LB!
`
`TUPELOQ
`
`Apotex (IPR2019-00400) Ex. 1048 p. 001
`
`_ The Science and
`eeGnQUmitialit(ey
`
`Parsons TET
`
`Apotex (IPR2019-00400) Ex. 1048 p. 001
`
`

`

`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
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`
`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 copy-
`right owner.
`
`Thepublisher is not responsible (as a matter of productliability, 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. Manufacturer’s 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 Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Informationis available
`ISBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. Ifthey 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 responsible 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 substitutefor the official
`United States Pharmacopeia (USP) and/or the National Formulary (NF). In the event of any difference or discrepancy betweenthe
`current official USP or NF standardsof strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the contexi and effect of the official compendia shall prevail.
`
`To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301)
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`Apotex (IPR2019-00400) Ex. 1048 p. 002
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`

`

`activity against bacteria can be variable because of
`ability. Thus, sorbic acid is frequently used in com-
`th other antimicrobial preservatives or glycols in
`“tic effects occur,
`
`
`
`_ esters of p-hydroxybenzoic acid and include the
`| propyl, and butyl derivatives. The water solubil-
`
`“bens decreases as the molecular weight increases
`for the methyl ester to 0.02% for the butyl ester.
`unds are used widely in pharmaceutical products,
`
`H range of 4 to 8, and have a broad spectrum of
`iio] activity, although they are mosteffective against
`
`) olds. Antimicrobial activity increases as the chain
`Amo
`]kyl moiety is increased, but aqueous solubility
`refore, a mixture of parabensis frequently used
`
`tive preservation. Preservative efficacy is also
`the addition of propylene glycol (2—5%) or by using
`sombination with other antimicrobial agents such
`
`Activity is reduced in the presenceofnonionic sur-
`nts due to binding. In alkaline solutions, ioniza-
`
`nd this reduces their activity; in addition, hy-
`omposition of the ester group occurs with a loss of
`
`
`
`Ammonium Compounds
`im chloride is a mixture consisting principally of
`ogs C\zHo5 and C,4Hap. This preservative is used at
`low concentration, 0.002% to 0.02%, depending on
`of the pharmaceutical product. This class of
`
`CHAPTER 39: SOLUTIONS, EMULSIONS, SUSPENSIONS, AND EXTRACTS
`
`749
`
`compounds has an optimal activity over the pH rangeof 4 to
`10 and is quite stable at room temperature. Because of the
`cationic nature ofthis type of preservative, it is incompatible
`with many anionic compounds such as surfactants and can
`bind to nonionic surfactants. It is used generally in prepara-
`tions for external use or those solutions that come in contact
`with mucous membranes. In ophthalmic preparations, benza-
`Ikonium chloride is widely used at a concentration of
`0.01-0.02% w/w. Often it is used in combination with other
`preservatives or excipients, particularly 0.1% w/v disodium
`edetate, to enhance its antimicrobial activity against strains
`of Pseudomonas. A concentration of 0.002—-0.02% is used in
`nasal and otic formulations, sometimes in combination with
`0.002-0.005% thimerosal. Benzalkonium chloride 0.01% w/v
`is also employed as a preservative in small-volume parenteral
`products.
`Clearly, when the pharmacist dispenses or compounds liq-
`uid preparations, responsibility is assumed, along with the
`manufacturer, for the maintenance of product stability. Gen-
`eral chapter (1191) of the USP describes stability considera-
`tions for dispensing, which should be studied in detail. Stock
`should be rotated and replaced if expiration dates on the label
`so indicate. Products should be stored in the manner indicated
`on the manufacturer's label or in the compendium. Further,
`products should be checked for evidence of instability. With re-
`spect to solutions, elixirs, and syrups, major signs of instability
`are color change, precipitation, and evidence of microbial or
`chemical gas formation. Emulsions may cream, but if they
`break (ie, there is a separation of an oil phase) the productis
`considered unstable. Sedimentation and caking are primary in-
`dications of instability in suspensions. The presence oflarge
`particles may mean that excessive crystal growth has occurred
`(Ostwald Ripening). Additional details on these topics are pro-
`vided in the pertinent sections of this chapter.
