`
`
`
`InnoPharma Exhibit 1106.0001
`
`

`

`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 Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia Cullege of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, .1970, 1975,1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`'
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60—53334
`ISBN 0-912734-04-3
`
`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 substitute for the officiai United States Pharmacopeiu (USP) and/or the National
`Formulary (NF).
`In. the event of any difference or discrepancy 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.
`
`Printed in the United States of America by the Mach Printing Company, Eastern, Pennsylvania
`
`
`
`InnoPharma Exhibit 11060002
`
`

`

`Table of Contents
`
`Part 1
`
`Orientation
`
`. . ..
`. . . . . . .
`. u u . . - . u . . . .
`Scope IllllllI-II . .
`1
`-
`-
`- -
`EVOlUfiOfl 9f Pharmacy - - - - - - t
`-
`- - - - - - - - - -
`2
`.
`. . .
`3 Ethics
`.
`. .
`. . . . . . . . . .
`. . . . . . . . . .
`. . . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . .
`. . .
`‘5 Opportunities for Pharmacists in the Phormaceutl—
`-
`cal lndusttv . ------------------- -
`- - - - - -
`-
`-
`-
`6 PhOImOClSlS in GOVemmenl
`- -
`-
`-
`-
`- - - - - - - - ~ I
`- - -
`7 Druginformation...........................
`3
`RESEOI'Ch
`- - -
`- - - - -
`
`Part 2
`
`Pharmaceutics
`
`. . . .
`. . . . . . .
`. .
`9 Metrolagy and Calculation . . . . . .
`. .
`. .
`. . . . . . . . .
`10 Statistics . . . . . . . . . . . . . . . . . . . . .
`-
`n
`-
`-
`-
`- - - - - - - -
`1‘1 Compute“ 5618M? - 1 -
`- - - - - - - - -
`-
`12 Calculus . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . .
`. .
`.
`13 Molecular Structure. Properties and States Of
`.
`. . .
`Matter
`. . . . . . . . . . . .
`.
`. . . . . . .
`.
`.
`.
`.
`.
`. . . . . .
`.
`. . .
`14 Complex Formation . . .
`. . . . . .
`.
`. . . . . . . . . .
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibrio .
`.
`. . . . . . . . . . .
`. . .
`17
`Ionic Solutions and Electrolytic Equilibrlo . . . . .
`. . .
`16 Reaction Kinetics .
`. .
`.
`. . . . . . . t
`. .
`. . . . . . . . . .
`. . .
`19 DIsperseSystems.... . . .
`. . .
`20 Rheology . . . . . . . . . . . . . . . . . .
`
`. . . .
`
`. . . . .
`
`.
`
`. . . .
`
`.
`
`Part 5
`
`Pharmaceutical chemistry
`
`. . . . .
`inatganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. .
`.
`. . . . .
`. . . .
`. . . .
`. . . . . . . .
`24 Drug Nomenclature—United States Adopted
`Names . .
`. . . . . . . . . . . . . . . . . . .
`. . . .
`. . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design
`
`. . .
`. . .
`.
`. .
`
`1
`Part 4
`
`.
`Testing and Analysis
`
`.
`. . . . . . . . .
`. . . . . . . . . .
`. . .
`.
`.
`. . . . . . . . .
`. .
`. .
`
`. .
`26 Analysis of Medicinals
`27 Biological Testing . . . . . .
`25 ClInIcaiAnaiysls
`.
`.
`29 Chromatography . .
`. .
`30 instrumental Methods of Analysis
`31 Dissolution . . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`
`. . . . . . . .
`. . . . . . . .
`
`. . .
`. . .
`
`3
`8
`20
`28
`
`33
`33
`49
`5°
`
`69
`104
`138
`145
`
`153
`182
`197
`207
`226
`247
`257
`010
`
`329
`356
`380
`
`412
`
`422
`
`485
`464
`495
`529
`555'
`589
`
`pa" 5
`
`Radioisotopfl in pharmuy and Medial“
`
`.
`. .
`32 Fundamentals of Radioisotope: . . . . . . . . . . . .
`33 Median] Applications of Radiolsotopes
`. . . . . . . . .
`
`605
`624
`
`.
`pharmaceun‘nl “d medicinal Agents
`pa" 6
`34 Diseases: Manifestations and pmho.
