recent developments in drug delivery systems for the eye

IAN H. PITMAN, Ph.D. School of Pharmaceutics Victorian College of Pharmacy

SUMMARY The advent of the OcusertR Systems for topical

delivery of drugs to the eye has significantly improved the efficiency of ocular drug therapy. Similar advances will follow the introduction of other new preparations for the eye. This paper attempts to relate the development of these new methods of administering drugs to an increased understanding of factors which are involved.

Intensive efforts are being made to improve the efficiency of all types of drug therapy. A defini- tion of an efficient drug therapy is one which employs the smallest amount of drug that is necessary to produce the desired pharmacological response while minimizing the number and severity of side effects.

One method of maximizing the efficiency of drug therapy is to employ a system which delivers drug in a controlled manner to its site of action. The development of such drug delivery systems depends on a clear understanding of ( a ) the location of the site of action (b) the most desirable drug concentration versus time profile at the site of action, and (c) the nature of the chemical interactions that occur between the drug and its biological envi- ronments within the body.

In many respects drug product formulators are in a better position to-day to prepare efficient drug delivery systems for chemotherapy of diseases of the eye than for most other organs. This situation exists because the site of action for most drugs for the eye can be clearly defined as being either in the precorneal area

Delivered at the Victorian Day Congress, October 22, 1976.

Address for reprints: Professor Ian Pitman, Victorian College of Pharmacy, 381 Royal Parade, Parkville, Victoria 3052.

(e.g. eye-lids, conjunctiva, or the cornea itself) or in tissues within the eye. Hence, a topical route of administration which involves introduction of drugs into lacrimal fluid is readily available for many useful ocular drugs. Nevertheless, until quite recently little attention was paid to the effect on drug delivery to the eye of such factors as instilled fluid drainage, tear turnover, protein binding and metabolism of drugs, and to the precise mechanism of corneal absorption. This situation has led, in many cases, to erratic therapy and serious side effects.

This paper reviews some of the factors which influence topical drug delivery to the eye and describes some of the newer preparations that have been developed to produce efficient therapy.

FACTORS WHICH INFLUENCE DRUG DELIVERY TO

(i) Instilled Fluid Drainage The volume of liquid that the pre-corneal

region of an adult eye can accommodate has been estimatedl to be about 30 pl. The volume of a normal eye-drop is 50-75 pl. A comparison of these two figures shows that more than 50% of a properly instilled eye-drop cannot be accom- modated by the eye. Most of the excess drains away immediately via the lacrimal drainage system to the back of the throat. Some liquid splashes out of the eye. These facts raise several problems:

( a ) the fact that most of a drop is immediately lost to the eye means that the concentration of drug in the eye-drop must be adjusted in such a way that an effective amount of drug remains in the lacrimal fluid after the initial drainage is complete;

(b) the drainage system from the eye is quite vascular and hence, although the 'drained' drug is not available to the eye it may enter the systemic system and cause unwanted effects;

THE EYE FOLLOWING TOPICAL ADMINISTRATION

RECENT DEVELOPMENTS IN DRUG DELIVERY SYSTEMS FOR THE EYE 101

( c ) the drug which is splashed out of the eye comes in contact with skin and other tissue and may cause a sensitivity reaction.

It has recently been demonstrated by Patton and Robinson,? that fluid drainage is by far the major cause of loss of pilocarpine from a rabbit’s eye following the instillation of pilocarpine nitrate eye-drops.

The above considerations lead to the conclusion that optimal drug delivery would be achieved by minimizing the volume of instilled solution. However, consideration of point (ii) , which deals with tear production and turnover, suggests that if the volume of instilled solution is too small the concentration of drug in the lacrimal fluid will undergo gross changes and the bioavailability of the drug will be reduced. Nevertheless it is evident that the current practice of instilling 50-75 p1 of drug solution does not lead to efficient therapy. The above factor also indicates a possible advantage of combination eye-drops as compared to the need for instilling relatively large volumes of solutions of a number of different drugs.

(ii) Tear Production and Turnover The normal volume of lacrimal fluid in the

eye has been estimatedl to be 7 pl and this is being turned over at a rate of 16% per minute. When the effect of this ‘diluting factor’ is combined with the previously mentioned ‘drainage factor’ it becomes evident that the effective concentration of drug in the lacrimal fluid is very different to that in the original preparation, and that it is changing continuously.

