ALCON 2050
`Apotex Corp. v. Alcon Research, Ltd.
`Case IPR2013-00428
`
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`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
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`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
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`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
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`Copyright 2000, by the University of the Sciences in Philadelphia
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`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683—306472
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`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
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`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon-
`sible for any inaccuracy contained herein.
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep-
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations of them herein, the
`context and effect of the official compendia shall prevail.
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`. A treatise on the theory
`.
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chair
`
`Nicholas G Popovich
`
`Ara H Der Marderosian
`
`Glen R Hanson
`
`Thomas Medwick
`
`Roger L Schnaare
`
`Joseph B Schwartz
`
`H Steve White
`
`AUTHORS
`
`The ’l ’19 chapters of this edition of Remington were written by the
`
`editors, by members of the Editorial Board, and by the authors
`
`listed on pages viii to x.
`
`Managing Editor
`
`John E Hoover, BSc (Pharm)
`
`Editorial Assistant
`
`Bonnie Brigham Packer, RNC, BA
`
`Director
`
`Philip P Gerbino 1995—2000
`
`Twentieth Edition—2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
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`4.
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`OPHTHALMIC PREPARATIONS
`
`829
`
`from very large walk-in units to small, laboratory bench—scale
`units suitable for small hospitals, laboratories, or pharmacies.
`In using gas sterilization the possibility of human toxicity must
`be kept in mind. Care should be taken to restrict exposure to
`ethylene ordde during the loading, venting, and unloading of
`the sterilizer. Ethylene oxide sterilization produces irritating
`by—products that remain as residues in or on the articles
`sterilized. Residues include ethylene glycol and ethylene chlo-
`r0hyd1in (when in contact with chloride ions) in addition to
`ethylene oxide itself. To minimize such residues the sterilized
`articles should be aerated for at least 72 hr, preferably at 40
`to 50°.
`Ambient aeration time for sterilized polyethylene bottles
`should be about 48 hr. Ethylene oxide is recommended for the
`sterilization of solid materials that will not withstand heat
`sterilization. The FDA has recommended maximum residues in
`the parts per million range for ethylene oxide, ethylene glycol,
`and ethylene chlorohydrin.
`RADIATION—Sterilization by exposure to ionizing radia-
`tion is an acceptable procedure for components of ophthalmic
`preparations or indeed for the total product, such as certain
`ophthalmic ointments. Sources of radiation are twofold and
`include linear electron accelerators and radioisotopes. The lin-
`ear accelerators produce high—energy electrons with very little
`penetrating power. Radioisotopes, particularly 6000, are em-
`ployed more widely for sterilization. Sterilization by radiation
`may produce untoward effects such as chemical changes in
`product components as well as changes in color or physical
`characteristics of package components.
`
`the low-density polyethylene Drop-
`ie,
`Plastic packaging,
`Tainer (Alcon) that represents a patient convenience, may
`prove detrimental to stability by permitting oxygen permeation
`resulting in oxidative decomposition of the drug substance.
`The attainment of optimum stability most often imposes a
`series of compromises on the formulator. The optimum pH may
`be lower than that preferable for product comfort, although this
`effect may be minimized by adjusting pH with a buffer of
`minimum capacity. Additives such as chelating agents and
`antioxidants may be required, and convenience packaging may
`diminish shelf life of the product.
`It should be stressed that stability refers to total product
`stability not just the chemical stability of a single product
`component. That is an oversimplification. A well-planned sta-
`bility program Will consider and evaluate the chemical stability
`of the active ingredient, chemical stability of the preservative
`substance, continuing preservative emcacy against selected
`test organisms, and adequacy of the package as a function of
`time (ie, does the package protect sterility in addition to vari-
`ous physical measures such as pH, clarity, resuspendability of
`suspensions, and the like?). One also must support the thesis
`that the material on test is representative of all lots of a given
`product.
`BUFFER AND pH—Ideally, ophthalmic preparations
`should be formulated at a pH equivalent to the tear fluid value
`of 7.4. Practically, this seldom is achieved. The large majority
`of active ingredients used in ophthalmology are salts of weak
`bases and are most stable at an acid pH. This generally can be
`extended to suspensions of insoluble corticosteroids. Such sus-
`pensions usually are most stable at an acid pH.
