`
`REPLACEMENT EXHIBIT 2051
`
`REPLACEMENT EXHIBIT 2051
`
`
`
`
`
`NOVARTIS EXHIBIT 2051
`Noven v. Novanis and LTS Lohmann
`IPRZO14-00549
`Page 1 of6
`
`
`
`Drug and Cosmefic: Indus‘!-ry
`
`Contents
`
`November ‘I963 Vol. 93 No. 5
`
`Cover by Bill Giocalone
`
`_
`Publisher and Editor FRAZER V. SINCLAIR
`
`Ethical Drug Market Research '
`by Ricbdyd L.
`
`JOSEPH KALISH, Ph D
`xerutive Editor
`JERRY THORNTON
`Managing Editnr
`M GN TTA
`A
`’
`Ed’
`‘Harm: My JOHN A
`0
`Erlzlarml Assistant LAURA POCKELL
`Art Director MARTIN BROTMAN
`
`The New Face of Cosme": Retailing
`by pay” Vqflfifl
`,
`Pharmaceutical Aspects of Dextromethorphan
`Hydrobromide
`by Law": Magid
`
`CMm.I”m.ng Ema”
`E:rgi'mert'ng and Mzmngrmcnt FRANCIS CHILSON, Sc.D.
`T h '
`I OSEPH KALISH, Ph.D.
`H "W J
`Patents and Trademarks THOMAS CIFELLI, JR.
`BM’ HARRY 6’ KELBLY
`L95“! HOWARD N- MORSE
`
`Industry is published
`Drug at Cosmetic
`monthly by Drug Markets, InC., Frazer V.
`Sinclair, President and Treasurer; Paul W.
`Alexander,
`Fxceutive Vice-president
`and
`Secretary. Editorial and General Office: 101
`West 31st s:., New York 1, N. Y., U.S.A.
`Telephone, Lorigacre 5-3177. Publications
`Address: Sun Printing Corp..
`28 Renne
`Ave.,
`l-‘ittstield, Mass., U.S.A.
`
`Advertising Manager, Paul W’. Alexander;
`Advertising Representatives, Walter M.
`Btauneiss, C. R. Keeley: Production Man-
`ager, Kath ‘
`H d -, Cr
`1 tion Manager.
`Hwy G_ °£E':;ly_y °
`' C“ a
`
`Representative;
`Advertising
`Midwestern
`Dwight Early and Sons. 221 No.
`I.aSalle
`St., Chicago 1, Telephone, CBntral 6-2184.
`West Coast Advertising Representativc:
`Dillenbeck-Galavan,
`Inc., 3376 West First
`St., Los Angeles 4, Telephone, DU 5-5991,
`
`in advance.
`Subscription price $3.00 a year,
`Foreign Countries, $5.00. Single copies, 35¢.
`Back issues Soc. Second-class postage paid
`at Pittsfield, Mass. Member of Audit Bureau
`of Circulation.
`
`Copyright 1953
`
`by Drug Markets,
`
`Inc, Vol. 93. No.
`
`5
`
`_
`By the publishers of Drug and Cosmetic Industry
`Beauty Fashion. The magazine of personal selling.
`Yearly subscription in the U.S.A., $3.00.
`Drug and Cosmetic Catalog. Directory and data for
`manufacturers. Published every two years. $4.00
`'" ”‘e U-3-A
`Trade Mark Record and Supplements. Complete
`trade-mark listing
`of perfumes and cosmetics.
`$20_00_
`
`information for manufacturers of
`Books. Technical
`drugs and cosmetics.
`
`What FDA Expects Good Manufacturing
`Practices To Be
`by R’ E Duggdn
`_
`‘
`Worldwide Ethical Drug Markets
`by R,'[;M,.d C. Fgmm,
`Cosmetic PVP Part 2
`by F. I. Prexrotz, E. Halmel, and D. Day
`Hexadecyl Alcohol/A new Material For
`Cosmetic Formulations
`by W/. W’. Edmcm and W. H. Lowden
`,
`,
`Packaging and Selling
`635
`P
`k
`.
