LIBRARY
`
`!!||WI“WEI!”llHWWWIWIIHWIHINHIHHIHIW
`
`000000000491 1‘1
`
`1 The Science and
`Practice of Pharmacy
`
`
`
`21 st EDITION
`
`‘
`-
`.4:-
`IthPINCOTT WILLIAMS a WILKIN'S.
`
`Apotex (IPR2019-00400) Ex. 1048 p. 001
`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
`
`530 Walnut Street
`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 copy-
`right 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. 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 Information is available
`lSBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If'they hove inadvertently overlooked
`any, they will be pleased to males the necessary arrangements at the first opportunity.
`
`The use ofstrnctural formulas from USAN and the USP Dictionary ofDrng 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 substitute for the official
`United States Plior'mocopeio (USP) ondl or the Notionot Formttlory (NF). in the event ofnny difference or discrepancy between. the
`current official USP or NF standards ofstrength, quality, purity, packaging and labeling Jfor drugs and representations of them
`herein, the context and effect of the official contpendio shall prevail.
`
`To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301]
`824-7390. International customers should call (301) 714-2324.
`
`12345678910
`
`Apotex (IPR2019-00400) Ex. 1048 p. 002
`Apotex (IPR2019-00400) EX. 1048 p. 002
`
`

`

`..
`
`tjvity against bacteria can be variable because of
`abilitY' Thus, sorbic acid is frequently used in com-
`other antimicrobial preservatives or glycols in
`
`__
`
`- tic effects occur.
`
`__ esters of p-hydroxybenzoic acid and include the
`l pmpyl, and butyl derivatives. The water solubil-
`’benfi decreases as the molecular weight increases
`-
`for the methyl ester to 0.02% for the butyl ester.
`
`was, are used widely in pharmaceutical products,
`pH range of 4 to 8, and have a broad spectrum of
`
`.-. activity, although they are most effective against
`limit!
`"'W ldfi- Autimicrobial activity increases as the chain
`1le moiety is increased, but aqueous solubility
`refore, a mixture of parabons is frequently used
`
`five preservation. Preservative efficacy is also
`the addition of propylene glycol (2—5%) or by using
`
`'
`bination with other antimicrobial agents such
`mthrity is reduced in the presence ofnonionic sur~
`
`.ts due to binding. In alkaline solutions, ioniza-
`nd this reduces their activity; in addition, hy-
`‘ position of the ester group occurs with a loss of
`
`
`
`
`Ammonium Compounds
`._. chloride is a mixture consisting principally of
`{,5 ; Cull” and Cliflgg. 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 range of4 to
`10 and is quite stable at room temperature. Because of the
`cationic nature ol'this 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—
`lkonium chloride is widely used at a concentration of
`001—03295 w/w. Often it is used in combination with other
`preservatives or excipients, particularly 0.1% wfv disodium
`edetate, to enhance its antimicrobial activity against strains
`of Pseudomonos. 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.9 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 product is
`considered unstable. Sedimentation and calcing are primary in—
`dications of instability in suspensions. The presence of large
`particles may mean that excessive crystal growth has occurred
`(Ostwald Ripeningil. Additional details on these topics are pro-
`vided in the pertinent sections of this chapter.
`
`
`
`
`
`homogeneous mixture that is prepared by dis-
`
`liquid, or gas in another liquid and represents a
`time in which the molecules of the solute or
`
`one are dispersed among those of the solvent.
`”3.9-“ unsaturated with the solute, in other words,
`
`ahenof the solute in the solution is below its solu-
`" The WEngths of pharmaceutical solutions are usu-
`
`ed “1 taHos of 95; strength, although for very dilute
`‘ ”Emissions of ratio strength are sometimes used.
`
`when used without qualification (as with wiv, va,
`
`li-
`. weight-in—volume for solutions or suspensions
`WGIIUIdfl;_% Weight—in-volume for solutions of gases in
`. umh'm‘vtllume for solutions of liquids in liquids;
`
`'elght for mixtures of solids and semisolids.