`
`
`
`SOLUTIONS
`
`
`homogeneous mixture that is prepared by dis-
`
`liquid, or gas in anotherliquid and represents a
`tions in which the molecules of the solute or
`
`ance are dispersed amongthoseof the solvent.
`nsare unsaturated with the solute, in other words,
`
`ationof the solute in the solution is below its solu-
`»
`+He strengths of pharmaceutical solutions are usu-
`
`ed in terms of % strength, although for very dilute
`*
`€xpressions of ratio strength are sometimesused.
`when used without qualification (as with w/v, v/v,
`
`ns % Weight-in-volumefor solutions or suspensions
`
`a weight-in-volumefor solutions ofgases in
`
`eume-in-volume for solutions of liquids in liquids;
`n-weightfor mixtures of solids and semisolids.
`© may be classified on the basis of physical or
`ties, Method of preparation, use, physical state,
`
`es “ents, and particle size. For the pharmacist,
`:
`‘ore defined by site of administration and com-
`
`eA xophysicochemical definitions. For instance,
`
`ion, ophthal ons maybe classified as an oral solution,
`
`also be ae solution, or topical solution. These so-
`
`aqueous “lassified based upon their composition.
`id
`roalehyeins containing a sugar; elixirs are
`Spirits are rs (combinations of water and ethanol)
`*holic or ga Utions of aromatic materials if the sol-
`
`Z On their eee waters if the solvent is aqueous.
`
`2
`extn ethod of preparation and concentration,
`
`vents
`‘acts are solutions prepared by extracting
`
`Armaceutical sree orUss:
`nt and “nee chemicals are only slowly solubleina
`
`eASethe t 2n extended time for complete disso-
`Issolution rate, a pharmacist may em-
`
`ploy one or several techniques such as applying heat, reducing
`the particle size of the solute, utilizing of a solubilizing agent,
`or subjecting the ingredients to rigorous agitation. In most
`cases, solutes are more soluble in solvents at elevated temper-
`atures than at room temperature or below dueto the endother-
`mic nature of the dissolution process. The pharmacist should
`ensure that the materials are heat stabile and non-volatile
`when using heatto facilitate the dissolution rate,
`
`AQUEOUS SOLUTIONS
`The narrowerdefinition in this subsection limits the solvent to
`water and excludes those preparations that are sweet and/or
`viscid in character and nonaqueoussolutions, This section in-
`cludes those pharmaceutical forms that are designated as Aro-
`matic Waters, Aqueous Acids, Solutions, Douches, Enemas,
`Gargles, Mouthwashes, Juices, Nasal Solutions, Otic Solutions,
`and Irrigation Solutions.
`
`Aromatic Waters
`
`The USPdefines Aromatic Waters as clear, saturated aqueous
`solutions (unless otherwise specified) of volatile oils or other
`aromatic or volatile substances.® Their odors and tastes are
`similar, respectively, to those of the drugs or volatile sub-
`stances from which they are prepared, and they are free from
`empyreumatic and other foreign odors. Aromatic waters may be
`prepared by distillation or solution of the aromatic substance,
`with or without the use of a dispersing agent. They are used
`ApotexUPR30TS60400) Ex:1048 p. 003
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`

`750
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`Peppermint Water USP and Stronger Rose Water USP are
`examples of aromatic waters. Concentrated waters, such as
`peppermint, dill, cinnamon, and caraway, may be prepared as
`follows:
`
`Dissolve 20 mL of the volatile oil in 600 mL of 90%ethanol.
`Add sufficient purified water in successive small portions to
`produce 1000 mL. Shake vigorously after each addition. Add
`50 g of sterilized purified tale, shake occasionally for several
`hours, and filter.
`
`The aromatic water is prepared by diluting the concentrate
`with 39 times its volumeof water.
