CA2161434A1 - Polymeric x-ray contrast compositions containing iodinated polymeric beads - Google Patents
Polymeric x-ray contrast compositions containing iodinated polymeric beadsInfo
- Publication number
- CA2161434A1 CA2161434A1 CA002161434A CA2161434A CA2161434A1 CA 2161434 A1 CA2161434 A1 CA 2161434A1 CA 002161434 A CA002161434 A CA 002161434A CA 2161434 A CA2161434 A CA 2161434A CA 2161434 A1 CA2161434 A1 CA 2161434A1
- Authority
- CA
- Canada
- Prior art keywords
- ray contrast
- contrast composition
- group
- galactose
- polymeric material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0461—Dispersions, colloids, emulsions or suspensions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising a polymeric material in combination with a divalent cation capable of forming a coating on the gastrointestinal tract and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000µ wherein said iodinated polymeric beads comprise a polymer containing repeating units of formula (I) wherein A is a repeating organic unit in the backbone chain of the polymer; and X is an organic moiety containing or iodinated aromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based on the molecular weight of X, in a pharmaceutically acceptable carrier.
Description
wo s4/2so7s ~ ~ ~ 6 ~ 4 3 4 PCTlusg4lo39l9 PO~.~R~(~, ~ ~4.Y (~,-)NTE~;T (',()~PO~ )N~ NTAn~
I(~nl~AT~n P~ R~Ar~
(~ ~.~ . ~ ~ to R~ ~j~
Thi8 iB a ~ont;n~ n-in-part of App~ t;on Serial Number 07/877,690 filed on May 1, 1992.
~(~.R~ FTRF r~ ~ON
~g~d o~he Iu~Lion This invention relates to an X-ray contrast comroEit;on for oral or retrograde ~miniRtration to a mommol co~l ~-ising water-insoluble o~linotod polyme~c beads as the contrast pro~ rine agent and a film-fo~ g material.
Roentgenographic e~ominP.~;on -tili7in~ X-rays and computed tomography (hereinafter CT) scans of fractures and other cQn~lit,jQnc
I(~nl~AT~n P~ R~Ar~
(~ ~.~ . ~ ~ to R~ ~j~
Thi8 iB a ~ont;n~ n-in-part of App~ t;on Serial Number 07/877,690 filed on May 1, 1992.
~(~.R~ FTRF r~ ~ON
~g~d o~he Iu~Lion This invention relates to an X-ray contrast comroEit;on for oral or retrograde ~miniRtration to a mommol co~l ~-ising water-insoluble o~linotod polyme~c beads as the contrast pro~ rine agent and a film-fo~ g material.
Roentgenographic e~ominP.~;on -tili7in~ X-rays and computed tomography (hereinafter CT) scans of fractures and other cQn~lit,jQnc
2 5 A~soriAted with the RkPlet-ol system is ro~tinely pr~o~cticetl without the use of contrast agents. X-ray v~s~-oli7-o-ti~n of organs c~ e soft tissue, such as the gastrointestinal (hereinafter GI) tract, requires the use of contrast agents which attenuate X-ray rQ~iotion D. P. Swanson et al in "Pharmaceuticals In Metlic-ol Im-o-~ing", 1990, l\lrorMills~n pllhliRhine
3 0 C~ompony, provides an e~ccellent background in medical imogin~
t;li~ine contrast agents and c~ o~;~ions therewith.
The desiderata for an ideal GI contrast agent includes: good to~icological profile; the ability to fill the entire bowel~lumen and evenly 3 5 coat the gut ml~ços~o 80 that the presence of the bowel is ~'?t~ctohle when the lumen is not distentle~l; palatability and nonirritation to the intestinal mucosa; and p-ofisin~ through the GI tract without prollllring artifacts or stimulating vigorous intestinal peristalsis.
WO 94/25075 2 ~ 6 ~ ~ 3 4 PCT/US94/03919 The most widely used contrast agents for the vis~Q~ t;on of the GI tract i8 barium sulfate ~timiniRtered as a suspension orally or rectally as an çnem~ (&e for ~mple, U.S. Patent Nos. 2,659,690;
2,680,089; 3,216,900; 3,235,462; 4,03~379 and 4,120,946) Notwitl~c~ontlin~
5 its relatively good contrast characteristics, n~ ihle absorption from the GI tract following oral or rectal ~mini~tratio~l and speedy escretion from the body, barium sulfate has ce.lai~ disadvantages. In the presence of intest;n~l fluids, it lacks hf~ o~ eity which can result in poor s-ray images. In the colon, when ~3mini~tered as sn çnem~, it 10 flocc~ te~ and forms irregular clumps with fecal m~tter~ The prior art considers as a serious problem the difficulty in achieving u~ifoL~
adherence, and co~ting of, the mucosa of the GI tract by the water in~o~ le barium sl~lf~te to provide high quality s-ray photographs. As a re~ult of inadequate adherence to, and non-uniform co~tin~ of the 15 mucosa, the ~c-ray results are often inferior, misleading to the L oner and the ims~E~in~ process must be ~4~eAt~ It has also been observed that the barium sl~lf~te, and other solid inorganic particulate radiopaque agents tend to set~e out in the p~ti~nt after ev~cll~t;on but before and during x-ray im~in~, which again ~iPlQteriously ~ffçctc the 2 0 quality of the s-ray pictures.
These dl~ vback6 were sddressed by many invçetig~tQrs and their efforts resulted in great i~ o-velllents over the years. The drawbacks of u~evenly co~t;n~ of the ml~coE~ with an in~llffi~ently adherence thereto 25 y~oved to be rather ~iffic~lt to solve. To that end, the use of certain polymer additives were proposed as illustrated hele~der.
U.S. Patent No. 4,069,306 ~lisclose~ an X-ray contra6t ~ aldtion which is ~aid to adhere to the walls of body cavitie6. The ~ a~ation 3 0 comprises a finely divided water-insoluble inorganic X-ray contrast agent and minute particles of a ~drophilic polymer which is insoluble in wster but is water-~wellable. The body cavity is ~upplied with such aiation s-.cpen-3e-1 in water. The X-ray co~trast agent i8 present in admisture with and/or enclosed in and/or adhered to said minute 3 5 polymer particles.
2l6l434 U.S. Patent No. 4,120,946 discloses a pharmaceutical composition for ba.;~ op-ocific-otion of the digestive tract, comprising colloidal bal;u~ sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viacous solution at low concentration which S mo~ it po~ihle to mointoin the bh,;~ s~lfote in s~R~enRion and at the same time permit good adherence of the ~let,h,..Lion to the wall~ of the organ which it is desired to X-ray.
U.S. Patent No. 5,019,370 ~ lose~ a bio~le~radable radiographic 10 contrast medium cc~ ;sing biodegrQtl~Ahle polymeric spheres which carry a radiographically opaque element, ~uch as iodine, bromine, samarium and erbium. The contrast me~itlm is provided either in a dry or liquid state and may be A~3mini~tered i~t~c.vt:~lously, orally and intra-arterially.
1 ~
While these polymeric materials greatly enhonce ~t~ochment of the contrast agent used therewith to the walls of organs for better vis..-oli7otioIl thereof, they do not provide a ~ ~ coAtin~ thereon. As such, there is still a need for an im~ ved X-ray imagi~ medium that 2 0 uniformly coats the soft tissues subjected to diagnostic X-ray ~omin -otiOn.
In U.S. Patent Applicat~on Serial No. 07/938,786, it was disclosed that the ul ifc,~ coPt,;-,~ of the mn~oSA of the intestine can be obt-oine-l 25 by barium sulfate in cQmhinAtior with a film-forming material to provide high quality ~c-ray results.
It has now been discove~ed that high quality X-ray results can be obtained by ~t~1i7in~ a form~lAt;-~n c~ L;6ing water-insoluble jo~inAted 3 0 polymeric beads in comhinQtion with a film-forming material.
WO 94/25075 ~ 43 4 4 PCT/US94/03919 1 ~l~MARY F T~ TIW~I~II )N
It i8 the object of the present ~Y~llLion to provide comT)o~ on~ for co~t;n~ the gastrointestinal tract of m~mmplR to form an ef~ective S radiopaque co~*r g thereon by which ~iagnoE~;c e~min~;on of the GI
tract may be ~C~4 .~ he~ To that end, a thin ro~ i8 formed on the inner ~ ce of the GI tract çffectsd by ingesting, prior to v~ i7~ n by an X-ray emitting device, a polymeric film former, which has inco~ ted therein water-in~ol~lhle io~ t~ polymenc beads, r~Pp~hle 0 of co~t.in~ the GI tract. Upon completion of the GI ims~ine n, ~he i~mov~l of the co~t;n~ occurs as a result of the no~nal ~no~,e. of cells, that is, within about 24 to 48 hours. Such co~ ogil;on~
must meet ~everal requiremçntfi: the film former must be non~o~ic;
must not contain leachable or digestible components that would 15 ~eleteliously affect the p~t;ent; and the composition must be r~sp~hle of fo. ..~;-~ a film in the pH r~nge of from about 5 to about 8.
The object of the present invention is achieYed by a c~nposition cum~llsing: water-insoluble iodinated polymeric beads; polymeric 2 0 material which iB 8t least partially water soluble and cOI toinR
polarizable or ioni7~hle ~;lOU~8; and a divalent metal ion ~electetl from the group consisting of Mgt I, Ca~+, Zn I I and Ba++ which potentiates the effect of the polymeric material as a fi!m former on the n ~cos~ of the GI tract.
2~
The water-insoluble io~insted polymeric beads, the polymeric film former and the divalent metal ion are incul~olated in a solid or liquid media for s~rlmini~tration to a m~mm~l for X-ray vis--~1i7~tion of the GI
tract.
The ioAin~t~l polymeric beads are water-insoluble, non-water swellable in finely-divided form having a particle size of from about 0.01 to about 1000~. The iodinated polymer from which the beads are produced by co~nution or other techni~ues known in the art, has an 3 5 iodine col~nt in e~cess of 35 weight percent based on the day weight of the polymer and cont~inc repe~tin~ units of the formula:
~ wo 94/25075 2 1 6 1 4 3 4 PCTIUSg4/03919 X
wherein S A i8 a repeating organic unit in the h-o-rkhQne chain of the poly-mer, and X is an organic moiety confoining an io~in-o-te~ aromatic group and a hy~o~hilic group, said moiety having an iodine cQnt~nt within 10 the range of from about 40 to 80 weight ~e~ t based on the molecular weight of X.
A l,~efe~ed emboAimPnt of the invention features a crogRlinkPrl, iorlin~ts~l polymer of formula I wherein A ~e~e~ents the residue of a 1 5 le~e~ g unit in the horkhone chain of a polymer having appenAptl Lyd~o~yl groups, the Lyd~o~yl ~oul s providing cro~linking sites and reaction sites for ~ft-o-rhmRnt of the moiety X.
The io~lin~ote~ polymeric beads, the polymeric film former and the 2 0 divalent metal ion are incorporated in a solid or liquid media for ~mini~tration to a ms~mmsll for X-ray vicl.~li7~hnn of the GI tract.
WO 94/2~07~ Çj PCT/US94/03919 ~
~ 6~ 434 n~r~ . n~ oN F ~ n~ N
Starting materials, reagents and solvents can be obt~in~ from rh~mirs-l guppliers, ~uch as Aldrich, Baker, DuPont and Eastman 5 ChPmir~l Comp~nie~ or they may be l"~pa~æd by ter~nillues known in the prior art.
The polymers that were found to be sllit~ble for fG.~g a thin co~*ne on the GI tract can be rlRc~ifiPA as s~niC!niC, rfltiQniC and neutral 10 polymers, a Ae6~ on of which follows. U. S. Patent No. 4,623,539, the ~i~rlo~llre of which is inc~ o~ated herein by ,efere~ce, ~e.l,ai~s to such polymers. '' The water-insoluble iodinated polymeric beads ~t;li7e~ in the 15 present invention are disclosed in U. S. Patent No. 4, 406, 878, the disclosure of which is inco.~o.ated herein by reference.