`-_-
`Elma? be classified on the basis of physical or
`
`I'tles, method of preparation, use, physical state,
`
`moments’ and particle size. For the pharmacist,
`. b
`fiefi'ned by site of administration and corn-
`
`9&1 :0? gSIf-‘ochemical definitions. For instance.
`._
`. flphthgg 095 maybe classified as an oral solution,
`
`also be ml“ Solution, or topical solutton. These so—
`:Bqueoug h aEntitled based upon their composition.
`
`'. hydroalcolfolliltlons containing a sugar; elixirs are
`
`JePl‘f‘its are sol“: {combinations of water and ethanol)
`hole; or or: “none of aromatic materials if the soi-
`
`:- 'on their m room: waters if the solvent IS aqueous.
`
`Rid Formal-10d of preparation and concentration,
`“ants Profits are solutions prepared by extracting
`firms
`-
`In crude drugs.
`
`t; 3115:3131”! Chemicals are only slowly soluble in a
`liner-sage thujrh an extended time for complete disso-
`
`-
`e dissolution rate. a pharmacist may em-
`
`SOLUTIONS
`
`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 due to the endother-
`mic nature of the dissolution process. The pharmacist should
`ensure that the materials are heat stabile and non»volatile
`when using heat to facilitate the dissolution rate.
`
`AQUEOUS SOLUTIONS
`The narrower definition in this subsection limits the solvent to
`water and excludes those preparations that are sweet andi‘or
`viscid in character and nonaqueous solutions. This section in-
`cludes those pharmaceutical forms that are designated as Aro—
`matic Waters, Aqueous Acids, Solutions, Douches, Enema-s,
`Gorgies, Mouthwashes, Juices, Nasal Solutions, Otto Solutions,
`and Irrigation Solutions.
`
`Aromatic Waters
`
`The USP defines 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
`Alfitits‘l‘iitlfé‘fiidé’fdfi’ihiii fiiiill5048 p. 003
`Apotex (IPR2019-00400) Ex. 1048 p. 003
`
`
`

`

`75°
`
`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 carawsy, 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 talc. shake occasionally for several
`hours, and filter,
`
`The aromatic water is prepared by diluting the concentrate
`with 39 times its volume of 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 nonofii-
`cia] preparatious.
`The principal difficulty experienced in compounding pre-
`scriptions containing aromatic waters is setting out certain in-
`gredients such as very soluble salts. A replacement of 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. This is 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 366%
`to 38.0% by weight of HCl, whereas Nitric Acid Contains from
`69% to 71% by weight of HNOa.
`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 Mia the
`mass in g of absolute acid contained in 1’ mL of solution having
`a specific gravity S and a fractional percentage strength F.
`As an example, Hydrochloric Acid containing 36.93% by
`weight of HG] has a specific gravity of 1.1875. Therefore, the
`amount of pure HC] supplied by 100 mL of this solution is
`given by:
`
`M =100 >< 1.1875 X 0.3693 = 43.85 gHCl
`
`Although many of the reactions characteristic of 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 developed to 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 benroates. Boric acid likewise is precipitated
`from concentrated solutions of berates. By a similar reaction,
`certain soluble organic compounds are 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
`
`
`preparing soluble salts of these substances. Certain
`syrups, elixirs, and other pharmaceutical prepara '3'-
`contain free acid, which causes these preparations "i:
`
`the incompatibilities characteristic of the acid. Acids ‘3:
`sees the incompatibilities of the anions that they con
`in the case of organic acids, these are fi'equently Ofp '.':"-
`portance. These are discussed under the specific anin __'.
`
`
`Diluted Acids
`
`-'
`
`
`The diluted acids in the USP are aqueous solutions of h -.
`suitable strength (usually 10% win but Diluted militia ;.
`
`,'
`6% role) for internal administration or for the manuf.
`other preparations.
`The strengths ofthe official undiluted acids are Expr:_..;;..
`
`percentages in weight cum, whereas the strengths of l.
`cial diluted acids are expressed as percent in V0]l]_tne( ,.
