Ocular Pharmacokinetics And Pharmacology

Pharmacokinetics generally encompasses the process of absorption, distribution, metabolism, and excretion (ADME) of drugs. For the most part, ADME deals with systemically administered drugs that reach their pharmacological target by way of the systemic circulation, that is, blood, following oral or parenteral administration. Ocular pharmacokinetics embraces many features of ADME, but on a smaller scale and specifically applied to the eye. However, owing to the previously discussed unique...

Ocular Pharmacokinetics

The general process of ocular absorption from an eyedrop is surprisingly complex considering the simplicity of the administration method. Transcorneal absorption involves a series of events, including drug instillation, dilution in tear fluid, diffusion through the tear mucin layer, corneal penetration (epithelium, stroma, and endothelium), and transfer from cornea to aqueous humor. Parallel absorption via the conjunctiva sclera also occurs however, for the majority of drugs, this pathway is...

Contact Lens Care Products

Contact lenses are optical devices that are either fabricated from preformed polymers or polymerized during lens manufacture. The main purpose of contact lenses is to correct defective vision, and they are generally referred as corrective lenses. However, due to the recent advances in material manufacturing, reduction in fabrication cost, and their availability in many colors, they are extensively used to change the appearance of the eye. For this application, they are called cosmetic lenses....

Lymphatic Uptake

Following extravasation, drug molecules can either reabsorb into the bloodstream directly by the enlarged postcapillary interendothelial cell pores found in most tissues (67) or enter into the lymphatic system and then return with the lymph (a constituent of the interstitial fluid) to the blood circulation (Fig. 5). Also, drugs administered by subcutaneous, intramuscular, transdermal, and peritoneal routes can reach the systemic circulation by the lymphatic system (Fig. 1). Figure 5 Schematic...

Extravasation

Many diseases result from the dysfunction of cells located outside the cardiovascular system. Thus, for a drug to exert its therapeutic effects, it must exit from the central circulation and interact with its extravascular-extracellular or extravascular-intracellular target(s). This process of transvascular exchange is called extravasation, and it is governed by the permeability of blood capillary walls. The main biological features that control permeability of capillaries include the structure...

General Safety Considerations Sterility

Every ophthalmic product must be manufactured under conditions validated to render it sterile in its final container for the shelf life of the product (65,66). Sterility testing is conducted on each lot of ophthalmic product by suitable procedures, as set forth in the appropriate pharmacopoeia and validated in each manufacturer's laboratory. While the majority of topical ophthalmic preparations contain preservatives for multiple-dose use, sterile preparations in special containers for...

Long Acting Formulations

Crestar Implanter Ear

The reasons for developing a long-acting product for animals differ from those typically associated with their human counterparts. In the case of animals, the reasons to develop long-acting preparations include reduction of stress to the animal, reduced herding, and reduced labor costs. In the human field, drugs incorporated into long-acting formulations need to possess certain physicochemical properties such as high potency and low dose. These characteristics do not necessarily need to be...

Bibliography

Inhalation Delivery of Therapeutic Peptides and Proteins. New York Marcel Dekker, 1997. Byron PR. Respiratory Drug Delivery. Boca Raton CRC Press, 1990. Derendorf H, Hochhaus G. Handbook of Pharmacokinetic Pharmacodynamic Correlation. Boca Raton CRC Press, 1995. Fuchs NA. Mechanics of Aerosols. Minneola Dover Press, 1964. Ganderton D, Jones T. Drug Delivery to the Respiratory Tract. New York VCH Ellis Horwood, 1987. Gehr P, Heyder J. Particle-Lung Interactions. New York...

