U.S. patent application number 11/933780 was filed with the patent office on 2008-05-08 for radio-opaque polymeric biomaterials.
Invention is credited to Durgadas Bolikal, Joachim B. Kohn, Sanyog M. Pendharkar.
Application Number | 20080107709 11/933780 |
Document ID | / |
Family ID | 22059024 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080107709 |
Kind Code |
A1 |
Kohn; Joachim B. ; et
al. |
May 8, 2008 |
RADIO-OPAQUE POLYMERIC BIOMATERIALS
Abstract
Iodinated and/or brominated derivatives of aromatic dihydroxy
monomers are prepared and polymerized to form radio-opaque
polymers. The monomers may also be copolymerized with other
dihydroxy monomers. The iodinated and brominated aromatic dihydroxy
monomers can be employed as radio-opacifying, biocompatible
non-toxic additives for other polymeric biomaterials. Radio-opaque
medical implants and drug delivery devices for implantation
prepared from the polymers of the present invention are also
disclosed.
Inventors: |
Kohn; Joachim B.; (Highland
Park, NJ) ; Bolikal; Durgadas; (Edison, NJ) ;
Pendharkar; Sanyog M.; (Old Bridge, NJ) |
Correspondence
Address: |
FOX ROTHSCHILD LLP;PRINCETON PIKE CORPORATE CENTER
997 LENOX DRIVE, BUILDING #3
LAWRENCEVILLE
NJ
08648
US
|
Family ID: |
22059024 |
Appl. No.: |
11/933780 |
Filed: |
November 1, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11418943 |
May 5, 2006 |
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11933780 |
Nov 1, 2007 |
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10691750 |
Oct 23, 2003 |
7056493 |
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11418943 |
May 5, 2006 |
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10288076 |
Nov 5, 2002 |
6852308 |
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10691750 |
Oct 23, 2003 |
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09554027 |
Jul 3, 2000 |
6475477 |
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PCT/US98/23777 |
Nov 6, 1998 |
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10288076 |
Nov 5, 2002 |
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60064905 |
Nov 7, 1997 |
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Current U.S.
Class: |
424/423 ;
514/772.4; 523/113 |
Current CPC
Class: |
C08G 69/44 20130101;
C08G 65/3317 20130101; C08K 5/20 20130101; A61K 49/0447 20130101;
A61K 49/0438 20130101; C08G 63/6826 20130101; C08G 64/1633
20130101; A61L 31/16 20130101; C08G 64/10 20130101; C08G 64/1641
20130101; C08G 63/6856 20130101; A61L 31/10 20130101; A61L 2300/00
20130101; C08G 63/672 20130101; C08G 64/12 20130101; A61K 38/00
20130101; A61K 9/204 20130101; C08G 64/183 20130101; A61K 49/0442
20130101; C08K 5/13 20130101; A61L 31/18 20130101 |
Class at
Publication: |
424/423 ;
514/772.4; 523/113 |
International
Class: |
A61K 47/30 20060101
A61K047/30; A61F 2/82 20060101 A61F002/82 |
Goverment Interests
GOVERNMENT LICENSE RIGHTS
[0002] The U.S. Government has a paid-up license in this invention
and the right in limited circumstances to require the patent owner
to license others on reasonable terms as required by the terms of
Grant Nos. GM-39455 and GM-49849 awarded by the National Institutes
of Health.
Claims
1. A radio-opaque polymer comprising monomeric repeating units with
one or more iodine or bromine substituted aromatic rings.
2. The radio-opaque polymer of claim 1, comprising aromatic rings
with more than one iodine or bromine ring-substituent.
3. The radio-opaque polymer of claim 1, comprising a poly(alkylene
oxide) block copolymer.
4. A tissue-implantable or blood-contacting radio-opaque medical
device comprising the radio-opaque polymer of claim 1.
5. The radio-opaque medical device of claim 4, wherein said device
is formed from or coated with said radio-opaque polymer.
6. An angioplastic stent coated with or formed from the
radio-opaque polymer of claim 1.
7. A drug delivery device comprising a biologically or
pharmaceutically active compound in combination with a polymer of
claim 1, wherein said active compound is present in an amount
effective for therapeutic site-specific or systemic drug
delivery.
8. The drug delivery device of claim 7, wherein said active
compound is covalently bonded to said polymer.
9. The drug delivery device of claim 7, wherein said active
compound is physically admixed with said polymer or physically
embedded or dispersed in a matrix formed by said polymer.
10. A method of producing a radio-opaque polymer comprising
polymerizing a monomer comprising an iodide- or bromide-substituted
aromatic ring, in the presence or absence of other polymerizable
compounds.
11. A biocompatible angioplastic stent formed from or coated with a
biocompatible polymer, said polymer comprising a drug for delivery
by said stent, wherein said drug is physically admixed with said
polymer or said drug is a pendant group covalently bonded to said
polymer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/418,943, which was filed on May 5, 2006,
which application, in turn, is a continuation of U.S. patent
application Ser. No. 10/691,750 filed on Oct. 23, 2003, which
application, in turn, is a continuation of U.S. patent application
Ser. No. 10/288,076, which was filed on Nov. 5, 2002 with the
United States Patent and Trademark Office, which application, in
turn, is a Divisional of U.S. patent application Ser. No.
09/554,027 filed on Jul. 3, 2000 which issued as U.S. Pat. No.
6,475,477 on Nov. 5, 2002, and which claims priority benefit under
35 U.S.C. .sctn. 371 of PCT/US98/23777 filed Nov. 6, 1998, which,
in turn, claims priority benefit of U.S. Provisional Patent
Application No. 60/064,905, filed on Nov. 7, 1997. The disclosures
of the aforementioned applications are incorporated herein by
reference.
TECHNICAL FIELD
[0003] The present invention relates to radio-opaque biodegradable
polycarbonates and polyarylates and the block copolymers thereof
with poly(alkylene oxides). In particular, the present invention
relates to polycarbonates and polyarylates and the poly(alkylene
oxide) block copolymers thereof that are radio-opaque as a
consequence of being homopolymers and copolymers of dihydroxy
monomers having iodinated or brominated aromatic rings as part of
their structure.
BACKGROUND OF THE INVENTION
[0004] Diphenols are monomeric starting materials for
polycarbonates, polyiminocarbonates, polyarylates, polyurethanes,
and the like. Commonly owned U.S. Pat. Nos. 5,099,060 and 5,198,507
disclose amino acid-derived diphenol compounds, useful in the
polymerization of polycarbonates and polyiminocarbonates. The
resulting polymers are useful as degradable polymers in general and
as tissue-compatible bioerodible materials for medical uses, in
particular. The suitability of these polymers for their end use
application is the result of their polymerization from diphenols
derived from the naturally occurring amino acid, L-tyrosine. The
disclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are hereby
incorporated by reference. These previously-known polymers are
strong, water-insoluble materials that can best be used as
structural implants.
[0005] The same monomeric L-tyrosine derived diphenols are also
used in the synthesis of polyarylates as described in commonly
owned U.S. Pat. No. 5,216,115 and in the synthesis of poly(alkylene
oxide) block copolymers with the aforementioned polycarbonates and
polyarylates, which is disclosed in commonly owned U.S. Pat. No.
5,658,995. The disclosures of U.S. Pat. Nos. 5,216,115 and
5,658,995 are also hereby incorporated by reference.
[0006] Commonly owned International Application No. WO 98/36013
discloses dihydroxy monomers prepared from .alpha.-, .beta.- and
hydroxy acids and derivatives of L-tyrosine that are also useful
starting materials in the polymerization of polycarbonates,
polyiminocarbonates, polyarylates, and the like. The preparation of
polycarbonates, polyarylates and polyiminocarbonates from these
monomers is also disclosed. The disclosure of International
Application No. WO 98/36013 is also hereby incorporated by
reference.
[0007] Synthetic, degradable polymers are currently being evaluated
as medical implants in a wide range of applications, such as
orthopedic bone fixation devices, drug delivery systems,
cardiovascular implants, and scaffolds for the
regeneration/engineering of tissue. Such polymers, when used as
implants, are non-traceable without invasive procedures. A
radio-opaque polymer would offer the unique advantage of being
traceable via routine X-ray imaging. The fate of such an implant
through various stages of its utility could be followed without
requiring invasive surgery.
[0008] Davy et al., J. Dentist., 10(3), 254-64 (1982), disclose
brominated derivatives of poly(methyl methacrylate) that are
radio-opaque. Copolymerization with non-brominated analogs was
required to obtain the thermomechanical properties required for its
desired use as a denture base. Only in a small range of certain
percentage concentrations of the bromo-derivative does the material
exhibit acceptable thermomechanical properties. In addition, there
is no disclosure that the materials exhibiting acceptable
properties remain biocompatible following the addition of bromine
to the polymer structure. In contrast to the polymers disclosed in
this application, the brominated poly(methyl methacrylates) do not
degrade. However, because the bromine atoms are located on the
aliphatic ester side chain, upon side chain ester cleavage, the
polymer loses its radio-opacity.