`phwlology“Hun.”"nounuuuunn
`35 Drug Absorption. Action and Disposition . , . .
`,
`.
`, ,
`36 Basic Pharmacakinefics . _ _ I _
`_ _ I
`I . _ _ _ . , _ I
`.
`. . . I
`37 ClinicaiPharmacokinetlcs... . .
`.
`. . . .
`. . . . . . .
`. ..
`38 Topical Drugs . . . . . . .
`. .
`. . . . . .
`.
`. . . . . . . .
`. . .
`. . .
`39 Gastrointestinal Drugs . . . . . . . . . .
`. . . . . . . . . . . . .
`40 Blood. Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`. .
`. .
`.
`. . . . . . . . .
`41 Cardiovascular Drugs
`. .
`. . . . . .
`.
`.
`.
`. .
`. . . . . . .
`. . .
`42 RespiratoryDrugs
`. . . .
`. ..
`43 Sympathomlmetic Drugs . . . . . .
`. . . .
`. . .
`.
`. .
`
`. . . .
`
`.
`
`V
`
`655
`597
`725
`746
`757
`774
`
`600
`681
`860
`870
`
`xv
`
`889
`‘
`
`.
`
`.
`
`. . . . . . . . . .
`. . . . . . . .
`44 Chollnomimetic Drugs .. .. .
`45 Adrenergic and Adrenergic Neuron Blocking
`. Drugs III-IIIIIIIIIIIIIIIIIIIIIIIIIIIII-to-
`907
`46 Antlmuscarinic and Antispasmodic Drugs
`. . . . . . .
`916
`47 ‘ Ske]eta| Muscle Relaxants , , , , . , , . , I , , -,
`,
`, , . . .
`929
`45 mmefic Drugs
`, I , , , , . _ _ .
`.
`_ , . ,
`_ _ , , , , , , , , , , , _
`943
`49 Uterine and Antlmlgmlne Drugs
`. . . . . . . . . . , , , ,
`948
`50 Hormones . . . .
`. .
`. . . . . . . .
`. .-............... ..
`1002
`51 Vitamins and Other Nutrients . . . . . . . . . . . . . . . . .
`1035
`52 Enzymes
`1039
`53 GeneralAnesthetics.............. . .
`1043
`54 Local Anesthetics. . . . . .
`. . . .
`1057
`. . . . .
`. .
`. . . .
`55 Sedatives and Hypnotic: . . . . . . . . . .
`1072
`. . . . . ..
`. . . .
`56 Antlepileptics
`1052
`.
`. . . . . .
`. . . . . .
`. . .
`57 Psychopharmacologic Agents
`1097
`.
`. . . . . .
`. . . . . .
`53 Analgesics and Antipyretics . . . . .
`1123
`59 Histamine and Antihistamines . . . . . . . . . .
`. . . . . .
`1132
`60 Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1136
`61 Antineoplastic and immunosuppressive Drugs . . .
`1163
`62 Antimicrobial Drugs . . . . . . . .
`. . . . . . . . . .
`.
`.
`. . . . .
`1242
`6.3
`Parasiticides . .
`. . .
`. . . . . . .
`. . . . .
`. . . . . . .
`. . . . . . .
`1249
`64 Pesticides . . .
`. . . . . . . . .
`. .
`.
`.
`. . . . . . . . . . . . . . . ..
`1272
`as Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . . .
`. . . . . .
`1266
`66 Pharmaceutical Necessities
`. . . . . .
`. . . .
`.
`.
`. . . . . .
`1330
`67 Adverse Drug Reactions .
`. . . . . . . . . . . .
`.
`.
`. . . . . .
`be‘Pharmacogenetics............................1844
`69 Pharmacological Aspects of Drug Abuse .
`. . . . . . .
`1349
`70
`introduction of New Drugs
`.
`. . . . . . . . . . . . . . . . . .
`1365
`
`Biological Products
`
`Part 1
`'
`. . .
`. . .
`Principles ofimmunoiogy . . . . . . .
`71
`72 immunizing Agents and Diagnostic Skin
`. . . .
`. . .
`Antigens . . . . . . . . . . . . . . . . . . .
`. . . . . . . .
`. . . .
`73 Allergenic Extracts . . . . . . . .
`. . . . . . . .
`. . . .
`. .
`74 Biotechnology and Drugs . .
`. . . . . . . . . . .
`.
`.
`. . . . .