References

Joeres S, Tsong JW, Updike PG, et al. Invest Ophthalmol Vis Sei 2007 49 4300 1307. 2. The United States Pharmacopeia 31 (USP) The National Formulary 26. Sections (771) Ophthalmic Ointments and (1151) Pharmaceutical Dosage Forms. Rockville, MD U.S. Pharmacopeial Convention 2008. 3. Rozier A, Mazuel C, Grove J, et al. Int J Pharm 1997 153 191. 4. Lang JC, Keister JC, Missel PJT, et al. U.S. patent 5,403,841. 1995. 5. Missel PJT, Lang JC, Jani R. U.S. patent 5, 212,162. 1993. 6. Bawa R, Hall R,...

Physical Stability

In solution, the structure is not infinitely stable in the folded state (18,36), and therefore the structure is affected by production conditions, stress during preparation of the formulation, etc. The term denaturation is used to denote a process (or sequence of processes) in which the spatial arrangement of the polypeptide chains within the molecule is changed from that typical of the native protein to a more disordered arrangement (33), where spatial arrangemenf' can be replaced by...

Viable Epidermis

The animate cells of the epidermis make a sharp, upper interface with the lifeless stratum corneum. They also have a well-demarcated, deep interface with the dermis (Figure 1). When physicochemically considered, the viable epidermis is nothing more than a wedge of tightly massed, live cells. Consequently, the whole of this live, cellular mass is regarded as a singular diffusional field (resistance) in percutaneous absorption models, although, when viewed under microscope, the tissue is clearly...

Loss

(M e ta bol is rnrdeg reflation) Excretion Figure 2 Anatomical and physiological pathways for site-specific delivery. Source From Ref. 5. macromolecular assemblies and hence cannot enter into cells by such simple processes. Instead, they are taken up by a process called endocytosis, which involves internalization of the plasma membrane, concomitant with engulfment of the extracellular material. It is divided into two types phagocytosis and pinocytosis. The former refers to the capture of...

Info

Solubility is high when the highest dose strength is soluble in no more than 250 mL of aqueous media over the pH range 1 to 7.5. bPermeability is considered high when total fraction absorbed is at least 90 or is measured in vitro to be higher than that of standard compounds. Class 1 drugs must have wide therapeutic index, and their dissolution must be rapid for an in vivo bioequivalence study to be waived. An immediate release product is considered rapidly dissolving when not less than 85 of...

Mechanism of Drug Clearance and Pharmacokinetics of Disposition

The first purified and characterized drug substances were administered as aerosols as a topical treatment for asthma approximately 50 years ago. More recently, drugs have been evaluated for systemic delivery by this route. For each category of drug, the mechanism of clearance from the airways must be considered. These mechanisms may be listed as mucociliary transport, absorption, and cell-mediated translocation. The composition and residence time of the particle will influence the mechanism of...

Chemical Stability

The major pathways of chemical degradation are, among others, hydrolysis and oxidation as shown in Table 2. An unfolded polypeptide chain in a protein is more prone to chemical degradation than the native and folded protein (46). These chemical degradation reactions may be modifications involving changes in the covalent bonds, for example, deamidation, oxidation, or disulfide bond shuffling (47), and the reactions are usually irreversible (28). The breaking of peptide bonds is referred to as...

Manufacturing Techniques

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water, and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, then this sterile solution is mixed with the additional required sterile components, such as previously sterilized...

Solids

The primary solid dosage forms for veterinary medicine include tablets, capsules, and feed additives. Because animals cannot self-administer, tablets as a single-unit dosage form are used less often in veterinary medicine compared with human medicine. However, they are still a prevalent dosage form. Tablets are used in a wide variety of indications, with several species, are available in a large size range, and are manufactured by several different processes. The primary species treated with...

Staughton Laurocapram Emulsio

We acknowledge the assistance provided by K. Carlson and B. Selvamani for figures. REFERENCES 1. Lemberger AP. Eczema and psoriasis remedies. In Griffernhagen GB, Hawking LL, eds. Handbook of Non-Prescription Drugs. Washington, DC American Pharmaceutical Association, 1973 161-166. 2. Wilkes GL, Brown IA, Wildnauer RH. The biomechanical properties of skin. CRC Crit Rev Bioeng 1973 l(4) 453 t95. 3. Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev 1971 51(4) 702-747. 4. Montagna W....