[0009] Horak et al., Biomater, 8, 142-5 (1987), disclose the
triiodobenzoic acid ester of poly(2-hydroxyethyl methacrylate) to
be useful as a radio-opaque X-ray imaging marker compound. The
iodine content was reported to affect the contrast, volume,
mechanical properties and hydrophobicity of the polymer. A proper
balance of properties, including radio-contrast and swellability,
was achieved through optimization of the iodine content. Again,
this material does not degrade through the main chain and loses
radio-opacity upon side chain ester cleavage because the iodine
atoms are located on the ester side chain.
[0010] Cabasso et al., J. Appl. Polym. Sci., 38, 1653-66 (1989),
disclose the preparation of a radio-opaque miscible polymer
coordination complex of poly(methyl methacrylate) and a uranium
salt, uranyl nitrate. The polymer does not degrade through the main
chain and the biocompatibility of the uranyl nitrate complex is not
reported, nor has the long-term stability of the complex in vivo
been established.
[0011] Cabasso et al., J. Appl. Polym. Sci., 41, 3025-42 (1990),
discloses the preparation of radio-opaque coordination complexes of
bismuth bromide and uranyl hexahydrate with polymers prepared from
acrylated phosphoryl esters containing 1,3-dioxalane moieties
derived from polyols such as glycerol, D-mannitol, D-sorbitol,
pentaerythritol and dipentaerythritol. The phosphoryl group was
selected to provide stronger coordinating sites for the bismuth and
uranium salts and to impart adhesive properties toward hard
tissues. Preliminary biocompatibility data indicated satisfactory
performance, but the polymer does not degrade through the main
chain and the long-term stability of the complex in vivo is not
reported.
[0012] Jayakrishnan et al., J. Appl. Polym. Sci., 44, 743-8 (1992),
discloses radio-opaque polymers of triiodophenyl methacrylate and
of the iothalamic ester of 2-hydroxyethyl methacrylate. Polymers of
useful molecular weight were not obtained, attributable to the
presence of bulky iodine atoms in the monomer side chain. It was
possible to obtain copolymers with non-iodinated analogs in the
presence of crosslinking agents, such that up to 25% of the
iodinated monomer could be incorporated. Preliminary
biocompatibility data indicated that the presence of triiodophenyl
methacrylate caused blood hemolysis. In addition, the materials
also do not degrade through the main chain, and in the event of
side chain ester cleavage, would lose their radio-opacity because
of the iodine atoms being located in the side chain.
[0013] Kraft et al., Biomater., 18, 31-36 (1997), discloses the
preparation of radio-opaque iodine-containing poly(methyl
methacrylates). The monomers were ortho- and para-iodo and
2,3,5-triiodobenzoic acid esters of 2-hydroxymethyl methacrylate,
and the para-iodophenol ester of methyl methacrylic acid. The
monomers were copolymerized with one or more non-iodinated analogs
and a small amount of crosslinkers to produce polymer hydrogels
with varying iodine contents. It was reported that the hydrogels
were well tolerated by subcutaneous tissues and that the presence
of iodine did not severely alter the swellability of the hydrogel.
No tissue necrosis, abscess formation or acute inflammation was
observed, although all implants were surrounded by a fibrous
capsule. However, these materials also do not degrade through the
main polymer chain, and upon side chain ester cleavage, lose
radio-opacity because of the iodine atoms being located in the
ester side chain.
[0014] Currently, no technology is available to provide
radio-opaque polymers that degrade through the main polymer chain,
such as the above-discussed tyrosine-derived polymers. For their
intended use as medical implants, radio-opaqueness is a valuable
property. A need exists for radio-opaque polymers that degrade
through the main polymer chains, such as the tyrosine-derived
polymers discussed above.
SUMMARY OF THE INVENTION
[0015] These needs are met by the present invention. It has now
been found that iodination or bromination of the aromatic rings of
dihydroxy monomers renders the resulting polymers radio-opaque.
Significantly, the resulting polymers exhibit good mechanical and
engineering properties while degrading into relatively non-toxic
products after implantation in vivo.
[0016] In general, the ability of a species to absorb X-rays is
related directly to atomic number and is approximated by the
relationship. m=kl.sup.3Z.sup.4+0.2 wherein m is the absorption
coefficient, l is the wavelength of the incident X-ray, Z is the
atomic number of the absorbing species and k is the proportionality
constant. Iodine and bromine atoms, because of their high mass,
scatter X-rays and impart radio-opaqueness. This is highly
significant and allows clinicians to visualize any implanted device
prepared from a radio-opaque polymer by simple X-ray imaging.
[0017] Thus, iodinated and/or brominated derivatives of dihydroxy
monomers may be prepared and polymerized to form radio-opaque
polycarbonates and polyarylates. These monomers may also be
copolymerized with poly(alkylene oxides) and other dihydroxy
monomers. In addition, the iodinated and brominated dihydroxy
monomers can be employed as radio-opacifying, biocompatible
non-toxic additives for other polymeric biomaterials.
[0018] Therefore, according to one aspect of the present invention,
a diphenolic radio-opacifying, biocompatible, non-toxic additive
for polymeric biomaterials is provided having the structure of
Formula I: ##STR1##
[0019] Formula I represents a diphenol compound substituted with at
least one bromine or iodine atom, wherein each X.sub.1 and X.sub.2
is independently an iodine or bromine atom, Y1 and Y2 are
independently between zero and two, inclusive, and R.sub.9 is an
alkyl, aryl or alkylaryl group with up to 18 carbon atoms.
Preferably, R.sub.9 contains as part of its structure a carboxylic
acid group or a carboxylic acid ester group, wherein the ester is
selected from straight and branched alkyl and alkylaryl groups
containing up to 18 carbon atoms in addition to the rest of the
R.sub.9 structure, and ester derivatives of biologically and
pharmaceutically active compounds covalently bonded to the
diphenol, which are also not included among the carbons of R.sub.9.
R.sub.9 can also contain non-carbon atoms such as iodine, bromine,
nitrogen and oxygen.
[0020] In particular, R.sub.9 can have a structure related to
derivatives of the natural amino acid tyrosine, cinnamic acid, or
3-(4-hydroxyphenyl) propionic acid. In these cases, R.sub.9 assumes
the specific structure shown in Formula II: ##STR2## R.sub.0 is
selected from (--CH.dbd.CH--), (--CHJ.sub.1-CHJ.sub.2-) and
(--CH.sub.2--).sub.d and R.sub.4 is selected from (--CH.dbd.CH--),
(--CHJ.sub.1-CHJ.sub.2-) and (--CH.sub.2--).sub.a, in which a and d
are independently 0 to 8, inclusive, and J.sub.1 and J.sub.2 are
independently Br or I. Z is H, a free carboxylic acid group, or an
ester or amide thereof. Z preferably is a pendent group having a
structure according to Formula IV: ##STR3## wherein L is selected
from hydrogen and straight and branched alkyl and alkylaryl groups
containing up to 18 carbon atoms and derivatives of biologically
and pharmaceutically active compounds covalently bonded to the
dihydroxy compound.
[0021] Z can also be a pendent group having a structure according
to Formula IVa: ##STR4## wherein M is selected from --OH,
--NH--NH.sub.2, --O--R.sub.10--NH.sub.2, --O--R.sub.10--OH,
--NH--R.sub.10--NH.sub.2, --NH--R.sub.10--OH, ##STR5## a C-terminus
protecting group and a derivative of a biologically or
pharmaceutically active compound covalently bonded to the pendent
functional group by means of amide bond, wherein in the
underivatized biologically of pharmaceutically active compound a
primary or secondary amine is present in the position of the amide
bond in the derivative.
[0022] Z can also be a pendent group having a structure represented
by Formula IVb: ##STR6## wherein M is a derivative of a
biologically or pharmaceutically active compound covalently bonded
to the pendent functional group by means of R.sub.3, wherein
R.sub.3 is a linkage selected from --NH--NH-- in the case when in
the underivatized biologically or pharmaceutically active compound
an aldehyde or ketone is present at the position links to the
pendent functional groups by means of R.sub.3; and --NH--NH--,
--NH--R.sub.10--NH--, --O--R.sub.10--NH--, --O--R.sub.10--O-- or
--NH--R.sub.10--O-- in the case when in the underivatized
biologically or pharmaceutically active compound a carboxylic acid
is present in the position linked to the pendent functional group
by means of R.sub.3; and ##STR7## in the case when in the
underivatized biologically or pharmaceutically active compound a
primary or secondary amine or primary hydroxyl is present in the
position linked to the pendent functional group by means of
R.sub.3.
