U.S. patent application number 11/732653 was filed with the patent office on 2007-08-23 for therapeutic polyanhydride compounds for drug delivery.
This patent application is currently assigned to Rutgers, The State University of New Jersey. Invention is credited to Kathryn E. Uhrich.
Application Number | 20070196417 11/732653 |
Document ID | / |
Family ID | 24513719 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070196417 |
Kind Code |
A1 |
Uhrich; Kathryn E. |
August 23, 2007 |
Therapeutic polyanhydride compounds for drug delivery
Abstract
Polyanhydrides which link low molecular weight drugs containing
a carboxylic acid group and an amine, thiol, alcohol or phenol
group within their structure into polymeric drug delivery systems
are provided. Also provided are methods of producing polymeric drug
delivery systems via these polyanhydride linkers as well as methods
of administering low molecular weight drugs to a host via the
polymeric drug delivery systems.
Inventors: |
Uhrich; Kathryn E.;
(Plainfield, NJ) |
Correspondence
Address: |
VIKSNINS HARRIS & PADYS PLLP
P.O. BOX 111098
ST. PAUL
MN
55111-1098
US
|
Assignee: |
Rutgers, The State University of
New Jersey
Nerw Brunswick
NJ
|
Family ID: |
24513719 |
Appl. No.: |
11/732653 |
Filed: |
April 4, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10646336 |
Aug 22, 2003 |
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11732653 |
Apr 4, 2007 |
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09917231 |
Jul 27, 2001 |
6613807 |
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10646336 |
Aug 22, 2003 |
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09627215 |
Jul 27, 2000 |
6486214 |
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09917231 |
Jul 27, 2001 |
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Current U.S.
Class: |
424/422 ;
424/426 |
Current CPC
Class: |
C08L 73/02 20130101;
A61K 47/55 20170801; A61L 2300/41 20130101; A61L 27/34 20130101;
C08L 73/02 20130101; C08L 73/02 20130101; C08L 73/02 20130101; A61L
27/54 20130101; A61L 27/18 20130101; A61L 17/10 20130101; C08L
73/02 20130101; A61Q 19/08 20130101; A61L 27/18 20130101; A61Q
19/00 20130101; A61K 8/368 20130101; A61L 31/148 20130101; A61K
8/85 20130101; A61K 47/59 20170801; A61K 47/54 20170801; A61L 31/10
20130101; A61P 35/00 20180101; A61L 17/005 20130101; A61K 47/552
20170801; A61P 7/02 20180101; A61L 31/06 20130101; A61L 27/58
20130101; A61K 9/2031 20130101; A61P 31/04 20180101; A61P 31/10
20180101; A61L 31/10 20130101; C08G 67/04 20130101; A61K 31/765
20130101; A61L 31/16 20130101; A61L 27/34 20130101; A61L 31/06
20130101; A61P 29/00 20180101; A61L 2300/406 20130101; A61P 37/06
20180101; A61K 47/595 20170801; A61Q 5/006 20130101; A61P 25/16
20180101; A61L 2300/416 20130101 |
Class at
Publication: |
424/422 ;
424/426 |
International
Class: |
A61F 2/02 20060101
A61F002/02 |
Claims
1. A medical device comprising a polymer that comprises a backbone,
wherein the backbone comprises an anhydride linkage, wherein the
backbone comprises one or more groups that will yield a
biologically active compound upon hydrolysis of the polymer,
provided that the biologically active compound is not an
ortho-hydroxy aryl carboxylic acid or an alpha-hydroxy carboxylic
acid.
2. The medical device of claim 1, wherein the medical device is a
stent, a vascular graft, a bone plate, a suture, an implantable
sensor, or an implantable drug delivery device.
3. The medical device of claim 2, wherein the medical device is a
stent.
4. The medical device of claim 1, wherein the biologically active
compound is an anti-inflammatory compound.
5. The medical device of claim 1, wherein the biologically active
compound is an antibiotic compound.
6. The medical device of claim 1, wherein the biologically active
compound is an antineoplastic compound.
7. The medical device of claim 1, wherein the polymer is comprised
in a coating.
8. The medical device of claim 1, wherein the polymer comprises one
or more units of formula (I) in the backbone:
--C(.dbd.O)R.sup.1--X--R.sup.2--X--R.sup.1--C(.dbd.O)--O-- (I)
wherein each R.sup.1 is a group that will provide a biologically
active compound upon hydrolysis of the polymer; each X is
independently an amide linkage, a thioester linkage, or an ester
linkage; and R.sup.2 is a linking group.