`.
`
`.
`
`. . . . . .
`
`1379
`
`1369
`1405
`1416
`
`Part 6
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`75 Preformulation . . . . . .'. . . . . . . . . . . . . . . . . . . . . . .
`76 Blonvailability and Bioequivoiency Testing . . . . .
`77 Separation................................
`78 Sterilization . . . . . .
`. . . .
`. .
`79 Tonlcity, Osmoticitv, Osmoiality and Osmoiarity .
`80
`Plastic Packaging Materials
`.
`. . . . . . . . . . .
`.
`. . . . .
`61
`Stabmty of Pharmaceutical Products
`. . . . . .
`. . . . .
`
`. . . . . .
`
`. . . . . .
`. . .
`82 Quality Assurance and Control
`63 Solutions, Emulsions, Suspensions and
`. . .
`. . .
`ExtractIVes . . . . .
`.
`.
`.
`. . . .
`. . . . .
`.
`. . . . . . . .
`. . . . ..
`84 Parenteral Preparations . . . . . . . . . . . . . . .
`35
`intravenous Admixtures . . . . . . . . . . . . . . . . . . . . .
`66 Ophthalmic Preparations . . .
`. . . . . . . . . . . . . . . . .
`87 Medicated Applications .
`. .
`. . . . . . . . . . . . . .
`.
`. . .
`88 Powders . . . . . .
`. . . .
`. . . . . . . .
`.
`. . . . . . . . . . . . . . .
`B9 OralSolldDosageForms .
`. . . . .
`. . . . . . . . .
`. . . . ..
`90 Coating of Pharmaceutical Dosage Forms .
`. . . . . .
`91 Sustained-Release Drug Delivery Systems
`. . . . . .
`92 Aemmls‘----------°----'--H-------------
`
`1435
`1451
`1459
`1470
`1451
`1499
`1504
`
`1513
`
`1519
`1545
`1570
`1561
`1596
`1615
`1638
`166a
`1676
`1694
`
`Pa" 9
`
`Pharmageufigql Practice
`
`93 Ambulatory Patient Care t .
`94
`institutional Patient Care .
`.
`95 Lang-TermCoreFaciiities
`96 The Pharmacist and Public Health . .
`
`. . . . . . .
`.
`. . . . . .
`
`. . . . . .
`. . . .
`. .
`
`. . . . .
`. . . . .
`
`. . . .
`
`.
`
`.
`
`. . . . .
`
`1715
`1737'
`1755
`1773
`
`InnoPharma Exhibit 11060003
`
`

`

`. . . . . ..
`97 The Patient: Behavioral Determinants . . .
`. . . . . .
`.
`93 Patient Communication . . . . . . .
`. . .. . . .
`. . . . . .
`.
`99 Drug Education . . .
`.
`. . .
`. . . .
`. . .
`. . .. . . .
`100 Patient Compliance
`. . .
`.
`. . . . . . . .
`. . . . . . . . . . . .
`101 The Prescription . . . .
`. . .
`. . . ., . . .
`. . . .
`. . .
`. . . . .
`.
`.
`102 Drug interactions . .
`.
`. .
`.
`. . . . . . .
`. . . .
`. . .
`. . . . .
`.
`.
`103 Clinical Drug Literature .
`. . . . . . . . .
`. . . . . . . . . . .
`.
`104 Health Accessories
`.
`.
`. .
`. . . .
`. . . . .
`.
`.
`. . . . . . . . .
`.-
`
`1768
`1796
`1803
`1613
`1023
`1842
`1659
`1664
`
`.
`. . . . . . .
`.
`.
`. . . . . . . .
`.
`. .
`. . .
`106 Poison Control
`. . . . . . . .
`. .
`107 Laws Governing Pharmacy . . .
`106 Community Pharmacy Economics and
`. . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . . .
`.
`. . . .
`109 Dental Services . .
`.
`.
`-. . .'. . . . . . .
`., . . .
`. . . .
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`. ..
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`Index
`
`105 Surgical Supplies . .
`
`. . .
`
`.
`
`. . . . . . .
`
`. . . .
`
`. . . . . . . .
`
`. .
`
`1895'
`
`Alphabetic Index . . . . . . . . . . . .
`
`. . . .
`
`. .
`
`. . . . . . . .