The rate of turnover of lacrimal fluid is even greater than 16% per minute when the eye is irritated by a foreign body or by the introduction of an irritating solution. This latter factor is one of the reasons why eye-drops and other preparations for the eye should be iso-osmotic with, and have the same pH value as, lacrimal fluid.

(iii) Protein Binding Tears normally contain a considerable amount

of protein. These proteins facilitate the wetting of the surface of the eye by the lacrimal fluid but they bind strongly to many drugs and make them unavailable for absorption. A further complication arises because irritation or inflam- mation of the eye leads to an increase in the protein content of the lacrimal fluid and hence increases protein binding.

Little can be done using formulation approaches to combat this problem, but it must be born in mind when deciding on the concentration of drug in the eye-drops and their compati- bility with the tissues of the eye.

(iv) Metabolism The lacrimal fluid and ocular tissues are rich

in enzymes, and drugs that are administered by the topical route must, in common with drugs administered by other routes, run the gauntlet of metabolizing systems.

(v) Mechanism of Corneal Absorption The cornea is a membrane that all drugs must

cross in order to pass from the lacrimal fluid to the interior of the eye. The predominant mechanism of transport involves passive diffusion and, because the corneal membrane is hydrophobic, neutral molecules cross the membrane more rapidly than ions.

Many of the drugs that are used in the eye are weak acids (e.g. sulphacetamide) or weak bases (e.g. pilocarpine) and hence can exist as ions and neutral molecules, the relative propor- tion of each being determined by the pH value of the fluids in which they are dissolved. Because the lacrimal fluid has a very low buffer capacity its pH value is greatly influenced by the acidity or basicity of any preparation that is introduced into the eye. Consideration of the above factors leads to the conclusion that the pH value of eye-drops and related preparations should be adjusted so that any acidic or basic drugs exist predominantly as neutral molecules. However, the advantages that may be gained for cornea1 penetration by this approach are often offset by considerations of the chemical stability of the drug in the preparation, or the increased turnover of tears that accompanies the introduction of a solution with a very different pH value to that of lacrimal fluid.

Because drug transport into “the inner eye” and into other tissues such as eyelids occurs by passive diffusion, the concentration of drug in the lacrimal fluid must be as large as possible and the ‘contact time’ of the drug in the lacrimal fluid with the tissues must be as long as possible. Both of these factors are known to facilitate the passive transport of drugs.

An interesting calculation can be done to illustrate the possible benefits of using small drops of concentrated solutions of drugs rather than large drops of less concentrated solutions. Hence, the instillation of a 25 pl drop of a 1% solution of drug into an eye that contains

102 AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

7 yl of lacrimai fluid results in an initial drug concentration in the lacrimal fluid of 0.78%. On the other hand, the instillation of 5 pl of a 5% solution of drug (i.e. the same amount of drug) results in an initial concentration in the lacrimal fluid of 2.1%. The latter dosage form would thus facilitate the absorption of a drug that was absorbed by a ‘passive mechanism’.

One of the major factors that reduces the mntact time of drugs with absorbing tissues is the turnover of lacrimal fluid. There is little evidence that the attempts to increase contact time, such as increasing the viscosity of drug vehicles, has any significant effect on corneal absorption.

(v i ) Drug Concentration versm Time Profiles

The ideal drug delivery system would be based on a clear knowledge of the most desirable concentration of drug versus time at the site of action. This information is rarely accessible. In its absence, very useful information is the desired concentration of drug versus time profile at the site of administration.

The instillation of eye-drops results in a first order change in concentration of drug in the lacrimal fluid. A typical profile is shown as the dotted line in Figure 1. One consequence of drug delivery that has a profile of this type is that there is a period when the drug concentration is much higher than is desirable for good therapy (and may lead to toxic reactions) and a considerable period when the Concentration is below a therapeutically useful level. Another type of profile is attainable if drug is released at the site of administration at a constant rate (i.e. in a zero order manner). Under these circumstances it is relatively easy to ensure that the concentration of drug at the site of administration remains constant and a zero order profile such as illustrated by the dashed line in Figure 1 is created.

It must be emphasized that it is not known. a priori, what the most desirable delivery pattern is for any particular drug in a specific disease. This must be established by experiment.

