Free Declaration - District Court of Delaware - Delaware

Case1:04-cv—00884-SLR D0cument71-20 Filed 07/17/2006 Page10f4
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Case 1 :04-cv—00884-SLR Document 71 -20 Filed 07/17/2006 Page 2 of 4
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Uruted States Patent my {nn 1- t t N mb s 047 398
p Hagstam et al. I · [4s] Date of Patent: Sep. 10, 1991
{$4] DDAVP ANTIDIURETIC AND METHOD ` 4 _
THEREFOR I OTHER PUBLICATIONS
` · · Kintcr et al, cited in Chem. Abstracts, vol. 97:l93479x
' [75] Inventors: Helmet- Hagntam, Malmo, Sweden: l982. .
Hans Vllhazdt, Espergardc, ' American Heritage Dictionary 2nd ed p. 924. `
Denmark _ Remington: Pharm. Sciences l5th Ed. 0975) pp. B3 &
[13] Assignee: Ferrlag B.V., Haarlem. Netherlands Pdmary ExbmMer_Jacq“e|i¤c. sm":
_ . {zi] App`; N0; 809.93-, _ ézllgrm-Hopgood, Calimafde. Kalil.
_ [22] Filed: ` Dec. 17, 1985 _ · [51] Ag5·¤{Ag]·
There is disclosed, in one aspect, an antidiuretic compo-
. Related U.S. Application Data _ sition in oral dosage form for humans. This composi;ion
· · _ comprises an antldiuretlcally effective amount o l-
“”' "§.Zi“.i.'L°§?;§i‘j"*25.,.¥2;?52°;‘i?.."-}l.°;`2C,‘L2.2£1’¤.:
M 24, 19 . · P ° J ¤ ·
ly A is capable of dissolving and being absorbed in the gas-
[30] ` Foreign Application Priority Data · trtgintestinal tract of at human. me composcglon tsgsed in
_ ta et.capsue or ot er genera y accept ora osage 4
_ Nov. 18. tm (SE) Sweden ..-.-..........- ..... -.,... azosssv fom and gcuénuy from about 50 to about 200 mlgm
grams of DDAVP is used per unit dosage ln another
gl; (és "` ````'` " ''''''`'``''''``'''`'''“'``'' aspect, there is disclosed a method for treating diabetes
[58] F. lh ``'`''`°'` """` ``````'```' SI;/807 15 insipidus. This method comprises orally administering
R ° ''`' ' `'`'`''''` " '`''`'``'`'''``'' ' an amidiuretically effective amount of DDAVP to a _
. human. The DDAVP is substantially dissolved and
[$6] Rdlucncu cud absorbed in the gastrointestinal tract of the person so
U.S. PATENT DOCUMENTS t,,,tcd_ _ · ‘ ‘ ·
1,454,549 7/1969 Botswana; ..... .......J., ......... 514/807
3.497.49l 2/l910 Zaoral ...... .. ..... .. .... .... ..... ..... S14/801 ll Claims, No Drawings U

Case 1 :04-cv—00884-SLR Document 71 -20 Filed 07/17/2006 Page 3 of 4
$,047,298 *
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' _ Yet another object of the present invention is to pro- _
DDAVP ANTIDIURETIC AND METHOD vide DDAVP compositions in astable form without the `
THEREFOR · need for preservatives and/or refrigeration.
_ A further object of the invention is to provide a ‘
CROSS REFERENCE TO RELATED s method for orally administering DDAVP.