The general structural formula of io~in~ted polymers of the ~ el~Lon is ,e:~eecnteA by structural formula I above. The b~kbor~
2 0 chain of the ioAin~tetl polymer can ~ e~e~t:
(i) a condensation polymer such as a polyester, polyamide, polyurethane, polycarbonate, polyepo~cide, polyether, a phenol-forTn~ Phyde polymer and equivalent c~rAPns~iQn polymers;
(ii) an addition polymer produced by the polymeri7-~t;or- of one or more addition polymerizable mo~omers cont~inin~ a polymerizable lncs-t...~ted double bond, e.g., vinyl mrmc~msrs~ including such Pd~ on polymers as poly(vinyl alcohol), poly(alkylmethacrylates), 3 0 poly(alkylacrylates), and equivalent addition polymers; or (iii) a naturally GCCu~ g polymer, for e~mple, a polys~cçh~ide cor~t~ining repe~*ng glucose units such as ~tarch, glycogen, cellulose, cellulosic d~ atives, and equivalent naturally occuring polymers.
r~efe.aUy, repeating units A of formula I represents the residue of a repeating unit having an appended hyd~o~yl group, such as the ~ WO 94/25075 7 PCT/US94/03919 repeo-tine unit of poly (vinyl o-lCQhol)~ the repeating epoxy unit of a polyt:~o~ e, the repe~o~tir~E unit of a LyLo~ylated acrylic polymer such as poly (hydrosyethylacylate), or the repeo-tinE glucose unit of a naturally occu~,~g polyso-crhLo-~ide. The appended hydlo~yl group can S serve either a6 a cros~linking site or as a reaction site for ~lecu~or compounds of the organic moiety X in formula I. Such precursor compounds can be chemically linlret3 to the repeating units of the polymer bo-~kbone chain through a condensation reaction with the appen~lP~ LyLO~y group.
The organic moiety X of formula I above represents an iodine-contoininE organic frogment cv,.~ ising an io~in-oted arom-otic group and one or more hydrophilic groups. To obtain the high iodine content characteristic of the polymers used in the invention, the iodinated 15 arom~t;c group have ml~ltiple iodine substituents bon~3e~ directly to the aromatic carbon ring atoms. Especi~11y preferred ~monE these io~linots~3 aromatic groups are aromatic group~ cor~t~ininE three, ylefelably four, carbon ring atoms substituted by jo~lin~. A y.~efell~d io~in-o-te~l arom-o-tic group is an io~lin~te~ phenyl ring, although napthyl 20 ring6 and ~lo~ cont-oininE hetelo..~clic rings contoininE 5 to 7 ring atoms can also be used. An especially preferred iodinated aromatic group i6 a phenyl ring bearing iodine 6ubstituents on a 4 of the carbon ring atoms.
2 5 The hydrophilic group(s) of X are typically present as a ~ubstituent(6) bonded directly, or indirectly through a chemical linking group, to one or more of the Ca~lJGll ring atoms of the io~lin~te~ arom~tic group. rleÇ~l,ed linkine groups in~ e short chain ~1ipl ~tic groups, e.g., alkylene groups, amido groups and equivalent aliphatic groups, 3 0 having 1 to 4 carbon atoms. Typically h~.llol,hilic ~lOUlJ8 can be se1ecte~1 from a variety of such group6 including carboxyl ~;lOLi~8; ~ulfo groups;
amino groups; salts thereof such a6 ca~l)G~ylate salts, sulfonate salts, ~mmor~ium ~alts; polyols such as glucose groups; and equivalent hydrophilic groups.
Typically, the precur60rs from which the organic moiety X of formula I i6 derived contain~ a reactive group which forms a chemic~1 -WO 94/25075 8 PCT/US94/03919 ~
2~6~434 linki~ group with the repe~ting unit of the polymer backbo~e chain. In the l..efe..ed e~nho~limPnt of the il,~e~tion wherein the repe~tin~ unit of the polymer b~trkhone chain .ey-c~cnts the residue of a repe~t;ng unit beanng a l~o"yl group, the reactive group cQnt~ine~ on the y~.~c~or S of X i8 a group reactive with the Lytlo~y group. For e~mple~ the reactive group can be a carbo~yl group which con~n~es with the appen~ iyLv~y group of the b~ rhonç chain to form an ester group linlril~g an jo~in~tgtl aroms~tic moiety cf the polymer h~rl~hone. A variety of other reactive groups which react with a LydloAy group to form such 10 ~hçmir~31 linkinE groups as ethers, amides, thioesters, carbonates, car~m~tefi, ~lfi~i~S, and equiv~lpnts~ can also be used.
A partial liæting of ylec.llsors for the moiety X of formula I
includes, for e~mple, 3-(3-a_ino-2,4,6-triiodophenyl)-2-ethylpropionic 1 ~ acid; 3-(3-hydlu~y-2,4,6-triiodophenyl)-2-etklyly~v~ionic acid; sodium 3-t3-butyryl~mino-2~4~6-triiodophenyl)-2-ethylacrylate; 3,5-diiodo-4-pyridone-N-acetic acid; 3-scetamido-2,4,6-triiodobenzoic acid;
tetraiodophtll~lic anhydride; and the like. Tetraiodophtt~ c a~hydride can be particularly u6eful her~n~e of its high iodine cQnt^nt~
Based on the foregoing description, a ~tructural formula of ain l.,efe.,ed io~lin~ted polymer6 ca~ be illu6tratet a6 L--Rl ;5~R3 2~
wherein:
A i6 a6 ~efined in formula I above;
X i6 a6 tlçfinetl in formula I above;
L .e~sents one of the above-described linking groups, e.g. e~ter, 3 0 ether, amide, thioester, carbonate, carb~mate, sulfide and the ~ WO 94/25075 9 PCT/US94/03919 like; and each of Rl to R6 which may be the same or di~erellt, represents hydrogen, an iodine-cor toining substituent, or a L~d.o~hilic group-contoining substituent, with the proviso that the iodine contff~nt of X is from about 40 to ~0 percent (based on the S molec~ o~ weight of X). I
I~fe,,ed io~lin-o~tfffff-l polymers are cro~linlre~ Thi~ can Pnh~nre the water-insolubility and re~i~tonce to ~well properties of the polymer.
Cros~linl~ine can be effected by incorporstion of suitable cros~linking 10 sites either on the polymer backbone chain or on the moiety X or both.
For e~omple, in a ~lere--sd ~rnho~impnt wherein the polymer cont-oin~
a repe~o-tine b-o-rlrbo~P unit bea~ng an appen~e~ LylLo~yl group and a ~i~Pchoin group A cont~ining a carboxyl group as a Ly-lrolJhilic group, a hyLo~yl group appended to the backbone chain of one polymer can 15 react with the carboxyl group ~tt~che-l to the siflech~in X of another polymer, thereby cros~linwng the two polymers through an ester linksge.
The polymeric contrast agents of the invention cort~in both 20 hydrophilic and hydrophobic groups. Repe~ting h~ckhoT~e units A of formula I are ~ubstantially hydrophobic as are many portions of the moiety X. Of course X also cont~inc one or more L~d.c~hilic groups.
This comhin~tion of hydrophobic and hydrophilic groups is believed important to provide the proper polymer surface and electrical 25 characteristics which, in turn, provide proper polymer compatibility with body organs and ti~s~lPs.
The iodinated polymers can be prepared by any of a variety of coll~,elltional polymerization and chemical reaction techniques. A
3 0 preferred re~ct;Qn sequence i~ to chemically react ~.ccu.~o. c.,~l,ou~ds for the cide-chain group X with a ~efo,med polymer cont~ining appended groups serving as fiuitable reaction sites, e.g., hydro~yl groups. The preformed polymer can be prepared by addition or con~en~tion polymerization, depeT-~ing on the polymer; or it can be 35 obtained from naturally occurring sources in the case of naturally occurring polymers; e.g., polys~cch~rides. The precursor compounds for the moiety X can be reacted with the reaction site on the polymer w094~2so752~ 6~ 434 1 o PCT/US94/03919 ~
be-tlrhonP by a variety of well-known re-o-rt;on y,ocedu~s, ~ep~n~inE on the nature of the linl~in~ group L in formula II above which is formed in this reaction. Advantageously, the reaction of these precursor co~ou~ds is carried out under em~ ifying conditions 80 that the S resultsnt polymers are obtained in finely-divided particulate form.
Cros~in~ ro-n be carried out during or following ~ttor-hmpnt of the moiety X of the polymer b~L~ P
.... ,1P 1 Five and one-half grams of poly (vinyl alcohol), PVA, purch-o-~e~
under the tr~em~rk Elvanol 62-22 from DuPont was fiwelled with stirring overnight in 300 ml of pyridine. The ...;~(-..e wss stirred for 4 days at room temperature with 65 g of tetraiodopht~olic anhydride to 1 5 react the PVA with the anhydride. The ...; ~ . . was then he~ to 60C
for 8 hours to effect cro~linl~in~. A copious ~ec;l,;tate of the io~in~te l polymeric reQct;on product formed. This was filtered off and washed with water and dried. Analysis shuwed that the polymeric reS~ct;Qn product has an iodine content of 61.7 percent comp~red with a 2 0 tl~eo.eLcal value of 73.0 percent for çomrlet~ n The structure of a repe~t~ng unit of this iodinated polymeric re~ction product was as follows:
t CH2 fH
o I
C'O
HOOC~I
Having obtained a water-insoluble and non-wster-swellable iodinated polymer as described above, the polymer can be subjected to grin~ing or milljng treatment to obtain polymer particles of the 1~ WO 94/25075 1 1 2 1 ~ 1 4 3 4PCT/US94/03919 a~y,o~,;ate size range. Of course, in cases where the polymers are e~ared under suitable conditions, such as bead polymenzation or ~mtllRifying conditions, the polymers may already have an a~ L;ate particle size 80 that additional milling or grinding may be llnnecesS~ry.
5 A useful particle size for these polymer particles i8 within the range of from about 0.01 to 1000 microns, ~.efeLsbly 0.1 to 100 microns.
The io!3inS~te~1 polymeric beads, the polymeric material and divalent cation are blended together and then formulated for 1 0 - lminipt~ ation using phyRioloEicAlly acceptable carriers or ~-ciriçntc in a m~nner within the skill of the art. The io~in~te~ polymeric beads, with the addition of pharmaceutically acceptable aids (such as surfActsnts and eml~lRifiers) and e2ccipients may be suspended in an aqueous medium resulting in a dispersion, suspension or emulsion.
15 Alternstively, the io~in~ted polymeric beads, the polymeric material and divalent cation may be formtllAte-l into a solid form, such as tablets or capsules.
Solid comrositio~7 of the present illv~ntion shall c~n~in~ inRtePd 20 of surfA~t~ntQ~emlllRifiers and water used in the liquid cQmroEition~
bl~lking agents and other pharmAcell~;cally acceptable ingredients advantageoufily employed to render the cQmro~itions p~lAt~hle.
When the ~-ray comrosition is formnl~te~ as a tablet, the bulking 2~ agent should have good co ~.~ssion characteristics. Suitable bulking agents are well known in the art and include a sweetener such as sugars, e.g. ~ucrose, and polyhydric Alcohols, e.g. mAnnitol, sorbitol and sylitol, and -~;Yl-~cs thereo When formlllAtQ~ as a tablet, it is preferable to incorporate in the composition one or more tablet 3 0 lubricating agents, such as stearic acid, m~ne~ium stearate and talc.
The amount of the tablet lubricating agent as well as any other ingredients required to easily ~lcl~&re the solid compositions, can readily be determined by ~e Rkille-l forml~ t~r. The solid c~ pQ6;tion6 may have incorporated therein optional pharmaceutically acceptable 3 ~ ingredients in order to impart thereto additional de~irable properties, such as flavo~ants and colorants.
