioerodible and biocompatible systems consisting of microscopic vesicles composed of lipid bilayers surrounding aqueous compartments. Liposomes have demonstrated prolonged drug effect at the site of action but with reduced toxicity. Ophthalmic studies have included topical, subconjunctival, and intravitreal administration, but no commercial preparations are currently available for ophthalmic use.

Nanoparticles are polymeric colloidal particles that consist of drug-entrapped macromolecular materials. Nanoparticles represent a comfortable, extended-duration, drug delivery system that has the potential to preferentially adhere to inflamed eyes.

Cyclodextrins

Cyclodextrins are a group of cyclic oligosaccharides consisting of a hydrophilic outer surface of six to eight glucose units incorporating lipid-soluble drugs in their center. They are soluble in water and are often used to improve solubility, stability, or irritability of various compounds. They have demonstrated increased ocular bioavailability and have been studied for potential ophthalmic administration.

Drug Release Systems

Soft contact lenses and collagen shields absorb drugs from solution and then slowly release them when placed on the eye. This form of drug therapy can be valuable when continuous treatment is desired (see Chapter 3).

Two major types of advanced drug release systems have been designed on the basis of insertion of a solid device in the eye.The first is a device of low permeability filled with drug (Ocusert), which has been discontinued. The second is a polymer that is completely soluble in lacrimal fluid, formulated with drug in its matrix (Lacrisert). Both systems can be made to approach zero-order kinetics. However, patient acceptance has been poor.

In recent years intraocular delivery of medication, including anti–vascular endothelial growth factor, corticosteroids and related compounds, and antiviral agents, has either been approved or is under study for treatment of macular degeneration, uveitis, cytomegalovirus, or diabetic macular edema (Table 2-5).This area of research and development is growing rapidly.

A ganciclovir intravitreal implant (Vitrasert, Chiron Vision, Claremont, CA) that has been developed provides release of 4.5 mg ganciclovir from a PVA and ethyl-vinyl-acetone polymer pellet at approximately