MEDA_APTX03505611
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0193 e
`
`xhibitsticker.com
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`PTX0193-00001
`
`1
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`CIP2040
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`BRITIS H
`PHARMACEUTICAL
`CODEX
`I973
`
`Prepared in the Department of Pharmaceutical Sciences
`of the Pharmaceutical Society of Great Britain
`and published by direction of the Society's Council
`
`\ \
`
`LONDON
`THE PHARMACEUTICAL PRESS
`17 BLOOMSBURY SQUARE WCIA 2NN
`
`MEDA_APTX03505612
`
`PTX0193-00002
`
`2
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`

`

`Copyright © I973
`by the Pharmaceutical Society of Great Britain
`
`Made and printed in Great Britain by
`William Clowes & Sons, Limited, London, Beccles and Colchester
`
`MEDA_APTX03505613
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`PTX0193-00003
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`3
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`

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`DRUGS AND PHARMACEUTICAL ADJUVANTS
`
`232
`having a unicellular spherical head. It contams similar
`action of purgatives and to relieve spasm in
`alkaloids to those in H. niger.
`the urinary tract.
`Some Indian henbane is derived from H . ruicu/aws L.
`and contains about 0·12 to 0·24 per cent of alkaloids.
`POISONING. As for Atropine (page 36).
`Preparations
`Storage. It should be stored in a cool dry place,
`HYOSCYAMUS DRY EXTRACT, B.P.C. (page 683)
`protected from light.
`Actions and uses. Hyoscyamus has actions HvoscYAMus LIQUID ExTRACT, B.P.C. (page 683)
`similar tO those described under Belladonna
`GELSEM!UM AND HYOSCYAMUS MIXTURE, COMPOUND,
`Herb (page 42), but the hyoscine which it B.P.C. (page 743)
`POTASSIUM CITRATE AND HYOSCYAMUS MIXTURE,
`contains makes it less likely to give rise to B.P.C . (page 751 )
`cerebral excitement. Preparations of hyo-
`HYoscYAMus TINCTURE, B.P. It contains 0·005 per cent
`scyamus are used to counteract the griping
`of alkaloids. Dose: 2 ro 5 millilitres.
`OTHER NAME: Henbane Leaf
`
`HYPROMELLOSE
`SYNONYM: Hydroxypropylmethylcellulose
`
`f
`f ·-~
`
`Hypromellose may be prepared by reacting
`alkali cellulose with a mixture of methyl
`chloride and propylene oxide. The name
`"hypromellose" is followed by a number
`indicating the approximate viscosity of a
`2·0 per cent solution.
`Solubility. Soluble in cold water, forming a viscous
`colloidal solution; insolubk in alcohol, in ether, and in
`chloroform.
`Standard
`IDENTIFICATION TESTS; ACIDITY OR
`DESCRIPTION;
`ALKALINITY; Loss ON DRYING; SULPHATED ASH. It
`complies with the tests described under Methyl(cid:173)
`cellulose 20, page 307.
`the method given for
`VISCOSITY. Determine by
`Methyl cellulose 20, page 307. The limits for various
`viscosity grades and the viscometer to be used are
`indicated in the following table:
`
`Viscosity
`Capillary diameter
`Viscosity I'
`at 20"
`grade
`of viscometer
`(centistokcs)
`(mm)
`-------------1----------------
`15 to 25
`0 84 + 0·02
`1·15 + 0·03
`40 to 60
`II 0 to 140
`I· 51 :;: 0·03
`2·06 ± 0·04
`350 to 550
`1200 to 1800
`2·74 ~ 0·04
`3 ·70 :;: 0· 04
`3750 to 5250
`4· 97 ± 0·04
`12,000 to 18,000
`
`I
`
`Hypromellose is a mixed ether of cellulose in which the ether groupings are mainly methoxyl
`groups with a small proportion of hydroxypropoxyl groups.
`CONTENT OF HYDROXYPROPOXYL. 4·0 to 7·5 per cent,
`calculated as CaH;O~, with reference to the substance
`dried under the prescribed conditions, determined by
`the method given in Appendix 22, page 903.
`CoNTENT OF METHOXYL. 27 ·0 to 30·0 per cent, calcu(cid:173)
`lated as CHaO, with reference to the substance dried
`under rhe prescribed conditions, determined by the
`method given m Appendix 22, page 903.
`Storage. It should be stored in airtight containers, in
`a cool place.