NEW DRUG DELIVERY SYSTEMS FOR THE EYE

(i) The OcusertR System The OcusertR System for topical drug delivery

to the eye was introduced to the American market in 1975 by the Alza Corporation. It is currently being considered for the Australian market by May and Baker Ltd.

at the Site of Action

The OcusertR System is a small plastic device which is designed to sit in the cul-de-sac of the eye. It is programmed to release drug at a particular rate for a pre-determined period of time.

The first two OcusertR Systems to be released were the Ocusert Pilo-20 and Ocusert Pilo-40 Systems. The former releases pilocarpine at the rate of 20 mcg/hr for 7 days and the latter releases the same drug for 7 days at a rate of 40 mcg/hr. These Ocusert Pilo Systems consist of a reservoir of pilocarpine ( a synthetic

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T I M E FIGURE 1 : Hypothetical drug concentration wrsus

time profiles at the site of administration.

membrane that is saturated with the liquid drug) which is enveloped in a synthetic polymeric membrane. An opaque inert ring is included in the device to make it visible in the eye and thus facilitate its removal. The drug is released from the device when the outer polymeric membrane is wetted by lacrimal fluid. The rate of release of drug is determined by the chemistry of both the drug (pilocarpine) and the membrane and thus a particular membrane is usually only suitable for fabricating dosage forms of a single drug.

The physical and chemical properties as well as the clinical effectiveness of the Ocusert Pilo Systems for the treatment of glaucoma has been extensively reviewed e l s e ~ h e r e . ~ - ~ The improve-


ment in the efficiency of drug treatment of patients may be refracted to compensate glaucoma that they represent when compared to for the lower, but constant, level of pilocarpine eye-drops can be summarised as induced myopia. follows: (b) Elderly patients, who may undergo less

(a) Ocusert Pilo Systems produce a zero impaired night vision from the OcusertR order drug concentration versus time System, compared to pilocarpine eye- profile in the lacrimal fluid. Eye-drops drops, due to less miosis. &at are instilled periodically result in (c) The Patient in whom other forms of first order delivery. It has been established therapy are less practical. Examples of that a.zero order pattern of release of these situations are congenital glaucoma, pilocarpine gives rise to excellent control and cases involving patient non-com- of ocular pressure in glaucomatous pliance on the eyedrop regimen. patients. 3. Experience has shown that all patients

placed on the OcusertX System must be taught (b) The total amount of pilocarpine released how to wear it. Following recommendation of by an Ocusert Pilo-20 system during days is 3.5 mg. This is sufficient drug the system by the physician, and minimal train-

ing of the patient in its use, most patients have to control the ocular pressure in patients no difficulties. Some patients do have difficulties, who would normally instill 2 drops of however, in placing, locating or removing the 2% pilocarpine solution four times a day. The patient on the latter therapy would, unit, or particularly in retaining the unit in the

eye. Most of these patients, if encouraged to however, receive 28 mg and not 3.5 mg stick with it for the first few days, go through something of a 'learning curve', and have no of drug in a week.

Of problems afterwards. Certain patients cannot,

been established that this diurnal control OcusertR System. In general, most patients learn

that obtained with eye-drops that are instruction and encouragement.?, normally only used over a '6 hour period. One limitation of the current OcusertR Systems from Pilo- is that the rate of drug release is controlled by

carpine eYe-droPs are miosis and changes the specific chemistry of the drug (pilocarpine) in refraction. The use of Ocusert Pilo and of the enveloping synthetic polymeric Systems significantly reduces the severity membrane. Because other drugs which may be of these side effects. required for the treatment of glaucoma, such as

An interesting summary of clinical findings adrenaline, are chemically very different from on the Ocusert Pilo Systems has recently been pilocarpine, they cannot be combined with pilo- made by Dr. John Shell of the Aha Corporation. carpine in the same delivery system. A step He states: towards overcoming this problem has been made