[0023] R.sub.10 is selected from alkyl groups containing from 2 to
6 carbon atoms, aromatic groups, .alpha.-, .beta., ?- and ?-amino
acids and peptide sequences.
[0024] According to another aspect of the present invention, a
radio-opacifying, biocompatible, non-toxic dihydroxy additive for
polymeric biomaterials is provided having the structure of Formula
III: ##STR8## Formula III represents a dihydroxy compound
substituted with at least one bromine or iodine atom and having a
structure related to derivatives of tyrosine joined by way of an
amide linkage to an .alpha.-, .beta.- or ?-hydroxy acid or
derivative thereof. Each X.sub.2 is independently an iodine or
bromine atom; Y2 is 1 or 2; R.sub.5 and R.sub.6 are each
independently selected from H, bromine, iodine and straight and
branched alkyl groups having up to 18 carbon atoms; R.sub.0 is
(--CH.sub.2--).sub.d, --CH.dbd.CH-- or (--CHJ.sub.1-CHJ.sub.2-) and
R.sub.15 is (--CH.sub.2--).sub.m, --CH.dbd.CH-- or
(--CHJ.sub.1-CHJ.sub.2-), wherein J.sub.1 and J.sub.2 are
independently Br or I and d and m are independently between 0 and
8, inclusive. Z is the same as described above with respect to
Formula II.
[0025] According to another aspect of the present invention,
radio-opaque biocompatible polymers are provided having monomeric
repeating units defined in Formulae Ia and IIIa: ##STR9## ##STR10##
Formula Ia represents a diphenolic unit wherein X.sub.1, X.sub.2,
Y1, Y2 and R.sub.9 are the same as described above with respect to
Formula I. Formula IIIa represents an aromatic dihydroxy unit
wherein X.sub.2, Y2, R.sub.0, R.sub.5, R.sub.6, R.sub.15 and Z are
the same as described above with respect to Formula III.
[0026] Copolymers in accordance with the present invention have a
second dihydroxy unit defined in Formulae Ib or IIIb. ##STR11##
[0027] In the diphenolic subunit of Formula Ib, R.sub.12 is an
alkyl, aryl or alkylaryl group with up to 18 carbon atoms,
preferably substituted with a pendent free carboxylic acid group or
an ester or amide thereof, wherein the ester or amide is selected
from straight and branched alkyl and alkylaryl esters containing up
to 18 carbon atoms, in addition to the rest of the R.sub.12
structure, and derivatives of biologically and pharmaceutically
active compounds covalently bonded to the polymer, which are also
not included among the carbons of R.sub.12. R.sub.12 can also
contain non-carbon atoms such as nitrogen and oxygen. In
particular, R.sub.12 can have a structure related to derivatives of
the natural amino acid tyrosine, cinnamic acid, or
3'(4'-hydroxyphenyl) propionic acid.
[0028] For derivatives of tyrosine, 3'(4'-hydroxyphenyl) propionic
acid and cinnamic acid, R.sub.12 assumes the specific structure
shown in Formula II in which R.sub.o is --CH.dbd.CH-- or
(--CH.sub.2--).sub.d and R.sub.4 is --CH.dbd.CH-- or
(--CH.sub.2--).sub.a, in which a and d are independently 0 to 8,
inclusive. Z is the same as described above with respect to Formula
II.
[0029] In the dihydroxy subunit of Formula IIIb, R.sub.16 and
R.sub.17 are each independently selected from H or straight or
branched alkyl groups having up to 18 carbon atoms; R.sub.18 is
--CH.dbd.CH-- or (--CH.sub.2--).sub.d and R.sub.19 is --CH.dbd.CH--
or (--CH.sub.2--).sub.e, in which d and e are independently between
0 and 8, inclusive. Z is again the same as described above with
respect to Formula II.
[0030] Some polymers of this invention may also contain blocks of
poly(alkylene oxide) as defined in Formula VII. In Formula VII,
R.sub.7 is independently an alkylene group containing up to 4
carbon atoms and k is between about 5 and about 3,000.
--(O--R.sub.7).sub.k--O-- (VII)
[0031] A linking bond, designated as "A" is defined to be either
##STR12## wherein R.sub.8 is selected from saturated and
unsaturated, substituted and unsubstituted alkyl, aryl and
alkylaryl groups containing up to 18 carbon atoms. Thus, polymers
in accordance with the present invention have the structure of
Formulae VIII and VIIIa: ##STR13## In both formulae, f and g are
the molar ratios of the various subunits. The range of f and g can
be from 0 to 0.99. It is understood that the presentation of both
formulae is schematic and that the polymer structures represented
are true random copolymers where the different subunits can occur
in any random sequence throughout the polymer backbone. Formulae
VIII and VIIIa provide a general chemical description of
polycarbonates when A is ##STR14## Formulae VIII and VIIIa provide
a general description of polyarylates when A is ##STR15##
Furthermore, several limiting cases can be discerned: When g=0, the
polymer contains only iodine or bromine-substituted monomeric
repeating units. If g is any fraction greater than 0 but smaller
than 1, a copolymer is obtained that contains a defined ratio of
monomeric repeating units substituted with bromine or iodine and
monomeric repeating units that are bromine- and iodine-free.
[0032] If f=0, the polymer will not contain any poly(alkylene
oxide) blocks. The frequency at which poly(alkylene oxide) blocks
can be found within the polymer backbone increases as the value of
f increases.
[0033] The radio-opaque bromine- and iodine-substituted dihydroxy
compounds of the present invention meet the need for biocompatible
biodegradable additives that are miscible with radio-opaque
polymeric biomaterials and enhance the radio-opacity of the
polymeric materials. Therefore, the present invention also includes
the radio-opaque bromine- and iodine-substituted dihydroxy
compounds of the present invention, physically admixed, embedded in
or dispersed in a biocompatible biodegradable polymer matrix.
Preferably, the dihydroxy compound is an analogue of a monomeric
repeating unit of the matrix polymer.
[0034] The bromine- and iodine-containing polymers of the present
invention also meet the need for radio-opaque processible
biocompatible biodegradable polymers, the radio-opacity of which is
not affected by anything other than degradation of the main polymer
chain. Therefore, the present invention also includes implantable
medical devices containing the radio-opaque polymers of the present
invention. The radio-opaque polymers of the present invention thus
find application in areas where both structural solid materials and
water-soluble materials are commonly employed.
[0035] Polymers in accordance with the present invention may be
prepared having good film-forming properties. An important
phenomena observed for the polymers of the present invention having
poly(alkylene oxide) segments is the temperature dependent face
transition of the polymer gel or the polymer solution in aqueous
solvents. As the temperature increases, the gel of the polymers
undergo a face transition to a collapsed state, while polymer
solutions precipitate at a certain temperature or within certain
temperature ranges. The polymers of the present invention having
poly(alkylene oxide) segments, and especially those that undergo a
phase transition at about 30.degree. to 40.degree. C. on heating
can be used as biomaterials for drug release and clinical
implantation materials. Specific applications include films and
sheets for the prevention of adhesion and tissue
reconstruction.
[0036] Therefore, in another embodiment of the present invention,
radio-opaque poly(alkylene oxide) block copolymers of
polycarbonates and polyarylates may be formed into a sheet or a
coating for application to exposed injured tissues for use as
barrier for the prevention of surgical adhesions as described by
Urry et al., Mat. Res. Soc. Symp. Proc., 292, 253-64 (1993).
Placement of the radio-opaque polymer sheets of the present
invention may be followed by X-ray imaging without invasive
surgery. This is particularly useful with endoscopic surgery.
Therefore, another aspect of the present invention provides a
method for preventing the formation of adhesions between injured
tissues by inserting as a barrier between the injured tissues a
sheet or a coating of the radio-opaque poly(alkylene oxide) block
copolymers of polycarbonates and polyarylates of the present
invention.
[0037] The poly(alkylene oxide) segments decrease the surface
adhesion of the polymers of the present invention. As the value of
f in Formulae VIII and VIIIa increases, the surface adhesion
decreases. Polymer coating containing poly(alkylene oxide) segments
according to the present invention may thus be prepared that are
resistant to cell attachment and useful non-thrombogenic coatings
on surfaces in contact with blood. Such polymers also resist
bacterial adhesion in this, and in other medical applications as
well. The present invention therefore includes blood contacting
devices and medical implants having surfaces coated with the
polymers of Formulae VIII and VIIIa in which f is greater than 0.
The surfaces are preferably polymeric surfaces. Methods according
to the present invention include implanting in the body of the
patient a blood-contacting device or medical implant having a
surface coated with the above-described polymers of the present
invention containing poly(alkylene oxide) segments.
