2 0 TH EDITION
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`

`
`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
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`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.
`
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`02 03 04
`2 3 4 5 6 7 8 9 10
`
`Page 2
`
`

`
`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
`
`Page 3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`

`
`830 (cid:9)
`
`CHAPTER 43
`
`methylcellulose, polyvinyl alcohol, and hydroxypropylmethyl
`cellulose are added frequently to increase viscosity.
`Various investigators have studied the effect of increased
`viscosity on contact time in the eye. In general terms, viscosity
`increased up to the 15 to 50 cps range significantly improves
`contact time in the eye. Results tend to plateau beyond the
`50-centipose range; higher viscosity values offer no significant
`advantage and have a tendency to leave a noticeable residue on
`the lid margins.
`ADDITIVES—The use of various additives in ophthalmic
`solutions is permissible; however the choices are few. An anti-
`oxidant, specifically sodium bisulfite or metabisulfite, is per-
`mitted in concentrations up to 0.3%, particularly in solutions
`containing epinephrine salts. Other antioxidants such as ascor-
`bic acid or acetylcysteine also may be used. The antioxidant
`acts in this case as a stabilizer to minimize oxidation of
`epinephrine.
`The use of surfactants in ophthalmic preparations is re-
`stricted similarly. Nonionic surfactants, the class of such com-
`pounds that are least toxic to the ophthalmic tissues, are used
`in low concentrations particularly in steroid suspensions and
`as aids in achieving solution clarity. Surfactants may be used
`rarely as cosolvents to increase solubility.
`The use of surfactants, particularly in any significant con-
`centration, should be tempered by recognition of the sorption
`characteristics of these compounds. Nonionic surfactants, in
`particular, may react by binding with antimicrobial preserva-
`tive compounds and inactivate much of the preservative
`system.
`Cationic surfactants are used frequently in ophthalmic so-
`lutions but almost invariably as antimicrobial preservatives.
`Benzalkonium chloride is typical of this class of substances.
`Concentrations are in the range of 0.005 to 0.02%, with toxicity
`the limiting factor on the concentration used. Because of its
`large molecular weight the benzalkonium cation is inactivated
`easily by macromolecules of opposite charge or by sorption.
`Despite such limitations, benzalkonium chloride is the preser-
`vative used in the large majority of commercial ophthalmic
`solutions and suspensions.
`
`PACKAGING
`
`The traditional ophthalmic glass container with accompanying
`glass dropper has been supplanted almost completely by the
`low-density polyethylene dropper unit called the Drop-Tainer
`(Alton). In only a very few instances are glass containers still in
`use, usually because of stability limitations. Large-volume in-
`traocular solutions of 250 and 500 mL have been packaged in
`glass, but even these parenteral-type products are beginning to
`be packaged in specially fabricated polyethylene/polypropylene
`containers.
`One should be ever mindful that plastic packaging, usually
`low-density polyethylene, is by no means interchangeable with
`glass. Plastic packaging is permeable to a variety of substances
`including light and air. The plastic package may contain a
`variety of extraneous substances such as mold-release agents,
`antioxidants, reaction quenchers, and the like, which readily
`may leach out of the plastic and into the contained solution.
`Label glues, inks, and dyes also may penetrate polyethylene
`readily. In the opposite sense, volatile materials may permeate
`from solution into or through plastic containers.
`Glass containers remain a convenient package material for
`extemporaneous preparation of ophthalmic solutions. Type 1
`glass should be used. The container should be well rinsed with
`sterile distilled water and may be sterilized by autoclaving.
`Droppers normally are available presterilized and packaged in
`a convenient blister pack.
`Ophthalmic ointments invariably are packaged in metal
`tubes with an ophthalmic tip. Such tubes are sterilized conve-
`niently by autoclaving or by ethylene oxide. In rare cases of
`
`metal reactivity or incompatibility, tubes lined with epoxy or
`vinyl plastic may be obtained.