WO 94/2~075 1 2 PCT/US94/03919 ~1 6~ 434 ~
(~nm,DoSit.inn~
Comro~itions of the present invention comprise the following pharmAcellt;cally acceptable compQnPnts based on % w/v:
s Polymeric Material 0.001- 25 Divalent Cation 0.001- 20 Io~inA~R~ Polymeric Beads 5 - 95 pi~nt 0 - 20 Aids (Surf~ctQnt~mnl~ifiers) 0.01-20 Water q.s. to 100 Solid ~om~ositionc of the present i~ve~ltion ~o,~,;se the following pharmAce-lt;c~lly acceptable com~onentc based on % w/w:
1~
Polymeric Material 0.001- 25 Divalent Cation 0.001- 20 Io~inAte~l Polyme~ic Beads 5 - 95 Bulking AgenttLubricant/Flavor q.s. to 100 Escipients advantageously used in the formulations include viscosity me~3iAting and st~hili~ing agents, such as microcrystalline cellulose, ethylcellulose, hydrogypropyl methylcellulose and gum arabic. Physiologically acceptable s~lhst~nces may also be included, 2 5 such as sodium citrate, sodium chloride, therapeutic 6u~st~nce~, antacid substances and flavoring agents. The inclusion of Ant;microbiaVantiseptiC agents such as methyl parah~dlo..yl~-~QAte et~yl paraL~o~Lyl~en7o~te~ propyl paraL~,d~c.,.r-hen70~te, hen7-oic acid or sorbic acid may also be desirable in some forrr~ ation~
Surfactants or en-ul~ifier~ can be used alone or in comhin~t;on with other emulsifying agents and surfactants. For e~Ample, Dow Corning Medical Antifoam AF, which is a coInposition of 30% w/v polydimethylsiloxane and silica aerogel, 14% w/v stearate em~ ifiers 3 5 and 0.075% w/v sorbic acid, the b~l~qnce being water, may be used by itsel Intralipid, which i6 an emulsion of fatty acids needs the presence of a sUsper~ing agent for it to form an acceptable emulsion with WO 94/2507~ t ~ PCT/US94/03919 216~434 contrast agent6 of the present invention. The amount of such surf~ctontQ may be in the range of from 0.01 to 5% w/v of the aqueou6 for~~ t;Qn~, altl o~lgh the amount, in general, is kept as low as possih1et l.iefe.ably in the range of 0.05 to 2% w/v. The surface active S agents may be r~tioniç~ ~nionic~ nn~io~tic, zwitterionic or a ...;~ .e of - two or more of these agents.
Suitable cationic surf~ct~ntF include c~ ~ethyl ~mmf~
bromitle. Suitable ~tni~nic agents include sodium lauryl sulphate, 10 sodium heptadecyl sulphate, alkyl bqn7~nesulrhnnic acids and salts thereof, sodium butylnapt~t~ler~e slllfor~te, and sulphosl~ccin~t~.
Zwittenonic surface active agents are subst~nces that when di6solved in water they behave as diprotic acids and, as they ionize, they behave both a6 a weak base and a weak acid. Since the two charges on the mo1e~l1e 1 5 h~l~nce each other out they act as ~eutral molec lles. The pH at which the zwitterion concentration is m~imum i8 knovm a6 the isoelectric point. Co~ ouud6, such as certain amino acids having an iRoelectric point at the desired pH of the formlll~tiQn~ of the present illv~tion are useful in pr~ctirin~ the present invention In ~le~ g the form~ tion~ of the present invention we prefer to use nQnionic ~tntll~;fier~ or surface active agents which, ~imils~rly to the nonioT-ic contrast agents, possess a superior toxicological profile to that of ~nionic~ cationic or zwitterionic agents. In the nonionic 25 emulsifying agent6 the ~.ol,o.lions of hydrophilic and hydrophobic groups are about evenly b~l~nced They differ from ~niQniC and c~ti~nic surfactants by the absence of charge on the molecllle and, for that reason, are generally less irritant than the cationic or anionic ~urf~ct~nt6~ Nonionic surf~ nt~ include c&~l,o"ylic esters, ca,bo~ylic 3 0 ~mides~ ethoxylated alkylph~nol~ and ethoxylated ~lirh~tic ~ QhO1~.
One particular type of carboxylic ester nonionic surface active agents are the partial, for e~mple mono-, esters formed by the re~l*ion of fatty and re6in acids, for e~mple of about 8 to about 18 carbon atoms, 3 5 with polyalcohols, for eY~mple glycerol, glycols such as mono-, di-, tetra-and he~aethylene glycol, sorbitan, and the like; and ~imil~r co~ o~lds W094/2507~ 2l 61 434 1 4 PCT/US94/03919 1 formed by the direct ~3diti~n of varying molar ratios of ethylene o~de to the L~ Lo"y group of fatty acids.
Ano~l er type of ca~l,o,-ylic esters iB the cor~lpn~t;on products of 5 fatty and resin partial acids, for e~mplç mono-, esters ethylene oside, 8uch as fatty or resin acid ester~ of pol~u~elhylene su~Ll~n and sorbitol, for e~mple polyu~atl~lene sorbitan, mono-tall oil esters. These may con~in, for ç~S....~le, from about 3 to about 80 o~cyethylene units per molecllle and fatty or resin acid groups of frûm about 8 to about 18 carbon 10 ~tJ~ln~ mple6 of naturally ocs~-~g fatty acid miYt~lres which may be used are those from cocon-~t oil and~tallow while eY~mples of single fatty acids are ~30~Pc~noic acid and oleic acid.
Carboxylic amide noI~ionic surface active agents are the primary 15 amide, monoethyl~mi~3e and diethyl~mi~e of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms.
The etho~cylated alkylphenol nonionic surface active agents include various polyethylene oside condensates of alkylphenol~, 2 0 especially the condensation products of mono-alkylphenols or dialkylphenol6 wherein the alkyl group cont~in~ about 6 to about lZ
carbon atoms in either br~nrhe~ chain or particularly straight chain configuration, for e~mple, octyl cresol, octyl ~hPno] or nonyl phenol, with ethylene o~de, said ethylene o~cide being present in ~mo~mt~ equal 25 to from about 5 to about 25 moles of ethylene o~cide per mole of slkylphPnol.
Ethosylated aliphatic alcohol nonionic ~urface active agents include the condPns~t;or~ products of aliphatic ~lcQholR having from 3 0 about 8 to 18 carbon atoms in either straight chain or br~nche~ chain configuration, for çY~mple oleyl or cetyl alcohol, vnth ethylene oYide, said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene o~nde per mole of ~lcrhol 3 5 Preferred nonio~ic surface active agents include:
(a) Sorbitan esters (sold under the trade nsme Span) having the formula:
~WO 94/25075 l 5 PCT/US94/03919 21~1434 HO ~1 ~CH-R2 or ~H2-R3 wherein Rl = R2 = OH, R3 = R for EO~ m~ oe~;lei~, S Rl = OH, R2 = R3 = R for soLLil~l diesters, Rl = R2 = R3 = R for 801bil~ triesters, where R = (C11H23) COO for laurate, (C17H33) COO for oleate, (C1gH31) COO for p~ te, 1 0 (C17H3s) COO for s~ te;
(b) Polyu~yethylene alkyl ethers (i.e. Brijs) having the formula 1 5 CH3(CH2)X(O-cH2-cH2)yoH
where (~c + 1) is the nllmher of carbon atoms in the alkyl chain, typically:
2 0 12 lauryl (dodecyl) 14 myristyl (tetradecyl) 16 cetyl (h~ ecyl) 18 stearyl (oct~lecyl) and y iB the nllmher of ethylene oside ~lOI~S in the L~d vyhilic chain, typically 10-60;
(c) PolyoAyethylene sorbitan fatty acid esters, ~old under the trade 3 0 names of Poly~o.l,ates 20, 40, 60, 65, 80 & 85; and (d) Polyo,.yetllylene stearates, such as:
3 5 poly(o~y-1,2-ethanediyl)-a-hydro-w-hy.l.oxy-octs-lec~no~te;
polyethylene glycol monostearate; and WO 94/2~075 ~ 6 PCT/US94/03919 poly(o~cy-1,2-et~ e~3iyl)-a-(l-o~-)oc~o~3ecyl)-w-L~d polyethylene glycol monostearate.
The film former polymeric "~teri~lR used in accordance with the pre~ent invent;Qn include ~nionic polymers, cationic polymerR and neutral polymers.
I . ~nil nic Polym~r~
The anionic polymer6 carrv negative charges in the ioni7e~ form and are capable of hin~in~ to cell s~faces mai~ly by electrost~t;c forces.
Sllitehle ~ni~nic polymere int~ e the following:
O o R--O-- O--M++ R--C--O--M++ R--O--R C--O--M++
o wherein 2 0 R is the polymeric chain;
~ O
~ ---- and C--o-- are ~nionic li~nllc; and o 2 5 M++ ie a divalent cation.
Specific anionic polymers ueeful in the practice of the present invention include:
(1) Sl-lf~ted polys~qcr,h~rides of the formula:
~ WO 94/2507~ 1 ~7 2 ~ 6 1 4 3 4 PCT/US94103919 R--O--S--O--M+~
o wherein R iB 3~6-anhydro-D-~l~rtQ~e linked through C-4 to D-e~ ctose; (kappa carrageenan) a-D-{~l~cto~e units (1-3) linked; (lambda carrageenan) D ~P1Art~e 3,6-P~ydro-D-~l~ct4se; (iota carrageenan) D-~ rt~se 1 0 3,6-anhydro-L-~l~ctose: (Agar - Agar) D-~l~ctQ~e 3,6-anhydro-D-~l~ctose; (Furcellaren) D-glucopyranose; tT-~min~in sulfate) c~n; and (G~ n sl~lfAte) Galactos~mino-glucuronans (Chondroitin sl~lf~te-s);
and M++ is Mg++, Ca++, Zn++, Ba++ or ;~ e8 thereof.
(2) Carboxylated polys~cch~ides of the formula:
R--C--0--M~
wherein R is D-~ ct~onoglycan; and (Pectin) anhydro-D-m~nnnronic acid and anhydro-~guluronic acid (Algin) residues; and M++ is Mg++, Ca++, Zn++, Ba++ or ....... .~ e8 thereof.
(3) Cellulose de~;v&tives of the fo~nulae:
W094/2507~ 1 8 PCTtUS94/03919 ~
o o o R'--0--R--0--s--o--M++ R'--0--C--R--0--I--0--M++ and O o R~--C--R--a--0 M++
wherein R i8 an anhy~o~lucose re~idue;
R' i~ CH3, C2Hs or C3H7;
E' iB CH3 or C2H~; and M++ is Mg~+, Ca++, Zn++, Ba++ or ;~ es thereof.
F.YQmple~ of cellulose derivatives in~ e sodium ethylcellulose sulfate, 60dium cellulose acetate sulfate and sodium carbo~cymethyl cellulose.
t;li~ine contrast agents and c~ o~;~ions therewith.
The desiderata for an ideal GI contrast agent includes: good to~icological profile; the ability to fill the entire bowel~lumen and evenly 3 5 coat the gut ml~ços~o 80 that the presence of the bowel is ~'?t~ctohle when the lumen is not distentle~l; palatability and nonirritation to the intestinal mucosa; and p-ofisin~ through the GI tract without prollllring artifacts or stimulating vigorous intestinal peristalsis.
WO 94/25075 2 ~ 6 ~ ~ 3 4 PCT/US94/03919 The most widely used contrast agents for the vis~Q~ t;on of the GI tract i8 barium sulfate ~timiniRtered as a suspension orally or rectally as an çnem~ (&e for ~mple, U.S. Patent Nos. 2,659,690;
2,680,089; 3,216,900; 3,235,462; 4,03~379 and 4,120,946) Notwitl~c~ontlin~
5 its relatively good contrast characteristics, n~ ihle absorption from the GI tract following oral or rectal ~mini~tratio~l and speedy escretion from the body, barium sulfate has ce.lai~ disadvantages. In the presence of intest;n~l fluids, it lacks hf~ o~ eity which can result in poor s-ray images. In the colon, when ~3mini~tered as sn çnem~, it 10 flocc~ te~ and forms irregular clumps with fecal m~tter~ The prior art considers as a serious problem the difficulty in achieving u~ifoL~
adherence, and co~ting of, the mucosa of the GI tract by the water in~o~ le barium sl~lf~te to provide high quality s-ray photographs. As a re~ult of inadequate adherence to, and non-uniform co~tin~ of the 15 mucosa, the ~c-ray results are often inferior, misleading to the L oner and the ims~E~in~ process must be ~4~eAt~ It has also been observed that the barium sl~lf~te, and other solid inorganic particulate radiopaque agents tend to set~e out in the p~ti~nt after ev~cll~t;on but before and during x-ray im~in~, which again ~iPlQteriously ~ffçctc the 2 0 quality of the s-ray pictures.
These dl~ vback6 were sddressed by many invçetig~tQrs and their efforts resulted in great i~ o-velllents over the years. The drawbacks of u~evenly co~t;n~ of the ml~coE~ with an in~llffi~ently adherence thereto 25 y~oved to be rather ~iffic~lt to solve. To that end, the use of certain polymer additives were proposed as illustrated hele~der.
U.S. Patent No. 4,069,306 ~lisclose~ an X-ray contra6t ~ aldtion which is ~aid to adhere to the walls of body cavitie6. The ~ a~ation 3 0 comprises a finely divided water-insoluble inorganic X-ray contrast agent and minute particles of a ~drophilic polymer which is insoluble in wster but is water-~wellable. The body cavity is ~upplied with such aiation s-.cpen-3e-1 in water. The X-ray co~trast agent i8 present in admisture with and/or enclosed in and/or adhered to said minute 3 5 polymer particles.