`Optimum pH adjustment generally requires a compromise
`on the part of the formulator. The pH selected should be opti-
`mum for stability. The buffer system selected should have a
`capacity adequate to maintain pH within the stability range for
`the duration of the product shelf life. Buffer capacity is the key
`in this situation.
`It generally is accepted that a low (acid) pH per se necessar-
`ily will not cause stinging or discomfort on instillation. If the
`overall pH of the tears, after instillation, reverts rapidly to pH
`7.4, discomfort is minimal. On the other hand, if the buffer
`capacity is sufficient to resist adjustment by tear fluid and the
`overall eye pH remains acid for an appreciable period of time,
`then stinging and discomfort may result. Consequently, bufi'er
`capacity should be adequate for stability but minimized so far
`as possible, to allow the overall pH of the tear fluid to be
`disrupted only momentarily.
`TONICITY—Tonicity refers to the osmotic pressure ex—
`erted by salts in aqueous solution. An ophthalmic solution is
`isotonic with another solution when the magnitudes of the
`colligative properties of the solutions are equal. An ophthalmic
`solution is considered isotonic when its tonicity is equal to that
`of an 0.9% sodium chloride solution.
`The calculation of tonicity at one time was stressed rather
`heavily. The fledgling pharmacist was taught in great detail
`the requirements of, and means of achieving, exact tonicity,
`sometimes to the detriment of other factors such as sterility
`and stability.
`In actuality the eye is much more tolerant of tonicity vari-
`ations than was at one time suggested. The eye usually can
`tolerate solutions equivalent to a range of 0.5 to 1.8% sodium
`chloride. Given a choice, isotonicity always is desirable and
`particularly is important in intraocular solutions. It need not,
`however, be an overriding concern when total product stability
`is to be considered.
`The tonicity of ophthalmic (and parenteral) solutions has
`been investigated intensively over the years. These studies
`have resulted in the accumulation and publication of a large
`number of sodium chloride equivalents that are useful in cal—
`culating tonicity values. See Chapter 18.
`VISCOSITY—The USP permits the use of viscosity—
`increasing agents to prolong contact time in the eye and thus
`enhance drug absorption and activity. Substances such as
`
`
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`OPHTHALMIC PREPARATION
`CHARACTERISTICS
`
`— C
`
`LARITY—Ophthalmic solutions are by definition free
`from foreign particles, and clarity normally is achieved by
`filtration. It is, of course, essential that the filtration equipment
`be clean and well rinsed so that particulate matter is not
`contributed to the solution by equipment designed to remove it.
`Operations performed in clean surroundings,
`the use of
`laminar-flow hoods, and proper nonshedding garments will
`contribute collectively to the preparation of brilliantly clear
`solutions free from foreign particles. In many instances clarity
`and sterility may be achieved in the same filtration step. It is
`essential to realize that solution clarity is equally a function of
`the cleanliness of the intended container and closure. Both
`container and closure must be thoroughly clean, sterile, and
`nonshedding. That is, the container or closure must not con-
`tribute particles to the solution during prolonged contact such
`as shelf-life storage. This normally is established by thorough
`stability testing.
`STABILITY—The stability of a drug in solution, ie, an
`ophthalmic product, depends on the chemical nature of the
`drug substance, product pH, method of preparation (particu—
`larly temperature exposure), solution additives, and type of
`packaging. Until two or three decades ago the stability of
`ophthalmic solutions was an exceedingly short-term concept;
`generally, it was the time required for a patient to complete the
`use of 15 or 30 mL of solution. Now, of course, the stability of
`ophthalmic products is expressed in terms of years. However,
`2- to 3-year stability often is achieved only by virtue of com-
`promise.
`Drugs such as pilocarpine and physostigmine are both ac-
`tive and comfortable in the eye at a pH of 6.8; however, at this
`pH chemical stability (or instability) can be measured in days
`or months. With either drug, a substantial loss in chemical
`stability will occur in less than 1 year. On the other hand, at pH
`5 both drugs are stable for a period of several years.
`In addition to optimal pH, if oxygen sensitivity is a factor,
`adequate stability may require the inclusion of an antioxidant.
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`4
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