`
`1967
`
`
`
`
`
`xvi
`
`InnoPharma Exhibit 11060004
`
`

`

`1538
`
`CHAPTER 53
`
`pressure {eg, 3000 to 5800 psi} and then through the second
`stage at a greatly reduced pressure (cg, 1800 psi}. This
`breaks down any clusters formed in the first step.
`For s2nsll~scsle extemporaneous preparation of emulu
`sinus, the inexpensive hand homogenizer (available from
`Med Times) is particularly useful.
`it is probath the most
`efficient emulsifying apparatus available to the prescription
`pharmacist. The two phases, previously mixed in a bottle,
`are hand pumped through the apparatus. Recirculation of
`the emulsion through the apparatus will improve its quality.
`A homogeniser does not incorporate air into the final
`product. air may ruin an emulsion because the emulsifying
`agent is adsorbed preferentially at the airfwater interface.
`followed hp an irreversible precipitation termed deoatcrizo»
`tion. This is particularly prone to occur with protein emuh
`sifying agents.
`Homogonlsstion may spoil an emulsion if the concentra-
`tion of the emulsifying agent in the formulation is less than
`that required to take care of the increase in surface area
`produced by the process.
`The temperature rise during homogenization is not very
`large. However, temperature does play an important role in
`the cmulsificntioo process. An increase in temperature will
`reduce the viscosity and, in certain instances, the interfacisl
`tension between the oil and the water. There are, however,
`many instances, particularly in the manufacturing of cos-
`metic creams and ointments, where the ingredients will fail
`to crnulsif'y properly if theyF are processed at too high a
`“temperature. Emulsions of this type are processed first at
`an elevated temperature and then homogenised at a tens
`rerature not exceeding 40“.
`Figure 836 shows the flow through the homogenizing
`valve, the heart of the high-pressure APV Gaulin homogo
`leer. The product enters the valve seat at high pressure,
`ours through the region between the valve and the seat at
`igh velocity with a rapid pressure drop and then is dis-
`charged as s homogenised product.
`It is postulated that
`circulation and turbulence are responsible mainly for the
`ornogeniaation that takes place. Different value assem-
`lies, two stage valve assemblies and equipment with a wide
`range of capacities are available.
`The Macro Flore-Master Kornwlrbrtntor employs a number
`of different actions, each of which takes the ingredients a
`little further along in the process of subdividing droplets}
`until complete homogenization results. The machine is
`equipped with a pump which carries the liquid through the
`various stages of the process.
`In the first stage. the ingxndiw
`eats are forced between two specially designed rotors {genre}
`which shoot the liquid in opposite directions in a small
`chamber and, in this way, are mixed thoroughly. These
`rotors also set up a swirling action in the nest chamber into
`
`
`
`
`
`floatation of the homogenizcr value assembly {Courtesy
`Fig 33-6.
`APE.“ Genus}.
`
`which the liquid is forced and swirled hack and forth in
`eddies and crosscurrents. The second stage is a pulsing or
`vibrating action at rapid frequency. The product then
`leaves this chamber, goes through a small salve opening and
`is dashed against the wall of the homogenizing chamber.
`Pressure is applied, but it is not as great as that used in other
`types of homogenizers. Pressure is controlled accurately by
`adjusting (lesions on the front of the machine. and tempera-
`ture is controlled by passing coolants through the stators.
`Ultrasonic DevicesmThe preparation of emulsions by
`the use of ultrasonic vibrations also is possible. An oscilla-
`tor of high frequency (100 to 500 kiln) is connected to two
`electrodes between which is placed a piezoelectric quarts
`plate. The quarts plate and electrodes are immersed in an
`oil bath and, when the oscillator is operating, high-frequency
`waves flow through the fluid. Emulsificatiou is accom-
`plished by simply immersing a tube containing the emulsion
`ingredients into this oil bath. Considerable research has
`been done on ultrasonic emulsification, particularly with
`regard to the mechanism of emulsion formation by this
`method. Limited data indicate that these devices will pro
`duce stable emulsions only with liquids of low Viscosity.
`The method is not practical, however, for large-scale produc-
`tion of emulsions.
`Special techniques and equipment in certain instances,
`will produce superior emulsions, including rapid coolings
`reduction in particle also or ultrasonic devices. A wide as-
`lection of equipment for processing both emulsions and sus-
`pensions has been described by Eisberg.” A number of
`improvements have been made to malts the various process-
`es more effective and energy-efficient.