`The chemical composition of many of the volatile oils is
`known, and suitable synthetic substances may be used in
`preparing pharmaceuticals and cosmetics. Similarly, many
`synthetic aromatic substances have a characteristic odor; for
`example, geranyl phenyl acetate has a honey odor, Such sub-
`stances, either alone or in combination, can be used in nonoffi-
`cial preparations.
`The principal difficulty experienced in compounding pre-
`scriptions containing aromatic waters is salting out certain in-
`gredients such as very soluble salts. A replacementof part of
`the aromatic water with purified water is permissible when no
`other function is being served than that of a vehicle. Aromatic
`waters will deteriorate with time and should, therefore, be
`made in small quantities, protected from intense light and ex-
`cessive heat, and stored in airtight, light-resistant containers.
`
`Aqueous Acids
`Inorganic acids and certain organic acids, although of minor
`significance as therapeutic agents, are of great importance in
`pharmaceutical manufacturing and analysis. Thisis especially
`true of acetic, hydrochloric, and nitric acids. Many of the more
`important inorganic acids are available commercially in the
`form of concentrated aqueous solutions. The percentage
`strength varies from one acid to another and depends on the
`solubility and stability of the solute in water and on the manu-
`facturing process, Thus, Hydrochloric Acid contains from 36.5%
`to 38.0% by weight of HCl], whereas Nitric Acid contains from
`69% to 71% by weight of HNOg.
`Because the strengths of these concentrated acids are stated
`in terms of percent by weight, it is essential that specific grav-
`ities also be provided if one is to be able to calculate conve-
`niently the amount of absolute acid contained in a unit volume
`of the solution as purchased. The mathematical relationship in-
`volved is given by the equation M = V x S x F, where Mis the
`mass in g of absolute acid contained in V mLof solution having
`a specific gravity S and a fractional percentage strength F.
`As an example, Hydrochloric Acid containing 36.93% by
`weight of HCl has a specific gravity of 1.1875. Therefore, the
`amount of pure HC! supplied by 100 mL ofthis solution is
`given by:
`
`M = 100 = 1.1875 x 0.3693 = 43.85 g HC]
`
`Although manyofthe reactions characteristicof acids offer op-
`portunities for incompatibilities, only a few are of sufficient im-
`portance to require more than casual mention. Acids and acid
`salts decompose carbonates with liberation of carbon dioxide; in
`a closed container, sufficient pressure may be developedto pro-
`duce an explosion. Inorganic acids react with salts of organic
`acids to produce the free organic acid and a salt of the inorganic
`acid. If insoluble, the organic acid will be precipitated, Thus,
`salicylic acid and benzoic acid are precipitated from solutions of
`salicylates and benzoates. Boric acid likewise is precipitated
`from concentrated solutions of borates. By a similar reaction,
`certain soluble organic compoundsare converted into an insol-
`uble form, Phenobarbital sodium, for example, is converted into
`phenobarbital that will precipitate in aqueous solution.
`The ability of acids to combine with alkaloids and other or-
`ganic compounds containing a basic nitrogen atom is used in
`
`Diluted Acids
`
`
`preparing soluble salts of these substances. Certain
`syrups, elixirs, and other pharmaceutical prepara Shih
`
`contain free acid, which causes these preparations a
`the incompatibilities characteristic of the acid, Acids al
`sess the incompatibilities of the anions that they conta
`
`in the case of organic acids, these are frequently of p i
`portance. These are discussed underthe specific anion. =
`
`The diluted acids in the USP are aqueoussolutionsof a4
`suitable strength (usually 10% w/v but Diluted Acetie 4
`
`6% w/v) for internal administration or for the manufaoy
`other preparations.