`Regardless of the form of packaging, some type of tamper-
`evident feature must be used for consumer protection. The
`common tamper-evident feature used on most ophthalmic prep-
`arations is the moisture- or heat-sensitive shrink band. The
`band should be identified in such a way that its disruption or
`absence constitute a warning that tampering, either accidental
`or purposeful, has occurred.
`The eyecup, an ancillary packaging device, fortunately
`seems to have gone the way of the community drinking cup. An
`eyecup should not be used. Its use inevitably will spread or
`aggravate eye infections. Pharmacists should not fail to dis-
`courage such use just as they should take the time to instruct
`patients in the proper use and care of eye medications. While
`ophthalmic administration may seem simple enough, it may be
`a foreign and difficult task for many people. The suggestions
`and precautions given on page 824 may be useful in instructing
`patients.
`
`ANTIMICROBIAL PRESERVATIVES
`
`The USP states that ophthalmic solutions may be packaged in
`multiple-dose containers. Each solution must contain a sub-
`stance or mixture of substances to prevent the growth of, or to
`destroy, microorganisms introduced accidentally when the con-
`tainer is opened during use. The preservative is not intended to
`be used as a means of preparing a sterile solution. Appropriate
`techniques, discussed elsewhere, are to be employed to prepare
`a sterile solution.
`Preservatives are not to be used in solutions intended for
`intraocular use because of the risk of irritation. Ophthalmic
`solutions prepared and packaged for a single application, ie, a
`unit dose, need not contain a preservative because they are not
`intended for reuse.
`The need for proper control of ophthalmic solutions to pre-
`vent serious contamination was recognized in the 1930s. The
`first preservative recommended for use in ophthalmics was
`chlorobutanol, as an alternative to daily boiling!
`The selection of an ophthalmic preservative can be a rather
`difficult task, in part because of the relatively small number of
`suitable candidates. There is, of course, no such thing as an
`ideal preservative; however, the following criteria may be use-
`ful in preservative selection.
`1. The agent should have a broad spectrum and be active against
`gram-positive and gram-negative organisms as well as fungi. The
`agent should exert a rapid bactericidal activity, particularly against
`known virulent organisms such as P aeruginosa strains.
`2. The agent should be stable over a wide range of conditions including
`autoclaving temperatures and pH range.
`3. Compatibility should be established with other preparation compo-
`nents and with package systems.
`4. Lack of toxicity and irritation should be established with a reason-
`able margin of safety.
`
`Preservative substances must be evaluated as a part of the
`total ophthalmic preparation in the proposed package. Only in
`this way can the adequacy of the preservative be established.
`The USP includes a test for preservative effectiveness; addi-
`tionally, certain manufacturers have developed a panel of test
`organisms for further challenge and verification of preservative
`activity.
`In addition to preservative effectiveness as an immediate
`measure, its adequacy or stability as a function of time also
`must be ascertained. This often is done by measuring both
`chemical stability and preservative effectiveness over a given
`period of time and under varying conditions.
`Many of these test procedures are, of course, not com-
`pletely pertinent to the preparation of an extemporaneous
`ophthalmic solution. In such a situation the pharmacist
`must make selections based upon known conditions and
`
`Page 4
`
`

`
`OPHTHALMIC PREPARATIONS (cid:9)
`
`831
`
`INCOMPATIBILITIES
`Soaps
`Anionic materials
`Salicylates
`Nitrates
`Certain halides with
`phenylmercuric acetate
`
`Adsorption by
`macromolecules;
`marginal activity
`
`Stability is pH-dependent;
`activity concentration is
`near solubility
`maximum
`Low solubility in water;
`marginal activity
`
`Table 43-1. Ophthalmic Preservatives12
`TYPICAL
`STRUCTURE
`
`TYPE
`Quaternary ammonium
`compounds
`
`Organic mercurials
`
`CONCENTRATION RANGE
`0.004-0.02%, 0.01%
`most common
`
`0.001-0.01%
`
`Y
`
`R3
`SHgC,H,
`
`COONa
`
`Parahydroxy benzoates
`
`Maximum 0.1%
`
`OH
`
`0.5% (cid:9)
`
`0.5-0.9% (cid:9)
`
`CH3 (cid:9) C—CCI3
`
`dI
`
`x
`CH,OH
`
`Chlorobutanol
`
`Aromatic alcohols
`
`physical and chemical characteristics. In such circumstances
`it would be prudent to prepare minimum volumes for short-
`term patient use.