`F
`“‘ ‘'9"‘9 “"5
`-
`-
`Puckagmg and Senmg
`by F"’"’ V'S’”"‘"'
`The Impact of Container Design on Printing
`57 E» H- M573
`
`639
`
`642
`
`_
`The Ad Pumdei l‘°"V'" B°mb5he"
`.
`News ln Packaging
`New Products
`
`645
`
`649
`653
`
`655
`
`Depnrhnenis
`.
`603
`Keeping Posied
`by Fran’ V‘ Sifltlair
`Patents and Trademarks
`by Tbwm‘-" C’f9”1i I7‘-
`_
`,
`c°"" De"5'°“5
`by Howard Newmmb Mom
`News
`
`661
`
`665
`
`675
`
`SCC——-Boston
`
`689 Mamgemem Forum
`by Francis Cbilmn, SLD.
`Industry's Books
`by Harry Kelbly
`
`740
`
`746
`754
`
`Tmde I-li9"°lU|'8
`Coming Even”
`
`Technical Abs]-rqcls
`by ]o.rep/J Kali:/J, Pb.D.
`Perfumeifls shelf
`
`704
`
`713
`
`727
`736
`
`Cosmetic Compounding
`
`Advancing Therapy
`Skin Research
`
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`PHARMACEUTICAL
`-
`
`
`
`ASPECTS OFDEXTROMETHORPHAN
`
`HYDRQBRQMIDE, N. F. XI
`
`
`
`A SAFE NON - NARCOTIC, EFFECTIVE ANTITUSSIVE
`
`by LOUIS MAGID, Ph. D. HOFFMANN - LA ROCHE, INC.
`
`extromethorphan hydrobromide, N.F. XL is a safe,
`D effective, non-narcotic antitussive, approximately
`equal in activity to codeine. The effectiveness of dex-
`tromethorphan has been demonstrated in clinical ap-
`praisals by Cass and Frederil<_"” in patients Suffemng
`from disease entities associated with chronic cough
`and by Bickerman et al.” in citric acid aerosol stim-
`ulated cough response in normal huinan subjects.
`Clinical evaluation by Ralph” in human pathologic
`cough showed that dextromethorphan is an effeCtiV€
`and safe cough suppressing agent having the anti-
`tussive activity of codeine without sharing its addic-
`tive properties and without producing the side effects
`typical of codeine. In a series of double-blind inves-
`tigations, Cass et al.‘ '3'“ found that dextromethorphan
`has a specific effect on cough which is equal, if not
`superior.
`to that of codeine. Bickerman et al.“ ob-
`served no statistical difference in the antitussive ac-
`tivity of 10 mg. of dextromethorphan hydrobromide
`and 15 mg. of codeine. According to Ralph“, dextro-
`methorphan takes effect in about twenty minutes and
`has a good duration of action. Thus, administration
`of the drug from one to three times daily generally
`provides effective relief--even when the cough is
`chronic.
`
`Dextromethorphan has been widely used in pre-
`scription-type products and is now approved for
`OTC use. The Food and Drug Administration re-
`moved the prescription legend requirements on dex-
`tromethorphan hydrobromide in July 1956. Since
`that time the use of this non-narcotic antitussive has
`grown steadily.
`Dextromethorphan has become a leader“ in the
`
`antitussive field and is rapidly replacing codeine in
`cough preparations. Of the top fifty proprietary cough
`syrups. about 15 per cent are made with dextro-
`rnethorphan and this percentage represents more
`than 50 per cent of the dollar sales of the leading
`proprietary syrups. A review of the composition and
`sales of the leading dextromethorphan cough prep-
`arations was presented recently by Kalish°.
`Cough and cold sales have increased over 40 per
`cent during the past few years. Narcotic preparations
`with and without antihistamines have held their
`dollar sales, but have not increased their dollar vol-
`ume with the growing market. Several years ago
`narcotic cough preparations with and without anti-
`histamines accounted for more than two-thirds of the
`market. A few years later their share declined ap-
`proximately one-third. Tf proprietary products are
`included in this evaluation, the share of the market
`enjoyed by this group is further lowered by more
`than 20 per cent. The trend and comparison of sales
`of the important cough product groups are shown in
`the following graph.