6L1. The OcusertR System is indicated for in the new types of OcusertR Systems that are control of elevated intraocular pressure in certain being the Corporation* These glaucomatous patients, but it is not systems consist of a suspension of solid particles for use in every patient. Where of drugs within a polymeric membrane. When

this type of OcusertR System is placed in the properly used pilocarpine eyedrops fail, so will eye the first reaction that occurs is the diffusion the OcusertR System. of water across the membrane to a solid drug

to date with the OcusertR particle. This leads to dissolution of the drug System has three types Of patient and the creation of osmotic pressure. The device where the System appears to offer useful benefits. is designed in such a way that the osmotic These are: pressure bursts the membrane and releases the

(a) The active patient who needs unimpaired dissolved drug. The rate of release of drug is eyesight in his daily routine and who determined by the rate at which water penetrates suffers from induced myopia following the membrane and is virtually independent of eyedrop instillation. Studies have shown the chemistry of the drug. Hence this new type that patients experience a less intense of OcusertR System is capable of deliverying a induced myopia from the OcusertR wide variety of single drugs or a combination of System. Moreover, it is possible that drugs in any desired pattern.

('1 The OcusertR Systems give ocular Pressure during 24 hours and it has it would appear, ever be candidates for the

results in better than to use the system readily; yet require

(d) The major side effects

104 AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

(ii) Adrenaline Pro-drug McClure@ recently reported the development

of a new delivery system for adrenaline in the eye. This delivery system is not a device but it is a solution of a pro-drug of adrenaline. A pro-drug is a pharmacologically inactive chemical derivative of a drug which is trans- formed to the pharmacologically active agent following its administration to the body. The rationale for using a pro-drug rather than the

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ADRENALINE P I V A L I C A C I D

FIGURE 2: Transformation of adrenaline pro-drug to adrenaline.

active drug is that it overcomes some barrier to absorption or distribution, in a more efficient manner.

The pro-drug of adrenaline that Allergan Pharmaceuticals are investigating is the dipivalyl ester of adrenaline. The pro-drug and the chemical transformation that it must undergo within the body are represented in Figure 2. There is evidencelo to suggest that the pro-drug (prior to transformation to adrenaline) is pharmacologically inactive. However, the topical administration of the pro-drug to laboratory animals and humans results in a lowering of ocular pressure. The pro-drug appears to be approximately 100 times more potent than

adrenaline (i-e. 1/100th of the dose can be used). An added advantage of the pro-drug relative to adrenaline is that the effect of the former on blood pressure and pulse rate (two systemic side effects of topically applied adrenaline) is between 100 and 400 times weaker than that of adrenaline.

General pharmacological, toxicological and clinical experiences with this new dosage form are discussed by McC1u1-e.~ The advantage that the pro-drug appears to have relative to adrenaline are :

(a) increased duration of action; (b) increased bioavailability ; (c) increased potency ; (d) decreased side effects. A considerable amount of effort is currently

being expended in using the pro-drug approach for increasing the efficiency of other commonly used drugs. These efforts, together with develop ments of other types of drug delivery systems will lead to significant improvements in the effectiveness and efficiency of ocular chemotherapy.

REFERENCES ISHI HI MA, S., GASSET, A., KLYCE, S. D., and BAUM,

*PATTON, T. F., and ROBINSON, J. R. (1976), I . pharm.

'SHELL, J. W. (1974), Ophthal. Surg., 5: 71. 'SHELL, J. W., and BAKER, R. W. (1974). Ann.

Ophthal., 6: 1037. 'RICHARDSON, K. T., in "Symposium on Glaucoma",

Transactions of the New Orleans Academy of Ophthalmology, 1975: C. V. Mosby Co., St. Louis, pp. 50.

@PLACE, V. A., FISHER, M., HERBST, S., C o v o N , L., and MERRILL, R. C. (19751, Amer. I . Ophthal., 80: 706.

'QUIGLEY, H. A. (1975), Arch. Ophthal., 91: 771.

J. L. (1966), Invest. Ophthal., 5: 264.

Sci., 65: 1295.

'SETNIKAR, I., and MAGISTRETTI, M. J. (1975). Ann. Ottal., 101: 245.

'MCCLURE, D. A., in "Pro-drugs as Novel Drug Deli- very Systems", A.C.S. Symposium Serirs No. 14, eds. T. HiTuchi and V. Stella (1975). American Chemical Sncietv, Washington, D.C.. pp. 224.

'"HUSSAIN, A., and TRUELOVE, J. E. (197h), I . pharm. Sd.. 65: 1501.


recent developments in drug delivery systems for the eye

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