Advances in Delivery of Biotechnology Based Pharmaceuticals

The use of advanced drug delivery systems for the delivery of biomacromolecules is typically either as particles or as complex liquid formulations. However, relatively few products have reached and are still on the market (83). Part of the developments is centered on exploiting new routes of administration and improving the bioavailability across the biological barriers. The quest for novel approaches to avoid barriers of adsorption and to improve delivery of biomacromolecules is an...

The Structure Of Skin

Sketch Skin

Let us consider how the skin is structured to better understand how this tissue performs some of its vital functions. Consider the cross-section of the skin sketched in Figure 1. This illustration shows the readily distinguishable layers of the skin, from the outside of the skin inward, are (i) the 10- im-thin, fully differentiated, devitalized outer epidermal layer called the stratum corneum (ii) the 100- im-thin, live, cellular epidermis and (ill) the 1000- im-thin (1-mm-thin) dermis. Note...

Drug Delivery System and Compliance Issues

Hundreds of excipients have been approved by FDA for use as inactive ingredients in drug products. The FDA Division of Drug Information Resources compiles a list of all inactive ingredients in approved prescription drug products in the Inactive Ingredient Guide (available at The FDA requires the listing of excipients in pharmaceuticals other than oral. The labeling of inactive ingredients in oral drug products is voluntary. The reported incidence of adverse drug reactions to excipients is much...

Preservation and Preservatives

In 1953, the FDA required that all ophthalmic solutions be sterile (135). Preservatives are included as a major component of all multiple-dose eye solutions for the primary purpose of maintaining sterility in the opened product through its shelf life. Packaging ophthalmic solutions in the popular plastic eyedrop container has reduced, but not completely eliminated, the chances of inadvertent contamination. There can be a suckback of an unreleased drop when pressure on the bottle is released. If...

Liquids

The previously discussed dosage forms had a solid physical appearance. This section will explore those that are classified as liquids. The three main liquid dosage forms are those administered via the mouth, injected, or placed on the skin. Oral liquids would typically be aqueous, nonaqueous, or blends to create a solution. In some cases they may be a suspension if it is difficult to find a vehicle that completely solubilizes the active or yields chemical stability. The liquid may be used...

Ocular Pharmacodynamics

It is not the purpose of this text to present an in-depth review of the pharmacodynamics of ophthalmic drugs. For this purpose the reader is referred to one of the authoritative treatments of this subject (49-51). However, since this topic is not commonly covered in pharmacy school curricula, a brief treatment is presented here. For the most part, drugs used in the eye fall into one of several categories, including miotics, mydriatics (with or without cycloplegic activity), cycloplegics,...

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Unique Physicochemical Systems Used Topically

As one scans the products at the drug counter, one finds an enormous variety of formulation types available for topical therapy or for cosmetic purposes. Solutions are commonly found. They come in packages that allow them to be rubbed on, sprayed on by aerosol and atomizers, painted on, rolled on, swabbed on by premoistened pledgets, and dabbed on from applicators. Assorted medicated soaps are available for a range of purposes. Emulsions for the skin are found in the form of shampoos and as...

Pharmaceutical Elegance

There are a number of attributes of topical drug systems that may be classified as cosmetic that make patients more or less willing to use their medications (compliant). These include the ease of application, the feel of the preparation once it is on the skin, and the appearance of the applied film. Ideally, the application should be undetectable to the eye and neither tacky nor greasy. Certain items, such as ointments and pastes, are of course intrinsically greasy, and suspensions of all types...

Anatomy Of The Eye And Adnexa

Anterior Chamber Angle Structures

In-depth discussions of the anatomy of the eye and adnexa have been adequately covered elsewhere in the pharmaceutical literature (9-13) and in recent texts on ocular anatomy. Here a brief overview is presented of the critical anatomical features that influence the nature and administration of ophthalmic preparations. In this discussion, consideration will be given primarily to drugs applied topically that is, onto the cornea or conjunctiva or into the palpebral fornices. Increasingly, drugs...