9. The medical device of claim 8, wherein R.sup.2 is a divalent,
branched or unbranched, saturated or unsaturated, hydrocarbon chain
having from 1 to 25 carbon atoms, wherein one or more of the carbon
atoms is optionally replaced by (--O--) or (--NR--), and wherein
the chain is optionally substituted on at least one carbon atom
with one or more substituents (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkanoyloxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylthio, azido, cyano, nitro, halo, hydroxy,
oxo, carboxy, aryl, aryloxy, heteroaryl, or heteroaryloxy.
10. The medical device of claim 8, wherein R.sup.2 is a divalent,
branched or unbranched, saturated or unsaturated, hydrocarbon
chain, having from 1 to 25 carbon atoms, wherein the chain is
optionally substituted on at least one carbon atom with one or more
substituents (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkanoyloxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkylthio, azido,
cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy,
heteroaryl, and heteroaryloxy.
11. The medical device of claim 8, wherein R.sup.2 is an amino
acid.
12. The medical device of claim 8, wherein R.sup.2 is a
peptide.
13. The medical device of claim 8, wherein R.sup.2 is a divalent,
branched or unbranched, saturated or unsaturated, hydrocarbon chain
having from 3 to 15 carbon atoms.
14. The medical device of claim 8, wherein R.sup.2 is a divalent,
branched or unbranched, hydrocarbon chain, having from 3 to 15
carbon atoms.
15. The medical device of claim 14, wherein R.sup.2 is a divalent,
branched or unbranched, hydrocarbon chain, having from 6 to 10
carbon atoms.
16. The medical device of claim 15, wherein R.sup.2 is a divalent
hydrocarbon chain having 7, 8, or 9 carbon atoms.
17. The medical device of claim 16, wherein R.sup.2 is a divalent
hydrocarbon chain having 8 carbon atoms.
18. The medical device of claim 8, wherein the one or more units of
formula (I) are one or more units of formula (II) or (III):
--C(O)R.sup.1--OC(O)--R.sup.2--(O)CO--R.sup.1--C(O)--O-- (II)
--C(O)R.sup.1--C(O)O--R.sup.2--(O)OC--R.sup.1--C(O)--O-- (III).
19. The medical device of claim 19, wherein the one or more units
of formula (I) are one or more units of formula (II).
20. The medical device of claim 19, wherein the one or more units
of formula (I) are one or more units of formula (III).
Description
PRIORITY OF INVENTION
[0001] This application is a Continuation of U.S. patent
application Ser. No. 09/917,231, (filed 27 Jul. 2001), which is a
Continuation-in-Part of U.S. patent application Ser. No.
09/627,215, (filed 27 Jul. 2000), which is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Polymers comprising aromatic or aliphatic anhydrides have
been studied extensively over the years for a variety of uses. For
example, in the 1930s fibers comprising aliphatic polyanhydrides
were prepared for use in the textile industry. In the mid 1950s,
aromatic polyanhydrides were prepared with improved film and fiber
forming properties. More recently, attempts have been made to
synthesize polyanhydrides with greater thermal and hydrolytic
stability and sustained drug release properties.
[0003] U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the
preparation of polyanhydrides with improved sustained drug release
properties from pure, isolated prepolymers of diacids and acetic
acid. However, these biocompatible and biodegradable aromatic
polyanhydrides have radical or aliphatic bonds resulting in
compounds with slow degradation times as well as relatively
insoluble degradation products unless incorporated into a copolymer
containing a more hydrophilic monomer, such as sebacic acid. The
aromatic polyanhydrides disclosed in the '128 Patent and the '904
Patent are also insoluble in most organic solvents. A bioerodible
controlled release device produced as a homogenous polymeric matrix
from polyanhydrides with aliphatic bonds having weight average
molecular weights greater than 20,000 and an intrinsic velocity
greater than 0.3 dL/g and a biologically active substance is also
described in U.S. Pat. No. 4,888,176. Another bioerodible matrix
material for controlled delivery of bioactive compounds comprising
polyanhydride polymers with a uniform distribution of aliphatic and
aromatic residues is disclosed in U.S. Pat. No. 4,857,311.