`-
`therefore, becomes necessary to consider the specific .4,_'
`_
`
`of the concentrated acids when calculating the volumer
`_
`to make a given quantity of diluted acid. The following ;. 7,
`will give the number of milliliters required to make 1 lit-1.2
`diluted acid:
`'
`
`Strength of diluted acid 3 1.000
`Strength of undiluted acid
`it Specific gravity of undiluted acid
`
`
`Thus, if one wishes to make 1000 mL of Diluted Hydmir
`Acid USP (10% wfvl using Hydrochloric Acid that assays :'.
`HCl (sp gr 1.18), the amount required is
`
`
`
`
`10 x 1,000
`37.5 x 1.13 = 226 mL
`
`
`
`
`Diluted Hydrochloric Acid, USP has been used in the t - _-
`-
`of achlorhydria. However, it may irritate the mucous.
`
`brane of the mouth and attack the enamel of the tee ‘.'-
`usual dose is 2 to 4 mL, well-diluted with water. In
`merit of achlorhydria no attempt is made to administer"
`than a relief—producing dose.
`
`Douches
`
`A douche is an aqueous solution directed against a part
`a cavity of the body. It functions as a cleansing 01’ “W
`
`'ffi'.
`agent. An eye douche, used to remove foreign particles =
`._
`charges from the eyes, is directed gently at an oblicltile
`
`allowed to run from the inner to the outer corner of
`
`Plioryngeol douches are used to prepare the interlflr'_'-. _
`throat for an operation and cleanse it in suppurative con
`Similarly,
`there are nasal don-ch85 and vaginal
`
`Douches usually are directed to the appropriate bod!" P "
`_-.
`using bulb syringes.
`
`_
`,1:
`Douches are often dispensed in the form of a poll-"lar
`
`rections for dissolving in a specified quantity of water i“ ' 1.
`warm). However, tablets for preparing solutions are av .
`
`(eg. Dobell’s Solution Tablets) or the solution may be. Pr: j_.
`by the pharmacist. If powders or tablets are Suppl"3 ‘9.
`
`must be free from insoluble material in order to Illr'lldt“:e
`
`solution. Tablets are produced by the usual processed
`lubricants or diluents used must be readily soluble "It ,i
`Boric acid may be used as a lubricant and sodium Chm;
`mally is used as a diluent. Tablets deteriorate 0“ exp
`
`moist air and should be stored in airtight contain?“-
`Douches are not official as a class of preparation5
`era] substances in the compendia frequently are 3:11P}; ,.-.,:
`
`such in weak solutions. Vaginal douches are the me“ an};
`type of douche and are used for cleansing the “33“}? .iri; '
`
`gienic purposes. Liquid concentrates or powders. Whndflu- -'
`r r'-'
`prepared in bulk or as single-use packages, should be e '
`
`dissolved in the agrariate amount ofwarm water P“
`
`Apotex (IPR2019-00400) Ex. 1048 p. 004
`Apotex (IP
`19-00400) EX. 1048 p.
`
`.
`
`

`

`
`
`CHAPTER 39: SOLUTIONS. EMULSIDNS. SUSPENSIONS, AND EXTRACTS
`
`751
`
`.‘I'I
`
`
`5 used in vaginal douches include antimicrobial
`.dient
`h as benzalkonium chloride,
`the parabens or
`:' I.
`"'- Sun 1 and anesthetics or antipruritics such as phenol
`
`mashingeuts such as zinc sulfate or potassium alum,
`tI've agents such as sodium lauryl sulfate. and chom-
`:ftelr the pH such as sodium bicarbonate or citric acid
`
`used-
`
`
`- 1. ofsolutions are administered rectally for the local ef-
`medjcation leg, hydrocortisonel or for systemic ab-
`3' aminophyllinel. In the case of aminophylline, the
`w’uf administration minimizes the undesirable gas-
`”final reactions associated with oral therapy?“ Clini-
`
`ctive blood levels of the agents are usually obtained
`
`i, 30 minutes following rectal Instillation. Corticosteroids
`
`r. ,inistered as retention enemas or continuous drip as ad-
`. treatment of some patients with ulcerative colitis.