`The choice of preservatives suitable for ophthalmic use is
`surprisingly narrow. The classes of compounds available for
`such use are described in Table 43-1.12 In each case or category
`there are specific limitations and shortcomings.
`QUATERNARY AMMONIUM COMPOUNDS—Benz-
`alkonium chloride is a typical quaternary ammonium com-
`pound and is, by far, the most common preservative used in
`ophthalmic preparations. Over 65% of commercial ophthal-
`mic products are preserved with benzalkonium chloride. De-
`spite this broad use the compound has definite limitations.
`As a cationic surface-active material of high molecular
`weight it is not compatible with anionic compounds. It is
`incompatible with salicylates and nitrates and may be inac-
`tivated by high-molecular-weight nonionic compounds. Con-
`versely, benzalkonium chloride has excellent chemical sta-
`bility and very good antimicrobial characteristics. Given the
`alternative it would be preferable to modify a formulation to
`remove the incompatibility, rather than include a compatible
`but less effective preservative.
`The literature on benzalkonium chloride is somewhat
`mixed; however, this is not unexpected given the wide variation
`in test methods and, indeed, the chemical variability of benz-
`alkonium chloride itself. The official substance is defined as a
`mixture of alkyl benzyldimethylammonium chlorides including
`all or some of the group ranging from n-C81117 through
`n-C16I-133.The n-C12H25 homolog content is not less than 40%
`on an anhydrous basis.
`Reviews13 of benzalkonium chloride indicate that it is well
`suited for use as an ophthalmic preservative. Certain early
`negative reports have been shown to be quite erroneous; in
`some cases adverse tissue reactions were attributed to benz-
`alkonium chloride when, in fact, a totally different compound
`was used as the test material. Although benzalkonium chloride
`is by far the most common quaternary preservative, others
`occasionally referred to include benzethonium chloride and
`cetyl pyridinium chloride. All are official compounds. More
`recently, quaternary ammonium compounds have been at-
`tached to soluble, reasonably high molecular weight polymers.
`These agents possess good antimicrobial effectiveness with
`fewer compatibility problems than the official quaternary
`preservatives.
`
`ORGANIC MERCURIALS—It generally is stated that
`phenylmercuric nitrate or phenylmercuric acetate, in 0.002%
`concentration, should be used instead of benzalkonium chloride
`as a preservative for salicylates and nitrates and in solutions of
`salts of physostigmine and epinephrine that contain 0.1% so-
`dium sulfite. The usual range of concentrations employed is
`0.002 to 0.004%. Phenylmercuric borate sometimes is used in
`place of the nitrate or acetate.
`Phenylmercuric nitrate has the advantage over some other
`organic mercurials of not being precipitated at a slightly acid
`pH. As with other mercurials, it is slow in its bactericidal
`action, and it also produces sensitization reactions. Phenylmer-
`curic ion is incompatible with halides, as it forms precipitates.
`The effectiveness of phenylmercuric nitrate against P
`aeruginosa is questionable; it has been found that pseudo-
`monads survive after exposure to a concentration of 0.004% for
`longer than a week.
`Development of iatrogenic mercury deposits in the crystal-
`line lens resulting from use of miotic eye drops containing
`0.004% phenylmercuric nitrate, 3 times daily, for periods of 3 to
`6 years, has been reported. No impairment of vision was found,
`but the yellowish brown discoloration of the lens capsule is
`reported to be permanent.