`General methods are available for testing the instability of
`emulsions including bulk changes, centrifugal and ultrason-
`trifugsl studies, dielectric measurement, surfacensrea mea-
`surement and accelerated—motion studies. Lowshesr rheo~
`logical studies measuring viscoelasticity are suggested as the
`optimal method of stability testing.
`
`Suspensions
`The physical chemist defines the word “suspension” as a
`pm, and it is the preparations containing dispersed solids of
`two-phase system consisting of a finely divided solid dis
`this magnitude or greater that are defined pharmaceutically
`as suspensions.
`persed in a solid. liquid or gas. The pharmacist accepts this
`Certain authors also include linirnents, and the newer
`definition and can show that a variety of dosage forms fall
`sustained~relesse suspensions. in any discussion of this paw
`within the scope of the preceding statement. There is. how—
`ever, a reluctance to be all—inclusive, and it is for this reason
`ticular subject. The former preparations now usually are
`that the main emphasis is placed on solids dispersed in
`considered as solutions although a number of older lini—
`rnents were.r in fact, suspensions. The sustained-release
`liquids.
`in addition, and because there is a need for more
`specific terminology, the pharmaceutical scientist differen—
`suspensions represent a very specialised class of preparation
`tiates between such preparations as suspensions, mixtures,
`and, as such, are discussed in more detail in Chapter 91.
`magmas, gels and lotions.
`In a general sense, each of these
`Some insoluble drugs also are administered in aerosol form;
`preparations represents a suspension, but the state of suhdi~
`one example is dexamethasnne phosphate suspended in a
`propellant mixture of fluorochlorocsrhons. More detail on
`vision of the insoluble solid varies from particles which settle
`gradually on standing to particles which are colloidal
`in
`aerosols is available in Chapter 92.
`nature. The lower limit of particle else is approximately 0.1
`Suspension formulation and control is based on the prin—
`
`InnoPharma Exhibit 1106.0005
`
`

`

`SGLMYICJNS. EMULSFONS. SUSPENSlflNS AM} EXTRAGTNEE
`
`1539
`
`ciples outlined in Chapters 19 and 20. Formulation involves
`more than suspending a solid in a liquid. A knowledge of
`the behavior of particles in liquids, of suspending agents and
`of flavors and colors is required to produce a satisfactory
`suspension.
`’
`\
`Briefly, the preparation of a stable suspension depends
`upon the appropriate dispersion of the drug in the suspend-
`ing medium. To ensure that the particles are wetted by the
`dispersion medium. a surfacedaotire agent should he used,
`especially if the dispersed phase is hydrophobic. The one
`pending ag ant in the aqueous medium than can be added.
`alternatively. the dry suspending agent can be mixed thor-
`oughly with the drug particles and then trituratcd with the
`diluent. Other approaches to suspension preparation Em
`clude the formation of a flocculated suspension and also a
`flocculatsd preparation in a suspending vehicle. Details of
`these procedures are given in Chapter 19.
`The most efficient method of producing fine particles is in:
`dry milling prior to suspension. Suspension equipment
`such as colloid mills or hornogenisers normally are used in
`wet—milling finished suspensions to reduce particle sgglom~
`crates. These machines (Fig 83-4} usually have a stator and
`a rotor which affects the dispersion action. Several methods
`of producing small uniform dry particles are mieropulucries—
`tion fluid-energy grinding, spray-drying and controlled pre-
`cipitation with ultrasound as described by Nash?’
`The choice of an appropriate suspending agent depends
`upon the use of the products {external or internal), facilities
`for preparation and the duration of storage.
`Preparations made extomporaneously for internal use
`may include, as suspending agents, acacia, mothyicellulose
`or other cellulose derivatives, sodium alginate or tragacanth.
`Extemporsneous preparations of suspensions for internal
`use showing good [low and suspending properties are prorid»
`ed by sodium carboxrmethylcellulosc 2.5%.
`tragacanth
`1.25% and goat gum 0.5%. Arise} R0691. a copreoipitate of
`microcrystallinc cellulose and sodium esrhosymethylecllu—
`lose stabilised with hydroxypropyl rnethylcellulose, has
`been used as a suspending vehicle for propranolol and on
`phcnadrine hydrochloride dispersions prepared from tab—
`lets.
