Free Redacted Document - District Court of Delaware - Delaware

Case 1:04-cv-00171-GIVIS Document 116-2 Filed 07/10/2006 Page 1 014

Case 1:04-cv-00171—Gl\/IS Document 116-2 Filed 07/10/2006 Page 2 of 4
Ullitéd $1521208 Piltéllt [19] [11] Patent Number: 5,068,249
Long [45] Date of Patent: Nov. 26, 1991

[54] AQUEOUS RANITIDINE COMPOSITIONS [56] References Cited
STABMZED WITH ETHANOL " FOREIGN PATENT DOCUMENTS ·
[75] Inventor: David R. Long, Royston, England 254-,-,2-, ,2/,984 Func: _
· . · - 2120938 5/1983 U tea Kin o .
[73] Assign"' gaggrgmup Lm°°d’ L°“d°°’ 2142s20 moss Uggtcd toning; .
[21] APPL NOS 4;,;,304 OTHER PUBLICATIONS
22 Filed, Mah 1 1990 Chem. Abst. (97)-610146 (1982).
[ 1 4* Chem. Abst. (104)-102280Z (1986).
R¢¤¤*¤¤ U5- APP“¤¤°¤ ¤¤¤ Primary Examine-Frederaok E. wooden
[63] Continuation or ser. No. :+44,620, Apr. 28, 1989, aban- A—¤i$¥¤¤l` E¤¢mf¤¢f—~·—Di¤¤¤ G¤1‘d¤¢f
cloned, which is a continuation of Ser. No. 131.442, Aifvmqv. Agent, or Fffm—Ba¤0n & Thomas
Dec. 11, 1987, abandoned. [57] Cr
I3?] Fomin Awuéam _Pri°ruy mu The stability of aqueous formulations of ranitidine or a.
Dec. 12, 1986 [GB] United Kingdom . ............... 86 29781 physiologically acceptable salt thereof is enhanced by
[s 1] nit. 01.5 ....,......................................... nom sim ¢h= ¤¤¤i1i¤¤ ¤f <·=¤¤¤¤¤¤1-
[52] U.S. Cl. .................................................... 514/471
[58] Field or Search ............ :.., ................ 514/461, 471 12 Claims, No Drawing

