ocular drug delivery conventional ocular formulations

advanced

drug delivery reviews

ELSEVIER Advanced Drug Delivery Reviews 16 (1995) 39-43

Ocular drug delivery conventional ocular formulations

John C. Lang Alcon Laboratories. Inc., 6201 S. Freeway, Fort Worth, TX 76101, USA

(Received 13 March 1995; accepted 16 March 1995)

Abstract

Within the last few decades, in response to the advent of potent and versatile therapeutic agents, the diversity of conventional ophthalmic formulations has gradually evolved, extending well beyond simple solutions, and now includes a variety of types of drug administration. In most recent publications, authors have broadened the notion of conventional ophthalmic delivery systems to encompass more than simple solutions and suspensions [l]. While not strictly ‘conventional’, the ready availability of several commonly used drug vehicles suggests they have achieved acceptance, have been elevated to the category of conventional, and will be considered in this comparison.

In this article, I have summarized the types of commonly used ophthalmic formulations, indicated the generality of their applicability and acceptance, differentiated their characteristics and utility, and projected anticipated use and development in the decade to come. This should also serve to put into perspective the discussions of more sophisticated components and elaborations described in this issue.

Keywords: Ocular drug delivery; Conventional formulation; Ophthalmic dosage forms

Contents

1. Conventionaldosageforms ...................................................................................... 39 2. Dosageformsforthe21stcentury ................................................................................ 41 3. Conclusion ..................................................................................................... 43 References ........................................................................................................ 43

1. Conventional dosage forms

The data in Table 1 result from analysis of the medications listed in the current Physicians’ Desk Reference for Ophthalmology [2], summa- rizing ophthalmic medications available in the U.S.A. In terms of availability of the dosage form, solutions, ointments, and suspensions ac- count for nearly 90% of currently accessible

Table 1 Common dosage forms

Formulation Number %

Gels 2 0.7 Injectables 11 3.8 Inserts 11 3.8 Ointments 50 17.4 Orals 9 3.1 Solutions 179 62.4 Suspensions 25 8.7

0169-409X/95/$29.00 0 1995 Elsevier Science B.V. All rights reserved SSDI 0169-409X(95)00012-7

40 J.C. Lang I Advanced Drug Delivery Reviews 16 (199.5) 39-43

formulations. Because some of the components found in the more common dosage forms can also be incorporated into the other types, the compositions and properties of these three dosage forms will be described and contrasted first.

Provided in Table 2 is a list of the generic components found in these three common formulations. None of those listed in the Physi- cians’ Desk Reference [2] will include all of the components listed in the Table in a single formulation; however, the contrasting components for the different vehicles suggest the types of use and applications anticipated. In Table 2, X indicates the component is included-or generally included-in the formulation, Y is optional.

The complexity of ophthalmic formulation is evident from Table 2, in which the number of components and hence the multiplicity of interactions, can be extensive. The consequence is that each generic component, included at a particular concentration as a means to impart a specific property of selected magnitude, is often influenced by the presence of one or more other ingredients. For example, a cationic preservative can degrade the efficacy of either an anionic drug or an anionic solubilizer, the latter being essen- tial for increasing transcorneal flux. The influence of a mixture of components on each other’s chemical activity is well known [3,4], and in these ophthalmic applications may result in conse-

Table 2

Formulation components for common dosage forms

Component descriptor Solution

quences influencing drug transport, drug stability, and ultimately efficacy [5,6].

Of even greater consequence are USP requirements for sterility and absence of foreign par- ticles [7]. These requirements are compounded as the number of components or their phases is increased. Especially when the suspension con- sists of drug, not drug carrier, the opportunity for either degradation or morphological change dur- ing sterilization exists and must be prevented.

Many variables control availability and each is dependent on composition. For solutions or solubilized compositions, chemical activity, total drug concentration and kinetics of transport to/ from any carrier (e.g., microemulsion) all play a significant part in controlling total transmem- brane flux. The physical properties of the drug itself are known to influence final drug disposi- tion and availability in ocular tissue [8]. For suspensions, the size and physical properties of the carrier (or the drug itself if the drug is insoluble) contribute to control of availability. The complex role of the interaction between membrane permeability, drug properties and vehicle /formulation design has been described in numerous publications and reviews [6]. There, the significance of competing kinetic processes has been shown to possess the capacity to in- Auence, and in some instances extend, the duration of the effects of drug administration.