`it also may serve as a generahpurpose suspending
`agent. Carbopol 1384, 0.3% or greater, was a satisfactory
`suspending agent for sulfsmethasine 10%, maintaining a
`permanent suspension for more than 6 months.
`Agents suitable for external use include bantonite,
`mothyicellulose or other cellulose derivatives, sodium algi«
`note or tragacanth. Agents which may require high-speed
`equipment and which are suitable for internal or external
`use include aluminum magnesium silicates and earhou’ierdil
`Preparations such as those mentioned shove possess cer-
`tain advantages over other dosage forms. Some drugs are
`insoluble in all acceptable media and. therefore, must be
`administered as a solid, nonsolution dosage form itshlet,
`capsule, etc}, or as a suspension. Because of its liquid char—
`acter, the last preparation insures some uniformity of dosage
`but does present some problems in maintaining a consistent
`dosage regimen. Disagreeahle tastes can he covered by us—
`ing a suspension of the drug or a derivative of the drug, an
`example of the latter being chlorampheniool palmitate.
`Suspensions prepared from ion-exchange resins containing
`an ionic drug can he used not onljs,r to minimise the taste of
`the drug but also to produce a prolongedaction product.
`since the drug is exchanged slowly for other ions Within the
`gastrointestinal tract.
`Suspensions also are chemically more stable than solu-
`tions. This particularly is important with certain antibiot—
`ics, and the pharmacist often is called on to prepare such a
`suspension just prior to dispensing the medication.
`In addi~
`tion, a suspension is an ideal dosage form for patients who
`have difficulty swallowing tablets or capsules, which is par»
`
`ticulerl}; important in administering drugs to children. an
`alternate method to enhance compliance includes flavored
`nystatin “popsioles” which can he prepared hy freezing a
`suspension of the drug so that the taste is improved during
`the treatment of oral candidiasis.
`
`Suspensions should possess certain basic properties. The
`dispersed phase should settle slowly and he redispersed
`readily on shaking. They should not cake on settling and
`the Viscosity should be such that the preparation pours easi~
`1y. As with all dosage forms, there should he no question as
`to the chemical stability of the suspension. Appropriate
`pressrratircs should he incorporated in order to minimise
`microbiological contamination. The suspension must he
`acceptable to the patient on the basis of its taste> color and
`cosmetic qualities {elegance}, the latter two factors being of
`particular importance in preparations intended for external
`use.
`
`Gels
`
`Pharmaceutical terminologjs;r is, at best, confusing and no
`two authors will classify gels, jellies, magmas, milks and
`mixtures in the same way. The N)?“ described Gels as a
`special class of pharmaceutical preparations hut considered
`Jellies under the some heading. The latter preparations
`usually contain water—soluble active ingredients and, there
`fore, are considered in another part of this chapter. The
`USP definition for Gels is
`
`Gels are semisolid systems of either suspensions made up of small
`inorganic partittics or large organic molecules interneusiraied b}: a liq"
`uid. Wth the gel mass consists of a network of small discrete particles.
`the gel is classified as s twopliasc system leg. aluminum Hydroxide
`Gel}.
`in a two-phase system, if the particle size of the dispersed phase is
`relatively large. the gel mass sometimes is referred to as a magma (as;
`Beotonite Magma}. Both gels and magmas may he thixotropic. formng
`semisolicls on standing and becoming liquid on agitation. They should
`he shaken before use to ensure homogeneity; and should be labeled to
`that effect.
`Single-phase gels consist of organic macromolecules distrihuted uni-
`formly throughout a liquid in such a manner that no apparent bound»
`arias exist between the dispersed macromolecules and the liquid. Sinv
`gio-phase may he made from synthetic macromolecules (cg, Carhornerl
`or from normal gums (cg, Tragacsnth}. The latter preparations also are
`called mucilsgos. although these gels are commonly aqueous, alcohol
`and oils may he. used as the continuous phase. For csaoiple, mineral oil
`can be combined with a polyethylene resin to form an oleaginous oint-
`ment base.