`Thimerosal (Merthiolate, Lilly) is an organomercurial with
`bacteriostatic and antifungal activity and is used as an anti-
`microbial preservative in concentrations of 0.005 to 0.02%. Its
`action, as with other mercurials, has been reported to be slow.
`PARAHYDROXYBENZOIC ACID ESTERS—Mixtures
`of methylparaben and propylparaben sometimes are used as
`ophthalmic antimicrobial preservatives; the concentration of
`methylparaben is in the range of 0.1 to 0.2%, while that of
`propylparaben approaches its solubility in water (-0.04%).
`They are not considered efficient bacteriostatic agents and are
`slow in their antimicrobial action. Ocular irritation and sting-
`ing have been attributed to their use in ophthalmic prepara-
`tions. In a review of OTC drugs for use in ophthalmology, the
`FDA expert panel found the parabens unacceptable as ophthal-
`mic solution preservatives.
`SUBSTITUTED ALCOHOLS AND PHENOLS—Chloro-
`butanol is stated to be effective against both gram-positive and
`gram-negative organisms, including P aeruginosa and some
`fungi. It broadly is compatible with other ingredients and nor-
`mally is used in a concentration of 0.5%. One of the products of
`hydrolysis is hydrochloric acid, which causes a decrease in the
`
`Page 5
`
`

`
`832 (cid:9)
`
`CHAPTER 43
`
`pH of aqueous solutions. This decomposition occurs rapidly at
`high temperatures and slowly at room temperature, in unbuf-
`fered solutions that were originally neutral or alkaline. There-
`fore, ophthalmic solutions that contain chlorobutanol should be
`buffered between pH 5 and 5.5. At room temperature it
`dissolves slowly in water, and although it dissolves more
`rapidly on heating, loss by vaporization and decomposition is
`accelerated.
`A combination of chlorobutanol and phenylethyl alcohol
`(0.5% of each) has been reported to be more effective against P
`aeruginosa, Staphylococcus aureus, and Proteus vulgaris than
`either antimicrobial singly. Also, preliminary solution of the
`chlorobutanol in phenylethyl alcohol effects solution of the
`former in water without the use of heat.
`
`OPHTHALMIC PREPARATIONS FOR OTC USE
`
`A comprehensive review of OTC ophthalmic preparations re-
`cently has been completed by an expert panel approved by the
`FDA. The panel review extended over the period 1973 through
`1979. The findings of this panel, in the form of a tentative final
`monograph, appeared in the Federal Register.14
`In a comprehensive assessment the panel considered the
`following conditions amenable to OTC drug therapy.
`Tear Insufficiency—Rational formulations used to treat tear in-
`sufficiency are aqueous solutions containing demulcent agents, tonicity
`agents, and pH and buffering agents. Tear insufficiency includes
`1. Keratoconjunctivitis sicca
`2. Sjogren's syndrome
`3. Dry eye in the elderly
`Corneal Edema—Increased water content in the cornea usually is
`treated with hypertonic solutions of sodium chloride, either 2 or 5%.
`Inflammation and Irritation of the Eye-
`1. Presence of loose foreign material in the eye. Commonly treated
`with an isotonic eyewash properly buffered and preserved.
`2. Irritation from airborne pollutants and chlorinated water. Manage-
`ment consists of avoiding the offending allergens and the use of
`vasoconstrictors, astringents, demulcents, and emollients for symp-
`tomatic relief.
`3. Allergic conjunctivitis. Treatment by topically applied vasoconstric-
`tors and astringents, demulcents, emollients, and cold compresses.
`Only in mild cases, when edema and congestion are slight, is OTC
`treatment alone adequate.