APPLICATIONS Another object of the present invention is to provide _
- application is a continuation of our application Q for orally administering DDAVP tn a safe and
Ser. 0. 'I0$,70l filed Feb. 26, l9S5 which, in tum, is a _ am": ' ,
continuation of our application Ser. N0. 6l3.7'l9 which sti" (mia °b-lens md Idvmugcs °r me mfscm In- `
wu mod on May 24 wu , l0 ventton will become apparent from the following sum-
-' ` _ mary of the invention and description of its preferred , 1
Background ofthe Invention cmbqdgmcng _ Y ‘ `E
This invention relates generally to antidiuretic com- TM P'f$¢¤t i'“'°f*fi°“_P*”°"id°*• in °¤° ¤$P°°‘· °¤ E F
posltlona and methods for treating humans with said •¤¤dl¤¢¢¤{¤ ¤¤mP°¤fl}°¤ W Wal d°$*8° (QM f°f h“‘ `
compositions. In particular, this invention relates to the U ¥¤¤¤$·_Tl”¤5 ¤¤¤¤P0¤i¤¤¤ ¢¤¥¤P•’l$¤$ ¤¤ ¤¤¤ antidiuretic compound l-deamlno·$-D—arginine vaso~ ¢n`¤¢lW¢ ¤¤°“¤¥ °f DDAVP md ¤ Ph“m¤€°““°¤“Y `
pressin, which is commonly known as DDAVP._ acceptable carrier. The composition is capable of dis-
DDAVP exhlblts a high and speeitie antidiuretic _. scllvtzg and being absorbed in the gastrointestinal tract r_
‘ activity and is useful in tr ating diabetes ins` `dus as 0 ¤ ¤¤*¤¤· `
disclosed in U.S. Pat. No. £491,49l. IPI N ln another aspect, the present invention provides a
tt no been tnemernnty accepted unt proteins me ¤¤e¤h¤9 for rr¤¤¤¤z_¤3¤l>=¤¤ ¤¤¤¤•<§¤§- TQM ¤¤¤¤l¤¤<1
pgpjdcgj such gg DDAVH are dgggmpgggd in (hc C0l'l`lpl’lSCS~Dl'Illy Bdlllllllfoltlillg lll Illl.ldl\ll¢[l¢&lly CNCC- ` 5
stomach and intestines neat suasnnn 1, r an .n». tivc ¤¤¤¤¤• ¤f DDAVP •¤ ¤ l¤¤m¤¤» The DDM/P
gzyprlgn (gking l,1,cc_ 1::,,. pclllgdc ,l,d.l,,:,);,;,,.L$,d H dllspolves and is absorbed in the gastrointestinal tract of
V p armaeeutieals have been traditionally administered ¤ umm-
. subcutaneously or via absorption through the mucous ‘ ` *
membranes ofthe nose or mouth. The above·noted U.S. DEScRlY1tIl?l§B%‘;fgE;§EFERRED `
Pat. N0. 3,497,491 discloses that DDAVP is preferably _ _ _ _
, udminisjcrcd sllgculallgcllsgy °,»g,,l,,n,,,;|y_ _ The_anttdturetle_efl`ect of the DDA}/P used an this
The l,,,,,,,,l most common {Om, pm. ,d,n;n;,lC,g,,g JO invention ts most likely due to absorption ot` the intact
DDAVP requires the use of a rhinyle. A rhinyle is a ‘DDA·VP_m°l§°“}° Since *“Y °“zY[“*“i° fi°$l*’“$ll°“ Qi ·
graded pnsne mae. me appropriate amount on solu- t*·¢ ¤=¤¤¤=-*¤¤5*·¤a_ ¤¤. ¤F tlgs d·§¤¤v*3·¤= _*>¤<§s¤ ·¤
tion to be administered isdrawn into this tube. Then one DDAVP kafis "‘°Y““b\Y i° b‘°i°8‘°*l ‘““°“"*“°“· In
. end is placed into the nostril and the other end is placed 35 mc mVcnflQ¤· u}° Pcmui df)$¢$ °f_ DDAVP
no nre mount. nre contents ofthe tube may thus be ;·;:¤a::_;:·=;¤=; {*3;-;:5;:5;:1 QM? =¤·cl·llv lé·s¤¤r stm- _ _
aspirated intranasally. This mode oi administration is n S _ _‘ l" {anim Y Y P““°*' S
dlmcull lc may Om l-Ol. scm mlicnlg particularly who are sutferrng from diabetes rnslpidus to control