`Thestrengthsoftheofficial undiluted acidsare expregy
`
`percentages in weight (w/w), whereas the strengths of},
`cial diluted acids are expressed as percent in volume (yj
`
`therefore, becomes necessary to consider the specific gps
`
`ofthe concentrated acids when calculating the volumereqy
`to make a given quantity of diluted acid. The followingegy
`will give the numberof milliliters required to make 100(yy)
`diluted acid:
`
`Strength of diluted acid * 1,000
`Strength of undiluted acid
`x Specific gravity of undiluted acid
`
`
`Thus, if one wishes to make 1000 mL of Diluted Hydrodh
`Acid USP (10% w/v) using Hydrochloric Acid that assays @
`HCl(sp gr 1.18), the amount required is
`
`10 * 1,000
`876% 118 mh
`
`
`
`
`
`Diluted Hydrochloric Acid, USP has been used inthe treatm
`of achlorhydria. However, it may irritate the mucous me
`
`brane of the mouth and attack the enamel of the teeth.
`usual dose is 2 to 4 mL,well-diluted with water. In thet
`ment of achlorhydria no attempt is made to administer
`than a relief-producing dose.
`
`
`
`Douches
`A doucheis an aqueoussolution directed against a part am
`a cavity of the body. It functions as a cleansing or anes
`
`agent. An eve douche, used to remove foreign particles! a
`chargesfrom the eyes,is directed gently at an oblique angle :
`
`allowed to run from the inner to the outer corner OF".
`
`Pharyngeal douches are used to prepare the interior 0
`throat for an operation and cleanseit in suppurative cone”
`Similarly,
`there are nasal douches and vaginal
`
`Douches usually are directed to the appropriate body P®®
`jj
`using bulb syringes.
`
`Douchesare often dispensedin the form of a powder WT
`
`rections for dissolving in a specified quantity of water (uw vat
`warm). However, tablets for preparing solutions are 8V"
`
`(eg, Dobell’s Solution Tablets) or the solution may be re thi
`
`by the pharmacist. If powders or tablets are SUPP a
`mustbefree from insoluble material in order to pro¢4
`solution. Tablets are produced by the usual processes
`lubricants or diluents used must be readily soluble ™.deo
`
`Borie acid may be used as a lubricant and sodium alor ie
`mally is used as a diluent. Tablets deteriorate 0” exp"
`moist air and should be stored in airtight container®-
`Douches are not official as a class of preparations loved
`eral substances in the compendia frequently are emp
`af
`
`such in weak solutions. Vaginal douches are the most
`"ag
`type of douche and are used for cleansing the vagi™®
`gienic purposes. Liquid concentrates or powders, W wie ag
`preparedin bulk or as single-use packages, should be ‘ot
`ti !
`dissolvedin the ROOLO. amount ofwarm waterP™
`
`Apotex (IPR2019-00400) Ex. 1048 p. 004
`Apotex (IPR2019-00400) Ex. 1048 p.
`
`

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`
`
`CHAPTER 39: SOLUTIONS, EMULSIONS, SUSPENSIONS, AND EXTRACTS
`
`751
`
`
`dients used in vaginal douches include antimicrobial
`gre h as benzalkonium chloride,
`the parabens or
`
`gu |, and anesthetics or antipruritics such as phenol
`}
`“xstringents such as zinc sulfate or potassium alum,
`
` ol.
`nthve agents such as sodium lauryl sulfate, and chem-
`ae the pH such as sodiumbicarbonateor citric acid
`
`ysed.
`
`
`eas
`
`her ofsolutions are administeredrectally for the local ef-
`the medication (eg, hydrocortisone) or for systemic ab-
`a (eg, aminophylline). In the case of aminophylline, the
`Pee ute of administration minimizes the undesirable gas-
`
`i al reactions associated with oral therapy.** Clini-
`
`etive blood levels of the agents are usually obtained
`5 30 minutes following rectal instillation. Corticosteroids
`
`; ainistered as retention enemas or continuousdrip as ad-
`5 treatment of some patients with ulcerative colitis.
`
`a preparations are rectal injections employed to evac-
`owel (evacuation enemas), influence the general sys-
`
`hy absorption, or to affect a local disease. The latter two are
`
`er etention enemas, They may possess anthelmintic, nu-
`. sedative. or stimulating properties, or they may contain
`que substances for roentgenographic examination of
`
`bowel.