2l6l434 U.S. Patent No. 4,120,946 discloses a pharmaceutical composition for ba.;~ op-ocific-otion of the digestive tract, comprising colloidal bal;u~ sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viacous solution at low concentration which S mo~ it po~ihle to mointoin the bh,;~ s~lfote in s~R~enRion and at the same time permit good adherence of the ~let,h,..Lion to the wall~ of the organ which it is desired to X-ray.
U.S. Patent No. 5,019,370 ~ lose~ a bio~le~radable radiographic 10 contrast medium cc~ ;sing biodegrQtl~Ahle polymeric spheres which carry a radiographically opaque element, ~uch as iodine, bromine, samarium and erbium. The contrast me~itlm is provided either in a dry or liquid state and may be A~3mini~tered i~t~c.vt:~lously, orally and intra-arterially.
1 ~
While these polymeric materials greatly enhonce ~t~ochment of the contrast agent used therewith to the walls of organs for better vis..-oli7otioIl thereof, they do not provide a ~ ~ coAtin~ thereon. As such, there is still a need for an im~ ved X-ray imagi~ medium that 2 0 uniformly coats the soft tissues subjected to diagnostic X-ray ~omin -otiOn.
In U.S. Patent Applicat~on Serial No. 07/938,786, it was disclosed that the ul ifc,~ coPt,;-,~ of the mn~oSA of the intestine can be obt-oine-l 25 by barium sulfate in cQmhinAtior with a film-forming material to provide high quality ~c-ray results.
It has now been discove~ed that high quality X-ray results can be obtained by ~t~1i7in~ a form~lAt;-~n c~ L;6ing water-insoluble jo~inAted 3 0 polymeric beads in comhinQtion with a film-forming material.
WO 94/25075 ~ 43 4 4 PCT/US94/03919 1 ~l~MARY F T~ TIW~I~II )N
It i8 the object of the present ~Y~llLion to provide comT)o~ on~ for co~t;n~ the gastrointestinal tract of m~mmplR to form an ef~ective S radiopaque co~*r g thereon by which ~iagnoE~;c e~min~;on of the GI
tract may be ~C~4 .~ he~ To that end, a thin ro~ i8 formed on the inner ~ ce of the GI tract çffectsd by ingesting, prior to v~ i7~ n by an X-ray emitting device, a polymeric film former, which has inco~ ted therein water-in~ol~lhle io~ t~ polymenc beads, r~Pp~hle 0 of co~t.in~ the GI tract. Upon completion of the GI ims~ine n, ~he i~mov~l of the co~t;n~ occurs as a result of the no~nal ~no~,e. of cells, that is, within about 24 to 48 hours. Such co~ ogil;on~
must meet ~everal requiremçntfi: the film former must be non~o~ic;
must not contain leachable or digestible components that would 15 ~eleteliously affect the p~t;ent; and the composition must be r~sp~hle of fo. ..~;-~ a film in the pH r~nge of from about 5 to about 8.
The object of the present invention is achieYed by a c~nposition cum~llsing: water-insoluble iodinated polymeric beads; polymeric 2 0 material which iB 8t least partially water soluble and cOI toinR
polarizable or ioni7~hle ~;lOU~8; and a divalent metal ion ~electetl from the group consisting of Mgt I, Ca~+, Zn I I and Ba++ which potentiates the effect of the polymeric material as a fi!m former on the n ~cos~ of the GI tract.
2~
The water-insoluble io~insted polymeric beads, the polymeric film former and the divalent metal ion are incul~olated in a solid or liquid media for s~rlmini~tration to a m~mm~l for X-ray vis--~1i7~tion of the GI
tract.
The ioAin~t~l polymeric beads are water-insoluble, non-water swellable in finely-divided form having a particle size of from about 0.01 to about 1000~. The iodinated polymer from which the beads are produced by co~nution or other techni~ues known in the art, has an 3 5 iodine col~nt in e~cess of 35 weight percent based on the day weight of the polymer and cont~inc repe~tin~ units of the formula:
~ wo 94/25075 2 1 6 1 4 3 4 PCTIUSg4/03919 X
wherein S A i8 a repeating organic unit in the h-o-rkhQne chain of the poly-mer, and X is an organic moiety confoining an io~in-o-te~ aromatic group and a hy~o~hilic group, said moiety having an iodine cQnt~nt within 10 the range of from about 40 to 80 weight ~e~ t based on the molecular weight of X.
A l,~efe~ed emboAimPnt of the invention features a crogRlinkPrl, iorlin~ts~l polymer of formula I wherein A ~e~e~ents the residue of a 1 5 le~e~ g unit in the horkhone chain of a polymer having appenAptl Lyd~o~yl groups, the Lyd~o~yl ~oul s providing cro~linking sites and reaction sites for ~ft-o-rhmRnt of the moiety X.
The io~lin~ote~ polymeric beads, the polymeric film former and the 2 0 divalent metal ion are incorporated in a solid or liquid media for ~mini~tration to a ms~mmsll for X-ray vicl.~li7~hnn of the GI tract.
WO 94/2~07~ Çj PCT/US94/03919 ~
~ 6~ 434 n~r~ . n~ oN F ~ n~ N
Starting materials, reagents and solvents can be obt~in~ from rh~mirs-l guppliers, ~uch as Aldrich, Baker, DuPont and Eastman 5 ChPmir~l Comp~nie~ or they may be l"~pa~æd by ter~nillues known in the prior art.
The polymers that were found to be sllit~ble for fG.~g a thin co~*ne on the GI tract can be rlRc~ifiPA as s~niC!niC, rfltiQniC and neutral 10 polymers, a Ae6~ on of which follows. U. S. Patent No. 4,623,539, the ~i~rlo~llre of which is inc~ o~ated herein by ,efere~ce, ~e.l,ai~s to such polymers. '' The water-insoluble iodinated polymeric beads ~t;li7e~ in the 15 present invention are disclosed in U. S. Patent No. 4, 406, 878, the disclosure of which is inco.~o.ated herein by reference.
The general structural formula of io~in~ted polymers of the ~ el~Lon is ,e:~eecnteA by structural formula I above. The b~kbor~
2 0 chain of the ioAin~tetl polymer can ~ e~e~t:
(i) a condensation polymer such as a polyester, polyamide, polyurethane, polycarbonate, polyepo~cide, polyether, a phenol-forTn~ Phyde polymer and equivalent c~rAPns~iQn polymers;
(ii) an addition polymer produced by the polymeri7-~t;or- of one or more addition polymerizable mo~omers cont~inin~ a polymerizable lncs-t...~ted double bond, e.g., vinyl mrmc~msrs~ including such Pd~ on polymers as poly(vinyl alcohol), poly(alkylmethacrylates), 3 0 poly(alkylacrylates), and equivalent addition polymers; or (iii) a naturally GCCu~ g polymer, for e~mple, a polys~cçh~ide cor~t~ining repe~*ng glucose units such as ~tarch, glycogen, cellulose, cellulosic d~ atives, and equivalent naturally occuring polymers.
r~efe.aUy, repeating units A of formula I represents the residue of a repeating unit having an appended hyd~o~yl group, such as the ~ WO 94/25075 7 PCT/US94/03919 repeo-tine unit of poly (vinyl o-lCQhol)~ the repeating epoxy unit of a polyt:~o~ e, the repe~o~tir~E unit of a LyLo~ylated acrylic polymer such as poly (hydrosyethylacylate), or the repeo-tinE glucose unit of a naturally occu~,~g polyso-crhLo-~ide. The appended hydlo~yl group can S serve either a6 a cros~linking site or as a reaction site for ~lecu~or compounds of the organic moiety X in formula I. Such precursor compounds can be chemically linlret3 to the repeating units of the polymer bo-~kbone chain through a condensation reaction with the appen~lP~ LyLO~y group.
The organic moiety X of formula I above represents an iodine-contoininE organic frogment cv,.~ ising an io~in-oted arom-otic group and one or more hydrophilic groups. To obtain the high iodine content characteristic of the polymers used in the invention, the iodinated 15 arom~t;c group have ml~ltiple iodine substituents bon~3e~ directly to the aromatic carbon ring atoms. Especi~11y preferred ~monE these io~linots~3 aromatic groups are aromatic group~ cor~t~ininE three, ylefelably four, carbon ring atoms substituted by jo~lin~. A y.~efell~d io~in-o-te~l arom-o-tic group is an io~lin~te~ phenyl ring, although napthyl 20 ring6 and ~lo~ cont-oininE hetelo..~clic rings contoininE 5 to 7 ring atoms can also be used. An especially preferred iodinated aromatic group i6 a phenyl ring bearing iodine 6ubstituents on a 4 of the carbon ring atoms.
2 5 The hydrophilic group(s) of X are typically present as a ~ubstituent(6) bonded directly, or indirectly through a chemical linking group, to one or more of the Ca~lJGll ring atoms of the io~lin~te~ arom~tic group. rleÇ~l,ed linkine groups in~ e short chain ~1ipl ~tic groups, e.g., alkylene groups, amido groups and equivalent aliphatic groups, 3 0 having 1 to 4 carbon atoms. Typically h~.llol,hilic ~lOUlJ8 can be se1ecte~1 from a variety of such group6 including carboxyl ~;lOLi~8; ~ulfo groups;
amino groups; salts thereof such a6 ca~l)G~ylate salts, sulfonate salts, ~mmor~ium ~alts; polyols such as glucose groups; and equivalent hydrophilic groups.
Typically, the precur60rs from which the organic moiety X of formula I i6 derived contain~ a reactive group which forms a chemic~1 -WO 94/25075 8 PCT/US94/03919 ~
2~6~434 linki~ group with the repe~ting unit of the polymer backbo~e chain. In the l..efe..ed e~nho~limPnt of the il,~e~tion wherein the repe~tin~ unit of the polymer b~trkhone chain .ey-c~cnts the residue of a repe~t;ng unit beanng a l~o"yl group, the reactive group cQnt~ine~ on the y~.~c~or S of X i8 a group reactive with the Lytlo~y group. For e~mple~ the reactive group can be a carbo~yl group which con~n~es with the appen~ iyLv~y group of the b~ rhonç chain to form an ester group linlril~g an jo~in~tgtl aroms~tic moiety cf the polymer h~rl~hone. A variety of other reactive groups which react with a LydloAy group to form such 10 ~hçmir~31 linkinE groups as ethers, amides, thioesters, carbonates, car~m~tefi, ~lfi~i~S, and equiv~lpnts~ can also be used.
A partial liæting of ylec.llsors for the moiety X of formula I
includes, for e~mple, 3-(3-a_ino-2,4,6-triiodophenyl)-2-ethylpropionic 1 ~ acid; 3-(3-hydlu~y-2,4,6-triiodophenyl)-2-etklyly~v~ionic acid; sodium 3-t3-butyryl~mino-2~4~6-triiodophenyl)-2-ethylacrylate; 3,5-diiodo-4-pyridone-N-acetic acid; 3-scetamido-2,4,6-triiodobenzoic acid;
tetraiodophtll~lic anhydride; and the like. Tetraiodophtt~ c a~hydride can be particularly u6eful her~n~e of its high iodine cQnt^nt~
Based on the foregoing description, a ~tructural formula of ain l.,efe.,ed io~lin~ted polymer6 ca~ be illu6tratet a6 L--Rl ;5~R3 2~
wherein:
A i6 a6 ~efined in formula I above;
X i6 a6 tlçfinetl in formula I above;
L .e~sents one of the above-described linking groups, e.g. e~ter, 3 0 ether, amide, thioester, carbonate, carb~mate, sulfide and the ~ WO 94/25075 9 PCT/US94/03919 like; and each of Rl to R6 which may be the same or di~erellt, represents hydrogen, an iodine-cor toining substituent, or a L~d.o~hilic group-contoining substituent, with the proviso that the iodine contff~nt of X is from about 40 to ~0 percent (based on the S molec~ o~ weight of X). I
I~fe,,ed io~lin-o~tfffff-l polymers are cro~linlre~ Thi~ can Pnh~nre the water-insolubility and re~i~tonce to ~well properties of the polymer.
Cros~linl~ine can be effected by incorporstion of suitable cros~linking 10 sites either on the polymer backbone chain or on the moiety X or both.