`
`In providing such OTC medications the pharmacist should take
`the opportunity to point out that unsupervised use of these
`products should be limited to 72 hr when based on self-
`diagnosis. If the condition persists or worsens at any time,
`
`treatment should be discontinued and a physician consulted at
`once.
`
`CONTACT LENSES
`
`Contact lenses are optical and/or therapeutic ophthalmic de-
`vices divisible into four general categories. The rigid, hydro-
`phobic, so-called hard contact lenses, principally PMMA (poly-
`methyl methacrylate); rigid, semihydrophobic; flexible
`hydrophilic; flexible hydrophobic and rigid, gas-permeable.
`Each lens class is accompanied by its support solution products
`and devices. Solutions used with hard contact lenses are rather
`conventional compositions, usually regarded as OTC products.
`Conversely, solutions ancillary to the hydrophilic lenses may be
`classed as new drugs or devices from a regulatory standpoint.
`Such preparations require great care and considerable phar-
`maceutical skill to formulate. Lens materials and support prod-
`ucts are further classified and identified in Table 43-2.
`HARD CONTACT LENS—Some evidence is available to
`show that contact lenses were visualized by Leonardo da Vinci
`in 1508 and later, in 1637, by Rene Descartes. In 1827, the
`British astronomer Sir John Herschel described the mathemat-
`ics of these devices. He speculated on the possibility of filling a
`glass contact lens with transparent gelatin to correct for cor-
`neal irregularities. Not until 1888 was the original concept
`executed by the artificial eye maker, Albert Muller. He made a
`glass protective shell for the cornea of a lagophthalmic patient
`who had carcinoma of the upper lid. The patient wore the
`device for 20 years, and corneal clarity was maintained. Other
`cases were reported in Europe of glass shells placed on the eye
`as corneal protective devices.
`Until the latter part of the 1940s almost all contact lenses
`had a portion resting directly on, or arching over, the cornea,
`with a supporting flange resting beyond the limbus on the
`sclera. Thus, they were scleral lenses. However, contact lenses
`without scleral portions (corneal lenses) were in existence at
`least as early as 1912, when they were being manufactured by
`Carl Zeiss.
`The glass scleral contact lenses that were made from 1888 to
`1938 were fitted by a tedious method of trial and error using a
`fitting set that might contain more than 1000 lenses. The
`lenses were heavy, and adjustments on them by the fitter were
`impossible. Their life in the eye was short, because the glass
`was attacked vigorously by lacrimal fluid; in about 6 months
`the lenses became too rough to wear or to see through.
`However, they had the advantage that tears readily wet glass.
`In 1922 Dallos, in Budapest, perfected a molding technique by
`
`Table 43-2. Contact Lens Classes, Characteristics, and Support Products
`
`LENS TYPE
`Hard, rigid, hydrophobic (cid:9)
`
`CHEMICAL CLASSIFICATION
`PMMA (polymethyl
`methacrylate)
`
`Soft, flexible, hydrophilic
`
`HEMA (hydroxyethyl (cid:9)
`methylmethacrylate) (cid:9)
`
`Flexible hydrophobic
`
`Silicone rubber (cid:9)
`
`Rigid, hydrophilic
`
`Silicone
`vinylpyrollidone
`CAB (cellulose acetate
`butyrate)
`
`MAJOR CHARACTERISTICS
`Negligible gas permeability, low
`water content, medium
`wettability
`
`High water content, low gas
`permeability, good
`wettability
`Good gas permeability; poor
`wettability
`
`Good gas permeability; good
`wettability
`Good gas permeability; good
`wettability
`
`TYPICAL SUPPORT PRODUCTS
`Wetting solutions
`Soaking solutions
`Cleaning solutions
`Combination
`Artificial tears
`Cleaning solutions
`Disinfection solutions
`
`Wetting solutions
`Cleaning solutions
`Soaking solutions
`
`Wetting solutions
`Cleaning solutions
`Soaking solutions
`Rewetting solutions
`
`Page 6