`ar
`i : chloride, sodium bicarbonate, sodium monohydro-
`
`osphate, sodium dihydrogen phosphate, glycerin, do-
`
`notassium, and light mineral oil are used in enemas to
`te the bowel. These substances may be used alone, in
`
`ation with each other, or in combination withirritants
`; soap. Evacuation enemas usually are given at body
`
`ature in quantities of 1 to 2 pt injected slowly with a
`
`
`in
`official retention enema used for systemic purposes is
`nophylline. Retention enemas are to be retained in the in-
`
`Gné and should not be used in larger quantities than 150 mL
`
`An adult, Usually, the volumeis considerably smaller, such
`mL. Microenema is a term used to describe these small-
`
`ime preparations. Vehicles for retention microenemas have
`ilrmulated with smal! quantities ofethanol and propylene
`
`i,
`and no significant difference in irritation, as compared
`
`er, was found. A number of other drugs such as val-
`@cid,indomethacin, and metronidazole have been formu-
`
`a5Microenemas for the purpose of absorption.
`
`
`
`re aqueous solutions frequently containing antisep-
`lotics, and/or anesthetics used for treating the phar-
`Rasopharynx by forcing air from the lungs through the
`
`that is held in the throat: subsequently, the gargle is ex-
`- Many gargles must be diluted with water prior to
`
`Sugh mouthwashesare considered as a separate class
`
`Ma uticals, many are used as gargles eitherasis,or di-
`
`4 Water,
`€/mouthwash containing the antibiotie tyrothricin
`
`Wn to provide levels ofgramicidin, a componentof
`42 Saliva when used as a gargle rather than a
`
`igher saliva levels of gramicidin were obtained
`ge formulation was employed. Rapid relief of pha-
`
`go pain was obtained when Cepacaine solution,
`
`tin 4 & topical anesthetic, was used as a gargle.”®
`
`fon administeredin both powder andliquid form to
`8al infections,” The medication is taken by plac-
`ie the dose in each side of the mouth, swishingit
`an..2 28 Possible, then gargling and swallowing. Hy-
`© 18 a source of nascent oxygen and a weak topi-
`
`* agent. Hydrogen peroxide topical solution has
`i. Vi mouthwash or gargle in the treatment of
`Icent’s stomatitis.7*" Hydrogen peroxide has
`
`
`
`
`also been applied in root canals of teeth or other dental pulp
`cavities. While usedtopically as a 1.5-3% solution for cleansing
`wounds, hydrogen peroxideis usually diluted with an equalvol-
`umeof water for use as a mouthwashor gargle. Hydrogen per-
`oxide gel is used topically as a 1.5% gel for cleansing minor
`woundsorirritations of the mouth or gums. A small amount of
`the gel is applied to the affected area, allowed to remain in
`place for at least 1 minute, and then expectorated: the gel may
`be used up to 4 times daily (after meals and at bedtime).
`
`Mouthwashes
`
`Mouthwashes are aqueous solutions often in concentrated form
`containing one or more active ingredients and excipients de-
`scribed below. They are used by swishing the liquid in the oral
`cavity. Mouthwashes can be used for two purposes, therapeutic
`and cosmetic. Therapeutic rinses or washes can be formulated
`to reduce plaque, gingivitis, dental caries, and stomatitis, Cos-
`metic mouthwashes may be formulated to reduce bad breath
`through the use of antimicrobial and/orflavoring agents.
`Recent information indicates that mouthwashes are being
`used as a dosage form for a number of specific problems in
`the oral cavity; for example, mouthwashes containing a combi-
`nation of antihistamines, hydrocortisone, nystatin, and tetra-
`eycline have been prepared from commercially available
`suspensions, powders, syrups, or solutions for the treatment of
`stomatitis, a painful side effect of cancer chemotherapy. Other
`drugs include allopurinol, also used for the treatment of stom-
`atitis,”’ pilocarpine for xerostoma (dry mouth),"’ amphotericin
`B fororal candidiasis,®” and chlorhexidine gluconatefor plaque
`control.** Mouthwashes may be used for diagnostic purposes.
