2 0 TH EDITION
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`MYLAN Ex. 1005, Page 1
`
`

`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
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`Baltimore, Maryland 21201-2436 USA
`
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`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`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
`
`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
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-306472
`
`I
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`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.
`
`To purchase additional copies of this hook call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
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`
`02 03 04
`2 3 4 5 6 7 8 9 10
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`MYLAN Ex. 1005, Page 2
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`

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`Remington: The Science and Practice of Pharmacy . , . A treatise on the theory
`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 Schnaore
`
`Joseph B Schwartz
`
`H Steve White
`
`AUTHORS
`
`The 119 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 (cid:9)
`
`John E Hoover, BSc (Phorm)
`
`Editorial Assistant (cid:9)
`
`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
`
`MYLAN Ex. 1005, Page 3
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`bicarbonate, concentrated peppermint emulsion, and double-
`‘strength chloroform water. Extemporaneously compounded
`preparations include allopurinol at a strength of about 0.1%
`prepared from tablets in a suspending vehicle of 0.5% methyl-
`cellulose sweetened and flavored. Modifications of this prepa-
`ration have been shown to have considerable stability.
`
`
`
`VJUICES j
`
`
`
`A juice is prepared from fresh ripe fruit, is aqueous in charac-
`ter, and is used in making syrups that are employed as vehi-
`cles. The freshly expressed juice is preserved with benzoic acid
`and allowed to stand at room temperature for several days,
`until the pectins that naturally are present are destroyed by
`enzymatic action, as indicated by the filtered juice yielding a
`clear solution with alcohol. Pectins, if allowed to remain, would
`cause precipitation in the final syrup.
`Cherry Juice (RPS-18 page 1320) is described in the USP
`XXI and Raspberry Juice in USP XVIII. Concentrated Rasp-
`berry Juice (PC, 11th ed) is prepared from the clarified juice
`of raspberries. Pectinase is stirred into pulped raspberries
`and the mixture allowed to stand for 12 hours. The pulp is
`pressed, the juice clarified, and sufficient sucrose added to
`adjust the weight at 20° to 1.050 to 1.060 g per mL. The juice
`then is concentrated to one-sixth of its original volume.
`Sufficient sulfurous acid or sodium metabisulfite is added as
`a preservative.
`,
`Artificial flavors now have replaced many of the natural fruit
`juices. Although they lack the flavor of the natural juice, they are
`more stable and easier to incorporate into the final pharmaceuti-
`cal form. Commercial juices such as orange, apple, grape, and
`mixed vegetables have been used recently to prepare extempora-
`neous preparations of cholestyramine and nizatidine.
`Information on cranberry juice indicates that it may be
`effective in controlling some urinary tract infections and
`urolithiasis.
`
`NASAL SOLUTIONS
`
`
`Nasal solutions are usually aqueous solutions designed to be
`administered to the nasal passages in drops or sprays. Other
`nasal preparations may be in the form of emulsions or suspen-
`sions. Although many of the drugs are administered for their
`local sympathomimetic effect—such as Ephedrine Sulfate or
`Naphazoline Hydrochloride Nasal Solution USP, to reduce na-
`sal congestion——a few other official preparations, Lypressin
`Nasal Solution USP and Oxytocin Nasal Solution USP, are
`administered in spray form for their systemic effect for the
`treatment of diabetes insipidus and milk letdown prior to
`breast feeding, respectively. The current route of administra-
`tion of peptides and proteins is limited to parenteral injection
`because of inactivation within the gastrointestinal tract. As a
`result, there is considerable research on intranasal delivery of
`some of these drugs such as analogs of enkephalins or luteinizing-
`hormone—releasing hormone and insulin. Other drugs that are
`absorbed poorly from the GI tract, such as gentamicin sulfate,
`are being administered in the form of nasal solutions to obtain
`appropriate blood levels. Some pharmaceuticals such as meper-
`idine HCl and lidocaine HCl may be administered in the form
`of nasal solutions for analgesia and headaches, respectively.
`Nasal solutions are prepared so that they are similar in
`many respects to nasal secretions in regard to toxicity,_ pH, and
`
`SOLUTIONS, EMULSIONS, SUSPENSIONS, AND EXTRACTS
`
`729
`
`tions, and appropriate drug stabilizers, if required, are in-
`cluded in the formulation.