Composition of Contact Lenses

Contact lenses are broadly classified as PMMA, RGP, and soft hydrogel (HEMA) lenses. Dyes may be added during polymerization or after fabrication to improve lens handling or to change the color of the lens wearer's eyes. Lenses made from numerous polymers are available today (374). In soft hydrogel lenses, HEMA is a commonly used monomer. However, to avoid infringement of existing patents, many comonomers, as, for example, methyl methacrylic acid or a blend of comonomers, are used. Comonomers...

Solid Dosage Forms Ocular Inserts

In earlier times, it has been reported that lamella or disks of glycerinated gelatin were used to supply drugs to the eye by insertion beneath the eyelid. The aqueous tear fluids dissolved the lamella and released the drug for absorption. The medical literature also describes a sterile paper strip impregnated with drug for insertion in the eye. These appear to have been the first attempts at designing a sustained-release ocular dosage form. In 1975, the first controlled-release topical dosage...

Intraocular Dosage Forms

Ophthalmic products, which are introduced into the interior structures of the eye either during ocular surgery or via an intravitreal injection, are a special class that requires the application of technology from parenteral dosage forms in their design, packaging, and manufacture. The development of cytomegalovirus (CMV) retinitis as a common opportunistic infection in patients with AIDS has resulted in the initial expansion of this class of ocular product to include solid inserts and...

Evolution of Contact Lenses

In 1508, Leonardo da Vinci conceived the concept of the contact lens. It was not until 1887 that scleral contact lenses were fabricated by Dr. A. E. Fick, a physician in Zurich F. A. Mueller, a maker of prosthetic eyes in Germany and Dr. E. Kalt, a physician in France. Muller, Obrig, and Gyorry fabricated contact lenses made from polymethyl methacrylate (PMMA) in the late 1930s. K. Tuohy filed the patent for contact lens design in 1948, which were made of PMMA material (371). Although they were...

Semisolid Dosage Forms Ophthalmic Ointments and Gels

The principal semisolid dosage form used in ophthalmology is an anhydrous ointment with a petrolatum base. The ointment vehicle is usually a mixture of mineral oil and white petrolatum. The mineral oil is added to reduce the melting point and modify the consistency. The principal advantages of the petrolatum-based ointments are their blandness and anhydrous and inert nature, which make them suitable vehicles for moisture-sensitive drugs. Ophthalmic ointments containing antibiotics are used...

Topical Eyedrops

Although many alternate experimental methods have been tried, eyedrops remains the major method of administration for the topical ocular route. The usual method of self-administration is to place the eyedrop from a dropper or dropper bottle into the lower cul-de-sac by pulling down the eyelid, tilting the head backward, and looking at the ceiling after the tip is pointed close to the sac and applying a slight pressure to the rubber bulb or plastic bottle to allow a single drop to form and fall...

Stratum Corneum

The outermost layer of the skin appearing in the exploded epidermal sketch of Figure 1 represents the stratum corneum the horny layer . Stratum corneum, the principal barrier element of the skin, is an essentially metabolically inactive tissue that comprises acutely flattened, stacked, hexagonal cell-building blocks formed from once-living cells. These cellular building blocks are layered 15 to 25 cells deep over most of the body 2 . At some sites, the cells appear to be stacked in neat...

Contributors

G ran Alderborn Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, Uppsala, Sweden J rg Breitkreutz Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine University, D sseldorf, Germany James Chastain Alcon Research, Ltd., Fort Worth, Texas, U.S.A. Masood A. Chowhan Alcon Research, Ltd., Fort Worth, Texas, U.S.A. Barry Crean L.B.S.A. and Formulation Insights Group in Drug Delivery, School of Pharmacy, The University of Nottingham, Nottingham, U.K. Terry Dagnon...