`For example, oral cancer and lesions are detected using tolui-
`dine blue mouth rinse.“*
`Commercial products (eg, Cepacol, Listerine, Micrin, or
`Scope) vary widely in composition. Tricca has described the ex-
`cipients generally found in Mouthwashes as alcohols, surfac-
`tants, flavors, and coloring agents.** Alcohol is often present in
`the range of 10% to 20%. It enhances the flavor, provides sharp-
`ness to the taste, aids in masking the unpleasanttaste ofactive
`ingredients, functions as a solubilizing agent for some flavoring
`agents, and may function as a preservative. Humectants such
`as glycerin and sorbitol may form 5% to 20% of the mouthwash.
`These agents increase the viscosity of the preparation and pro-
`vide a certain body or mouth feel to the product. They enhance
`the sweetness of the product and, along with the ethanol, im-
`prove the preservative qualities of the product.
`Surfactants of the nonionic class such as polyoxyethylene/
`polyoxypropylene block copolymers or polyoxyethylene deriva-
`tives of sorbitol fatty acid esters may be used. The concentra-
`tion range is 0.1% to 0.5%, An anionic surfactant occasionally
`used is sodium lauryl sulfate. Surfactants are used because
`they aid in the solubilizationof flavors and in the removal of de-
`bris by providing foaming action. Cationic surfactants such as
`cetylpyridinium chloride are used for their antimicrobial prop-
`erties, but these tend to imparta bitter taste.
`Flavors are used in conjunction with alcohol and humec-
`tants to overcome disagreeable tastes, at the same timeflavors
`must be safe to use. The principle flavoring agents are pepper-
`mint, spearmint, cinnamon, wintergreen oils, menthol, or
`methyl salicylate. Other flavoring agents may be used singly
`or in combination. Finally, coloring agents also are used in
`these products.
`
`Juices
`
`A juice is prepared from fresh ripe fruit, is aqueous in charac-
`ter, and is used in making syrups that are employed as vehicles.
`The freshly expressed juice is preserved with benzoic acid and
`allowed to stand at room temperaturefor several days, until the
`pectins that naturally are present are destroyed by enzymatic
`action, as indicated by thefiltered juice yielding a clear solution
`Apotex (IPR2019-00400) Ex. 1048 p. 005
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`

`752
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`with alcohol. Pectins, if allowed to remain, would cause precip-
`itation in the final syrup.
`Cherry Juice and Tomato Juice are described in the USP.
`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 phar-
`maceutical form. Commercial juices such as orange, apple,
`grape, and mixed vegetables have been used recently to prepare
`extemporaneous preparations of cholestyramine®® and nizati-
`dine.*” Information on cranberry juice indicates that it may be
`effective in controlling some urinary tract infections and
`urolithiasis.**
`
`than the spray, and three drops cover most of the wal]s of4
`nasal cavity with the patient in a supine position and heaq 4,
`
`back and turned left and right.**“*
`It is suggested that di
`delivery, with appropriate movement by the patient, |g .
`extensive coverage ofthe walls of the nasal cavity.
`_
`
`Most nasal solutions are packaged in dropperor spray)
`
`tles, usually containing 15 to 30 mL of medication. The fiye
`lator should ensure the productis stable in the containers .
`
`the pharmacist should keep the packages tightly closed q..
`periods of nonuse, The patient should be advised that g)
`the solution becomediscolored or contain precipitated may,
`it must be discarded,
`q
`
`Nasal Solutions
`
`Otic Solutions
`
`
`
`
`
`
`These solutions occasionally are referred to as ear or ayy
`
`preparations, Otherotic preparations include suspensions ay
`
`ointments for topical application in the ear. Ear preparatigy
`are usually placed in the ear canal by dropsor in small amoupy
`for the removal of excessive cerumen (ear wax) orfor the
`
`ment of ear infections, inflammation, or pain.