`Uses. Hypromellose has properties similar to
`those of methylcellulose, but produces
`aqueous solutions having higher gel-points
`and greater clarity; for example, a 2 per cent
`solution of methylcellulose 4500 gels at about
`50" and a 2 per cent solution of hypromellose
`4500 gels at about 65·". Because of the greater
`clarity of aqueous solutions and the lower
`proportion of undispersed fibres, it is used in
`preference to methylcellulose to increase the
`viscosity of ophthalmic solutions; an anti(cid:173)
`microbial agent such as benzalkonium chloride
`should be incorporated.
`Hypromellose has also been used in the
`preparation of anhydrous adhesive ointments
`for the protection of the skin surrounding
`ileostomies, fistulas, and exuding ulcers. In
`the preparation of Plaster of Paris Bandage,
`hypromellose is used for the same purpose as
`methylcellulose.
`
`1
`
`20
`50
`125
`450
`1500
`4500
`15,000
`
`ARSENIC. It complies with the test given in Appendix
`6, page 878 (2 pans per million).
`LEAD. It complies with the test given in Appendix 7,
`page 882 (5 parrs per million).
`
`Preparation
`HYPROMELLOSE EYE-DROPS, B.P.C. (page 692)
`
`ICHTHAMMOL
`SYNONYM : Ammonium Ichthosulphonate
`
`Ichthammol consists mainly of the ammonium salts of the sulphonic acids prepared by sul(cid:173)
`phonating the oily substances resulting from the destructive distillation of a bituminous schist
`or shale. It contains, in addition, 5 to 7 per cent of ammonium sulphate.
`Solubility. Soluble in water ; partly soluble in alcohol
`Standard
`and in ether; completely soluble in a mixture of equal
`DESCRIPTION. An almost black, viscid liquid; odour
`strong and characteristic.
`parts of alcohol and ether.
`
`MEDA_APTX03505614
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`PTX0193-00004
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`4
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`METHYLATED SPIRIT/ METHYLCELLULOSE
`INDUSTRIAL METHYLATED SPIRIT (ACETONE-FREE)
`Industrial Methylated Spirit (Acetone-free) is a mixture, made by a legally authorised methy(cid:173)
`lator, of 19 volumes of alcohol (95 per cent) with 1 volume of approved wood naphtha or other
`denaturant approved by the Board of Customs and Excise, and is of the quality known as
`"66 O.P. Industrial Methylated Spirits" but free from acetone.
`
`307
`
`Other strengths of industrial methylated spirit
`(acetone-free) are available, such as "Absolute
`Industrial Methylated Spirits (Acetone-free)",
`which is 74 O.P., and "64 O.P., Industrial
`Methylated Spirits (Acetone-free)".
`Standard
`transparent, mobile,
`DESCRIPTION. A colourless,
`volatile liquid; odour of alcohol modified by the
`odour of the denaturant.
`IDENT!FICATION TEST. Dilute 0·5 ml to 5 ml with water,
`add 2 ml of potassium permanganate and phosphorz'c
`acid solution, allow to stand for 10 minutes, and add
`2 ml of oxalic acid and sulphuric add solutio"; to the
`colourless solution add 5 ml of decolorised magenta
`solution and allow to stand at 15 ' to 30° for 30 minutes;
`a deep violet colour is produced.
`ACIDITY OR ALKALINITY. 25 ml requires not more than
`0·2 ml of O·lN sodium hydroxide co give a pink
`colour with phenolphthalein solution, or not more than
`1·0 ml of O·lN hydrochloric acid to give a red colour
`with methyl •·ed solution.
`
`SPECIFIC GRAVITY (20°/20"). Not higher than 0 ·814.
`AcETONE. Dilute 5 ml. to 10 ml with water, add 1 ml of
`2-nicrobenzaldchydc solution followed by l ml of a
`15 per cent w.lv solution of sodium hydroxide in water,
`and allow to stand for 15 minutes; any colour which
`develops is not deeper than that produced by 10 ml
`of a 0·025 per cent v/v solution of acetone in alcohol (50
`pe>· cent) when similarly
`treated
`(500 parts per
`million).
`OILY AND RESINOUS SUBSTANCES. Mix 5 ml with 95 m]
`of water; the solution remains clear.
`NoN-VOLATILE MATTER. Not more than 0 01 per cent
`wfv, determined by evaporating to dryness and drying
`the residue to constant weight at 105°.
`Uses. Industrial methylated spirit (acetone(cid:173)
`free) is used in the preparation of alcoholic
`solutions of iodine intended for external use.
`UNDESIRABLE EFFECTS; POISOKING. As for
`Industrial Methylated Spirit (above).