`
`a preparations _are rectal injections employed to evac-
`uwel [evacuation enemas-l, influence the general sys-
`
`-” absorption. or to affect a local disease. The latter two are
`etention enemas. They may possess anthelmintic, nu-
`
`' sedative, or stimulating properties. or they may contain
`.ue substances for roentgenographic examination of
`.
`nwsl.
`
`:
`.. chloride, sodium bicarbonate. sodium monohydro—
`
`sphate, sodium dihydrogen phosphate, glycerin. do-
`
`t
`tassium. and light mineral oil are used in enemas to
`-: the bowel. These substances may be used alone, in
`
`.tion with each other. or in combination with irritants
`. soap. Evacuation enemas usually are given at body
`
`ture in quantities of 1 to 2 pt injected slowly with a
`
`
`-
`ufficial retention enema used for systemic purposes is
`._.__ylline. Retention enemas are to be retained in the in-
`
`- -}8.l'ld should not be used in larger quantities than 150 mL
`-
`ult. Usually. the volume is considerably smaller, such
`niL. Micro-memo is a term used to describe these small-
`
`
`
`preparations. Vehicles for retention microenemas have
`_. mulated with small quantities of ethanol and propylene
`
`-
`. no significant difference in irritation, as compared
`
`er. was found. A number of other drugs such as val-
`.
`."duindomethacin, and metronidazole have been formu-
`
`gmcroenemas for the purpose of absorption.
`
`
`
`
`_ aqueous solutions frequently containing antisep-
`‘WCS, andfor anesthetics used for treating the phar-
`m‘lopharyux by forcing air from the lungs through the
`
`-
`It is held in the throat; subsequently. the gargle is ex-
`- - Many gargles must be diluted with water prior to
`
`rugh mouthwashes are considered as a separate class
`_
`_ “heals.- many are used as gargles either as is, or di-
`' Water.
`
`Elmouthwash containing the antibiotic tyrothricin
`
`, n to Provide levels ofgrarnicidin, a component of
`2:511 saliva when used as a gargle rather than a
`'
`
`' Higher saliva levels of gramicidin were obtained
`Ugo formulation was employed. Rapid relief of pha-
`
`_Dral Pain was obtained when Cepacaine solution,
`
`,1 . £3 a I30pical anesthetic, was used as a gargle?‘3
`
`Tun l1l'l-l‘lllrustered_iri both powder and liquid form to
`
`of
`infecuons.2’ The medication is taken by plac~
`0n the dose in each side of the mouth, swishing it
`‘g a? Possible, then gurgling and swallowing. Hy-
`.e 18 a source of nascent oxygen and a weak topi-
`
`as
`Elgent. Hydrogen peroxide topical solution has
`-nr ‘1 mouthwash or gar le in the treatment of
`Incent’s stomatitis.“ 9 Hydrogen peroxide has
`
`
`._
`
`also been applied in root canals of teeth or other dental pulp
`cavities. While used topically as a 1.543% solution for cleansing
`wounds, hydrogen peroxide is usually diluted with an equal vol~
`ume of water for use as a mouthwash or gargle. Hydrogen per—
`oxide gel is used topically as a 1.5% gel for cleansing minor
`wounds or irritations of the mouth or gums. A small amount of
`the gel is applied to the afi‘ected 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 helow. They are used by swishing the liquid in the oral
`cavity. Mouthwashes can be used for tvvo 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 andfor flavoring 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, nystatia, and tetra-
`cycline have been prepared from commercially available
`suspensions, powders, syrups, or solutions for the treatment of
`stomatitls, a painful side effect of cancer chemotherapy. Other
`drugs include allopurinol, also used for the treatment of stom-
`atitis,” pilocarpine for xerostoma (dry mouthlf” amphotericin
`B for oral candidiasis.“ and chlorhexidine gluconate for plaque
`control.33 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 agentsas 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 unpleasant taste of active
`ingredients, functions as a solubilizing agent for some flavoring
`agents, and may function as a preservative. Homectants such
`as glycerin and sorbitol may form 5% to 20% oftlie 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 polyoxyet-hylene!