`
`Commercial nasal preparations, in addition to the drugs
`listed above also include antibiotics, antihistamines, and drugs
`for asthma prophylaxis.
`A formula for Ephedrine Nasal Drops (PC, 11th ed) is:
`Ephedrine Hydrochloride
`0.5 g
`Chlorobutanol
`0.5 g
`Sodium Chloride
`0.5 g
`Water for preparations
`to 100 mL
`
`Current studies indicate that nasal sprays are deposited
`mainly in the atrium and cleared slowly into the pharynx with
`the patient in an upright position. Drops spread more exten-
`sively than the spray, and three drops cover most of the walls
`of the nasal cavity with the patient in a supine position and
`head tilted back and turned left and right. It is suggested that
`drop delivery, with appropriate movement by the patient, leads
`to extensive coverage of the walls of the nasal cavity.
`
`OTIC SOLUTIONS
`
`
`These solutions occasionally are referred to as aural prepara-
`tions. Other otic preparations often include formulations such
`as suspensions and ointments for topical application in the ear.
`The main classes of drugs used for topical administration to
`the ear include analgesics, such as benzocaine; antibiotics, such
`as neomycin; and anti-inflammatory agents, such as cortisone.
`The USP preparations include Antipyrine and Benzocaine Otic
`Solution. The Neomycin and Polyrnyxin B Sulfates and Hydro-
`cortisone Otic Solutions may contain appropriate buffers, sol-
`vents, and dispersants usually in an aqueous solution. The
`main solvents used in these preparations include glycerin or
`water. The viscous glycerin vehicle permits the drug to remain
`in the ear for a long time. Anhydrous glycerin, being hygro-
`scopic, tends to remove moisture from surrounding tissues,
`thus reducing swelling. Viscous liquids like glycerin or pro-
`pylene glycol are used either alone or in combination with a
`surfactant to aid in the removal of cerumen (ear wax). Sodium
`Bicarbonate Ear-Drops BP may be used if wax is to be removed
`from the ear. This preparation contains sodium bicarbonate (5
`g), glycerin (30 mL), and purified water (a sufficient quantity to
`make 100 mL).
`To provide sufficient time for aqueous preparations to act, it
`is necessary for patients to remain on their side for a few
`minutes so the drops do not run out of the ear. Otic prepara-
`tions are dispensed in a container that permits the adminis-
`tration of drops.
`
`IRRIGATION SOLUTIONS
`
`
`Irrigation solutions are used to wash or bathe surgical inci-
`sions, wounds, or body tissues. Because they come in contact
`with exposed tissue, they must meet stringent requirements of
`the USP such as sterility, total solids, and bacterial endotoxins.
`These products may be prepared by dissolving the active ingre-
`dient in Water for Injection. They are packaged in single—dose
`containers, preferably Type I or Type II glass, or suitable plas-
`tic containers, and then sterilized. See Chapter 40 for steriliza-
`tion procedures. A number of irrigations are described in the
`USP, eg, Acetic Acid Irrigation for bladder irrigation, Dimethyl
`Sulfoxide Irrigation for relief of internal cystitis, Neomycin and
`Polymyxin B Sulfates Solution for Irrigation for infection, and
`Sodium Chloride Irrigation for washing wounds.
`
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`segment of the globe and to affect the nerves and other struc-
`tures in that space.
`
`PREPARATION
`
`The preparation of ophthalmic solutions, suspensions, or oint-
`ments by the community pharmacist or even the hospital phar-
`macist is becoming less common. The pharmacist may be called
`upon to prepare a special concentration, particularly of an
`antibiotic, in the hospital setting. However, the extemporane-
`ous compounding of ophthalmic prescriptions is becoming rare.
`In those cases when the pharmacist is called upon to compound
`an ophthalmic preparation extemporaneously, careful docu-
`mentation along with physician consultation is required. Me-
`ticulous attention to detail and the use of a detailed, preap-
`proved preparation plan must be in place prior to
`compounding." In the view of many, the advantages of com-
`mercial preparations, such as stability, uniformity, and steril-
`ity, outweigh possible disadvantages such as standardization of
`dosage. A general discussion concerning the preparation of
`ophthalmic solutions is found in USP 23, which lists 59 items.
`VEHICLES—Sterile isotonic solutions, properly preserved,
`are suitable for preparing ophthalmic solutions (see Chapter 18).