`
`METHYLCELLULOSE
`Methylcellulose is a methyl ether of cellulose. It may be prepared by methylating alkali cellulose
`with methyl chloride. The name "methylcellulose" is followed by a number indicating the
`approximate viscosity of a 2·0 per cent solution. The gel-point of a 2 per cent solution in water
`of Methylcellulose 4500 is about 50°,
`
`Solubility. Soluble in cold water, forming a viscous
`colloid•! solution; insoluble in hot water, in alcohol,
`in ether, and in chloroform.
`Standard
`
`METHYLCELLULOSE 20
`DESCRIPTION. A white or creamy-white powder;
`odourless.
`IDENTIFICATION TESTS. I. Add I g to 100 ml of water;
`the powder swells and disperses, forming a viscous
`colloidal solution. Boil; a white precipitate is formed
`which redissolves on cooling.
`2. Pour 2 ml of the colt! solu tion prepared in test l
`onto a glass plate and allow the water to evaporate; a
`thin self-sustaining film is produced.
`3. To 10 ml of the cold solution prepared in test I add
`0·5 ml of a 0·05 per cent wfv solution of brilhmzt
`yellow in water, 0·05 ml of O·!N sodium hydroxide,
`and 10 ml of a saturated solution of sodium sulphate in
`water; a voluminous, flocculent, red precipitate is
`formed. Filter; the filtrate is colourless.
`4. Soak in iodine water for a few minutes and remove
`the excess of reagent; the powder is stained yellow.
`Add one or two drops of sulphuric acid (66 per cent v fv ) ;
`it is stained dark brown (distinction from microcry(cid:173)
`stalline cellulose).
`ACIDITY OR ALKALINITY. pH of a 1·0 per Cent W/V
`solution in carbon dio.-.:idc-free water, 6·0 to 8·0.
`VISCOSITY. At 20·', 17·0 to 23·0 centistokes, determined
`by the following method:
`Transfer 2·0 g, calculated with reference to the sub(cid:173)
`stance dried under the prescribed conditions, to a
`wide-mouthed bottle, add 100 ml of water previously
`heated to 85° to 90°, close the bottle with a stopper
`
`fitted with a stirrer, and stir for 10 minutes; place the
`bottle in an
`icc-bath, continue stirring until the
`solution is of uniform consistence, remove the boule
`from the icc-bath, and allow the solution to attain
`room temperature.
`Determine the viscosity of this solution by the method
`of the British Pharmacopoeia, Appendix IVH, for the
`determination of the viscosity of Methylcellulose,
`using a suspended-level viscometer with capillary
`d iameter of 0·84 :t 0·02 mm.
`ARSENIC. It complies with the test given in Appendix
`6, page 879 (1 part per million).
`LE1\D. It complies with the test given in Appendix 7,
`page 883 (5 parts per million).
`Loss oN DRYING. Not more than I 0·0 per cent, deter(cid:173)
`mined by drying to constant weight at 105°.
`SuLPliATED ASH. Not more than 1·0 per cent.
`CONTENT OF METliOXYL. 27·0 to 29·0 per cent, calcu(cid:173)
`lated as CHaO, with reference to the substance dried
`under the prescribed conditions, determined by the
`following method:
`Carry out the method of the British Pharmacopoeia,
`Appendix X(! ), for the determination of methoxy!, using
`about 0·05 g, accurately weighed, and a 25 per cent
`wfv solution of sodium acetate in the scrubber; each ml
`of O·lN
`sodium
`thiosulphate
`is equivalent
`to
`0·0005 172 g of CH,O.
`
`METHYLCELLULOSE 450
`It complies with the requirements of the British
`Pharmacopoeia.
`It has a viscosity at 20• of 400 to 500 centistokes.
`
`MEDA_APTX03505615
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`PTX0193-00005
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`5
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`308
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`DRUGS AND PHARMACEUTICAL ADJUVANTS
`METHYLCELLULOSE 2500
`!DEN >IFICATION TESTS; ACIDITY OR
`DESCRIPTION;
`ALKALINITY; ARSENIC; LEAD; LOSS ON DRYING;
`SULPHATED ASH; CONTENT OF METHOXYL. !t complies
`with the rests described under ,\ierhylcellulose 20.
`VISCOSITY. At 20'', 2200 ro 2800 cenrisrokes, deter(cid:173)
`mined by the method given above for Methylcellulose
`20, a suspended-level viscometer with capillary
`diameter of 3·70 ± 0·04 mm being used.
`METHYLCELLULOSE 4500
`lDENT!F[CATION TESTS; ACIDlTY OR
`DESCRIPTION;
`ALKALINITY; ARSENIC j LEAD; LOSS ON DRYING;
`SULPHATED ASH; CONTENT OF METHOXYL. It comp!Ies
`with the tests described under Merhylcellulose 20.