`The main classes of drugs used for topical administratipn
`the ear include analgesics, such as benzocaine; antibiotic
`
`as neomycin; and anti-inflammatory agents, suchas co
`(Table 39-4). The USP preparations include Antipyrine anf
`
`Benzocaine Otic Solution. The Neomycin and Polymyxin BS
`fates and Hydrocortisone Otic Solutions may contain appro
`
`ate buffers, solvents, and dispersants usually in an aq
`
`solution. The main solvents used in these preparations ine
`glycerin or water. The viscous glycerin vehicle permits the¢
`
`to remain in the ear for a long time. Anhydrousglycerin, b
`hygroscopic, tends to remove moisture from surrounding
`
`sues, thus reducing swelling. Viscous liquids suchas glyceri
`
`propylene glycol are used either alone or in combination wi
`
`surfactant to aid in the removal of cerumen (ear wax). To pr
`
`vide sufficient time for aqueous preparationsto act,it is nete
`
`sary for patients to remain ontheir side for a few minutes sou
`drops do not run outof the ear. Otic preparationsare dispens®
`in a container that permits the administration of drops.
`
`
`irrigation Solutions
`
`Irrigation solutions are sterile, non-pyrogenic solutions 4
`wash or bathe surgicalincisions, wounds, or body tissue
`cause they comein contact with exposedtissue, they must m™
`
`stringent USP requirements for sterility, total solids, ane”
`O88
`terial endotoxins. These products may be prepared by
`
`ing the active ingredient in Water for Injection. They 2% P”
`
`(JP
`aged in single-dose containers, preferably Type I of
`glass, or suitable plastic containers, and then sterilized. A :
`
`ber ofirrigations are described in the USP,including
`
`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. The adult nasal cavity has about a 20 mL capacity with
`a large surface area (about 180 cm*) for drug absorption af-
`forded by the microvilli present along the pseudo-stratified
`columnar epithelial cells of the nasal mucosa.** The nasaltis-
`sue is highly vascularized making it an attractivesite for rapid
`and efficient systemic absorption. Another advantage of nasal
`delivery is that it avoids first-pass metabolism by the liver. For
`some peptides and small molecular compounds, intranasal
`bioavailability has been comparable to that of injections. How-
`ever, bioavailability decreases as the molecular weight of a
`compound increases, and for proteins composed of more than 27
`amino acids bioavailability may be low.“° Various pharmaceu-
`tical techniques and functional excipients, such as surfactants,
`have been shown to be capable of enhancing the nasal absorp-
`tion of large molecules.*)”
`Many drugs are administered for their local sympath-
`omimetic effects to reduce nasal congestion, such as Ephedrine
`Sulfate Nasal Solution, USP or Naphazoline Hydrochloride
`Nasal Solution, USP. A few other 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. Examples of commercial products
`for nasal usearelisted in Table 39-3.
`Nasal solutions are formulated to be similar to nasal secre-
`tions with regard to toxicity, pH, and viscosity so that normal
`ciliary action is maintained. Thus, aqueous nasal solutions usu-
`ally are isotonic and slightly buffered to maintain a pH of5.5 to
`6.5. In addition, antimicrobial preservatives, similar to those
`used in ophthalmic preparations, and appropriate drug stabi-
`lizers, if required, are included in the formulation.