elderly patient:. Furthermore, intranasal administration th°“' P°lY“'“· _ _ _ _ _ _
adversely alfects the eilia such that virus and bacteria 40 ¥¤¤·=¢<>¤¤1>¤s·¤¤¤ °r'h° Prcscm ““'““P’°“• an “““d"
may more readily pass to the mucosa. ;_“mc”“Y :g‘°;;°_;;{°“m °r ?D?YP ‘;_”l d°;*S¤
Also, DDAVP in its dry fomt ls stable but when used °"“ may u · is °m°"“ is Yp'Q“ Y mm ° °m
ln solution form. the solution should be refrigerated and · i’(£?u‘;g;,‘:t§g10;;;_‘ggg$;b§;;g':p;b§:; i;;‘:n“;°;’g
‘ d ° . . * —
° `iSii$i`i?i}`Z`L$tS.i°$`Z,ii·°.iii°$°.dmtl¤.t.lc¤- vt. . ,5 *<¤s>¤¤¤¤z· w=g*=* ¤t¤ ¤~¤=:·¤g\·<*;·gl_v=· ¤¤=*· ml ¤¤=¤¤=
conventional pump spray. Dosage is unreliable with this :;:;13:§;r d°$°$° mm S im ° uk"' [w° °r mr°°
' device, however, and there is a fair amount of waste ‘ . . . . . ·
when the contents ln the bottle are reaching an end. The ' TM °l:ml’°°'"°“ may b° m TY f°"}‘t:`°" °"' “;:“““$‘
so-called sublingual tablet is also objectionable since it mmm °l}""°$ ‘°u°”' °°ps° °° °r °‘ °r r?""° "°“l"
mqulm I nlallvcly long dlsmlvlus time and ls dcwb to those sknlledin this art. The tablet form ts pretzerred.
dem upon a Pulau., ml`,. sccmlom · JO Other ingredients well known to those sktlled in this
, . The Search has Continued lm, improved DDAVP art may be used tn these compositions. These tngredt· ·
composldcns useful for unl mlmlnlumlon to humans include well known tillers and other inert constttu— I
·' for gastrointestinal absorption and methods of adrninis- _ _ ’ . . . . ` - ‘i
· ‘ mg ;‘;j=,5,j·;;5g,§***¤¤=· mi ¤v=¤ ** ¤*· we ·····*= M ¤ ss ·r¤i§`t$l.l’§“€?€.£iI§£@' §ZJ“£3ir%i’£2°iii·E’éir$ t
. ‘ AMPLE. · E
OBJ ECTS AND SUMMARY OF THE ‘ ` `
_ .lNvEN.HON _ · EXAMPLES l and 2 - _
· A¤¤¤r¤i¤sbr· it i¤ ¤ z¤¤=r¤¤ ¤¤i<=¤¤ ¤i the 1>r¢==¤¤ so Two time are prepared containing the renewing '
invention to avoid _or substantially alleviate the hlgrcdgcnls, ·
abovedescribed problems of the prior art. » ·
A more speciiie object of the invention is to provide _ ;;
- DDAVP compositions in a. single dosage fonn for oral A lnrraaunr Example t compte z .
administration. 6; Du/tvr (synthesized ay Ferrlng Am so too
Another object of the invention `is to provide lets.)
' DDAVP compositions which dissolve in the gastroin- ;'_?3';?:&;Ls';5:°:°l{'f{;;) ” n
. . . . . . gr.! 60 60
. testtnal tract in order to allow for the gastrointestinal Mlc,°c,y,,,lll,,, ullulw tmpl 60 W
8b$Ol`pllOl\ of DDAYP. Ctpstlinked earboxyntethylcellulore 2 2

Case 1 :04-cv—OO884-SLR Docu ment 71 -20 Fi led 07/17/2006 Page 4 of 4
- . 5,047,398
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_c0m{nued immediate antidiuretic response when a corresponding
increase in tl: ismolziity and Fogdxgctgyity Tiithelurine
was observe . art rom n s s t eei tension nn
ml Eur nn (mn) I I - the stomach in cgnnecticn wig: the ini‘i%?0verhydra·
M•;nesIumktearaie(P11.Eur. fm z z 5 tk?. B0 Sid¢·¢W¢¤\$ were experienced by any of the
_ (mg:.) su jects.