`VIscosiTY. At 20', 4000 to 5000 centisrokes, deter(cid:173)
`mined by the method given above for Mcthylccllulose
`20, a suspended-level viscometer with capillary diameter
`of 3 ·70 ± 0·04 mm being used.
`Storage. Methylcellulose should be stored in airtight
`containers, in a co ol place.
`Actions and uses. Methylcellulose disperses
`in cold water to form a viscous colloidal
`solution. A mucilage may be prepared by
`adding the methylcellulose to about one-third
`the required amount of boiling water and,
`when the powder is thoroughly hydrated,
`adding the remainder of the water, preferably
`in the form of ice, and stirring until homo(cid:173)
`geneous.
`Various viscosity grades of methylcellu!ose
`are available. High-viscosity grades, such as
`Preparation
`methylcellulose 2500 and 4500, are used as
`thickening agents for medicated jellies and METHYLCELLULOSE GRANULES, B.J'.C. (page 703)
`OTHER NAMES: Ce/aco/ M®; Methoce/ MC®
`
`creams, as dispersing agents in suspensions,
`and as binding and disintegrating agents in
`tablets. A 0 ·5 to 1 per cent solution of a
`high-viscosity grade of methylcellulose
`is
`sometimes used to increase the viscosity of
`ophthalmic solutions, but for this purpose
`hyprome!lose (page 232) is usuaJly preferred;
`an antimicrobial agent such as benzalkonium
`chloride should be incorporated.
`Special grades with a high content of meth(cid:173)
`oxyl, or having hydroxypropyl groups in place
`of some of the methyl groups (hypromellose,
`page 232) are used as adhesives in Plaster of
`Paris Bandage.
`A low-viscosity grade, such as methylcellulose
`20, is used as an emulsifying agent for liquid
`paraffin and other mineral oils and also for
`arachis and olive oils; it is less efficient for
`emulsifying cod-liver oil. Emulsions are
`prepared by mixing the oil with a methyl(cid:173)
`cellulose mucilage, preferably using a mech(cid:173)
`anical stirrer.
`Medium- and high-viscosity grades, such as
`methylcellulose 450, 2500, and 4500, are
`used as bulk laxatives, usually in the form of
`granules or tablets.
`Dose. As a laxative: 1 to 4 grams daily in
`divided doses.
`
`METHYLDOPA
`
`Methyldopa is the sesquihydratc of ( ·- )-,8-(3,4-dihydroxyphenyl)-a(cid:173)
`meth y I-L-alanine.
`
`Solubility. Soluble, at 20', in 100 parts of water, in
`400 parts of alcohol, and in less than I part of dilute
`hydrochloric acid; very slightly soluble in ether.
`Standard
`It complies with the requirements of the British
`Pharmacopoeia.
`It is a white
`to yellowish-white, odourless, fine
`powder which may contain friable lumps and contains
`not less than 98·5 and not more than the equivalent of
`101·0 per cent of C,oH~:,NO,, calculated with reference
`to the anhydrous substance. It contains lO 0 to 13·0
`per cent w/w of water.
`Storage. Ir should be stored in airtight containers,
`protected from light.
`Actions and uses. Methyldopa inhibits the
`conversion of dopa to dopamine by competing
`for the enzyme dopa decarboxylase. In con(cid:173)
`sequence, after the administration of methyl(cid:173)
`dopa there is a reduction in the amount of
`noradrenaline formed from dopamine, but it
`has not been proved that this is entirely re(cid:173)
`sponsible for its hypotensive effect. Postural
`hypotension, although it occurs after ad(cid:173)
`ministration of methyldopa, is never severe,
`
`nor does the blood pressure fall much on
`exercise.
`Methyldopa is used in the treatment of
`moderate to severe hypertension. A thiazide
`diuretic may be given concurrently to poten(cid:173)
`tiate the hypotensive effect.
`The daily dosage of methyldopa is usually the
`equivalent of 0·5 to 2 grams of anhydrous
`methyldopa in divided doses; 1·13 grams of
`methyldopa is approximately equivalent to
`1 gram of anhydrous methyldopa. Occasional(cid:173)
`ly, the daily dosage may be increased to the
`equivalent of 4 grams.
`UNDESIRABLE EFFECTS. Tolerance to methyl(cid:173)
`dopa is rarely progressive and can usually be
`overcome by increasing the dose.
`Undesirable effects include drowsiness, de(cid:173)
`pression, dryness of the mouth, diarrhoea,
`and hyperpyrexia; liver damage, thrombo(cid:173)
`cytopenia, and granulocytopenia have been
`reported.
`Cases of acquired haemolytic anaemia have
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`MEDA_APTX03505616
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`PTX0193-00006
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`6
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