`In most cases, when the concentration of active ingredient is low,
`ie, less than 2.5 to 3.0%, the drug can be dissolved directly in the
`isotonic vehicle. The finished solutions will be hypertonic some-
`what but well within the comfort tolerance of the eye.
`Typical stock solutions are as follows:
`Isotonic Sodium Chloride Solution
`
`Sodium Chloride USP
`1:10,000
`Sterile Distilled Water
`
`Boric Acid Solution
`
`Boric Acid US?
`1:10,000
`Sterile Distilled Water
`
`0.9 g
`Benzalkonium Chloride
`qe 100 mL
`
`1.9 g
`Benzalkonium Chloride
`qs 100 mL
`
`Boric acid solution at pH 5 is an appropriate vehicle for the
`following:
`
`Cocaine
`Neostigmine (cid:9)
`Phenacaine (cid:9)
`Piperocaine
`
`Procaine
`Tetracaine
`Zinc salts
`
`Boric acid solution with an antioxidant is useful for oxygen-
`sensitive drugs such as epinephrine, phenylephrine, or phy-
`sostigmine. The following solutions are suggested. Phenylmer-
`curic nitrate replaces benzalkonium chloride as the
`preservative in the first solution.
`
`Boric Acid
`Sodium Sulfite Anhydrous (cid:9)
`Phenylmercuric nitrate (cid:9)
`Sterile Purified Water (cid:9)
`Sodium Acid Phosphate .NaH,PO4) anhydrous (cid:9)
`Disodium Phosphate (Na,H1204) anhydrous (cid:9)
`Sodium Chloride (cid:9)
`Disodium Edetate (cid:9)
`Benzalkonium Chloride (cid:9)
`Sterile Purified Water (cid:9)
`
`These vehicles are suitable for salts of
`Atropine (cid:9)
`Ephedrine (cid:9)
`
`Homatropine
`Pilocarpine
`
`1.9 g
`0.1 g
`1:50,000
`qe 100 mL
`0.56 g
`0.284 g
`0.5 g
`0.1 g
`1:10,000
`qs 100 mL
`
`OPHTHALMIC PREPARATIONS (cid:9)
`
`827
`
`STERILIZATION PROCEDURES—Those procedures
`suited best for the extemporaneous preparation of ophthalmic
`solutions are
`
`1. Solutions in final container
`a. Place the filtered solution in containers that have been
`washed and rinsed with distilled water.
`b. Seal dropper bottles with regular screwcaps. The dropper
`assembly should be stapled into a paper envelope.
`c. Sterilize 20 min at 15 psi (121°).
`d. Do not assemble until ready to use.
`
`2. Dropper bottles
`a. Wash container thoroughly and rinse with distilled wa-
`ter.
`b. Loosen caps and place bottles in autoclave.
`c. Autoclave 15 min at 15 psi (121°).
`d. Partially cool autoclave.
`e. Remove bottles from autoclave and secure caps.
`f. Store sterilized bottles in a clean, dustproof cabinet.
`
`3. Glassware and equipment
`a. Wrap adapters (containing filter), syringes, glassware,
`spatulas, etc, in autoclave paper and secure with mask-
`ing tape.
`b. Place articles in autoclave and sterilize in the manner
`described in Section 2 above.
`c. Store in separate cabinet until ready to use.
`
`4. Microbiological filtration
`a. All equipment and glassware as well as stock solutions
`should be sterile. The prescription should be dispensed in
`a sterile container.
`b. Unwrap sterile syringe and draw prepared solution into
`syringe.
`c. Unwrap sterile adapter containing bacterial filter and
`attach to syringe. These are available as single-filtration,
`presterilized, disposable units and should be used when-
`ever possible.
`d. Force solution through filter directly into sterile con-
`tainer (dropper or plastic Drop-Tainer (Alcon) type).
`e. By employing an automatic filling outfit, more than one
`container of the same prescription can be prepared.
`f. Cap container immediately.
`
`The procedures outlined above should be carried out in a clean
`area equipped with ultraviolet lighting and preferably in a
`laminar-flow hood.