For e~omple, in a ~lere--sd ~rnho~impnt wherein the polymer cont-oin~
a repe~o-tine b-o-rlrbo~P unit bea~ng an appen~e~ LylLo~yl group and a ~i~Pchoin group A cont~ining a carboxyl group as a Ly-lrolJhilic group, a hyLo~yl group appended to the backbone chain of one polymer can 15 react with the carboxyl group ~tt~che-l to the siflech~in X of another polymer, thereby cros~linwng the two polymers through an ester linksge.
The polymeric contrast agents of the invention cort~in both 20 hydrophilic and hydrophobic groups. Repe~ting h~ckhoT~e units A of formula I are ~ubstantially hydrophobic as are many portions of the moiety X. Of course X also cont~inc one or more L~d.c~hilic groups.
This comhin~tion of hydrophobic and hydrophilic groups is believed important to provide the proper polymer surface and electrical 25 characteristics which, in turn, provide proper polymer compatibility with body organs and ti~s~lPs.
The iodinated polymers can be prepared by any of a variety of coll~,elltional polymerization and chemical reaction techniques. A
3 0 preferred re~ct;Qn sequence i~ to chemically react ~.ccu.~o. c.,~l,ou~ds for the cide-chain group X with a ~efo,med polymer cont~ining appended groups serving as fiuitable reaction sites, e.g., hydro~yl groups. The preformed polymer can be prepared by addition or con~en~tion polymerization, depeT-~ing on the polymer; or it can be 35 obtained from naturally occurring sources in the case of naturally occurring polymers; e.g., polys~cch~rides. The precursor compounds for the moiety X can be reacted with the reaction site on the polymer w094~2so752~ 6~ 434 1 o PCT/US94/03919 ~
be-tlrhonP by a variety of well-known re-o-rt;on y,ocedu~s, ~ep~n~inE on the nature of the linl~in~ group L in formula II above which is formed in this reaction. Advantageously, the reaction of these precursor co~ou~ds is carried out under em~ ifying conditions 80 that the S resultsnt polymers are obtained in finely-divided particulate form.
Cros~in~ ro-n be carried out during or following ~ttor-hmpnt of the moiety X of the polymer b~L~ P
.... ,1P 1 Five and one-half grams of poly (vinyl alcohol), PVA, purch-o-~e~
under the tr~em~rk Elvanol 62-22 from DuPont was fiwelled with stirring overnight in 300 ml of pyridine. The ...;~(-..e wss stirred for 4 days at room temperature with 65 g of tetraiodopht~olic anhydride to 1 5 react the PVA with the anhydride. The ...; ~ . . was then he~ to 60C
for 8 hours to effect cro~linl~in~. A copious ~ec;l,;tate of the io~in~te l polymeric reQct;on product formed. This was filtered off and washed with water and dried. Analysis shuwed that the polymeric reS~ct;Qn product has an iodine content of 61.7 percent comp~red with a 2 0 tl~eo.eLcal value of 73.0 percent for çomrlet~ n The structure of a repe~t~ng unit of this iodinated polymeric re~ction product was as follows:
t CH2 fH
o I
C'O
HOOC~I
Having obtained a water-insoluble and non-wster-swellable iodinated polymer as described above, the polymer can be subjected to grin~ing or milljng treatment to obtain polymer particles of the 1~ WO 94/25075 1 1 2 1 ~ 1 4 3 4PCT/US94/03919 a~y,o~,;ate size range. Of course, in cases where the polymers are e~ared under suitable conditions, such as bead polymenzation or ~mtllRifying conditions, the polymers may already have an a~ L;ate particle size 80 that additional milling or grinding may be llnnecesS~ry.
5 A useful particle size for these polymer particles i8 within the range of from about 0.01 to 1000 microns, ~.efeLsbly 0.1 to 100 microns.
The io!3inS~te~1 polymeric beads, the polymeric material and divalent cation are blended together and then formulated for 1 0 - lminipt~ ation using phyRioloEicAlly acceptable carriers or ~-ciriçntc in a m~nner within the skill of the art. The io~in~te~ polymeric beads, with the addition of pharmaceutically acceptable aids (such as surfActsnts and eml~lRifiers) and e2ccipients may be suspended in an aqueous medium resulting in a dispersion, suspension or emulsion.
15 Alternstively, the io~in~ted polymeric beads, the polymeric material and divalent cation may be formtllAte-l into a solid form, such as tablets or capsules.
Solid comrositio~7 of the present illv~ntion shall c~n~in~ inRtePd 20 of surfA~t~ntQ~emlllRifiers and water used in the liquid cQmroEition~
bl~lking agents and other pharmAcell~;cally acceptable ingredients advantageoufily employed to render the cQmro~itions p~lAt~hle.
When the ~-ray comrosition is formnl~te~ as a tablet, the bulking 2~ agent should have good co ~.~ssion characteristics. Suitable bulking agents are well known in the art and include a sweetener such as sugars, e.g. ~ucrose, and polyhydric Alcohols, e.g. mAnnitol, sorbitol and sylitol, and -~;Yl-~cs thereo When formlllAtQ~ as a tablet, it is preferable to incorporate in the composition one or more tablet 3 0 lubricating agents, such as stearic acid, m~ne~ium stearate and talc.
The amount of the tablet lubricating agent as well as any other ingredients required to easily ~lcl~&re the solid compositions, can readily be determined by ~e Rkille-l forml~ t~r. The solid c~ pQ6;tion6 may have incorporated therein optional pharmaceutically acceptable 3 ~ ingredients in order to impart thereto additional de~irable properties, such as flavo~ants and colorants.
WO 94/2~075 1 2 PCT/US94/03919 ~1 6~ 434 ~
(~nm,DoSit.inn~
Comro~itions of the present invention comprise the following pharmAcellt;cally acceptable compQnPnts based on % w/v:
s Polymeric Material 0.001- 25 Divalent Cation 0.001- 20 Io~inA~R~ Polymeric Beads 5 - 95 pi~nt 0 - 20 Aids (Surf~ctQnt~mnl~ifiers) 0.01-20 Water q.s. to 100 Solid ~om~ositionc of the present i~ve~ltion ~o,~,;se the following pharmAce-lt;c~lly acceptable com~onentc based on % w/w:
1~
Polymeric Material 0.001- 25 Divalent Cation 0.001- 20 Io~inAte~l Polyme~ic Beads 5 - 95 Bulking AgenttLubricant/Flavor q.s. to 100 Escipients advantageously used in the formulations include viscosity me~3iAting and st~hili~ing agents, such as microcrystalline cellulose, ethylcellulose, hydrogypropyl methylcellulose and gum arabic. Physiologically acceptable s~lhst~nces may also be included, 2 5 such as sodium citrate, sodium chloride, therapeutic 6u~st~nce~, antacid substances and flavoring agents. The inclusion of Ant;microbiaVantiseptiC agents such as methyl parah~dlo..yl~-~QAte et~yl paraL~o~Lyl~en7o~te~ propyl paraL~,d~c.,.r-hen70~te, hen7-oic acid or sorbic acid may also be desirable in some forrr~ ation~
Surfactants or en-ul~ifier~ can be used alone or in comhin~t;on with other emulsifying agents and surfactants. For e~Ample, Dow Corning Medical Antifoam AF, which is a coInposition of 30% w/v polydimethylsiloxane and silica aerogel, 14% w/v stearate em~ ifiers 3 5 and 0.075% w/v sorbic acid, the b~l~qnce being water, may be used by itsel Intralipid, which i6 an emulsion of fatty acids needs the presence of a sUsper~ing agent for it to form an acceptable emulsion with WO 94/2507~ t ~ PCT/US94/03919 216~434 contrast agent6 of the present invention. The amount of such surf~ctontQ may be in the range of from 0.01 to 5% w/v of the aqueou6 for~~ t;Qn~, altl o~lgh the amount, in general, is kept as low as possih1et l.iefe.ably in the range of 0.05 to 2% w/v. The surface active S agents may be r~tioniç~ ~nionic~ nn~io~tic, zwitterionic or a ...;~ .e of - two or more of these agents.
Suitable cationic surf~ct~ntF include c~ ~ethyl ~mmf~
bromitle. Suitable ~tni~nic agents include sodium lauryl sulphate, 10 sodium heptadecyl sulphate, alkyl bqn7~nesulrhnnic acids and salts thereof, sodium butylnapt~t~ler~e slllfor~te, and sulphosl~ccin~t~.
Zwittenonic surface active agents are subst~nces that when di6solved in water they behave as diprotic acids and, as they ionize, they behave both a6 a weak base and a weak acid. Since the two charges on the mo1e~l1e 1 5 h~l~nce each other out they act as ~eutral molec lles. The pH at which the zwitterion concentration is m~imum i8 knovm a6 the isoelectric point. Co~ ouud6, such as certain amino acids having an iRoelectric point at the desired pH of the formlll~tiQn~ of the present illv~tion are useful in pr~ctirin~ the present invention In ~le~ g the form~ tion~ of the present invention we prefer to use nQnionic ~tntll~;fier~ or surface active agents which, ~imils~rly to the nonioT-ic contrast agents, possess a superior toxicological profile to that of ~nionic~ cationic or zwitterionic agents. In the nonionic 25 emulsifying agent6 the ~.ol,o.lions of hydrophilic and hydrophobic groups are about evenly b~l~nced They differ from ~niQniC and c~ti~nic surfactants by the absence of charge on the molecllle and, for that reason, are generally less irritant than the cationic or anionic ~urf~ct~nt6~ Nonionic surf~ nt~ include c&~l,o"ylic esters, ca,bo~ylic 3 0 ~mides~ ethoxylated alkylph~nol~ and ethoxylated ~lirh~tic ~ QhO1~.
One particular type of carboxylic ester nonionic surface active agents are the partial, for e~mple mono-, esters formed by the re~l*ion of fatty and re6in acids, for e~mple of about 8 to about 18 carbon atoms, 3 5 with polyalcohols, for eY~mple glycerol, glycols such as mono-, di-, tetra-and he~aethylene glycol, sorbitan, and the like; and ~imil~r co~ o~lds W094/2507~ 2l 61 434 1 4 PCT/US94/03919 1 formed by the direct ~3diti~n of varying molar ratios of ethylene o~de to the L~ Lo"y group of fatty acids.
Ano~l er type of ca~l,o,-ylic esters iB the cor~lpn~t;on products of 5 fatty and resin partial acids, for e~mplç mono-, esters ethylene oside, 8uch as fatty or resin acid ester~ of pol~u~elhylene su~Ll~n and sorbitol, for e~mple polyu~atl~lene sorbitan, mono-tall oil esters. These may con~in, for ç~S....~le, from about 3 to about 80 o~cyethylene units per molecllle and fatty or resin acid groups of frûm about 8 to about 18 carbon 10 ~tJ~ln~ mple6 of naturally ocs~-~g fatty acid miYt~lres which may be used are those from cocon-~t oil and~tallow while eY~mples of single fatty acids are ~30~Pc~noic acid and oleic acid.
Carboxylic amide noI~ionic surface active agents are the primary 15 amide, monoethyl~mi~3e and diethyl~mi~e of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms.
The etho~cylated alkylphenol nonionic surface active agents include various polyethylene oside condensates of alkylphenol~, 2 0 especially the condensation products of mono-alkylphenols or dialkylphenol6 wherein the alkyl group cont~in~ about 6 to about lZ
carbon atoms in either br~nrhe~ chain or particularly straight chain configuration, for e~mple, octyl cresol, octyl ~hPno] or nonyl phenol, with ethylene o~de, said ethylene o~cide being present in ~mo~mt~ equal 25 to from about 5 to about 25 moles of ethylene o~cide per mole of slkylphPnol.
Ethosylated aliphatic alcohol nonionic ~urface active agents include the condPns~t;or~ products of aliphatic ~lcQholR having from 3 0 about 8 to 18 carbon atoms in either straight chain or br~nche~ chain configuration, for çY~mple oleyl or cetyl alcohol, vnth ethylene oYide, said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene o~nde per mole of ~lcrhol 3 5 Preferred nonio~ic surface active agents include:
(a) Sorbitan esters (sold under the trade nsme Span) having the formula:
~WO 94/25075 l 5 PCT/US94/03919 21~1434 HO ~1 ~CH-R2 or ~H2-R3 wherein Rl = R2 = OH, R3 = R for EO~ m~ oe~;lei~, S Rl = OH, R2 = R3 = R for soLLil~l diesters, Rl = R2 = R3 = R for 801bil~ triesters, where R = (C11H23) COO for laurate, (C17H33) COO for oleate, (C1gH31) COO for p~ te, 1 0 (C17H3s) COO for s~ te;
(b) Polyu~yethylene alkyl ethers (i.e. Brijs) having the formula 1 5 CH3(CH2)X(O-cH2-cH2)yoH
where (~c + 1) is the nllmher of carbon atoms in the alkyl chain, typically:
2 0 12 lauryl (dodecyl) 14 myristyl (tetradecyl) 16 cetyl (h~ ecyl) 18 stearyl (oct~lecyl) and y iB the nllmher of ethylene oside ~lOI~S in the L~d vyhilic chain, typically 10-60;
(c) PolyoAyethylene sorbitan fatty acid esters, ~old under the trade 3 0 names of Poly~o.l,ates 20, 40, 60, 65, 80 & 85; and (d) Polyo,.yetllylene stearates, such as:
3 5 poly(o~y-1,2-ethanediyl)-a-hydro-w-hy.l.oxy-octs-lec~no~te;
polyethylene glycol monostearate; and WO 94/2~075 ~ 6 PCT/US94/03919 poly(o~cy-1,2-et~ e~3iyl)-a-(l-o~-)oc~o~3ecyl)-w-L~d polyethylene glycol monostearate.