`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 extensively
`
`Table 39-3. Examples of Commercial Nasal Preparations
`MANUFACTURER
`ACTIVE INGREDIENT
`PRODUCT NAME
`
`Atrovent Nasal Spray
`Beconase AQ Nasal Spray
`
`Miacalcin
`Nasalcrom Nasal Spray
`Nasarel Nasal Spray
`Nicotrol Nasal Spray
`Neo-Synephrine
`Rhinocort Aqua Nasal Spray
`Stadol Nasal Spray
`Stimate Nasal Spray
`
`Synare Nasal Solution
`Tyzine
`
`Boehringer Ingelheim
`GlaxoSmithKline
`
`Novartis
`Pharmacia
`VAX
`Pfizer
`Bayer
`Astra-Zeneca
`Bristol-Myers Squibb
`Aventis
`
`Searle
`Bradley Pharmaceuticals
`
`Ipratropium bromide 0.06%
`Beclomethasone dipropionate,
`monohydrate 42 mcg
`Calcitonin-salmon, 2200 1.U. per mL
`Cromolyn sodium 5.2 mg
`Flunisolide
`Nicotine 0.5 mg
`Oxymetazoline hydrochloride 0.05%
`Budesonide 32mcg
`Butorphanoltartrate, 1 mg
`Desmopressin Acetate 1.5 mg/mL
`
`
`
`
`INDICATION
`7
`ic RHINE
`SeasonalorAllerg! Rif
`Seasonal or Allerg!¢
`
`Postmenopausal osteor
`
`Seasonal or Allergi<* thi ;
`Seasonalor perenn!
`Smoking Cessation
`
`Decongestion
`ap
`inil
`Seasonal or allergicRr %
`Pain Relief, migra”
`Hemophilia A oF we
`
`Willebrand diseas
`Endometriosis
`Nafarelin acetate 2 mg/mL
`Decongestion
`!
`Tetrahydrozoline hydrochloride
`
`
`Apotex (IPR2019-00400) Ex. 1048 p. 006
`A POotex
`PRI01T9-00400
`X.
`048 p. 006
`
`
`
`

`

` es of Commercial Otic Preparations
`
`
`MANUFACTURER
`ACTIVE INGREDIENT
`INDICATION
`
`CHAPTER 39: SOLUTIONS, EMULSIONS, SUSPENSIONS, AND EXTRACTS
`
`753
`
`Celltech
`Purdue
`
`Pfizer
`Alcon
`
`GlaxoSmithKline
`
`GlaxoSmithKline
`Daiichi
`Savage
`
`Benzocaine
`Triethanolamine polypeptide
`oleate-condensate
`Chloramphenicol
`Ciprofloxacin hydrochloride
`and hydrocortisone
`Neomycin and Polymyxin B Sulfates
`and Hydrocortisone
`Carbamide peroxide
`Ofloxacin
`Antipyrine, Benzocaine,
`and Phenylephrine Hydrochloride
`
`Local anesthetics
`Removal of earwax
`
`Antiinfective
`Acute otitis externa
`
`Antibacterial and anti-inflammatory
`
`Removal of earwax
`Antiinfective
`Topical anesthetic
`
`
`-yigation for bladderirrigation, Dimethyl Sulfoxide Irri-
`ir e relief of internal cystitis, Glycine Irrigation for
`
`eval prostatic resection, Ringer's Irrigation for gen-
`srigation, Neomycin and Polymyxin B Sulfates Solution
`
`tion for infection, and Sodium Chloride Irrigation for
`
`ing wounds.
`.
`Il
`snporaneous formulations frequently are prepared us-
`
`tonic solution of sodium chloride as the solvent. For
`= cefazolin or gentamicin in 0.9% sodium chloride are
`
`“gnti-infective irrigations*® and 5-fluororacil in 0.9%
`oride is employed for bladderirrigation.** Alum,ei-
`tassium or ammonium,in either sterile water or 0.9%
`
`im
`chloride for irrigation has been used for bladder hemor-
`nphotericin in sterile water has been used for the
`
`of localized infections on the dermis, the bladder,
`ary tract.*” All the extemporaneous preparations
`eet the general requirements noted above for USP
`5.
`
`ARATION OF SOLUTIONS
`
`of preparation for many solutions is given in the
`These procedures fall into three main categories:
`tutions, solution by chemical reaction, and solution by
`
`containing 100 g of potassium iodide. Sufficient purified water
`then is added to make 1000 mLofsolution. One g of iodine
`dissolves in 2950 mL of water. However, solutions of iodides
`dissolve large quantities of iodine. Strong Iodine Sol