`Laminar-Flow Principles—A laminar-flow work area is a
`particularly convenient means of preparing sterile, particulate-
`free solutions. Laminar flow is defined as air flow in which the
`total body of air moves with uniform velocity along parallel
`lines with a minimum of eddies. Laminar flow minimizes the
`possibility of airborne microbial contamination by providing air
`free of viable particles and free of practically all inert particu-
`latep. Laminar-flow units are available in a variety of shapes
`and sizes and in two broad categories, horizontal and vertical
`laminar flow. It should be noted that laminar flow per se is not
`a guarantee of sterility. Correct procedures and sterile tech-
`niques remain necessary. See Chapter 40.
`
`General Considerations
`
`A number of requirements must be considered in the prepara-
`tion of ophthalmic solutions, suspensions, or ointments. These
`include sterility, clarity, buffer, buffer capacity and pH, tonic-
`ity, viscosity, stability, comfort, additives, particle size, pack-
`aging, and preservatives. Many of these requirements are in-
`terrelated and must be considered collectively in the
`preparation of an ophthalmic product. The buffer system must
`be considered with tonicity and comfort in mind. Stability can
`
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`626 (cid:9)
`
`CHAPTER 43
`
`be related to the pH, buffer system, and packaging. Steriliza-
`tion must be considered in terms of stability and packaging.
`Ophthalmic solutions are formulated to be sterile, isotonic,
`and buffered for stability and comfort. A viscosity-imparting
`agent may or may not be present. Solutions must be free
`from foreign particles. Solution pH must be selected for opti-
`mum drug stability. The pH then should be maintained by the
`inclusion of a buffer system of sufficient capacity to maintain
`pH throughout the extent of the shelf life of the product.
`The proper pH, buffer, and buffer capacity often represent a
`compromise between stability of the drug and comfort in the
`eye, since optimum patient comfort usually is found at the pH
`of the tear fluid, or about 7.4, while optimum stability for many
`drugs is generally lower, perhaps as low as 4 to 5. Buffer
`capacity should be sufficient to maintain pH, but minimized to
`the point where tear fluid can overcome capacity and readjust
`the pH to 7.4 immediately after instillation in the eye.
`Sterilization represents the major requirement of eye prod-
`ucts, and the method or methods employed depend on the
`active ingredient and product resistance to heat and on the
`packaging used. More than one means of sterilization may be
`used. The sterile solution or suspension usually will contain an
`antimicrobial preservative to deal with inadvertent contami-
`nation during use. The preservative should not be relied upon
`to produce a sterile product and should not be considered a
`substitute for sterile techniques and procedures.
`
`STERILIZATION
`
`Common methods of sterilization include moist heat under
`pressure (autoclave), dry heat, filtration, gas sterilization, and
`ionizing radiation.
`DANGERS OF NONSTERILE MEDICATIONS—The
`possibility of serious ocular infection resulting from the use of
`contaminated ophthalmic solutions has been documented am-
`ply in the literature. Such solutions repeatedly have been the
`cause of corneal ulcers and loss of eyesight. Contaminated
`solutions have been found in use in physicians' offices, eye
`clinics, and industrial infirmaries and dispensed on prescrip-
`tion in community and hospital pharmacies. The microbe most
`frequently found as a contaminant is the Staphylococcus group.
`Pseudomonas aeruginosa is a less frequent contaminant,
`and the solution most often found contaminated is sodium
`fluorescein.
`P aeruginosa (B pyocyaneus; Pseudomonas pyocyanea; blue
`pus bacillus) is a very dangerous and opportunistic organism
`that grows well on most culture media and produces both
`toxins and antibacterial products. The latter tend to kill off
`other contaminants and allow the P aeruginosa to grow in pure
`culture. This gram-negative bacillus also grows readily in oph-
`thalmic solutions, which may become the source of extremely
`serious infections of the cornea. It can cause complete loss of
`sight in 24 to 48 hr. In concentrations tolerated by tissues of the
`eye, it seems that all the antimicrobial agents discussed in the
`following sections may be ineffective against some strains of
`this organism.
`A sterile ophthalmic solution in a multiple-dose container
`can be contaminated in a number of ways unless precautions
`are taken. For example, if a dropper bottle is used, the tip of the
`dropper while out of the bottle can touch the surface of a table
`or shelf if laid down, or it can touch the eyelid or eyelash of the
`patient during administration. If the Drop-Tainer (Alcon) type
`of bottle is used, the dropper tip can touch an eyelash or the cap
`while removed to permit administration, or its edge may touch
`a table or finger, and that edge can touch the dropper tip as the
`cap is replaced.