[0038] Blood contacting or implantable medical devices formed from
the polymers of the present invention are also included in the
scope of the present invention as well. Such polymers may or may
not have poly(alkylene oxide) segments.
[0039] The present invention also includes microspheres of the
radio-opaque polymers of the present invention, useful as X-ray
contrast agents or as drug delivery systems, the location of which
can be traced by X-ray imaging. For purposes of the present
invention, the term "X-ray imaging" is defined as including
essentially any imaging technique employing X-rays, including the
extensively practiced procedures of radiography, photography and
Computerized Axial Tomography Scans (CAT scans). Methods in
accordance with the present invention for the preparation of drug
delivery systems can also be employed in the preparation of
radio-opaque microspheres for drug delivery.
[0040] In another embodiment of the present invention, the polymers
are combined with a quantity of a biologically or pharmaceutically
active compound sufficient for effective site-specific or systemic
drug delivery as described by Gutowska et al., J. Biomater. Res.,
29, 811-21 (1995), and Hoffman, J. Controlled Release, 6, 297-305
(1987). The biologically or pharmaceutically active compound may be
physically admixed, embedded in or dispersed in the polymer matrix
as if it were not a radio-opaque polymer, eliminating the need for
radio-opaque filler materials, thereby increasing the drug loading
capacity of the matrix polymer.
[0041] Another aspect of the present invention provides a method
for site-specific or systemic drug delivery by implanting in the
body of a patient in need thereof an implantable drug delivery
device containing a therapeutically effective amount of a
biologically or pharmaceutically active compound in combination
with a radio-opaque polymer of the present invention. As noted
above, derivatives of biologically and pharmaceutically active
compounds can be attached to the polymer backbone by covalent
bonds, which provides for the sustained release of the biologically
or pharmaceutically active compound by means of hydrolysis of the
covalent bond with the polymer backbone.
[0042] By varying the value of f in the polymers of Formulae VIII
and VIIIa, the hydrophilic/hydrophobic ratios of the polymers of
the present invention can be attenuated to adjust the ability of
the polymer coatings to modify cellular behavior. Increasing levels
of poly(alkylene oxide) inhibits cellular attachment, migration and
proliferation, increasing the amount of pendent free carboxylic
acid group promotes cellular attachment, migration and
proliferation. Therefore, according to yet another aspect of the
present invention, a method is provided for regulating cellular
attachment, migration and proliferation by contacting living cells,
tissues, or biological fluids containing living cells with the
polymers of the present invention.
[0043] A more complete appreciation of the invention and many other
intended advantages can be readily obtained by reference to the
following detailed description of the preferred embodiment and
claims, which disclose the principles of the invention and the best
modes which are presently contemplated for carrying them out.
BRIEF DESCRIPTION OF THE FIGURES
[0044] FIG. 1 is an X-ray image of a radio-opaque polymer pin
according to the present invention implanted into a section of a
rabbit femur.
BEST MODES OF CARRYING OUT THE INVENTION
[0045] The present invention provides radio-opaque polycarbonates
and polyarylates, as well as poly(alkylene oxide) block copolymers
thereof, in which the radio-opacity is derived from bromine- and
iodine-substitution of some or all of the aromatic rings in the
polymer backbone. The bromine- and iodine-substituted polymers are
prepared by brominating or iodinating a pre-monomer compound prior
to synthesis of the dihydroxy monomer. The dihydroxy monomer is
subsequently polymerized by established procedures, alone, or in
combination with dihydroxy compounds that are not bromine- or
iodine-substituted.
[0046] In particular, the bromine- and iodine-substituted dihydroxy
compounds include diphenols having the structure of Formula I
wherein R.sub.9 is the same as described above with respect to
Formula I. The diphenols preferably have the structure of Formula
II. Among the preferred diphenols are compounds in which R.sub.9
has the structure of Formula II in which R.sub.4 is --CH.sub.2-- or
--CHJ.sub.1-CHJ.sub.2- and R.sub.0 is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--. Most preferably, R.sub.4 is
--CHJ.sub.1-CHJ.sub.2- and R.sub.0 is --CH.sub.2--. These most
preferred compounds are bromine- and iodine-substituted tyrosine
dipeptide analogues known as desaminotyrosyl-tyrosine, and the
alkyl and alkylaryl esters thereof. In this preferred group, the
diphenols can be regarded as derivatives of tyrosyl-tyrosine
dipeptides from which the N-terminal amino group has been
removed.
[0047] Diphenol compounds that are not bromine- or
iodine-substituted have the structure of Formula Ic: ##STR16##
wherein R.sub.12 is the same as described above with respect to
Formula Ib. R.sub.12 preferably has the structure shown in Formula
II in which R.sub.o is --CH.dbd.CH-- or (--CH.sub.2--).sub.d and
R.sub.4 is --CH.dbd.CH-- or (--CH.sub.2--).sub.a, in which a and d
are independently 0 to 8.
[0048] Methods for preparing the diphenol monomers in which R.sub.9
or R.sub.12 contain as part of their structures a carboxylic acid
ester group are disclosed in commonly owned U.S. Pat. Nos.
5,587,507 and 5,670,602, the disclosures of both of which are
hereby incorporated by reference. The preferred
desaminotyrosyl-tyrosine esters are the ethyl, butyl, hexyl, octyl
and benzyl esters. For purposes of the present invention,
desaminotyrosyl-tyrosine ethyl ester is referred to as DTE,
desaminotyrosyl-tyrosine benzyl ester is referred to as DTBn, and
the like. For purposes of the present invention, the non-ester
desaminotyrosyl-tyrosine free carboxylic acid is referred to as
DT.
[0049] It is not possible to polymerize the polycarbonates,
polyarylates the poly(alkylene oxide) block copolymers thereof,
having pendent free carboxylic acid groups from corresponding
diphenols with pendent free carboxylic acid groups without
cross-reaction of the free carboxylic acid group with the
co-monomer. Accordingly, polycarbonates, polyarylates and the
poly(alkylene oxide) block copolymers thereof that are homopolymers
or copolymers of benzylester diphenol monomers such as DTBn may be
converted to corresponding free carboxylic acid homopolymers and
copolymers through the selective removal of the benzyl groups by
the palladium catalyzed hydrogenolysis method disclosed by
co-pending and commonly owned U.S. patent application Ser. No.
09/056,050, filed on Apr. 7, 1998. The disclosure of this
application is incorporated herein by reference. The catalytic
hydrogenolysis is necessary because the ability of the polymer
backbone prevents the employment of harsher hydrolysis
techniques.
[0050] The bromine- and iodine-substituted dihydroxy compounds also
include the aliphatic-aromatic dihydroxy compounds having the
structure of Formula III in which R.sub.o, R.sub.5, R.sub.6,
R.sub.15, X.sub.2, Y2 and Z are the same as described above with
respect to Formula III. Among the preferred aliphatic-aromatic
dihydroxy compounds are compounds of Formula III in which R.sub.15
is (--CH.sub.2--).sub.m, wherein m is 0, Y2 is 1 and R.sub.5 and
R.sub.6 are preferably independently selected from hydrogen and
methyl. Z preferably has a structure according to Formula IV in
which L is hydrogen or an ethyl, butyl, hexyl, octyl or benzyl
group. L is more preferably hydrogen or an ethyl or benzyl group.
When R.sub.5 and R.sub.6 are hydrogen, and R.sub.15
(--CH.sub.2--).sub.m, wherein m=0, the dihydroxy compound is
derived from glycolic acid. When R.sub.15 is the same, R.sub.5 is
hydrogen and R.sub.6 is methyl, the dihydroxy compound is derived
from lactic acid. Dihydroxy compounds derived from glycolic of
lactic acid are particularly preferred.
[0051] Aliphatic-aromatic dihydroxy compounds that are not bromine-
or iodine-substituted have the structure of Formula IIIc: ##STR17##
wherein R.sub.16, R.sub.17, R.sub.18, R.sub.19, and Z are the same
as described above with respect to Formula IIIb. Preferably,
R.sub.18 (--CH.sub.2--).sub.d, in which d is 0 and R.sub.16 and
R.sub.17 independently selected from hydrogen and methyl. Most
preferably, one of R.sub.16 and R.sub.17 is hydrogen, while the
other is methyl. The preferred species of Z are the same as
described above with respect to Formula III.
[0052] The bromine- and iodine-substituted dihydroxy monomers of
the present invention are prepared by well-known iodination and
bromination techniques that can be readily employed by those of
ordinary skill in the art without undue experimentation to prepare
the monomer compounds depicted in Formulae I and III. The
substituted phenols from which the dihydroxy monomers of the
present invention are prepared undergo ortho-directed halogenation.
For this reason, meta-iodinated and brominated dihydroxy monomers
are not readily prepared, and triiodo- and tribromophenyl compounds
have not been described. Such compounds are intended to be included
within the scope of the present invention, should a convenient
method for their synthesis be discovered.