Suspension Ointment

Drug

Drug carrier

Water

Buffer/acid and base

Preservative

Tonicity agent

Salts

Viscosifier

Bioadhesive agent

Phase modifier

Suspending agent

Solubilizer

Permeation enhancer

Wax/petrolatum/oil

Crosslinked polymer

X X Y Y

X X X Y Y

Y Y Y

Y

Y Y Y

X

J.C. Lang I Advanced Drug Delivery Reviews 16 (1995) 39-43 41

Similar considerations apply to the less common dosage forms whose generic compositions are summarized in Table 3. However, the in- fluences affecting bioavailability and efficacy directly in the simpler dosage forms now impact these properties both directly and indirectly; in particular, the interactions of ‘minor’ components with the ingredient responsible for impart- ing the defining property of the dosage form may also degrade or even eliminate that property. For example, pH or ionic composition can simul- taneously degrade the strength of a gel while increasing solubility and short-term transport of a drug. So the AUC and the total bioavailability may have been diminished even though drug transport characteristics were improved [9].

Once the drug has penetrated the outer layer of the cornea or sclera, transport is dictated by the diffusional characteristics of the therapeutic agent (as long as the transport is passive). These are related to molecular properties such as molecular weight or molecular volume, and binding characteristics of tissue binding sites, as well as clearance characteristics of the fluid reservoirs [6,10]. Therefore, after entry of the therapeutic agent into ophthalmic tissue, the dosage form no longer has any effect or impact, unless components of the dosage form concurrently enter the tissue. In some circumstances the effect can be beneficial, as in the case when a non-toxic permeation enhancer increases the transmem-

Table 3

Formulation components for less common dosage forms

Component Gel Oral/injection Insert

Drug X X X

Drug carrier Y Y Y

Water X X Y

Buffer/acid and base X X

Preservative X X

Tonicity agent Y Y

Salts Y Y

Viscosifier Y

Bioadhesive agent Y Yl- Y

Phase modifier X Y

Suspending agent Y

Solubilizer Y Y

Permeation enhancer Y Y Y

Wax/petrolatum/oil

Crosslinked polymer X

brane flux, but in others can be detrimental, as in the circumstance when a preservative is toxic or causes sloughing of outer layers of epithelia.

The selection of amount and specific material or compound, which is intended to provide the particular characteristics required to achieve its ‘generic’ function, is dependent on the comple- ment of other materials/quantities included in the entire formulation. The selection process is clearly sophisticated and interdependent. For example, a specific carrier may be required or selected on the basis of stability or toxicity of the active therapeutic agent. But its structure, includ- ing perhaps crosslinking or charge density, can affect binding of a viscosifier whose own properties can be influenced by ionic strength or stabilizer. Such intricate problems are generally solved by the pharmaceutical scientist by im- plicitly or explicitly defining a hierarchy of con- straints based on significance to the design of the final product and then iterating on the choice/ quantity of a compound based on the criteria established by the hierarchy.

The utility or selection of different dosage forms is generally based on the significance to the therapeutic agent. A summary of some cen- tral properties or principal concerns in selecting a particular form is provided in Table 4. While not comprehensive, the table includes major recur- rent, sometimes competing, considerations that affect feasibility and impact selection of dosage forms. As suggested by the first position in Table 4, the properties of the drug are often the most significant determinant of dosage form and design. More accurately, however, the table can be considered a matrix of choices, often one of which will be dominant for a particular drug and formulation.

2. Dosage forms for the 21st century

The continuing developments in materials and pharmaceutical technologies-especially the current trends toward specific, high-potency, targeted therapeutic entities-indicate the pivotal role of drug delivery and formulation design. A survey of dosage forms found in worldwide literature and both U.S. and foreign patents is

42

Table 4

J.C. Lang I Advanced Drug Delivery Reviews 16 (1995) 39-43

Criteria for selection of dosage form

Gels lniectables Inserts Ointments Orals Solutions Suspensions

Drug:

Long

duration

required/

provided

LOW

bioavailability

Drug:

Target site accessibility

Speed of response

Drug:

Long duration

required

Low bioavailability

Drug:

Long duration

required

Low bioavailability

Drug:

lmperme-

able topically

Few system.

side effects

Drug:

Soluble or

Solubilizable

Less potent.

requiring high

concentrations

Low to modest cost

Low cost

Little blurring

Selection: Selection: Drug design Convenient not optimized Accepted

Safety: Safety:

Solutions clear

Drug:

Insoluble drug

Potent

Intermediate

cost

Requires

physician

High cost per

dose

No blurring

Selection:

Good control

of rate admin.