`The solution may contain an effective antimicrobial, but the
`next use of the contaminated solution may occur before enough
`time has elapsed for all of the organisms to be killed, and living
`organisms can find their way through an abrasion into the
`
`corneal stroma. Once in the corneal stroma, any residual traces
`of antimicrobial agents are neutralized by tissue components,
`and the organisms find an excellent culture medium for rapid
`growth and dissemination through the cornea and the anterior
`segment of the eye.
`OTHER ORGANISMS—Bacillus subtilis may produce a
`serious abscess when it infects the vitreous humor. The patho-
`genic fungus considered of particular importance in eye solu-
`tions is Aspergillus fumigatus. Other fungi or molds may be
`harmful by accelerating deterioration of the active drugs.
`With regard to viruses, as many as 42 cases of epidemic
`keratoconjunctivitis were caused by one bottle of virus-
`contaminated tetracaine solution. Virus contamination is
`particularly difficult to control because none of the preser-
`vatives now available is virucidal. Moreover, viruses are not
`removable by filtration. However, they are destroyed by au-
`toclaving. The pharmacist and physician have not been made
`adequately aware of the dangers of transmitting virus infec-
`tion via contaminated solutions. This is particularly perti-
`nent to the adenoviruses (Types III and VIII), which are now
`believed to be the causative agents of viral conjunctivitis
`such as epidemic keratoconjunctivitis.
`
`Methods
`
`STEAM UNDER PRESSURE—Terminal sterilization by
`autoclaving is an acceptable, effective method of sterilization;
`however, the solution or suspension components must be suf-
`ficiently heat-resistant to survive the procedure. If sterilization
`is carried out in the final container, the container also must be
`able to survive the heat and pressure. A recent addition to this
`technique is the so-called air-over-steam autoclave. This com-
`bination allows pressure adjustments to be made during the
`autoclave cycle. Pressure manipulations permit the autoclave
`sterilization of materials that while heat-resistant tend to de-
`form (ie, polypropylene containers).
`FILTRATION—The USP states that sterile membrane fil-
`tration under aseptic conditions is the preferred method of
`sterilization. Membrane filtration offers the substantial advan-
`tage of room temperature operation with none of the deleteri-
`ous effects of exposure to heat or sterilizing gas.
`Sterilization by filtration does involve the transfer of the
`finished sterile product into previously sterilized containers,
`using aseptic techniques. The membrane filtration equipment
`itself usually is sterilized as an assembly by autoclaving.
`The application of filtration procedures to the extemporane-
`ous preparation of sterile ophthalmic solutions has been pro-
`posed by several workers. Several types of equipment are avail-
`able for small-scale work, as described in Chapter 36.
`Particular interest has been shown in the Swinny adapter
`fitted on a syringe and in the Millipore Swinnex disposable
`filter units. Empty sterile plastic squeeze containers and sterile
`plastic filtration units can be purchased directly from the man-
`ufacturers, eg, Wheaton (polyethylene containers) and Milli-
`pore (Swinnex filter units). They permit extemporaneous prep-
`aration of ophthalmic solutions that have a high probability of
`being sterile if the work is carried out under aseptic conditions.
`A supplementary device can permit automatic refilling of the
`syringe. The filter unit must be replaced after use.
`GAS—Gas sterilization of heat-sensitive materials may be
`carried out by exposure to ethylene oxide gas in the presence of
`moisture. Ethylene oxide gas for sterilization use is available
`commercially, diluted with either carbon dioxide or haloge-
`nated hydrocarbons. Ethylene oxide sterilization requires care-
`ful consideration of conditions required to effect sterility. Tem-
`perature and pressure conditions are quite nominal in contrast
`to wet or dry heat; however, careful control of exposure time,
`ethylene oxide concentration, and moisture is essential,
`Gas sterilization requires the use of specialized, but not
`necessarily elaborate, equipment. Gas autoclaves may range
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`I
`
`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 oxide 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-
`rohyd.rin (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 "Co, 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.
`
`OPHTHALMIC PREPARATION
`CHARACTERISTICS
`
`CLARITY—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 dear
`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.
`
`OPHTHALMIC PREPARATIONS (cid:9)
`
`829
`
`Plastic packaging, ie, the low-density polyethylene Drop-
`Tainer (Alcoa) 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 efficacy 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, buffer
`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-
`culati