In contrast to the above results with DDAVP, the .
. The micmcrymmnc cguukm AVICEL PHIOX is a oral administration of 4·AsntDDAVP in doses of from .
highly purified particulate funn of cellulose which is to 20 W lm m*°*’°8m¤* P'°"*d°* °¤lY ¤ m°d°m¢· °*‘
,,¤,,,mc,.c,,uy ,,,,;m,lc from FMC O°,p°,m°n· phu,,_ tremely short·lived. effect_with only the highest dose. 4
delphin, Pennz. The crosslinked carboztymethyleellm ¥°*’¤°"¤'» ¤ d¤$¢ 0f im ¤¤¤¤l‘¤$f¤¤¤S z¤V¤ no ihcfapw-
lose ls Ac-Di·Sol sodium cnboxymethyiceiluiose tw ¢“°°*; _ · _ ‘
which is also commercially available from FMC Corpo- UW P¤¤¤;P:$. Pl‘¢f`¤l'f¢d ;mb0d\!¥|¢¥:;$ Ind HQGGGS sf
ngfqm . _¤pctnti0¤ 0 t e invention ave been escribc in t e i
In addition tothe nbove, small amounts ofpoiyvinyl- B foregoing specification. The Invention which is in—
pyrroudoneethunot ue used as the binding agent in tended to i>cl{»r¤r¤c¤¤d lgcrcin. howcvfgr. is n¤tlt¤ be
making the tablets. construed as mited to r e particular arms disc osed
_ 'lfhe tablets were administered to three patients who since these are to be regarded as illustrative rather than
suffer from dinbetes insipidus. The administration took 20 restrictive. Variations and changes may be made by
place for n period of more than 3 months. The dose those skilled in this art without departing frumthe spirit
required to keep the polyuria under control for these nf the invention.
patents was 2 to 3 ofthe I00 microgram tablets every 24 We claim:
hours. No side~efi'ects‘were observed. The patients pre- , 1. An antidiuretic composition for humans compris·
f¢¤‘¢d UW *¤¥{lq ¤d{¥*i¤i$‘¥¤*i°¤ \° m¤ ¤¤¤V¤¤¥i¤¤¤! 25 ing ¤ gastnolntestinaliy ubsorbable. antldiureticaily eil
|¤¤’¤¤”¤] ¤dm*m$"'*“°" °r DDAVR fcctive. amount of l·de¤rnin0·8·D-arginine vasopressin
COMPARA1-NE EXAMPLE §nd rt pfmrmaleeutiaeszliy oeeeptagle carrier in soliii oral
r t t t t t i t
The etree: oforally administering ¤m.v1> www- °?;1$; ` ."° `°" "` ° E`; mm °s `"° '°°
r>¤¤=¤ Wim ¤¤¤ ¤ff=¤¤ 9( ¤¤¤¤s· ·¤¤¤i¤i=¤¤*¤z !4·=¤·¤i¤<> ,0 z. The composition ¤r cluim 1 wherein me eompesi-
g*gIA*3*g;";‘%gRé$?“*“°'V”°P'¤$}“ (4‘A$n‘ tidn is in the form of z tablet.
{ 3. • • • n • nl.