i_ Case 1 :04-cv-00171-GMS Document 116-2 Filed 07/10/2006 Page 3 of 4
5,068,249
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A preferred embodiment of the invention is an aque-
AQUEOUS RANITIDINE COMPOSITIONS ous formulation for oral administration. Such a formula-
STABILIZED WITH EH-IANOL tion may comprise ranitidine and/or one or more cf its
physiologically acceptable salts dissolved in water, eth-
This application is a continuation of application Ser. 5 anol, a preservative and a viscosity enhancing agent.
No. 07/344,620, filed Apr. 28, 1989, now abandoned, Preferably the required pH of the formulation is ob-
which is a continuation of Ser. No. 07/131,442, tiled tained by the use of appropriate buffer salts. Optionally
Dec. 11, 1987, now abandoned. _ the composition may also contain other conventional
The present invention relates to a pharmaceutical cxcipients such as a sweetener, a flavour and/or lla-
composition containing as active ingredient the hista. 10 VOU1'lI\§ aids.
mine Hg antagonist ranitidiue. Examples of suitable preservatives include on or
Ranitidine, [N-[2-{[[5-(dimethy1amiuo}methy1·2- mvrc alkyl hydroxybenzcates such as methyl, ethyl,
furanyl]methyl]tl1io]ethy1]-N'-methyl-2-nitro-I.l- Propyl and/or butyl hydroxybenzoates.-
ethenediaminc, and its physiologically acceptable salts Examples of suitable viscosity enhancing agents in- .
. are described in British Patent Specilication No. I5 clude Xanthan gum, sorbitol glycerol, sucrose or a
1565966. ln that specification there is reference to liquid cellulose derivative such as carboxymethylcellulose or
formulations for oral and parenteral administrations and a salt thereof of a C;.4 alkyl and/or a l1ydroxy·C;..4alkyl
there is a description cf an aqueous based formulation ether of cellulose such as methylceliulose, ethylcellu-
for intravenous use and another of an oral syrup. Both lose, hydroxyethylcellulose, hydroxypropylcellulose,
of these formulations contained sufiicient hydrochloric 20 hydroxyethylmethylcellulose and hydrcxypropylmo
acid to achieve a pH of 5.0 and the syrups also con- thylcellulose.
tained Sorbitol solution BPC and a flavour as required. Eixamples of suitable sweeteuers include saccharin
British Patent Application No. GB 2142820A de- sodium, sodium cyclamate, sorbitol and sucrose.
Scribes aqueous based formulations containing raniti~ E¤¤¤1pl=S Of Suitable flavouring agents include 'mint‘
dim: and/or one or more of its physiologically accept- M flavours Such as peppermint tlavouriug agents.
able salts thereof having a pH within the range 6,5..7.5, _ The concentration cf ranitidine in the oral formula-
In that specification there is reference to liquid formula- ¤°¤· ¤XP1'¤$¢d N {FM NSG. 15 ¤0¤V¤¤1¢¤¥lY within thc
tions for oral and parenteral administration and there ¤¤¤s¤ 20-400 ¤¤s_p<=r 10 ml. for example 20-200 mz per
are examples of aqueous formulations for intravenous 30 I0 ml- mere P¤m°“lm'lY UD mg P¤¥' in ml d¤S°·
and oral use. These formulations contain ranitidine The amount of ethanol in the formulation for oral
hyrocbloride and are buffered to a pH of approximately '=‘dmi“i$¤'¤ti°¤; ¢XPT¤$5¢d _¤$ 6 P¢1`0¤¤T·¤g¢ of the GON-
7 aud fm. iumvmcm administration the formulations plete fomiulation on a weight/volume basis, is prefera-
asc man ph ol or sodium emesde. For mnynmm- blt *·"i¤f*¤ *h= ¤¤s¤ 15 t¤ 10%. Md ¤=¤¤= p¤¤i¤¤1¤¤¤v
istration the formulation also contains hydroxypropyl- 35 between 5 to 10%- Pere especmlllf 7*8%· _
mbtllyl cellulose as a viscosity enhancing agent, a pm- The &m0}U1T ¤f_VlS¢0SlI)" cnhancmg agent in the for-
servative (parabens), a sweetening agent and a flavour. mP1“”°‘{ wdlprefembly be sl-lmelem te Swe eseiullen
These compositions have a signiiicantly greater sheIf· wlth a “$e°s“Y m the *`*§“Z° ef IU W 1O0_°F'“'PP*$°$·
life over those iu British Patent No. 1565966. The aqueous formulations for oral admlmstration are
We have now suprisingly found that the stability of 40 e°’{‘{ee~‘e“llY P¥eP’·¥ed bv mmm! all Qqueeus §°1“l{°“ Of
muiudiuu iu uquuuus based funuuiuiiuus and more pub ramtidme and/or one or more of its physiologically
ticuiuriy aqueous based formuimions for Om] admiuiy ¤COCp1L8:ble salts together with ethanol and the BxClp1·
moan my be suiamaany mmm by the amamu of :=¤¤=~ wh e<1¤=¤¤¤ =¤¥¤¤i¤¤ ¤r dispmipn ¤f nu vi¤=¤s-
ethanol to the formulation. HY ¤¤h¤n¤ms agent. _ _ _ __
Thus the present invention provides a pharmaceutical 45 The aqueeus f°*`m“l°**°'[$ *°°°{*l“{8 tq the ““’°m'°“
composition which is an aqueous formulation of raaiti- ?·"° P”f°?¤blY_PT°P¤T°d mm! ¤'¤¤¤¤d¤¤¤ ¤¤ the l`°¤`¤ pf
dine and/or one or more physiologically acceptable its hy°l'°°m°¥'d° salt _ _
suits mum; aim muiuiuiug ciiiuu0i_ The aqueous i-up illustrative example of a formulation according to
mulation is prepared using ingredient; of a pm-ity such the 1¤V§¤¤0¤ 15 as follows. In this example the relanvc
not at is suitable my administration to Pismo an will ,0 pt¤p¤¤=·¤¤¤ ¤f ¤·¤¤¤d¤¤¤ *w¤r¤•=h1¤¤¤·= and thp ¤>¤¤’=r
in general mama at new one eeamuaaai pnnmmu. Wu =¤¢ =¤·=¤ ¤=¤= mp f¤¤¤¤¤¤¤¤¤ lm = pH ¤f approxi-
. tical excipient in addition to the ethanol and ranitidine mately 7·
and/or physiologically acceptable salts thereofl
'I`he amount of ethanol resent in the formulation is
such that the rmulting follrnulation has the enhanced 55 ummm Dmuwnxiaumm nvm ml)
stability. Preferably the amount of ethanol in the com- st. wry
position on a weight/volume basis of the complete for-
mulation, is within therange 2.5% to 10%, and more Ethanol l as
particularly is between .5 to 10% w/v, more especially F¤¤¤i¤¤¤ dih¥¢¤¤¢·=¤ ¤¥¤¤¤pl•<>=ph•¢¤ 0995
7,,S% W/v_ 60 Disodium hydrogen crthophosphate anhydrous 0.350
Preferred compositions according to the invention g,°:;°::§f;°y]”myl"llu” 2:
are those in which the pH of the aqueous formulation is sweeteaiag agents qs
within the range 6.5 to 7.5, particularly 6.8 to 7.4 and Fl•Y¤¤f QS
more espeemiy 7 to vs. The required pH ofthe som-
lation is preferably obtained by the use of suitable buffer 65 ·
salts for example, potassium dihydrogen orthophos- I claim:
phnte and discdium hydrogen orthophosphate or citric 1. A pharmaceutical composition which is an aqueous
scid and disodium hydrogen orthophcsphate. formulation for oral administration of an effective