`The above trends are not surprising in view of the
`side effects common to the opiate derivatives. These
`toxic effects include anorexia, nausea, vomiting, con-
`stipation, drowsiness, headache and vertigo, together
`with addiction liability, which presents a hazard. par-
`ticularly in the chronic cougher.
`The numerous disadvantages of the opiates prompt-
`ed the search for a clinically effective. non—narcotic
`antitussive which was equiactive to codeine. Dextro-
`methorphan was one of the first synthetic non-nar-
`cotic antitussive agents. The studies by Isbell and
`
`620
`
`Drug and Cosmetic Industry
`
`N()\’PI11l)Cr ’63: 93, 5
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`Thematerialnnthismm:wascooledfromthecollectionoftheNationalLibraryofMedicinebyathirdpartyandmaybeprotectedbyL;S.Copvrtchtlai
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`that dextrometho1'—
`lt'1"aser“ in 1955 rlenionstraterl
`phan showed
`no addiction liability. Long—term
`clinical trials have disclosed no evidence of toxicity“.
`According to Biclterniaii”, Ralph" and Cass and Fred-
`erik‘,
`the incidence of adverse side effects was re—
`markably low and consisted of occational drowsiness
`or gastrointestinal intolerance which appeared to be
`of the same order of magnitude as that of placebo.
`Dextromethorphan has become the antitussive of
`choice in cough preparations for the following rea-
`sons:
`l#It is 1101X—11€1]'C()lltZ
`?.—It is safe and effective
`3—ExCellent stability
`4—It is approved for OTC sale
`5—«P\a[)i(l onset of action
`6—Adequate duration of action
`7—Phar1naceutically acceptable
`into various dosage forms.
`
`incorporation
`
`for
`
`CHEMICAL PROPERTIES
`
`Dextrometliorphan hydrobromide (d——3—lV1othoXy—N—
`inethylmorpliinan hydrobromido)
`is isolated as the
`crystalline monohydrate with the empirical formula
`C15H:5NO'HBr’Hg0
`and a molecular weight
`of
`570.35. The structural formula is a follows:
`
`alkalies to lorin the free base which is insoluble in
`water. It forms a nitrate of low solubility and is pre-
`cipitated from aqueous
`solutions by tannic 8C1d7
`salicylates and Concentrated solutions
`of
`iodides.
`In aqueous solutions it is slowly decompose’-.(l on expo-
`sure to sunlight. It is incompatible with some of the
`certified dyes (see section on compatibility).
`
`Physical Properties
`Appearance ..
`Color
`..
`. ...
`.
`Odor
`..
`Color of solution A-
`pH of
`'l°/Q solution .
`Residue on ignition .
`
`.. ...
`
`—.
`
`.
`
`.
`
`.7
`
`.. . .
`
`Cr>’5l°lll"e P°wder
`7 ~
`Wlllle
`N°”9
`—— C°l°'l955
`r 5-2 ' 5-5
`Max. 0.l°/o
`
`Solubility
`Water
`
`,.
`..
`
`..
`
`.
`
`H H .
`..
`
`.
`
`at 25°C ..
`at 50°C ,
`(ll 70°C
`ot 85°C
`..
`Alcohol, U.S.P.
`..
`Glycerin, U.S.P.
`.
`Propylene Glycol, U.S.P.
`.
`Chlorolorm, U.S.P.
`.
`NoCl equivalent of 1°/o solution
`
`.
`
`..
`
`.
`
`.
`
`.
`..
`
`.
`
`.
`
`_ About
`
`l.5°/0
`5%
`l0°/0
`—
`V
`.. .. . 25°/o
`.
`..
`25°/o
`.. 10%
`. Soluble
`. Soluble
`. 0.l58°/o
`
`..
`..
`
`,
`.