[0053] Iodine- and bromine-substituted diphenol monomers may be
prepared, for example, by coupling together two phenol compounds in
which either or both of the phenol rings are iodine- or
bromine-substituted. More specifically, desaminotyrosyl-tyrosine
esters may be prepared by the methods described in the
above-incorporated U.S. Pat. Nos. 5,587,507 and 5,670,602 using
desaminotyrosine and tyrosine alkyl esters in which either or both
compounds are bromine- or iodine-substituted. In a particularly
preferred embodiment, desaminotyrosine is mono-iodinated at the
ortho position on the phenolic ring and subsequently coupled with a
tyrosine alkyl ester to obtain an iodine-substituted diphenol
monomer.
[0054] Iodine- and bromine-substituted aliphatic-aromatic dihydroxy
monomers in accordance with the present invention are prepared by
coupling an .alpha.-, .beta.- or ?-hydroxy acid with a phenolic
compound in which either or both of the hydroxy acid and the
diphenol are iodine- or bromine-substituted. For example, a
tyrosine alkyl ester is mono-iodinated at the ortho position on the
phenolic ring and subsequently coupled with an .alpha.-, .beta.- or
?-hydroxy acid according to the method described in the
above-incorporated International Publication 98/36013 to obtain an
iodine-substituted aliphatic-aromatic dihydroxy monomer.
[0055] Polycarbonates, polyarylates, poly(alkylene oxide) block
copolymers thereof having pendent free carboxylic acid groups also
cannot be polymerized from an aliphatic-aromatic dihydroxy monomer
having a pendent free carboxylic acid group because of
cross-reaction with the co-monomer. Methods for preparing the
aliphatic-aromatic dihydroxy monomers of Formulae III and IIIc in
which L of Z is not hydrogen are disclosed in commonly owned
International Publication No. 98/36013, the disclosure of which is
hereby incorporated by reference. L of Z is preferably an ethyl,
butyl, hexyl, octyl or benzyl group. Polycarbonates, polyarylates
and the poly(alkylene oxide) block copolymers thereof having
pendent free carboxylic acid groups can also be prepared by the
palladium-catalyzed hydrogenolysis of the corresponding polymers
with benzyl esters prepared as described in the earlier-referenced
U.S. patent application Ser. No. 09/056,050. The catalytic
hydrogenolysis may be performed as described in this Provisional
patent application, as well.
[0056] Polyarylates and polycarbonates, alone, or as segments
within a poly(alkylene oxide) block copolymer, may be homopolymers
with each dihydroxy monomeric subunit having an iodine or a bromine
atom. The polymers of the present invention also include copolymers
of the same polymer units with dihydroxy monomers that are iodine-
and bromine-free. One can vary within the polymers the molar ratios
of the monomeric subunits having bromine- and iodine atoms and the
monomeric subunits that are bromine- and iodine-free.
[0057] Polymers in accordance with the present invention thus
include homopolymers of a repeating unit having at least one iodine
or bromine atom. Such homopolymers have the structure of Formulae
VIII and VIIIa in which f and g are both zero.
[0058] Polymers in accordance with the present invention thus also
include copolymers having monomeric repeating units that are
bromine- and iodine-free. Such copolymers have the structure of
Formulae VIII or VIIIa in which f is zero and g is a number greater
than zero but less than one. In copolymers in accordance with the
present invention, g is preferably between about 0.25 and about
0.75.
[0059] In the preferred homopolymers and copolymers of Formula
VIII, R.sub.9 has the structure of Formula II and R.sub.12 has the
structure of Formula V. The preferred species thereof are the same
as described above with respect to Formula II and Formula V.
[0060] When A of Formulae VIII and VIIIa is: ##STR18## the polymers
of the present invention are polycarbonates. When f is zero, the
iodine- and bromine-substituted polycarbonate homopolymers and
copolymers of the present invention may be prepared by the method
described by U.S. Pat. No. 5,099,060 and by U.S. patent application
Ser. No. 08/884,108, filed Jun. 27, 1997, the disclosures of both
of which are also incorporated herein by reference. The described
method is essentially the conventional method for polymerizing
dihydroxy monomers into polycarbonates. Suitable processes,
associated catalysts and solvents are known in the art and are
taught in Schnell, Chemistry and Physics of Polycarbonates,
(Interscience, New York 1964), the teachings of which are
incorporated herein by reference.
[0061] The polycarbonate homopolymers and copolymers in accordance
with the present invention in which f=0 have weight-average
molecular weights ranging between about 20,000 to about 400,000
daltons, and preferably about 100,000 daltons, measured by gel
permeation chromatography (GPC) relative to polystyrene standards
without further correction.
[0062] When A of Formulae VIII and VIIIa is: ##STR19## the polymers
of the present invention are polyarylates. The iodine- and
bromine-substituted polyarylate homopolymers and copolymers of the
present invention may-be prepared by the method described by U.S.
Pat. No. 5,216,115, in which dihydroxy monomers are reacted with
aliphatic or aromatic dicarboxylic acids in a carbodiimide mediated
direct polyesterification using
4-(dimethylamino)pyridinium-p-toluene sulfonate (DPTS) as a
catalyst to form aliphatic or aromatic polyarylates. The disclosure
of this patent is also incorporated herein by reference. It should
be noted that R.sub.8 should not be substituted with functional
groups that would cross-react.
[0063] Dicarboxylic acids from which the polyarylates materials of
the present invention may be polymerized have the structure of
Formula X: ##STR20## in which, for the aliphatic polyarylates,
R.sub.8 is selected from saturated and unsaturated, substituted and
unsubstituted alkyl groups containing up to 18 carbon atoms, and
preferably from 4 to 12 carbon atoms. For aromatic polyarylates,
R.sub.8 is selected from aryl and alkylaryl groups containing up to
18 carbon atoms, but preferably from 8 to 14 carbon atoms. Again,
R.sub.8 should not be substituted with functional groups that would
cross-react.
[0064] R.sub.8 is even more preferably selected so that the
dicarboxylic acids from which the polyarylate starting materials
are polymerized are either important naturally-occurring
metabolites or highly biocompatible compounds. Preferred aliphatic
dicarboxylic acids therefore include the intermediate dicarboxylic
acids of the cellular respiration pathway known as the Krebs Cycle.
These dicarboxylic acids include a-ketoglutaric acid, succinic
acid, fumaric acid, maleic acid and oxalacetic acid. Other
preferred biocompatible aliphatic dicarboxylic acids include
sebacic acid, adipic acid, oxalic acid, malonic acid, glutaric
acid, pimelic acid, suberic acid and azelaic acid. Among the
preferred aromatic dicarboxylic acids are terephthalic acid,
isophthalic acid and bis(p-carboxyphenoxy) alkanes such as
bis(p-carboxyphenoxy) propane. Stated another way, R.sub.8 is more
preferably a moiety selected from --CH.sub.2--C(.dbd.O)--,
--CH.sub.2--CH.sub.2--C(.dbd.O)--, --CH.dbd.CH-- and
(--CH.sub.2--), wherein z is an integer between two and eight,
inclusive.
[0065] Iodine- and bromine-substituted polyarylate homopolymers and
copolymers in accordance with the present invention have weight
average molecular weights between about 20,000 and about 400,000
daltons, and preferably about 100,000 daltons, measured by GPC
relative to polystyrene standards without further correction.
[0066] Iodine- and bromine-substituted polycarbonates and
polyarylates in accordance with the present invention also include
random block copolymers with a poly(alkylene oxide) with the
structure of Formulae VIII or VIIIa, wherein f is greater than zero
but less than one. The variable species, and the preferred
embodiments thereof, are the same as described above with respect
to formulae VIII and VIIIa, except that f is no longer zero and the
value for g is less than one, and g may or may not be greater than
zero.
[0067] The molar fraction of alkylene oxide in the block copolymer,
f, ranges between about 0.01 and about 0.99. For preferred block
copolymers, R.sub.7 is ethylene, k is between about 20 and about
200, and the molar fraction of alkylene oxide in the block
copolymer, f, preferably ranges between about 0.05 and about 0.75.
R.sub.7 may also represent two or more different alkylene groups
within a polymer.
[0068] The block copolymers of the present invention may be
prepared by the method described by U.S. Pat. No. 5,658,995, the
disclosure of which is also incorporated herein by reference. The
block copolymers have weight-average molecular weights between
about 20,000 and about 400,000 daltons, and preferably about
100,000 daltons. The number-average molecular weights of the block
copolymers are preferably above about 50,000 daltons. Molecular
weight determinations are measured by GPC relative to PEG standards
without further correction.