`polyoxypropylene block copolymers or polyoxyethylene deriva-
`tives of sorhitol 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 solubilization of' flavors and in the removal ofde~
`bris by protriding foaming action. Cationic surfactants such as
`cetylpyridinium chloride are used for their antimicrobial prop—
`erties. but these tend to impart a bitter taste.
`Flavors are used in conjunction with alcohol and humec—
`tents to overcome disagreeable tastes, at the some time flavors
`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 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
`
`Apotex (IPR2019-00400) Ex. 1048 p. 005
`Apotex (IPR2019-00400) EX. 1048 p. 005
`
`

`

`than the spray, and three drops cover most of the Walls 01,,
`nasal cavity with the patient in a supine position and head If
`
`back and turned lefi: and right.”
`It is suggested mail;
`delivery, with appropriate movement by the patienLI 1,,
`”I"
`
`extensive coverage of the walls of the nasal cavity.
`’ "
`Most nasal solutions are packaged in dropper or spray -
`
`tles, usually containing 15 to 30 mL of medication. The fin
`'f
`lator should ensure the product is stable in the containers '
`
`the pharmacist should keep the packages tightly closed d
`periods of nonuse. The patient should be advised that s.
`the Solution become discolored or contain precipitated
`it must be discarded.
`
`
`
`Nasal Solutions
`
`Otic Solutions
`
`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
`extem oraneous preparations of cholestyramine35 and nizati-
`dine.3 Information on cranberry juice indicates that it may be
`effective in controlling some urinary tract infections and
`urolithiasis.36
`
`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 n'iucosa.89 The nasal tis-
`sue is highly vascularized making it an attractive site 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, bioavailabilit-y decreases as the molecular weight of a
`compound increases, and for proteins com used of more than 27
`amino acids bioavailability may be low.‘1 Various pharmaceu-
`tical techniques and functional excipients, such as surfactants,
`have been shown to be capable of enhancing the nasal absorp-
`tion oflarge moleculesf‘“2
`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 ell‘ect for the
`treatment of diabetes insipidus and milk letdown prior to
`breast feeding, respectively. Examples of commercial products
`for nasal use are listed 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 of 5.5 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
`
`
`These solutions occasionally are referred to as car or :
`I.
`
`preparations. Other otic preparations include suspensions
`
`ointments for topical application in the ear. Ear prepara,',.__
`are usually placed in the ear canal by drops or in small amen. .
`for the removal of excessive cerumen (ear wax) or for the
`
`meat of ear infections, inflammation, or pain.
`The main classes of drugs used for topical administrati ..
`
`the ear include analgesics, such as benzocaine; antibiotic
`
`as neomycin; and anti-inflammatory agents, such as on
`(Table 39—4). The USP preparations include Antipyrine ._ ..
`
`Benzocaine Otic Solution. The Neomycin and Polymyxin
`fates and Hydrocortisone Otic Solutions may contain app .
`
`ate buffers, solvents, and dispersants usually in an no
`solution. The main solvents used in these preparations in-
`
`glyccrin or water. The viscous glycerin vehicle permits the .
`
`to remain in the ear for a long time. Anhydrous glycerin, l1
`hygroscopic, tends to remove moisture from surrounding
`
`'
`sues, thus reducing swelling. Viscous liquids such as gly
`
`propylene glycol are used either alone or in combination wi
`
`surfactant to aid in the removal of cerumen (ear wax). To ,-.
`
`vide sufficient time for aqueous preparations to act, it is
`
`sary for patients to remain on their side for a few minutes so. '-
`drops do not run out of the ear. Otic preparations are dis I -. r-'.
`in a container that permits the administration of drops.