`. ..
`
`CH3O
`
`NCH3 - 1-tBr - H20
`
`L2‘/2B0: +26 to +280 (2% solution in woterl
`
`Stability ,
`Crystals
`Light
`Air
`Moisture
`
`,
`
`,
`
`.
`
`Stable to normal
`
`indoor illumination
`
`.
`
`..
`
`..
`
`.. Non-hygroscopic
`
`Dextroniethorphan hydrobromide is unaffected by
`mild oxidizing or reducing agents. It is stable in the
`cold in 1N HC1 or 1N HaOH and is stable in the pH
`range of 4» to 5.6 under ordinary storage conditions
`and up to 3 months storage at 45°C. It reacts Willi
`
`Aqueous Solutions
`pH _
`.
`Air
`Ligl-it
`
`.
`
`Stable in pH range of 4 to 5.6
`Stable
`..
`_Stol:le on exposure to normal indoor illumination.
`Slowly decomposed on exposure to sunlight.
`
`COMPARISON or SALES or THE IMPORTANT
`COUGH PgRODU2CiT.iG,ROUPS
`E
`
`Co u GH a»;c;oi
`consign A151 0;
`
`. :Ittl§il‘lf_1.ttlfs_
`
`_
`iiN,yA.iRc.oT1.i
`ANTlHtSTA_M_
`
`sufaincorm
`‘P:R«EPAHRATlO.NiS'
`
`.
`
`V
`
`P
`
`.
`
`L
`
`November ’6ll: 93, 3
`
`Drug and Cosmetic Industry
`
`
`
`Tablets and Capsules
`Stoble under all normal conditions of storage.
`
`COMPATIBILITY
`
`There are relatively few incompatibilities encount-
`ered with dextromethorphan hydrobromide in the
`formulation of various
`types of
`liquid products.
`Among these are the formation of compounds having
`a reduced solubility in water, such as the nitrate,
`salicylate,
`tannate and the reaction products with
`concentrated solutions of iodides, and some of the
`certified dyes. However, all of these incompatibili-
`ties can be easily overcome by the judicious use of
`alcohol, sorbo and glycols. A list of various sub-
`stances, compatible and incompatible with syrup
`formulations of dextromethorphan hydrobromide,
`is
`presented below. Additional compatibility informa-
`tion has been published by Husa7.
`
`Compatible:
`p-Acetominophenol
`Ammonium chloride
`Antimony potassium tartrate
`Antipyrine
`Ascorbic acid
`Benzoic acid
`Chlorcil hydrate
`Chlorphemiramine moleate
`Citric acid
`Codeine phosphate
`Codeine sulfate
`Demerol HCl
`
`Desoxyephredrine HCl
`Emetine HCl
`Ephedrine sulfate
`Glyceryl guaiacolate
`Papaverine HCl
`Phenindamine tartrcite
`Phenylephrine HCl
`Phenylpropanolamine HCl
`Potassium citrate
`Potassium guaiacol sulfonate
`Sodium bromide
`Sodium citrate
`
`Incompatible:
`Cl1l0|’0l0|'m*
`Some certified dyes*
`MenihoI*
`Potassium iadide*(“l
`*These
`incompatibilities can be overcome by judicious use of
`alcohol and/or Sorbo and glycols.
`(“incompatible in concentrated solutions.