Case 1 :04-cv-00171-GMS Document 1 16-2 Filed 07/10/2006 Page 4 of 4
5,068,249
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amount of ranitidine and/or one or more physiologi- 8. A pharmaceutical composition as claimed in claim
cally acceptable salts thereof, said formulation compris~ 1, wherein the effective amount is 20-400 mg raniticline
ing a stabilizing eifective amount of ethanol and said per 10 ml dose expressed as free base.
composition having a pH in the range of 6.5-7.5 , 9. A pharmaceutical composition as claimed in claim
2. A pharmaceutical composition according to claim 5 1, wherein the effective amount is 20-200 mg ranitidine
1 containing 2.5% to 10% weight/volume. ethanol per 10 ml dose expressed as free base.
based on the complete formulation. · 10. A pharmaceutical composition as claimed in claim
3. A pharmaceutical composition according to claim 1, wherein the effective amount is 150 mg ranitidine per
1 containing 7% to 8% weight/volume ethanol based 10 ml dose expressed as free base.
on the complete formulation. I0 11. A pharmaceutical composition which is an aque-
4. A pharmaceutical composition according to claim ous formulation of ranitidine suitable for oral adminis-
1 having a pH in the range 6.8 to 7.4. tration containing 150 mg ranitidine per l0 ml dose
5. A pharmaceutical composition according to claim expressed as free base, said formulation having a pH in
1 having a pH in the range 7.0 to 7.3. the range 7.0 to 7.3 and also containing 7% to 8% _
6. A pharmaceutical composition according to claim 15 weight/volume ethanol based on the complete formula-
1 wherein said pH is obtained by the use of buffer salts. tion.
7. A pharmaceutical composition according to claim 12. A pharmaceutical composition according to claim
1 prepared using ranitidine in the form of the hydro- 11 wherein said pH is obtained bythe use of buffer salts.
chloride salt. A * ’ * * *
20
25
30
35
40
45
_ V i 50
ss
60
65

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