Ten healthy subjects of both sexes, aged IB through mm $§;“g;::`:?:> where"` md wmpm
_ 43 were treated with DDAVP and 4-Asn-DDAVP. _ · · · ` ·
¤¤= ¤> M *·¤··¤ =¤=¤ ·.¤¤r¤··* ¤¤==* j°°[° wc": hydntcd by drmkmg mc v°lum° °f up from about 50 to about 200 micrograms per 70 kilogram
water that corresponded tc 2% of their body weight. human Per dmgc _
_ Every I5 minutes, urine was collected and its volume I . . ‘
and osmolality were measured using nn Advanced Os- s¤% ·§;`;.c‘;m§gl:;::1fn·2?£t“Df `;/};°;c;n gw anxuaz
mometer Model 3Dl I. In order to overhydmte them- 40 fr m ab { 50 { bo I {00 . K E n n °;g‘;.|Ss
selves, the subjects substituted their loss of fluid by hs °“ d °° ° m’°f°K"m° p" i °g"‘m‘
drinking n volume 0t't¤p_w¤ter that corresponded to the ;"°2P°r fag? . . . . M. . . {
amount ofurine collected. Mier about 40 to 45 minutes, d '. . tm? ° °r "u.mm:§ wi 'guw; irmpnigg
the diuresis increased to about 200 miiliiiters per X5 °:“_:;§;l°r;';?cc:iV€°;t;;’;?.:: ;'_'H};c:m§g;_;_[;¤r°';:in:
· minum Pim°d' M that ¤m°' DDAYP °‘ LAS"' 45 uso regin to hiim for nbsor t'on in th agroi
DDAVP in amounts of from 2010 200 micrograms was , P I ° _ rim P ‘ ° 8 - “`
administered pemraiiy an so muismm orunmnee water. ‘°%;"};h“¤°* °‘ SM “!“°'*· .d
me ¤¤Avr» ....1 M.¤.¤¤».v¤> wm supplied by - ‘=¤¤=¤·¤¤ ¤€ ·=*·¤¤°W*==·s*¤.=*¤¤ ·m¤~·¤· ¤g==·
Fcnmx AB in lyophmzcd Wwdu. {mm wmch mum - I-deem n0·8:D-arginine vasopressin xs from about 0 to
muy he eamme in wm. me wm damn; wu 50 :*;¤¢ 200 ¤¤·¤r¤s¤¤¤ v¤· 70 ¤¤¤¤s¤¤¤¤ ¤¤·¤=¤¤ w ¤<¤·
followed continually up to 6 hours. · _ _
Two of the subjects were supplied with n duodenal 8- Ti? m°*h°d °{` {hun 7 wi{°"{i“_m° ”“°“'“ °r”‘d
~ (ubc which was gn",-ted through me nos; The md of I-de¤mtn¤·8:D-arginine vasopressin as from about S0 tc
the tube was placed with the help of X-rays in the distal ¤b°“* mo m\¤*'¤B¤`¤¤¤ PU 70 k*l°8*’¤m h“¤*¤¤ Pc? d°$* ·
_p¤rt of the duudenum. Overhydrution and urine sam- $5 *8* _ _ _ _
, pling were then carried out ns deseribedmbove. 9- '{hg method of glaun 6 v{hgrcm myd 1-dc¤mm¤-8-
Urine vglumgg gxcggdiug 2(X) miuilimpg pc; ]§ min. D·KT§1¤l¤¢ VI.S0pI'C$Gll1 IS Kdl'I\llIISKC('¤d lll the f`0I`m uf I
utes were taken as an indication that endogen secretion |¤bY¢¥· '
· gf yuqprgiu bgd been mggimauy gupprgggd, Aftgr 10. The method of claim 6 wherein Rid ].-d¢&IDi!10-8- I
this. 200 micrograms of DDAVP dissolved in to mini. 60 D-arginine vasopressin is administered in the form of n
·liters of water were injected through n tube. vnpittic. · `
These investigations illustrate that there is zi dosede- · ll. A method for treating diabetes Insipidus cc>mpris·, _ .
pendent effect of DDAVP, both on the magnitude and ing administering a gastrointestinaliy absorbuble. antidi-
dumion (the effect lasted atleast 6 hours) of the re- nreticnlly effective, amount of I-deamino-§-D-arginine
spouse. A themoeutic effect was obtained with q 20 65 vasopressin to a human for absorption in the gastroin-
miercgmm dosage of DDAVP. Those who were ad- testinal tract of said human.
ministered DDAVP through the duodenal tube had an · • • · ·
\ •