`
`Sodium iadide*(“’
`Tannic acid*
`Sodium Salicylate*
`
`TYPE OF PRODUCTS
`
`Dextromethorphan hydrobromide is a very stable
`compound and lends itself readily to incorporation in
`various pharmaceutical dosage forms. Among the
`various dextromethorphan dosage forms that have
`appeared are the following:
`
`Product Type
`Simple syrups
`Expectorant cough syrups
`
`Cough-cold
`
`preparations
`
`Analgesic cough-cold
`preparations
`
`Chewable tablet
`
`Usual Active Ingredients
`Dextromethorphan
`Dextromethorphan, ammonium chlo-
`ride, glyceryl guaiacolate, potas-
`sium guaiacol
`sulfonate
`Dextromethorphan, antihistamine, ex-
`pectorant, decongestant
`Same
`as
`above with N-acetyl-p-
`aminophenol
`(APAP)
`or
`sodium
`salicylate
`Dextromethorphan,
`
`ascorbic acid
`
`Lozenges
`
`Candies
`Ca psules—hard shell
`
`Capsules—soft shell
`Tablets
`
`Dextromethorphan, benzocaine, an-
`tiseptic, ascorbic acid, antihista-
`mine
`
`Same as above
`Dextromethorphan, antihistamine, an-
`olgesic, decongestcint
`Dextromethorphan
`Dextromethorphon
`
`DEXTROMETHORPHAN HYDROBROMIDE
`ABSORBATE POWDER
`The formulation of chewable tablets and lozenges,
`ect.,
`is now possible with a new form of dextrome-
`thorphan which is known as Dextromethorphan Hy-
`drobromide Adsorbate Powders. It is composed of
`dextromethorphan, along with a small amount of
`soluble saccharin, adsorbed on magnesium trisilicate.
`The product is compounded so that
`it contains 5
`per cent of the active ingredient. Dextromethorphan
`Hydrobromide Adsorbate Powder was specifically
`developed for use in the manufacture of chewable
`tablets,
`lozenges, cough drops and similar dosage
`forms. The advantage of the product over the un-
`compounded substance is that the slightly bitter taste
`of the dextromethorphan hydrobromide is practically
`eliminated and it is, therefore, the preferred form of
`the antitussive for preparing these forms that are per-
`sistent in the mouth. With the adsorbate powder it is
`possible to prepare pleasant—tasting chewable tablets
`and lozenges containing the equivalent of as much
`as 15 mg. equivalent of dextromethorphan hydrobro-
`mide. The adsorbate powder is stable and based on
`animal studies has an onset of activity ‘and a duration
`of antitussive action similar to that of dextromethor-
`
`phan hydrobromide per se.
`the dextromethorphan
`An important feature of
`adsorbate, in connection with its use in the prepara-
`tion of oral dosage forms, such as lozenges and chew-
`able tablets, is its ability to be combined with citric
`acid and possibly other organic acids without losing
`its tasteless qualities. The combination of dextro-
`methorphan adsorbate and citric acid in a formula-
`tion,
`followed by subsequent granulation, gives a
`product having an acidic reaction,
`thus widening
`the scope of flavors which may be used for the prod-
`uct.
`In addition, other medicinal
`substances,‘ not
`suitable for incorporation in alkaline media, can be
`combined with the" dextromethorphan adsorbate-
`citric acid mixture.
`
`PHARMACEUTICAL FORMULATION
`
`its
`Dextromethorphan hydrobromide, by virtue of
`excellent stability and relatively few incompatibili-
`ties, which can be overcome by use of alcohol, Sorbo
`or glycols,
`is easily incorporated in standard tablet,
`capsule and syrup formulations. In syrup formula-
`tions, dextromethorphan hydrobromide exhibits a
`slight bitter taste which is easily masked with suit-
`
`(Continued on page 757)
`
`7")
`(Mu
`
`.
`Drug and Cosmetic Industry
`
`November ’63: 93, 5
`
`NOVARTIS EXHIBIT 2051
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 5 of 6
`
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`TimmafnrialnnthisnamewasmniedfromthecollectionoftheNationalLibraryofMedicinebyathirdpartyandmaybeprotectedbyUS.Copyrightlaw
`
`
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`
`
`Chorionic Gonadotropin
`Estrogenic Substance (Natural)
`Estrone U.S. P. (Natural
`and Synthetic)
`Estradiol N. F.
`Ethinyl Estradiol U.S.P.
`Prednisone U.S. P.
`Prednisolone U.S.P.
`Progesterone U.S.P.
`Testosterone U.S.P.
`Hydrocortisone (Alcohol
`or Acetate) U.S.P.
`Neomycin Sulfate U.S.P.