The film former polymeric "~teri~lR used in accordance with the pre~ent invent;Qn include ~nionic polymers, cationic polymerR and neutral polymers.
I . ~nil nic Polym~r~
The anionic polymer6 carrv negative charges in the ioni7e~ form and are capable of hin~in~ to cell s~faces mai~ly by electrost~t;c forces.
Sllitehle ~ni~nic polymere int~ e the following:
O o R--O-- O--M++ R--C--O--M++ R--O--R C--O--M++
o wherein 2 0 R is the polymeric chain;
~ O
~ ---- and C--o-- are ~nionic li~nllc; and o 2 5 M++ ie a divalent cation.
Specific anionic polymers ueeful in the practice of the present invention include:
(1) Sl-lf~ted polys~qcr,h~rides of the formula:
~ WO 94/2507~ 1 ~7 2 ~ 6 1 4 3 4 PCT/US94103919 R--O--S--O--M+~
o wherein R iB 3~6-anhydro-D-~l~rtQ~e linked through C-4 to D-e~ ctose; (kappa carrageenan) a-D-{~l~cto~e units (1-3) linked; (lambda carrageenan) D ~P1Art~e 3,6-P~ydro-D-~l~ct4se; (iota carrageenan) D-~ rt~se 1 0 3,6-anhydro-L-~l~ctose: (Agar - Agar) D-~l~ctQ~e 3,6-anhydro-D-~l~ctose; (Furcellaren) D-glucopyranose; tT-~min~in sulfate) c~n; and (G~ n sl~lfAte) Galactos~mino-glucuronans (Chondroitin sl~lf~te-s);
and M++ is Mg++, Ca++, Zn++, Ba++ or ;~ e8 thereof.
(2) Carboxylated polys~cch~ides of the formula:
R--C--0--M~
wherein R is D-~ ct~onoglycan; and (Pectin) anhydro-D-m~nnnronic acid and anhydro-~guluronic acid (Algin) residues; and M++ is Mg++, Ca++, Zn++, Ba++ or ....... .~ e8 thereof.
(3) Cellulose de~;v&tives of the fo~nulae:
W094/2507~ 1 8 PCTtUS94/03919 ~
o o o R'--0--R--0--s--o--M++ R'--0--C--R--0--I--0--M++ and O o R~--C--R--a--0 M++
wherein R i8 an anhy~o~lucose re~idue;
R' i~ CH3, C2Hs or C3H7;
E' iB CH3 or C2H~; and M++ is Mg~+, Ca++, Zn++, Ba++ or ;~ es thereof.
F.YQmple~ of cellulose derivatives in~ e sodium ethylcellulose sulfate, 60dium cellulose acetate sulfate and sodium carbo~cymethyl cellulose.
(4) Sulfated, sulfonated or carbo~ylated synt-hPt;C polymer6 of the formula:
o R-- --0 r~ ~ R--O-- --O--M++ and R--C--O--M'+
~
wherem R is an ~liph~t;c or aromatic hyd~oca~lJull, such a6 2 ~ poly~ cl.e, poly(sulfon) resin or ca~lJw~ylated (poly) vinyl;
and M++ is Mg++, Ca++, Zn I +, Ba++ or mixtures thereof.
~ W094/2~075 1 9 PCT/US94/03919 I I t~s3t;orlic Polym~rs The c~t;onic polymers carry positive charges in the ionized form.
Suitable polymers for practicing the present invention include:
o R-- --0 r~ ~ R--O-- --O--M++ and R--C--O--M'+
~
wherem R is an ~liph~t;c or aromatic hyd~oca~lJull, such a6 2 ~ poly~ cl.e, poly(sulfon) resin or ca~lJw~ylated (poly) vinyl;
and M++ is Mg++, Ca++, Zn I +, Ba++ or mixtures thereof.
~ W094/2~075 1 9 PCT/US94/03919 I I t~s3t;orlic Polym~rs The c~t;onic polymers carry positive charges in the ionized form.
Suitable polymers for practicing the present invention include:
5 ~lermot~n sulfate, Icer~t~E~lf~te, hyaluronic acid, hep~n and chitin.
III Nellt.r~l Poly.~
10Neutral polymers having polarizable electrons such as o,~y el~, nitrogen, sulfur, fluoride, çhlon~e~ bromide and iodide are also suitable for pr~rti~ing the ~ese.lt i~lve..l r~n In the ~,eee"ce of a c~ion~ such as Mg++, Ca++, Zn++ or Ba++, the polymers are partially polarized thereby providing intermolecular inter~;QnC between the polymer and l 5 the inte~tin~l wall. Fy~mple~ ofthese polymers include:
(a) Polys~ch~rides, such as ~tarch, gly~ " glucan, fr~1~t~nc, m~nn~ng, ~ tom~nn-e ~, g~ om~nn~s~ ~P1s~t"nR~ sylans, ~,ly~u~ ...e~nc, destran and starch amylose;
(b) Cellulose derivatives, such as methylcellulose, hydrosyethylcellulose, ethylhydrosyethyl cellulose, hydlo~y~ro~yl methylcellulose and LYd~OAY~10~1 cellulose;
and (c) Synthetic polymers, such as polyvi~ y~o1i-1nne, polyvinyl ~1~4ho1 and ethylene oside polymërs.
FYçm~ y formulations of the present invention are as shown:
F~m,ple ~
Iotlin~t~ l Polymeric Beads 1.94 g (19.4% wh) Dow Corning Med. ~n~;fo~m AF çm~1sion 1.50 g (15% w/v) Tween 80 0.35 g (3.5% wh) 3 5 G~1~ct-e~n Sulfate 0.3 g (3% w/v) Calcium T--e~te~te 0.3 g (3% wh) Purified Water q. 8. to 10 ml WO 9412~07S 2. ~ 6 ~ 4 3 4 2 o PCT/US94/03919 f~
~,~3..Wle 3 Jo~inD~eA Polymenc Beads 1.50 g (lB.0% wh) T~L~v~c 908 0.45 g (4.5% wh) ~:o~ m Carrageenan 2.50gof2%(w/v) solution Calcium ~ te 0.3 g (3% wh) fie~ Water q. ~. to 10 ml 1 0 F.~m,Dle 4 n~ Polymeric Beads 2.00 g (20.0% w/v) Mineral Oil 0.50 g (5% w/v) Heparin 0.25 g (2.5% wh) Tween 21 0.25 g (2.5% wh) 1 S Pluronic F-68 0.25 g (2.5% wh) Calcium T ~ct~te 0.25 g (2.5% w/v) Purified Water q. 8. to 10 ml ~Dle Iotlin~tQ l Polymeric Beads 1.80 g (18.0% wh) Saf~lower Oil 0.50 g (5% w/v) ~ragne~ium Citrate 0.~0 g (6% w/v) Span 80 0.4 g (4% wh) 2 5 H~L OA,~ methylcellulose (4000 cPs) 2.50 g of 2% (w/v) solution Purified Water q. 8. to 10 ml The compositions of the invention may be a~miniRtered orally to the patient for radiological e~min~tion of the GI tract. The 3 0 compositions of the invention may also be ~mini6tered rectally in the form of çnem~C to a pPtient for rP~iologic e~ t;on of the colon.
The dosages of the contrast agent used acco,ding to the mçtl o-3 of the pre~ent invention will vary according to the precise nature of the 3 5 ingre-liçntc used. PreferaWy, howeve" the dosage should be kept as low a~ is consistent with achieving contrast e~h~nced im~Eing By employing as small amount of the composition as possible, tosicity pot^~ti~l i8 ..~;..i..~;7e~. For most form~ tisnc of the present invention doRPge8 will be in the range of from about 0.1 to about 20.0 g I/kg body weight, l"efe.ably in the rPnge of from about 0.4 to about 8.0 g I/kg of body weight, and most l.lefeLably, in the range of from about 1.0 to about 5 3.0 g I~kg body weight for regular X-ray vi~ 7p~t;Qn of the GI tract. For CT ~-~nni~ the contrast agents of the present invention will be in the range of from about 1 to about 800 mg I/l~g body weight, ~LefeL~.bly in the range of from about 15 to about 250 mg I/l~g body weight, and most ~,~fe.ably in the range of from about 35 to about 90 mg I/kg body weight.
The cQn~Pntration of the ioflin5~te~l polymeric beadR should be in the range of from about 5~o w/w to about 95% w/w of the form~ t;on, ~lefe~ably from about 10% w/w to about 60% w/w and most p.~fe.ably of from about 15% w/w to about 40% w/w.
The conc~ntration of the film fo.~l,g polymeric material depends on the particular polymer used, ho~t vel, it should be in the range of 0~01 to about 25% w/w or higher in comhin~t;on with a divalent subst~nce, such as calcium lactate, having a concentration range of 2 0 0.001 to 20% w/w of the rQt;QniC elempnt Dosage level of the polymeric material may be in the range of from about 2 to about 20 g/~g body weight or higher.
The compo~itions of the present invention possess very good 2~ adherence to the walls of the gastrointestinal tract by forming an es~en~ ly ~ ifollll coating thereon.
The invent;Qn, having been fully described, it will be a~ t to one skilled in the art that changes and modifications can be made 3 0 thereto without de~&~ lg from the spirit and scope thereo
III Nellt.r~l Poly.~
10Neutral polymers having polarizable electrons such as o,~y el~, nitrogen, sulfur, fluoride, çhlon~e~ bromide and iodide are also suitable for pr~rti~ing the ~ese.lt i~lve..l r~n In the ~,eee"ce of a c~ion~ such as Mg++, Ca++, Zn++ or Ba++, the polymers are partially polarized thereby providing intermolecular inter~;QnC between the polymer and l 5 the inte~tin~l wall. Fy~mple~ ofthese polymers include:
(a) Polys~ch~rides, such as ~tarch, gly~ " glucan, fr~1~t~nc, m~nn~ng, ~ tom~nn-e ~, g~ om~nn~s~ ~P1s~t"nR~ sylans, ~,ly~u~ ...e~nc, destran and starch amylose;
(b) Cellulose derivatives, such as methylcellulose, hydrosyethylcellulose, ethylhydrosyethyl cellulose, hydlo~y~ro~yl methylcellulose and LYd~OAY~10~1 cellulose;
and (c) Synthetic polymers, such as polyvi~ y~o1i-1nne, polyvinyl ~1~4ho1 and ethylene oside polymërs.
FYçm~ y formulations of the present invention are as shown:
F~m,ple ~
Iotlin~t~ l Polymeric Beads 1.94 g (19.4% wh) Dow Corning Med. ~n~;fo~m AF çm~1sion 1.50 g (15% w/v) Tween 80 0.35 g (3.5% wh) 3 5 G~1~ct-e~n Sulfate 0.3 g (3% w/v) Calcium T--e~te~te 0.3 g (3% wh) Purified Water q. 8. to 10 ml WO 9412~07S 2. ~ 6 ~ 4 3 4 2 o PCT/US94/03919 f~
~,~3..Wle 3 Jo~inD~eA Polymenc Beads 1.50 g (lB.0% wh) T~L~v~c 908 0.45 g (4.5% wh) ~:o~ m Carrageenan 2.50gof2%(w/v) solution Calcium ~ te 0.3 g (3% wh) fie~ Water q. ~. to 10 ml 1 0 F.~m,Dle 4 n~ Polymeric Beads 2.00 g (20.0% w/v) Mineral Oil 0.50 g (5% w/v) Heparin 0.25 g (2.5% wh) Tween 21 0.25 g (2.5% wh) 1 S Pluronic F-68 0.25 g (2.5% wh) Calcium T ~ct~te 0.25 g (2.5% w/v) Purified Water q. 8. to 10 ml ~Dle Iotlin~tQ l Polymeric Beads 1.80 g (18.0% wh) Saf~lower Oil 0.50 g (5% w/v) ~ragne~ium Citrate 0.~0 g (6% w/v) Span 80 0.4 g (4% wh) 2 5 H~L OA,~ methylcellulose (4000 cPs) 2.50 g of 2% (w/v) solution Purified Water q. 8. to 10 ml The compositions of the invention may be a~miniRtered orally to the patient for radiological e~min~tion of the GI tract. The 3 0 compositions of the invention may also be ~mini6tered rectally in the form of çnem~C to a pPtient for rP~iologic e~ t;on of the colon.