[0069] For homopolymers and copolymers in accordance with the
present invention having pendent carboxylic acid amide or ester
groups, the amide or ester group can be an amide or ester
derivative of a biologically or pharmaceutically active compound
covalently thereto. The covalent bond is by means of an amide bond
when in the underivatized biologically or pharmaceutically active
compound a primary or secondary amine is present at the position of
the amide bond in the derivative. The covalent bond is by means of
an ester bond when in the underivatized biologically or
pharmaceutically active compound a primary hydroxyl is present at
the position of the ester bond in the derivative. The biologically
or pharmaceutically active compounds may also be derivatized at a
ketone, aldehyde or carboxylic acid group with a linkage moiety
such as the linkage moiety R.sub.3 of Formula IIIa, which is
covalently bonded to the copolymer or diphenol by means of an amide
or ester bond.
[0070] Detailed chemical procedures for the attachment of various
drugs and ligands to polymer bound free carboxylic acid groups have
been described in the literature. See, for example, U.S. Pat. Nos.
5,219,564 and 5,660,822; Nathan et al., Bio. Cong. Chem., 4, 54-62
(1993) and Nathan, Macromolecules, 25, 44-76 (1992). The
disclosures of both patents in both journal articles are
incorporated herein by reference. These publications disclose
procedures by which polymers having pendent free carboxylic acid
group are reacted with moieties having reactive functional groups,
or that are derivatized to contain active functional groups to form
a polymer conjugate.
[0071] The order of reaction can also be reversed. The moiety may
first be attached to a monomer having a pendent free carboxylic
acid group, which is then polymerized to form a polymer in which
100% of the pendent free carboxylic acid groups have moieties
attached thereto.
[0072] When a polymer having pendent free carboxylic acid groups is
first polymerized and then reacted with a biologically or
pharmaceutically active compound or derivative thereof to form a
polymer conjugate not all of the pendent free carboxylic acid
groups will have a biologically or pharmaceutically active compound
covalently attached thereto. Typically, a conjugate is formed in
which biologically or pharmaceutically active compounds attach to
at least about 25% of the pendent free carboxylic acid groups.
[0073] Examples of biologically or pharmaceutically active
compounds suitable for use with the present invention include
acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,
daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,
biologically active peptides, chlorin e.sub.6, cephradine,
cephalothin, proline and proline analogs such as
cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic
acid, chemodeoxycholic acid, chlorambucil, and the like.
Biologically active compounds, for purposes of the present
invention are additionally defined as including cell attachment
mediators, biologically active ligand and the like. The compounds
are covalently bonded to the polycarbonate or polyarylate copolymer
by methods well understood by those of ordinary skill in the art.
Drug delivery compounds may also be formed by physically blending
the biologically or pharmaceutically active compound to be
delivered with the polymers of the present invention. Either way,
the polymers of the present invention provide a means by which drug
delivery may be monitored using x-ray imaging without having to
employ a filler material to provide x-ray contrast.
[0074] For purposes of the present invention, the alkyl ester and
amide groups within Z are also defined as including crosslinking
moieties, such as molecules with double bonds (e.g., acrylic acid
derivatives), which can be attached to the pendent carboxylic acid
groups for crosslinking to increase the strength of the
polymers.
[0075] As noted above, the polymers of the present invention are
iodine or bromine substituted at selected repeating subunits. For
the purposes of the present invention, homopolymers (Formula VIII
or VIIIa, x=0) are defined as containing an iodine or bromine at
each subunit. These homopolymers can be polycarbonates or
polyarylates which may contain polyalkylene oxide blocks. The
homopolymers are best described as new, radio-opaque polymers that
may have a number of pharmacological and biological activities.
Likewise, for the purposes of the present invention, copolymers
(Formula VIII or VIIIa, 0.ltoreq.x.ltoreq.1) are defined as
containing iodine or bromine at some of the diphenolic subunits.
These copolymers can be polycarbonates or polyarylates, which also
may contain polyalkylene oxide blocks.
[0076] The invention described herein also includes various
pharmaceutical dosage forms containing the polymers of the present
invention. The pharmaceutical dosage forms include those recognized
conventionally, e.g. tablets, capsules, oral liquids and solutions,
drops, parenteral solutions and suspensions, emulsions, oral
powders, inhalable solutions or powders, aerosols, topical
solutions, suspensions, emulsions, creams, lotions, ointments,
transdermal liquids and the like.
[0077] The pharmaceutical dosage forms may include one or more
pharmaceutically acceptable carriers. Such materials are non-toxic
to the recipients at the dosages and concentrations employed, and
include diluents, solubilizers, lubricants, suspending agents,
encapsulating materials, penetration enhancers, solvents,
emollients, thickeners, dispersants, buffers such as phosphate,
citrate, acetate and other organic acid salts, anti-oxidants such
as ascorbic acid, preservatives, low molecular weight (less than
about 10 residues) peptides such as polyarginine, proteins such as
serum albumin, gelatin, or immunoglobulins, other hydrophilic
polymers such as poly(vinylpyrrolidinone), amino acids such as
glycine, glutamic acid, aspartic acid, or arginine,
monosaccharides, disaccharides, and other carbohydrates, including
cellulose or its derivatives, glucose, mannose, or dextrines,
chelating agents such as EDTA, sugar alcohols such as mannitol or
sorbitol, counterions such as sodium and/or nonionic surfactants
such as tween, pluronics or PEG.
[0078] The drug-polymer compositions of the present invention,
regardless of whether they are in the form of polymer-drug
conjugates or physical admixtures of polymer and drug, are suitable
for applications where localized drug delivery is desired, as well
as in situations where a systemic delivery is desired. The
polymer-drug conjugates and physical admixtures may be implanted in
the body of a patient in need thereof, by procedures that are
essentially conventional and well-known to those of ordinary skill
in the art.
[0079] Hydrolytically stable conjugates are utilized when the
biological or pharmaceutical compound is active in conjugated form.
Hydrolyzable conjugates are utilized when the biological or
pharmaceutical compound is inactive in conjugated form. The
properties of the poly(alkylene oxide) dominate the polymer and
conjugate thereof.
[0080] Conjugates of the polymers of the present invention with
proline and proline analogs such as cis-hydroxy-L-proline may be
used in the treatment methods disclosed in U.S. Pat. No. 5,660,822.
The disclosure of this patent is incorporated herein by
reference.
[0081] Physical admixtures of drug and polymer are prepared using
conventional techniques well-known to those of ordinary skill in
the art. For this drug delivery embodiment, it is not essential
that the polymer have pendent free carboxylic acid groups.
[0082] The drug components to be incorporated in the polymer-drug
conjugates and physical admixtures of this invention may be
provided in a physiologically acceptable carrier, excipient
stabilizer, etc., and may be provided in sustained release or timed
release formulations supplemental to the polymeric formulation
prepared in this invention. The carriers and diluents listed above
for aqueous dispersions are also suitable for use with the
polymer-drug conjugates and physical admixtures.
[0083] Subjects in need of treatment, typically mammalian, using
the polymer-drug combinations of this invention, can be
administered drug dosages that will provide optimal efficacy. The
dose and method of administration will vary from subject to subject
and be dependent upon such factors as the type of mammal being
treated, its sex, weight, diet, concurrent medication, overall
clinical condition, the particular compounds employed, the specific
use for which these compounds are employed, and other factors which
those skilled in the medical arts will recognize. The polymer-drug
combinations of this invention may be prepared for storage under
conditions suitable for the preservation of drug activity as well
as maintaining the integrity of the polymers, and are typically
suitable for storage at ambient or refrigerated temperatures.
[0084] Aerosol preparations are typically suitable for nasal or
oral inhalation, and may be in powder or solution form, in
combination with a compressed gas, typically compressed air.
Additionally, aerosols may be used topically. In general, topical
preparations may be formulated to enable one to apply the
appropriate dosage to the affected area once daily, and up to three
to four times daily, as appropriate.
[0085] Depending upon the particular compound selected, transdermal
delivery may be an option, providing a relatively steady delivery
of the drug, which is preferred in some circumstances. Transdermal
delivery typically involves the use of a compound in solution, with
an alcoholic vehicle, optionally a penetration enhancer, such as a
surfactant, and other optional ingredients. Matrix and reservoir
type transdermal delivery systems are examples of suitable
transdermal systems. Transdermal delivery differs from conventional
topical treatment in that the dosage form delivers a systemic dose
of the drug to the patient.
[0086] The polymer-drug formulations of this invention may also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes may be used in any of the
appropriate routes of administration described herein. For example,
liposomes may be formulated that can be administered orally,
parenterally, transdermally, or via inhalation. Drug toxicity could
thus be reduced by selective drug delivery to the affected site.
For example, if the drug is liposome encapsulated, and is injected
intravenously, the liposomes used are taken up by vascular cells
and locally high concentrations of the drug could be released over
time within the blood vessel wall, resulting in improved drug
action. The liposome encapsulated drugs are preferably administered
parenterally, and particularly, by intravenous injection.