`
`The USP states that each 100 g of Aluminum Hydroxide
`Gel contains the equivalent of not less than 3.6 and not more
`than 4.4 g of aluminum oxide ($1303), in the form of alunii~
`uum hydroxide and hydrated oxide, and it may contain
`varying quantities of basic aluminum carbonate and bicsr»
`horiate. The gel itself usually is prepared by the interaction
`of a soluble aluminum salt, such as a chloride or sulfate, with
`ammonia solution, sodium carbonate or bicarbonate. The
`reactions which occur during the preparation are
`
`soozfi“ + stage at {ll-1003“ we sort“
`
`[wagers-ii + son“ —* {monuments + sage
`
`moo...— «r cog?“ + ago + co3
`
`The physical and chemical properties of the gel will he af~
`footed by the order of addition of reactants, pH of precipita-
`tion, temperature ofpreclpitation, concentration of the reac-
`tants, the reactants used and the conditions of aging of the
`precipitated gel.
`Aluminum Hydroxide Gel is soluble in acidic (or very
`strongly basic) media. The mechanism in acidic media is
`
`Aluminum Hydroxide Gel + SHQO "r [Al{ll20l3lOH)3]“
`lAlngOsI" + H30“ "a {Armstrong + ago
`
`InnoPharma Exhibit 1106.0006
`
`

`

`CHAPTER 84
`
`Parenteral Preparations
`
`Kenneth E Avls, D5:
`Emeritus Professor, Pharmaceutics
`College of Pharmacy
`University of Tennessee. Memphis
`The Health Science Comer
`Memphls. TN 36163
`
`Dosage forms of drugs are designed to make it possible to
`introduce a drug into the body of a human or animal patient.
`Since the well-being, or even the life, of the patient may be
`affected, the dosage form must be designed and prepared in
`a manner intended to promote the safety of the patient.
`Concurrently, it is essential that the dosage form compli—
`ment or enhance the therapeutic effectiveness of the drug.
`Parenteral (Gk, pom enteron = beside the intestine) is the
`route of administration of drugs by injection under or
`through one or more layers of the skin or mucous mem-
`branes. Since this route circumvents these highly efficient
`protective barriers of the human body, exceptional purity of
`the dosage formmust be achieved. The processes used in
`preparing it must embody good manufacturing practices
`that will produce and maintain the required quality of the
`product. New developments in process technology and
`quality control should be adopted as soon as their value and
`reliability have been established as a means for further im-
`proving the quality of the product.
`
`History1
`
`One of the most significant events in the beginnings of
`parenteral therapy was the first recorded injection of drugs
`into the veins of living animals, in about 1657, by the archi-
`tect Sir Christopher Wren. From such a very crude begin-
`ning, the technique for intravenous injection and knowledge
`of the implications thereof developed slowly during the next
`century and a half.
`In 1855 Dr Alexander Wood of Edin-
`burgh described what was probably the first subcutaneous
`injection of drugs for therapeutic purposes using a true by-
`podermic syringe.
`The latter half of the 19th century brought increasing
`concern for safety in the administration of parenteral solu-
`tions, largely because of the work of Robert Koch and Louis
`Pasteur. While Charles Chamberland was developing both
`hot-air and steam sterilization techniques and the first bac-
`tome-retaining filter (made of unglazed porcelain), Stanis—
`laus Limousin was developing a suitable container, the all-
`glass ampul.
`In the middle 19205 Dr Florence Seibert pro-
`vided proof that the disturbing chills and fever which often
`followed the intravenous injection of drugs was caused by
`patent products of microbial growth, pyrogens, which could
`be eliminated from water by distillation and from glassware
`by heating at elevated temperatures.
`0f the recent developments that have contributed to the
`high quality standards currently achievable in the prepara-
`tion of parenteral dosage forms, the two that have probably
`contributed most are the development of HEPA-filtered
`laminar airflow and the development of membrane microfil-
`tration for solutions; The former made it possible to
`achieve ultraclean environmental conditions for processing
`sterile products, and the latter made itpossible to remove
`from solutions by filtration both viable and nonviable parti-
`
`cles of microbial size and smaller. However, many other
`developments in recent years have produced an impressive
`advance in the technology associated with the safe and reliL
`able preparation of parenteral dosage forms. The following
`list identifies a few of the events which have contributed to
`that development.
`1926—Parenterals were accepted for inclusion in the fifth
`edition of the National Formulary.
`1933—The practical application of freeze-drying to clinical
`materials was accomplished by a team of scientists at
`the University of Pennsylvania.
`.1938-—~The Food, Drug and Cosmetic Act was passed by
`Congress, establishing the Food and Drug Adminis—
`tration (FDA).