The dosages of the contrast agent used acco,ding to the mçtl o-3 of the pre~ent invention will vary according to the precise nature of the 3 5 ingre-liçntc used. PreferaWy, howeve" the dosage should be kept as low a~ is consistent with achieving contrast e~h~nced im~Eing By employing as small amount of the composition as possible, tosicity pot^~ti~l i8 ..~;..i..~;7e~. For most form~ tisnc of the present invention doRPge8 will be in the range of from about 0.1 to about 20.0 g I/kg body weight, l"efe.ably in the rPnge of from about 0.4 to about 8.0 g I/kg of body weight, and most l.lefeLably, in the range of from about 1.0 to about 5 3.0 g I~kg body weight for regular X-ray vi~ 7p~t;Qn of the GI tract. For CT ~-~nni~ the contrast agents of the present invention will be in the range of from about 1 to about 800 mg I/l~g body weight, ~LefeL~.bly in the range of from about 15 to about 250 mg I/l~g body weight, and most ~,~fe.ably in the range of from about 35 to about 90 mg I/kg body weight.
The cQn~Pntration of the ioflin5~te~l polymeric beadR should be in the range of from about 5~o w/w to about 95% w/w of the form~ t;on, ~lefe~ably from about 10% w/w to about 60% w/w and most p.~fe.ably of from about 15% w/w to about 40% w/w.
The conc~ntration of the film fo.~l,g polymeric material depends on the particular polymer used, ho~t vel, it should be in the range of 0~01 to about 25% w/w or higher in comhin~t;on with a divalent subst~nce, such as calcium lactate, having a concentration range of 2 0 0.001 to 20% w/w of the rQt;QniC elempnt Dosage level of the polymeric material may be in the range of from about 2 to about 20 g/~g body weight or higher.
The compo~itions of the present invention possess very good 2~ adherence to the walls of the gastrointestinal tract by forming an es~en~ ly ~ ifollll coating thereon.
The invent;Qn, having been fully described, it will be a~ t to one skilled in the art that changes and modifications can be made 3 0 thereto without de~&~ lg from the spirit and scope thereo
Claims (68)
1. An x-ray contrast composition for oral or retrograde examination of the gastrointestinal tract of a patient comprising:
a polymeric material capable of forming a costing on the gastrointestinal tract, said polymeric material being selected from the group consisting of anionic polymers carrying negative charges in the ionized form, cationic polymers carrying positive charges in the ionized form, and neutral polymers having atoms containing polarizable electrons thereon, selected from the group consisting of oxygen, nitrogen, sulfur, fluoride, dichloride, bromide and iodide, in combination with a divalent cation; and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000µ wherein said iodinated polymeric beads comprise a polymer containing repeating units of the formula (I) I
wherein A is a repeating organic unit in the backbone chain of the polymer;
and X is an organic moiety containing or iodinated aromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based or the molecular weight of X, in a pharmaceutically acceptable carrier.
a polymeric material capable of forming a costing on the gastrointestinal tract, said polymeric material being selected from the group consisting of anionic polymers carrying negative charges in the ionized form, cationic polymers carrying positive charges in the ionized form, and neutral polymers having atoms containing polarizable electrons thereon, selected from the group consisting of oxygen, nitrogen, sulfur, fluoride, dichloride, bromide and iodide, in combination with a divalent cation; and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000µ wherein said iodinated polymeric beads comprise a polymer containing repeating units of the formula (I) I
wherein A is a repeating organic unit in the backbone chain of the polymer;
and X is an organic moiety containing or iodinated aromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based or the molecular weight of X, in a pharmaceutically acceptable carrier.
2. The X-ray contrast composition of claim I wherein X represents an organic moiety containing an iodinated aromatic group, said moiety being of the formula wherein L represents a linking group selected from the class consisting of ester groups, ether groups, amide groups, thioester groups, carbonate groups, carbamate groups, and sulfide groups; and each of R1 to R6, which may be the same or different, represents hydrogen, an iodine-containing substituent, or a hydrophilic group-containing substituent, with the provisos that (i) the iodine content of X is within the range of from 40 to 80 wt%; and (ii) said hydrophilic group is a member selected from the class consisting of carboxyl groups, sulfo groups, amino groups, salts of the aforementioned carboxyl, sulfo and amino groups, and polyol groups.
3. The x-ray contrast composition of claim 1 wherein said divalent cation is selected from the group consisting of Ca++, Mg++, Zn++, Ba++ and a mixture thereof.
4. The x-ray contrast composition of claim 1 wherein said pharmaceutically acceptable carrier is a liquid.
5. The x-ray contrast composition of claim 1 wherein said pharmaceutically acceptable carrier is a solid.
6. The x-ray contrast composition of claim 1 wherein said anionic polymer is of the formula:
, , wherein R is the polymeric chain;
and are anionic ligands; and M++ is a divalent cation.
, , wherein R is the polymeric chain;
and are anionic ligands; and M++ is a divalent cation.
7. The x-ray contrast composition of claim 6 wherein said anionic polymeric material is a sulfated polysaccharide having the formula:
wherein R is 3,6-anhydro-D-galactose linked through C-4 to D-galactose; (kappa carrageenan) .alpha.-D-galactose units (1-3) linked; (lambda carrageenan) D-galactose 3,6-anhydro-D-galactose; (iota carrageenan) D-galactose 3,6-anhydro-L-galactose: (Agar- Agar) D-galactose 3,6-anhydro-D-galactose; (Furcellaren) D-glucopyranose; (Laminarin sulfate) Galactan; and (Galactan sulfate) Galactosamino-glucuronans (Chondroitin sulfates);
and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
wherein R is 3,6-anhydro-D-galactose linked through C-4 to D-galactose; (kappa carrageenan) .alpha.-D-galactose units (1-3) linked; (lambda carrageenan) D-galactose 3,6-anhydro-D-galactose; (iota carrageenan) D-galactose 3,6-anhydro-L-galactose: (Agar- Agar) D-galactose 3,6-anhydro-D-galactose; (Furcellaren) D-glucopyranose; (Laminarin sulfate) Galactan; and (Galactan sulfate) Galactosamino-glucuronans (Chondroitin sulfates);
and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
8. The x-ray contrast composition of claim 6 wherein said anionic polymeric material is a carboxylated polysaccharide having the formula:
wherein R is D-galacturonoglycan; and (Pectin) anhydro-D-mannuronic acid and anhydro-L-guluronic acid (Algin) residues; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
wherein R is D-galacturonoglycan; and (Pectin) anhydro-D-mannuronic acid and anhydro-L-guluronic acid (Algin) residues; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
9. The x-ray contrast composition of claim 6 wherein said anionic polymeric material is a cellulose derivative of the formula:
, and wherein R is an anhydroglucose residue;
R' is CH3, C2H5 or C3H7;
R" is CH3 or C2H5; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
, and wherein R is an anhydroglucose residue;
R' is CH3, C2H5 or C3H7;
R" is CH3 or C2H5; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
10. The x-ray contrast composition of claim 9 wherein said cellulose derivative is selected from the group consisting of sodium ethylcellulose sulfate, sodium cellulose acetate sulfate and sodium carboxymethylcellulose.
11. The x-ray contrast composition of claim 6 wherein said anionic polymeric material is a sulfated, sulfonated or carboxylated synthetic polymer having the formula:
wherein R i8 an P~ tic or a,~ rl :c Lydloc~bo~; and M+~ iB Mgl'+, Ca++, Zn+ I, Ba++ or a ~u.~ thereof.
wherein R i8 an P~ tic or a,~ rl :c Lydloc~bo~; and M+~ iB Mgl'+, Ca++, Zn+ I, Ba++ or a ~u.~ thereof.
12. The s-ray contrast co~ ,o~;t:~n of claim 1 wherein ~aid cationic polymeric material iB selected from the group consisting of:
derm~t~n sulfate, kerstosulfate, byaluronic acid, heparin and chitin.
derm~t~n sulfate, kerstosulfate, byaluronic acid, heparin and chitin.
13. The s-ray contrast co~oD;ti.~n of claim 1 wherein said neutral polymeric material is a polys~crh~ e.
14. The s-ray contrast composition of claim 13 wherein said polys~crh~ride is selected from the group cQn~iFt;n~ of starch, glycogen, glucan, fructans, m~nn~ns~ galactom~nn~ns~
fl~ m~nn~ plprtonR~ ylans, ~y~.,r-~n~, de~tran and starch amylose.
fl~ m~nn~ plprtonR~ ylans, ~y~.,r-~n~, de~tran and starch amylose.
16. The s-ray contrast composition of claim 1 wherein said neutral polymeric material iB a cellulose de~;val~ive.
16. The s-ray contrast composition of claim 15 wherein said cellulose del;vative is sPlectetl from the group consisting of methylcellulose, hydroxyethyl cellulose, ethylhy~lro~yethyl and hyd, o~y~, ol.yl cellulose.
17. The s-ray contrast compo~ition of claim 1 wherein said neutral polymeric material i~ polyvinylpyrroli~lo~e, polyvinyl ~ hol or an ethylene oxide polymer.
18. The s-ray contrast composition of claim 1 in an aqueous dispersion.
19. The x-ray contrast composition of claim 1 in the form of a colloid.
20. The x-ray contrast composition of claim 1 wherein said pharmaceutical carrier contains at least one surfactant.
21. The x-ray contrast composition of claim 20 wherein said surfactant is cationic.
22. The x-ray contrast composition of claim 20 wherein said surfactant is anionic.
23. The x-ray contrast composition of claim 20 wherein said surfactant is zwitterionic.
24. The x-ray contrast composition of claim 20 wherein said surfactant is nonionic.
25. The x-ray contrast composition of claim 21 wherein said cationic surfactant is selected from the group consisting of cetyltrimethyl ammonium bromide and dodecyl dimethyl ammonium bromide.
26. The x-ray contrast composition of claim 22 wherein said anionic surfactant is selected form the group consisting of sodium lauryl sulfate, sodium heptadecyl sulphate, an alkyl benzene sulphonic acid, sodium butylnaphthalene sulfonate and sulphosuccinate.
27. The x-ray contrast composition of claim 24 wherein said nonionic surfactant is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols, sorbitan esters, polyoxyethylene alkyl ethers and polyoxyethylene sorbitan fatty acid esters.
28. The x-ray contrast composition of claim 1 further comprising a suspending agent.
29. The x-ray contrast composition of claim 1 further comprising a stabilizer.
30. The x-ray contrast composition of claim 1 further comprising an antioxidant.
31. The x-ray contrast composition of claim 1 further comprising an osmolality adjusting agent.
32. The x-ray contrast composition of claim 1 further comprising a buffering agent.
33. The x-ray contrast composition of claim 1 further comprising a pH
adjusting agent.
adjusting agent.
34. The x-ray contrast composition of claim 1 further comprising a flavoring agent.
35. The x-ray contrast composition of claim 20 wherein said surfactant is present from about 0.01% w/v to about 20% w/v in said aqueous formulation.
36. A method of carrying out x-ray examination of the gastrointestinal tract of a patient, said method comprises the oral or rectal administration to the patient an X-ray contrast formulation comprising:
a polymeric material capable of forming a coating on the gastrointestinal tract, said polymeric material being selected from the group consisting of anionic polymers carrying negative charges in the ionized form, cationic polymers carrying positive charges in the ionized form, and neutral polymers having atoms containing polarizable electrons thereon, selected from the group consisting of oxygen, nitrogen, sulfur, fluoride, dichloride, bromide and iodide, in combination with a divalent cation; and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000m wherein said iodinated polymeric beads comprise a polymer containing repearting units of the formula (I) wherein A is a repeating organic unit in the backbone chain of the polymer; and X is an organic moiety containing or iodinated eromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based or the molecular weight of X, in a pharmaceutically acceptable carrier.
a polymeric material capable of forming a coating on the gastrointestinal tract, said polymeric material being selected from the group consisting of anionic polymers carrying negative charges in the ionized form, cationic polymers carrying positive charges in the ionized form, and neutral polymers having atoms containing polarizable electrons thereon, selected from the group consisting of oxygen, nitrogen, sulfur, fluoride, dichloride, bromide and iodide, in combination with a divalent cation; and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000m wherein said iodinated polymeric beads comprise a polymer containing repearting units of the formula (I) wherein A is a repeating organic unit in the backbone chain of the polymer; and X is an organic moiety containing or iodinated eromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based or the molecular weight of X, in a pharmaceutically acceptable carrier.