[0087] Liposomes may be targeted to a particular site for drug
release. This would obviate excessive dosages that are often
necessary to provide a therapeutically useful dosage of a drug at
the site of activity, and consequently, the toxicity and side
effects associated with higher dosages.
[0088] The drugs incorporated into the polymers of this invention
may desirably further incorporate agents to facilitate their
delivery systemically to the desired drug target, as long as the
delivery agent meets the same eligibility criteria as the drugs
described above. The active drugs to be delivered may in this
fashion be incorporated with antibodies, antibody fragments, growth
factors, hormones, or other targeting moieties, to which the drug
molecules are coupled. The polymer-drug combinations of this
invention may be formed into shaped particles, such as valves,
stents, tubing, prostheses, and the like.
[0089] Therapeutically effective dosages may be determined by
either in vitro or in vivo methods. For each particular compound of
the present invention, individual determinations may be made to
determine the optimal dosage required. The range of therapeutically
effective dosages will naturally be influenced by the route of
administration, the therapeutic objectives, and the condition of
the patient. For the various suitable routes of administration, the
absorption efficiency must be individually determined for each drug
by methods well known in pharmacology. Accordingly, it may be
necessary for the therapist to titer the dosage and modify the
route of administration as required to obtain the optimal
therapeutic effect. The determination of effective dosage levels,
that is, the dosage levels necessary to achieve the desired result,
will be within the ambit of one skilled in the art. Typically,
applications of compound are commenced at lower dosage levels, with
dosage levels being increased until the desired effect is achieved.
The release rate of the drug from the formulations of this
invention are also varied within the routine skill in the art to
determine an advantageous profile, depending on the therapeutic
conditions to be treated.
[0090] A typical dosage might range from about 0.001 mg/k/g to
about 1,000 mg/k/g, preferably from about 0.01 mg/k/g to about 100
mg/k/g, and more preferably from about 0.10 mg/k/g to about 20
mg/k/g. Advantageously, the compounds of this invention may be
administered several times daily, and other dosage regimens may
also be useful.
[0091] In practicing the methods of this invention, the
polymer-drug combinations may be used alone or in combination with
other therapeutic or diagnostic agents. The compounds of this
invention can be utilized in vivo, ordinarily in mammals such as
primates such as humans, sheep, horses, cattle, pigs, dogs, cats,
rats and mice, or in vitro.
[0092] The polymers of the present invention also find application
in areas where both solid materials and solvent-soluble materials
are commonly employed. Such applications include polymeric
scaffolds in tissue engineering applications and medical implant
applications, including the use of the polymers of the present
invention to form shaped articles such as vascular grafts and
stents, bone plates, sutures, implantable sensors, scaffolds for
tissue regeneration, and other therapeutic agent particles that
decompose harmlessly within a known period of time. Shaped
particles can be formed by conventional techniques such as
extrusion, compression molding, injection molding, solvent casting,
spin casting, and the like.
[0093] The polymers of the present invention are soluble in both
water and organic media. Accordingly, they can be processed by
solvent casting techniques and are good film formers. The polymers
of the present invention having pendent free carboxylic acid groups
can also be used to influence the interactions with cells, as
disclosed in the above-referenced International Publication No.
98/36013.
[0094] The incorporation of polyalkylene oxide blocks decreases the
adhesiveness of the polymeric surfaces. Polymers for which f is
greater than 5 mole percent according to Formulae VIII or VIIIa are
resistant to cell attachment and may be useful as non-thrombogenic
coatings on surfaces in contact with blood. These polymers also
resist bacterial adhesion. The polymers thus can be formed as a
coating on the surface of medical devices by conventional dipping
or spray coating techniques to prevent the formation of blood clots
or the adhesion of bacteria on the surface of the device.
[0095] The film forming properties of polymers with poly(alkylene
oxide) can be advantageously combined with the resistance to cell
attachment to provide films for use as barriers for the prevention
of surgical adhesions. A coating of the polymer of the present
invention may also be applied to injured tissue to provide a
surgical adhesion barrier.
[0096] The polymers of the present invention can find application
in areas where both structural solid materials and water-soluble
materials are commonly employed. Such applications include
polymeric scaffolds in tissue engineering applications and medical
implant applications, including the use of the polycarbonates and
polyarylates of the present invention to form shaped articles such
as vascular grafts and stents, bone plates, sutures, implantable
sensors, barriers for surgical adhesion prevention, implantable
drug delivery devices, scaffolds for tissue regeneration, and other
therapeutic agent articles that decompose harmlessly within a known
period of time.
INDUSTRIAL APPLICABILITY
[0097] Shaped articles may be prepared from the polymers of the
present invention for medical implant and drug delivery
applications. The articles are radio-opaque and may be monitored
using x-ray imaging without having to employ a filler material to
provide x-ray contrast.
[0098] The following non-limiting examples set forth hereinbelow
illustrate certain aspects of the invention. All parts and
percentages are by mole percent unless otherwise noted and all
temperatures are in degrees Celsius. All solvents were HPLC grade.
All other reagents were of analytical grade and were used as
received.
[0099] The following Examples illustrate the preparation of
3-(3-iodo-4-hydroxyphenyl)propanoic acid-tyrosine ethyl ester
(DiTE), and its incorporation into a variety of polymer structures.
Since an iodine is present is the structure of DiTE, the materials
illustrated in the following Examples are radio-opaque.
EXAMPLE 1
Synthesis of DiTE
[0100] DiTE (3-(3-iodo-4-hydroxyphenyl)propanoic acid-tyrosine
ethyl ester) is a bisphenol carrying one iodine atom at position 3
of one of the two phenolic rings. This bifunctional molecule can be
polymerized as illustrated in the subsequent Examples. This Example
describes the method used to introduce the iodine atom in the
aromatic ring (4-hydroxyphenyl)propionic acid, and the coupling of
this iodinated derivative with tyrosine ethyl ester in order to
obtain DiTE.
[0101] Preparation of solution (a): to a 250 mL Erlenmeyer flask
were added 100 mL of distilled water, 24 g of potassium iodide, and
25 g of iodine. The mixture was stirred overnight until all solids
dissolved.
[0102] Preparation of solution (b): 16.6 g (0.1 mole) of DAT were
placed in a 3-necked Morton-type round bottom flask, equipped with
an overhead mixer and a 125 mL addition funnel. 140 mL of 40%
trimethylamine solution in water were added, and the mixture was
stirred until a clear solution was obtained.
[0103] Solution (a) was placed in the addition funnel, and added
dropwise to solution (b) while vigorously stirring. Addition of
each drop of solution (a) imparted a brown color to the reaction
mixture. The rate of addition was such that all the color
disappeared before the next drop was added. Stirring was continued
for one hour after the last addition, the 50 mL of sodium
thiosulfate 0.1 M were added to the reaction vessel. The same
solution was also used to wash the addition funnel.
[0104] 37% HCl was added dropwise with vigorous mixing until the
solution was slightly acidic to litmus, and a solid formed. The
mixture was concentrated to half its volume by rotary evaporation,
and then it was extracted with ether. The organic phase was dried
over magnesium sulfate, and decolorized using animal charcoal. The
slurry was then filtered through a small layer of silica gel, and
evaporated to dryness. The white solid was recrystallized twice in
toluene, recovered by filtration, dried under a stream of nitrogen,
and then under high vacuum.
[0105] Characterization: DSC analysis showed a melting point range
of 109-111.degree. C. .sup.1H-NMR (DMSO) of the product showed the
following peaks (ppm): 2.5 (t, 2H), 2.7 (t, 2H), 6.8 (d, 2H), 7.06
(d, 2H), 10.08 (s, 1H), 12.05 (s, 1H). Reverse-phase HPLC showed
3.8% DAT (the starting material), and 1.4% of diiodinated
product.
STEP 2: PREPARATION OF 3-(3-IODO-4-HYDROXYPHENYL)PROPIONIC
ACID-TYROSINE ETHYL ESTER (DiTE)
[0106] To a 250 mL 3-necked round bottomed flask equipped with an
overhead stirrer were added 17.0 g (0.0582 moles) of DiAT, 12.25 g
(0.0585 moles) or tyrosine ethyl ester, and 25 mL of NMP. The
mixture was stirred until a clear solution was obtained. The flask
was cooled in an ice-water bath, the 11.84 g (0.0619 moles) of EDCI
HCl were added in one portion, followed by 15 mL of NMP. The
cooling bath was removed after 2.5 hours, and the reaction was
allowed to continue overnight at room temperature. 71 mL of ethyl
acetate were added, and stirring was maintained for 15 more
minutes. The crude was then transferred into a 500 mL separatory
funnel, and extracted once with 75 mL of brine, then with two
aliquots (75 and 35 mL) of 3% NaHCO3/14% NaCl, followed by 35 mL
aliquots of 0.4 M HCl/14% NaCl, and finally with brine. The organic
phase was dried over magnesium sulfate and treated with activated
carbon, filtered and concentrated to a thick syrup, which
crystallized into a solid mass after a few hours. The product was
triturated in methylene chloride using mechanical stirring, then it
was recovered by filtration and dried under a nitrogen stream
followed by high vacuum.