`1944-—The sterilant ethylene oxide was discovered.
`1946—The Parenteral Drug Association was organized.
`1961—The concept of laminar airflow was developed by WJ
`Whitfield.
`1962—The FDA was authorized by Congress to establish
`current good manufacturing practices (CGMP) regu-
`lations.
`'
`1965—Tota1 parenteral nutrition [TPNJ was developed by
`SJ Dudrick.
`1972—The Limulus Amebocyte Lysatc test for pyrogens in
`parenteral products was developed by JF Cooper.
`
`Administration
`
`Injections may be classified in five general categories:
`1. Solutions ready for injection.
`2. Dry, soluble products ready to be combined with a solvent just
`prior to use.
`3. Suspensions ready for injection.
`4. Dry, insoluble products ready to be combined with a vehicle just
`prior to use.
`5. Emulsions.
`
`These injections may be administered by such routes as
`intravenous, subcutaneous, intradermal, intramuscular, in-
`traarticular and intrathecal. The nature of the product will
`determine the particular route of administration that may
`be employed. Conversely, the desired route of administra-
`tion will place requirements on the formulation. For exam-
`ple. suspensions would not be administered directly into the
`blood stream because of the danger of insoluble particles
`blocking capillaries. Solutions to be administered subcutav
`neously require strict attention to tonicity adjustment, oth-
`erwise irritation of the plentiful supply of nerve endings in
`this anatomical area would give-rise to pronounced pain.
`Injections intended for intraocular, intraspinal, intracister-
`us] and intrathecal administration require the highest puri-
`ty standards because of the sensitivity of nerve tissue to
`irritant and toxic substances.
`When compared with other dosage forms, injections pos-
`sess select advantages.
`If immediate physiological action is
`
`1545
`
`
`
`InnoPharma Exhibit 1106.000?
`
`

`

`1546
`
`CHAPTER 84
`
`needed from a drug, it usually can be provided by the intro-
`venous injection of an aqueous solution. Modification of
`the formulation or another route of injection can be used to
`slow the onset and prolong the action of the drug. The
`therapeutic response of a drug is controlled more readily by
`parenteral administration since the irregularities of intesti-
`nal absorption are circumvented Also, since the drug nor-
`mally is administered by a professionally trained person, it
`confidently may be expected that the dose was actually and
`accurately administered. Drugs can be administered paren-
`terally when they cannot be given orally because of the
`unconscious or uncooperative state of the patient, or because
`of inactivation or lack of absorption in the intestinal tract.
`Among the disadvantages of this dosage form are the re-
`quirement of asepsis at administration, the risk of tissue
`toxicity from local irritation, the real or psychological pain
`factor and the difficulty in correcting an error, should one be
`made.
`In the latter-situation, unless a direct pharmacologi—
`cal antagonist is immediately available, correction of an er-
`ror may be impossible. One other disadvantage is that daily
`or frequent administration poses difficulties, either for the
`patient to visit a professionally trained person or to learn to
`inject oneself.
`
`Parenteral Combinations
`
`Since there is a degree of discomfort for the patient with
`each injection, a physician frequently will seek to reduce this
`by combining more than one drug in one injection. This is
`encountered most commonly when therapeutic agents are
`added to large-volume solutions of electrolytes or nutrients,
`commonly called “IV additives,” during intravenous admin-
`istration. Since these are aqueous solutions, there is a high
`potential for chemical and physical interactions. See Chap-
`ter 85. The pharmacist is the professional best qualified to
`cope with these incompatibilities. However, in the past,
`these have been handled largely at the patient’s bedside by
`the nurse and physician. Only recently has it been recog-
`nized that this professional area is the proper function of a
`pharmacist and has been so stated by the Joint Commission
`on Accreditation of Hospitals.”-3
`As pharmacists have assumed increasing responsibility in
`this area, awareness has developed gradually of the wide-
`spread occurrence of visible, as well as invisible, physical,
`chemical and therapeutic incompatibilities when certain
`drugs are combined or added to intravenous fluids.
`The development of a precipitate or a color change when
`preparations are combined is an immediate warning that an
`alteration has occurred. Such a combination should not be
`administered to the patient because the solid particles may
`occlude the bloud vessels, the therapeutic agent may not be
`available for absorption or the drug may have been degraded
`into toxic substances. Moreover,
`in other instances,
`changes not visually