Younger patients

Low co\1 Low cost

Some blurring

Selection:

Simple

admin.

Reduced freq

administering

Severe blurring

Selection:

Sight

threatening

Little blurring

Selection:

Convenient

Accepted

Some extend. duration

Selection:

Last

alternative

Surgical application

Safety: Safety: Safety:

Unnoticed expulsion

Safety: Safety:

Solutions cloudy

provided in Table 5. The emergence of innova- tive means for improving therapeutic efficacy suggests that a greater choice of dosage forms will be provided physician and patient in the next decade.

The data were gathered consistently for ophthalmic dosage forms offering therapeutic benefit by means of modification in drug delivery. In almost every category some ambiguity might tend to invalidate the specific numerical assess- ment. Hydrogel components and properties, and non-therapeutic uses of artificial lenses were eliminated from inclusion as gel delivery devices/

phenomena. The injection of anesthetics was retained as a drug delivery dosage form under injectables. Surgical solutions used for intraocu- lar injection were included in the solution delivery forms. While not quite arbitrary, such deci- sions might be construed to bias the analysis. On the other hand, there was no intent to do so and the conclusions drawn from the data would appear not to be affected significantly.

The data in Tables 1 and 5, and in particular the decrease in relative number of recent patents (both U.S.A. and non-U.S.A.) devoted to solution dosage forms, measure the significant effort

Table 5

U.S. publications and patents for the last decade

Formulations Publications (total)

Number %

IJ.S. patents

Number %

Non-U.S. patents

Number %

Gels 105 2.6 62 21.2 12 12.2

Injectables 941 23.1 36 12.3 21 21.4

Inserts 73 1.x 48 16.4 Y 9.2

Ointments 164 4.1 28 9.6 10 10.2

Orals 567 14.3 s7 19.5 20 20.4

Solutions 2011 so.7 35 12.0 22 22.4

Suspensions 107 2.7 26 8.‘) 4 4.1

Total

J.C. Lang I Advanced Drug Delivery Reviews 16 (1995) 39-43 43

being addressed toward developing alternate dosage forms. While the number of publications still indicates an emphasis on solutions, the trends would suggest that despite the practical reasons for selecting solutions for research-the generally favorable patient acceptance, the generally favorable cost advantage, often the greater simplicity of formulation development and production-considerable effort is being directed toward patenting new formulations. The benefits to the patient are simplicity and diminished frequency of administration (higher potency), diminished toxicity especially for internal ophthalmic administration, reduction of side effects (increased therapeutic ratio), compatibility with adjuvant therapies, increased compatibility and stability for novel classes of drug capable of providing unique pharmacological control/response, or collateral benefit for newly developed surgical procedures.

3. Conclusion

There is a multiplicity of reasons for increased interest in alternate dosage forms. Also, with advancements in technology development in material science, factors such as new surgical procedures or new therapeutical classes, will dictate unique formulation requirements. These range from addressing deficiencies in drug stability, transport and kinetics, providing supplemental contributions in efficacy, increasing site specifici-

ty. While the principles of physical pharmacy are

well-known [II], and the number of patents and publications provide a wealth of specific infor- mation, the solution of specific problems in formulation relies on the ingenuity of the in- dividual formulator who inevitably needs to balance a variety of often conflicting requirements. The choice of a dosage form and its components needs to be compatible with drug, tissue, intended use (chronic or acute), concur- rent administration of other therapeutic agents

(e.g., systemic medications). and economics of the therapeutic benefit.

But at least as important, especially for dosage forms selected and utilized by the patient, the dosage form must take into consideration patient requirements, age, probability of alternative dis- ease processes, perceived comfort, patient safety and compliance. For a less conventional dosage form to become preferred, it will need to be justified by performance and patient acceptance.

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PI

[31

(41

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bl

[71

PI

191

[lOI

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ocular drug delivery conventional ocular formulations

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