37. The method of claim 36 wherein said divalent cation is selected from the group consisting of Ca++, Mg++, Zn++, Ba++ and a mixture thereof.
38. The method of claim 36 wherein said pharmaceutically acceptable carrier is a liquid.
39. The method of claim 36 wherein said pharmaceutically acceptable carrier is a solid.
40. The method of claim 36 wherein said x-ray contrast agent has particles of an effective particle size of from about 0.05 microns to about 100 microns.
41. The method of claim 36 wherein said x-ray contrast composition is in the form of a colloid.
42. The method of claim 36 wherein said pharmaceutically acceptable carrier contains at least one surfactant.
43. The method of claim 42 wherein said surfactant is cationic.
44. The method of claim 42 wherein said surfactant is anionic.
45. The method of claim 42 wherein said surfactant is zwitterionic.
46. The method of claim 42 wherein said surfactant nonionic.
47. The method of claim 43 wherein said cationic surfactant is selected from the group consisting of cetyltrimethylammonium bromide and dodecyl-dimethylammonium bromide.
48. The method of claim 44 wherein said anionic surfactant is selected from the group consisting of sodium lauryl sulfate; sodium heptadecyl sulphate, an alkyl benzene sulphonic acid, sodium butylnaphthalene sulfonate and sulphosuccinates.
49. The method of claim 46 wherein said nonionic surface active agent is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols, sorbitan esters, polyoxyethylene alkyl ethers and polyoxyethylene sorbitan fatty acid esters.
50. The method of claim 36 wherein said anionic polymer is of the formula , , wherein R is the polymeric chain;
and are anionic ligands; and M++ is a divalent cation.
and are anionic ligands; and M++ is a divalent cation.
51. The method of claim 36 wherein said anionic polymer is sulfated polysaccharide having the formula wherein R is 3,6-anhydro-D-galactose linked through C-4 to D-galactose; (kappa carrageenan) .alpha.-D-galactose units (1-3) linked; (lambda carrageenan) D-galactose 3,6-anhydro-D-galactose; (iota carrageenan) D-galactose 3,6-anhydro-L-galactose: (Agar - Agar) D-galactose 3,6-anhydro-D-galactose; (Furcellaren) D-glucopyranose; (Laminarin sulfate) Galactan; and (Galactan sulfate) Galactosamino-glucuronans (Chondroitin sulfates);
and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
52. The method of claim 36 wherein said anionic polymer is a carboxylated polysaccharide having the formula wherein R is D-galacturonoglycan; and (Pectin) anhydro-D-mannuronic acid and anhydro-L-guluronic acid (Algin) residues; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
53. The method of claim 36 wherein said anionic polymeric material is a cellulose derivative of the formula:
, and wherein R is an anhydroglucose residue;
R' is CH3, C2H5 or C3H7;
R" is CH3 or C2H5; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
, and wherein R is an anhydroglucose residue;
R' is CH3, C2H5 or C3H7;
R" is CH3 or C2H5; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
54. The method of claim 53 wherein said cellulose derivative is selected from the group consisting of sodium ethylcellulose sulfate, sodium cellulose acetate sulfate and sodium carboxymethylcellulose.
55. The method of claim 53 wherein said anionic polymeric material is a sulfated, sulfonated or carboxylated synthetic polymer having the formula:
, , wherein R is an aliphatic or aromatic hydrocarbon; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
, , wherein R is an aliphatic or aromatic hydrocarbon; and M++ is Mg++, Ca++, Zn++, Ba++ or a mixture thereof.
56. The method of claim 36 wherein said cationic polymer is selected from the group consisting of: dermatan sulfate, keratosulfate, hyaluronic acid, heparin and chitin.
57. The method of claim 36 wherein said neutral polymeric material is a polysaccharide.
68. The method of claim 57 wherein said polysaccharide is selected from the group consisting of starch, glycogen, glucan, fructans, mannans, galactomannans, flucomannas, galactans, xylans, glycuranans, dextran and starch amylose.
59. The method of claim 36 wherein said neutral polymeric material is a cellulose derivative.
60. The method of claim 59 wherein said cellulose derivative is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl and hydroxypropyl cellulose.
61. The method of claim 36 wherein said neutral polymeric material is polyvinylpyrrolidone, polyvinyl alcohol or an ethylene oxide polymer.
62. The method of claim 36 wherein said x-ray contrast composition further comprises a suspending agent.
63. The method of claim 36 wherein said x-ray contrast composition further comprises a stabilizer.
64. The method of claim 36 wherein said x-ray contrast composition further comprises an antioxidant.
65. The method of claim 36 wherein said x-ray contrast composition further comprises an osmolality adjusting agent.
66. The method of claim 36 wherein said x-ray contrast composition further comprises a buffering agent.
67. The method of claim 36 wherein said x-ray contrast composition further comprises a pH adjusting agent.
68. The method of claim 36 wherein said x-ray contrast composition further comprises a flavoring agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/054,119 US5342605A (en) | 1992-05-01 | 1993-04-26 | Polymeric X-ray compositions containing iodinated polymeric beads |
| US08/054,119 | 1993-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2161434A1 true CA2161434A1 (en) | 1994-11-10 |
Family
ID=21988918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002161434A Abandoned CA2161434A1 (en) | 1993-04-26 | 1994-04-12 | Polymeric x-ray contrast compositions containing iodinated polymeric beads |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5342605A (en) |
| EP (1) | EP0695195A1 (en) |
| JP (1) | JPH08509721A (en) |
| AU (1) | AU6630394A (en) |
| CA (1) | CA2161434A1 (en) |
| WO (1) | WO1994025075A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5443814A (en) * | 1992-05-01 | 1995-08-22 | Sterling Winthrop, Inc. | X-ray contrast compositions containing iodophenoxyalkanes and cellulose derivatives |
| US5316755A (en) * | 1993-02-02 | 1994-05-31 | Sterling Winthrop Inc. | Compositions of iodophenoxy alkanes and iodophenyl ethers for visualization of the gastrointestinal tract |
| US20020055710A1 (en) * | 1998-04-30 | 2002-05-09 | Ronald J. Tuch | Medical device for delivering a therapeutic agent and method of preparation |
| WO1995022995A1 (en) * | 1994-02-25 | 1995-08-31 | Nycomed Imaging A/S | X-ray contrast compositions containing cellulose derivatives |
| US5525327A (en) * | 1994-04-14 | 1996-06-11 | Sterling Winthrop Inc. | Polymeric x-ray contrast compositions containing iodinated polymeric beads and microcrystaline cellulose |
| US5628981A (en) * | 1994-12-30 | 1997-05-13 | Nano Systems L.L.C. | Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents |
| ES2112765B1 (en) * | 1995-08-02 | 1999-03-01 | Cantabria Ind Farmaceutica Sa | PROCEDURE FOR OBTAINING RADIOLOGICAL CONTRAST FORMULATIONS, FOR GASTROINTESTINAL EXPLORATIONS FOR EXTEMPORARY AND DIRECT USE. |
| US6106454A (en) * | 1997-06-17 | 2000-08-22 | Medtronic, Inc. | Medical device for delivering localized radiation |
| US6203536B1 (en) | 1997-06-17 | 2001-03-20 | Medtronic, Inc. | Medical device for delivering a therapeutic substance and method therefor |
| US6013099A (en) * | 1998-04-29 | 2000-01-11 | Medtronic, Inc. | Medical device for delivering a water-insoluble therapeutic salt or substance |
| US6426145B1 (en) | 1999-05-20 | 2002-07-30 | Scimed Life Systems, Inc. | Radiopaque compositions for visualization of medical devices |
| US6599448B1 (en) * | 2000-05-10 | 2003-07-29 | Hydromer, Inc. | Radio-opaque polymeric compositions |
| WO2009097277A1 (en) * | 2008-02-01 | 2009-08-06 | Trustees Of Boston University | Cationic contrast agents and methods of use thereof |
| US8808357B2 (en) * | 2010-04-06 | 2014-08-19 | Poly-Med, Inc. | Radiopaque iodinated and iodide-containing crystalline absorbable aliphatic polymeric materials and applications thereof |
| KR101334780B1 (en) * | 2010-08-13 | 2013-12-02 | 한국생명공학연구원 | Iodine-containing radial-shape macromolecular compounds, preparation method thereof and contrast medium compositions for CT comprising the same |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2832722A (en) * | 1953-07-15 | 1958-04-29 | Ortho Pharma Corp | Radiopaque formulation comprising pvp as bodying agent |
| DK106457C (en) * | 1962-01-23 | 1967-02-06 | Ernst Helmer Hagstam | X-ray contrast agent with low density and method of its preparation. |
| CA985626A (en) * | 1970-03-10 | 1976-03-16 | E.R. Squibb And Sons | Coating composition for moist surface |
| SE403255B (en) * | 1972-09-19 | 1978-08-07 | Pharmacia Ab | X-RAY CONTRAST AGENT IN WHICH AN X-RAY CONTRASTING SUBSTANCE CONSISTS OF A POLYMER WHICH DOES NOT INCLUDE IODO-SUBSTITUTED AROMATIC GROUPS |
| US4069306A (en) * | 1974-03-14 | 1978-01-17 | Pharmacia Aktiebolag | X-ray contrast preparation containing a hydrophilic polymer containing amino groups |
| JPS5296720A (en) * | 1976-02-06 | 1977-08-13 | Otsuka Pharma Co Ltd | Balium sulphate contrast medium |
| FR2352544A1 (en) * | 1976-05-26 | 1977-12-23 | Roussel Uclaf | NEW MEDICINAL PRODUCT FOR BARYTEE OPACIFICATION AND METHOD FOR PREPARING THIS NEW MEDICINAL PRODUCT |
| US4406878A (en) * | 1978-08-02 | 1983-09-27 | Eastman Kodak Company | Iodinated contrast agent for radiography |
| US4623539A (en) * | 1983-02-04 | 1986-11-18 | Tunc Deger C | Nutrient barrier polysaccharide compositions and method of use |
| US5186922A (en) * | 1985-03-15 | 1993-02-16 | See/Shell Biotechnology, Inc. | Use of biodegradable microspheres labeled with imaging energy constrast materials |
| JPS61272201A (en) * | 1985-05-28 | 1986-12-02 | Tetsuo Suami | 6-iodoehylated starch and production thereof |
| US5141739A (en) * | 1986-07-03 | 1992-08-25 | Advanced Magnetics, Inc. | Delivery of x-ray contrast agents using receptor mediated endocytosis |
| US5019370A (en) * | 1989-07-10 | 1991-05-28 | University Of Kentucky Research Foundation | Biodegradable, low biological toxicity radiographic contrast medium and method of x-ray imaging |
| US5318768A (en) * | 1992-05-01 | 1994-06-07 | Sterling Winthrop Inc. | Polymeric x-ray contrast compositions containing an organic crystalline x-ray contrast agent |
| CA2094893A1 (en) * | 1992-05-01 | 1993-11-02 | Carl R. Illig | X-ray contrast compositions containing film-forming materials |
-
1993
- 1993-04-26 US US08/054,119 patent/US5342605A/en not_active Expired - Fee Related
-
1994
- 1994-04-12 JP JP6524298A patent/JPH08509721A/en active Pending
- 1994-04-12 EP EP94914103A patent/EP0695195A1/en not_active Withdrawn
- 1994-04-12 AU AU66303/94A patent/AU6630394A/en not_active Abandoned
- 1994-04-12 WO PCT/US1994/003919 patent/WO1994025075A1/en not_active Application Discontinuation
- 1994-04-12 CA CA002161434A patent/CA2161434A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU6630394A (en) | 1994-11-21 |
| JPH08509721A (en) | 1996-10-15 |
| EP0695195A1 (en) | 1996-02-07 |
| WO1994025075A1 (en) | 1994-11-10 |
| US5342605A (en) | 1994-08-30 |
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