`
`
`
`Irrigation Solutions
`
`
`Irrigation solutions are sterile, non-pyrogenic solutions 11
`wash or bathe surgical incisions, wounds, or body tissues
`
`cause they come in contact with exposed tissue, they ml-‘Sl'
`'._;
`stringent USP requirements for sterility, total solids, an
`
`terial endotorins. These products may be prepared by 6W.-
`
`ing the active ingredient in Water for Injection. The? are ';_
`
`"‘[I
`aged in single-dose containers, preferably Type I 01'
`glass, or suitable plastic containers, and then sterilizefl- AI'
`
`ber of irrigations are described in the USP, infill-“1mg
`
`
`
`Table 39-3. Examples of Commercial Nasal Preparations
`ACTIVE lNGREDlENT
`PRODUCT NAME
`MANUFACTURER
`
`
`INDICATION
`
`Atrovent Nasal Spray
`Beconase AQ Nasal Spray
`
`Boehringer Ingelheim
`GlaxoSmithKline
`
`Miacalcin
`Nasalcrom Nasal Spray
`Nasarel Nasal Spray
`Nicotrol Nasal Spray
`NEO'SWEPWME
`Rhinocor‘t Aqua Nasal Spray
`Stadol Nasal Spray
`Stimate Nasal Spray
`
`Synare Nasal Solution
`Tyzine
`
`Novartis
`Pharmacia
`IVAX
`Pfizer
`Bayer
`Astra-Zeneca
`Bristol-Myers Squibb
`Ave-oils
`
`Searle
`Bradley Pharmaceuticals
`
`lpratropium bromide 0.06%
`Beclomethasone dipropionate,
`monohydrate 42 mcg
`Calcitonin-salmon, 2200 LU. per mL
`Cromolyn Sodium 52 mg
`Flunisolide
`Nicotine 0.5 mg
`Oxymetazoline hydrochloride 0.05%
`Budesonide 32mcg
`Butorphanol tartrate, 1 mg
`Desmopressin Acetate 1.5 mglmL
`
`.
`.'
`
`ic ill" I
`
`Seasonal or Aller9_ Rhl
`,
`Seasonal or AllBFQ"
`0pm"
`Postmenopausal oitizhl‘
`Seasonal or Allerglcal r
`I-
`
`Seasonal 0‘ perenfl'
`Smoking CessaiIO"
`
`c Rhl.
`Decongestion
`
`Seasonal or AIIEIQI' e5
`Pain Relief, Migra'"
`
`Hemophilia A or W:
`
`Willebrsnd Ellsea5
`
`Endometriosis
`Nafarelin acetate 2 mgr'ml.
`Decongestion
`_-
`Tetrahydrozoline hydrochloride
`
`Apotex (IPR2019-00400) Ex. 1048 p. 006
`
`
`po ex
`' 'Ol
`'-H‘H X. 08p. 0!.
`
`

`

` es of Commercial Dtic Preparations
`
`
`MANUFACTURER
`arrive INGREDIENT
`INDICATION
`
`CHAPTER 39: SOLUTIONS. EMULSIONS. SUSPENSIONS, AND EXTRACI'S
`
`753
`
`Celltech
`Purdue
`
`Pfizer
`Alcon
`
`GlaxoSmithKline
`
`GIaxoSmithKline
`Daiichi
`Savage
`
`Benzocaine
`Triethanolamine polypeptide
`cleats—condensate
`Chloramphenicol
`Ciprofloxacin hydrochloride
`and hydrocortisone
`Neomycin and Polymyxin B Sulfate-s
`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
`
`
`-.
`315011 for bladder irrigation, Dimethyl Suli‘oxide Ir1'i~
`u Er relief of internal cystitis, Glycine Irrigation for
`
`ghral prostatic resection, Ringer‘s Irrigation for gen-
`.
`atioo, Neomycin and Polymymn B Sulfates Solution
`
`fian for infection, and Sodium Chloride Irrigation for
`_
`.iwounds.
`_
`
`'poraneous formulations frequently are prepared us-
`tonic solution of sodium chloride as the solvent. For
`: cefazolin or gentamicin in 0.9% sodium chloride are
`
`_.’ant,i_infective irrigations‘i’ and 5-l'luororacil in 0.9%
`oride is employed for bladder irrigation.“ Alum. ei-
`vesium or ammonium. in either sterile water or 0.9%
`
`I
`‘ pride for irrigation has been used for bladder hemor-
`uphotericin in sterile water has been used for the
`
`of localized infections on the dermis, the bladder,
`ary tract.“7 All the extemporaneous preparations
`set the general