[0107] Characterization: DSC analysis showed a melting point range
of 110-113.degree. C. .sup.1H-NMR (DMSO) showed the following peaks
(ppm): 1.1 (t, 3H), 2.35 (t, 2H), 2.65 (m, 2H), 2.85 (m, 2H), 4.05
(q, 2H), 4.35 (m, 1H), 6.65/6.75/6.95 (m, 6H), 7.5 (s, 1H), 8.25
(d, 1H), 9.25 (s, 1H), 10.05 (s, 1H). Reverse-phase HPLC showed
2.2% of DTE (the non-iodinated monomer), and no diiodinated
product.
EXAMPLE 2
Poly(DiTE Carbonate) by Solution Polymerization
[0108] This material is the polycarbonate obtained by reacting
DiTE, obtained in Example 1, and phosgene.
Polymerization of DiTE with Phosgene
[0109] A 250 mL 3-necked flask equipped with a mechanical stirrer
and an addition funnel was purged with nitrogen for 15 minutes.
7.62 g (15.8 moles) of DiTE were added to the flask followed by 39
mL methylene chloride and 4.79 mL distilled pyridine. The mixture
was stirred until a clear solution was obtained, then it was
chilled in an ice-water bath. 9.8 mL of 20% phosgene solution in
toluene were placed in the addition funnel and added to the
reaction flask at a constant rate so that the entire addition was
complete in 1.5 hours. The mixture was stirred for one more hour,
then it was diluted with 200 mL THF, and the polymer was
precipitated by dropping the solution in a large excess of ether
through a filter funnel. The precipitated polymer was washed with
ether, transferred to an evaporating dish, and dried overnight
under a steam of nitrogen. It was redissolved in THF, and
precipitated again in a water/ice mixture, using a high-speed
blender. The product was then dried under a stream of nitrogen,
followed by high vacuum at 40.degree. C.
[0110] Characterization: The composition of the product was
confirmed by Elemental Analysis: % C=50.60 (theor: 49.52%); %
H=4.21 (theor: 3.96%); % N=2.65 (theor: 2.75%); % I=24.01 (theor:
24.92%). A Mw of 104K with a polydispersity of 1.8 was determined
by GPC in THF vs. polystyrene standards. DSC showed a Tg of
103.8.degree. C. .sup.1H-NMR (DMSO-D.sub.6) showed the following
peaks (ppm): 1.1 (t, 3H), 2.4 (broad, 2H), 2.75 (broad, 2H), 3.0
(broad, 2H), 4.05 (q, 2H), 4.45 (m, 1H), 7.3 (m, 6H), 7.8 (s, 1H),
8.4 (d, 1H).
EXAMPLE 3
Poly(DiTE-co-5% PEG1K Carbonate) by Solution Polymerization
[0111] In this Example, 5 mole % of PEG1000 was copolymerized with
DITE through phosgenation by means of a solution polymerization
technique similar to that described in Example 2. The resulting
material is a random polycarbonate.
Copolymerization of DiTE and PEG1000
[0112] A 100 mL 3-necked round bottomed flask equipped with an
addition funnel and an overhead stirrer was purged with nitrogen
for 30 minutes. The flask was charged with 5 g (10.33 mmoles) of
DiTE, and 0.545 g (0.55 mmoles) of PEG1000, then 23 mL of methylene
chloride and 3.3 mL of pyridine were added, and the mixture was
stirred until a colorless, clear solution resulted. The flask was
cooled in an ice-water bath, and 6.4 mL of 20% phosgene solution in
toluene were-added dropwise over a period of 90 minutes from the
addition funnel. The mixture was diluted with 90 mL of THE, and
stirred for one more hour. The product was isolated by
precipitation in 800 mL of ethyl ether, and dried under a stream of
nitrogen followed by high vacuum.
[0113] Characterization: A Mw of 75,500 with a polydispersity of
1.8 was determined by GPC vs. polystyrene standards, with THF as
the mobile phase. DSC showed Tg of 70.degree. C. .sup.1H-NMR
(CDCl.sub.3) showed the following peaks (ppm): 1.2 (t, 3H), 2.45
(broad, 2H), 2.8 (broad, 2H), 2.03 (broad, 2H), 3.65 (s, 4.5 PEG
protons), 4.15 (q, 2H), 4.85 (m, 1H), 6.05 (broad, 1H), 7.05/7.15
(m, 6H), 7.2 (s, 1H). The peaks at 7.05/7.15, and at 7.2 are
diagnostic for the presence of the iodine atom on the aromatic
system of the polymer. Broad-Band Decoupled .sup.13C NMR
(CDCl.sub.3) showed all the expected peaks, and in particular that
of the aromatic carbon bearing the iodine (90 ppm).
EXAMPLE 4
Poly(DiTE Adipate) by Solution Polymerization
[0114] This material is an alternating copolymer of the
iodine-containing diphenol DiTE, and adipic acid, an aliphatic
diacid. The monomers are linked through an ester bond to form a
polyarylate backbone. This Example illustrates the preparation of
this copolymer by means of a condensation reaction promoted by the
coupling agent diisopropylcarbodiimide (DIPC).
Copolymerization of DiTE and Adipic Acid
[0115] A 100 mL round bottomed flask equipped with an overhead
stirrer was purged with nitrogen for one hour, and then charged
with 4.349 g (9.0 mmoles) of DiTE, 1.315 g (9.0 mmoles) of adipic
acid, 1.06 of dimethylaminopyridinium p-toluene sulfonate (2.5
mmoles), and 68 mL of methylene chloride. The mixture was stirred
for five minutes, then 4.2 mL (27 mmoles) of DIPC were added in one
portion. Stirring was continued overnight at room temperature, then
the reaction crude was filtered, and the polymer was precipitated
in 600 mL of chilled isopropanol in a high-speed blender, and
isolated by filtration. The polymer was washed in the high-speed
blender with 600 mL of chilled isopropanol, and the 600 mL of a
water/ice mixture. The product was dried overnight under a stream
of nitrogen, and then was transferred to high vacuum at room
temperature.
[0116] Characterization: A Mw of 67,100 with a polydispersity of
1.9 was determined by GPC vs. polystyrene standards, with THF as
the mobile phase. DSC showed a T.sub.g of 66.5.degree. C.
.sup.1H-NMR (DMSO-D.sub.6) showed the following peaks (ppm): 1.1
(t, 3H), 1.75 (broad, 4H), 2.4 (broad, 2H), 2.7 (broad, 6H), 2.95
(broad, 2H), 405 (q, 2H0, 4.45 (m, 1H), 7.05/7.15 (m, 6H), 7.7 (s,
1H), 8.4 (d, 1H).
EXAMPLE 6
Fabrication and Implantation of Radio-Opaque Rods
[0117] Iodine-containing, radio-opaque polymers can be blended with
non radio-opaque materials in order to fabricate implantable
devices that are x-ray detectable. This example illustrates the
preparation of blends of poly(DTE carbonate) and poly(DiTE
carbonate) in three different ratios, their fabrication into rods,
and their implantation into an animal model.
Preparation of Radio-Opaque Polymer Blends
[0118] Three blends with different ratios of poly(DTE carbonate)
(Mw=103 K) to poly(DiTE carbonate) (Mw=106 K) were prepared. The
weight ratios were 90/10, 75/25 and 50/50. In each case, the
polymers were co-dissolved in methylene chloride, and the mixture
was precipitated in ether.
Fabrication and Implantation of Radio-Opaque Rods
[0119] Uniform rods of 10 mm length, 2 mm diameter were obtained by
melt extrusion at 180.degree. C. The rods were implanted in rabbit
long bones, and sites of implantation were x-rayed in order to
confirm the radio-opacity of the devices. Radio-opacity increased
with increasing content of poly(DiTE carbonate).
[0120] The foregoing examples illustrate that radio opacity may be
obtained by Br and I ring-substitution of essentially any aromatic
ring-containing polymer. These examples, and the foregoing
description of the preferred embodiment, should be taken as
illustrating, rather than as limiting, the present invention as
defined by the claims. As will be readily appreciated, numerous
variations and combinations of the features set forth above can be
utilized without departing from the present invention as set forth
in the claims. Such variations are not regarded as a departure from
the spirit and scope of the invention, and all such modifications
are intended to be included within the scope of the following
claims.
* * * * *