`
`A DEPENDABLE SOURCE
`FOR FINE CHEMICALS,
`NORMONES, INTERMEDIATES
`
`
`
`VITAMERIOAN CORPORATION
`151 PATERSON AVENUE
`LITTLE FALLS, NEW JERSEY
`-rrl muons: ¢‘.I irrolm 6 .4101
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`The Best For SKIN and SCALP
`
`MINK OIL
`
`For High Grade Cosmetics
`Prepared under Quality Control Methods
`Largest producers in the U. 8.
`Triple refined; also Esters of Mink Oil
`Data and samples on request
`
`
`
`._§1xrrIt l|Elltll.5
`V. .;.a
`‘mu.
`;. ‘I7
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`A. LAVA_I_.l.A, mt. its Weir um Snu1,NElK,ll,N.\'.
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`
`
`DEXTROMETHORPHAN
`
`(Continued from page 622)
`
`able flavors. Pleasant tasting products containing up
`to 15 mg. per dose in liquid products and 5 mg. per
`dose in candy lozenges can be prepared. Among the
`successfully used flavors for dextromethorphan hy-
`drobromide products are butterscotch, orange, lemon,
`maple, cherry, custard, mint, and anise. Menthol and
`chloroform have also been used to modify the flavor
`of the products.
`
`DOSAGE AND LABELLING
`
`Dosage and labelling information for prescription-
`exempt (OTC) preparations is given in the Federal
`Register of June 21, 1956, page 4341, July 25, 1956,
`page 5584, and September 13, 1963, page 9941.
`1. Cass, L. G. and Frederik, W.S.: New England J. Med., 249,
`132 (1953)
`2. Cass, L. G. and Frederik, \W.S.: J. Lab. and Clin. Med., 48,
`379 (1956)
`~
`3. Cass, L. G., Frederik, W. S. and Andosca, J. B.: Am. J.
`Med. Sci., 227, 291 (1954)
`4. Bickerman, H. A., Cohen, B. M., and German, 13.: Am. J.
`Med. Sci., 232, 57 (1956)
`J
`5. Bickerman, H. A., German,
`13., Cohen, B. M., and Itkin,
`S. 13.: Am. J. Med. Sci., 234, 191 (1957)
`6. Kalish, Joseph, Drug and Cos. Ind., 92, 696 (1963)
`7. Husa’s Pharmaceutical Dispensing———Martin, E.
`\W.—Mack
`Publishing Co., p. 5479-1959
`8. U. S. Patent No. 3,085,942
`9. Ralph, N.: Am. J. Med. Sci., 227, 297 (1954)
`10. Federal Register, July 25, 1956, page 5584
`11.
`lsbell, H., and Fraser. H. F.:
`J. Pharmacol. and Exp.
`Therap., 107, 524 (1953)
`
`CONTAINER DESIGN
`(Continued from page 646)
`
`foot. In sheet form, foamed polystyrene normally has
`a density of 4 to 7 pounds per cubic foot; steam im-
`pulse molded foamed polystyrene may have a density
`as low as 0.8 pounds per cubic foot, or an expansion
`ratio of about 80 fold. Printing on this material,
`whether in the Hat or in final package shape requires
`an essentially pressureless process. For foam poly-
`styrene then, a printing process which is pressure-
`less,
`low cost when used on preformed packages,
`and capable of yielding high quality is requiredand
`is presently unavailable.
`1
`For completeness, it will be noted that the older
`methods of plastics fabrication——injection molding,
`extrusion, compression molding—normally require
`printing of other than flat webs. The use of the re-
`sultant plastic objects for packaging adds the require-
`ment of high quality printing.
`Some of the newer materials, associated with both
`old and new fabrication processes, carry with them
`important
`restrictions on post printing methods.
`Finally, it may be concluded that post printing meth-
`ods represent a fruitful area for research and develop-
`ment by the packaging industry.
`
`November ’63: 93, 5
`
`Drug and Cosmetic Industry
`
`757
`
`NOVARTIS EXHIBIT 2051
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 6 of 6