[0004] Biocompatible and biodegradable aromatic polyanhydrides
prepared from para-substituted bis-aromatic dicarboxylic acids for
use in wound closure devices are disclosed in U.S. Pat. No.
5,264,540. However, these compounds exhibit high melt and glass
transition temperatures and decreased solubility, thus making them
difficult to process. The disclosed polyanhydrides also comprise
radical or aliphatic bonds which can not be hydrolyzed by
water.
[0005] Polyanhydride polymeric matrices have also been described
for use in orthopedic and dental applications. For example, U.S.
Pat. No. 4,886,870 discloses a bioerodible article useful for
prosthesis and implantation which comprises a biocompatible,
hydrophobic polyanhydride matrix. U.S. Pat. No. 5,902,599 also
discloses biodegradable polymer networks for use in a variety of
dental and orthopedic applications which are formed by polymerizing
anhydride prepolymers.
[0006] Biocompatible and biodegradable polyanhydrides have now been
developed with improved degradation, processing and solubility
properties, as well as utilities based upon their degradation
products.
SUMMARY OF THE INVENTION
[0007] The present invention provides biocompatible and
biodegradable polyanhydrides which serve as the polymeric backbone
linking drug molecules into polymeric drug delivery systems. The
polyanhydride polymers of the invention demonstrate enhanced
solubility and processability, as well as degradation properties
due to the use of hydrolyzable bonds such as esters, amides,
urethanes, carbanates and carbonates as opposed to radical or
aliphatic bonds. The polyanhydride backbone has one or more groups
that will provide a therapeutically active compound upon
hydrolysis. The polymers of the invention comprise one or more
units of formula (I) in the backbone:
--C(.dbd.O)R.sup.1--X--R.sup.2--X--R.sup.1--C(.dbd.O)--O-- (I)
wherein each R.sup.1 is group that will provide a therapeutically
active compound upon hydrolysis of the polymer; each X is
independently an amide linkage, a thioester linkage, or an ester
linkage; and R.sup.2 is a linking group; provided that the
therapeutically active compound is not an ortho-hydroxy aryl
carboxylic acid.
[0008] The polyanhydrides of the invention are used to link low
molecular weight drug molecules comprising within their molecular
structure one carboxylic acid group and at least one amine, thiol,
alcohol or phenol group. Accordingly, polyanhydrides of formula (I)
serve as the polymer backbone of polymeric drug delivery systems
comprising these low molecular weight drugs.
[0009] Thus, the present invention also relates to compositions,
methods of producing compositions and methods of using compositions
comprising a polyanhydride of Formula (I) and low molecular weight
drug molecules containing within their structure one carboxylic
acid group and at least one amine, thiol, alcohol or phenol group,
wherein molecules of the drug are linked to one another via the
polyanhydride. These polymeric drug delivery systems provide an
effective means to deliver drugs in a controlled fashion to any
site of a host. By "host" it is meant to include both animals and
plants.
[0010] The invention also provides a pharmaceutical composition
comprising a polymer of the invention and a pharmaceutically
acceptable carrier.
[0011] The invention also provides a therapeutic method for
treating a disease in an animal comprising administering to an
animal in need of such therapy, an effective amount of a polymer of
the invention.
[0012] The invention also provides a method of delivering a
therapeutically active compound to a host comprising administering
to the host a biocompatible and biodegradable polymer of the
invention, which degrades into the biologically active
compound.
[0013] The invention provides a polymer of the invention for use in
medical therapy, as well as the use of a polymer of the invention
for the manufacture of a medicament useful for the treatment of a
disease in a mammal, such as a human.
[0014] The invention also provides processes and intermediates
disclosed herein that are useful for preparing a polymer of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0015] The following definitions are used, unless otherwise
described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy,
etc. denote both straight and branched groups; but reference to an
individual radical such as "propyl" embraces only the straight
chain radical, a branched chain isomer such as "isopropyl" being
specifically referred to. Aryl denotes a phenyl radical or an
ortho-fused bicyclic carbocyclic radical having about nine to ten
ring atoms in which at least one ring is aromatic. Heteroaryl
encompasses a radical attached via a ring carbon of a monocyclic
aromatic ring containing five or six ring atoms consisting of
carbon and one to four heteroatoms each selected from the group
consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is
absent or is H, O, (C.sub.1-C.sub.6)alkyl, phenyl or benzyl, as
well as a radical of an ortho-fused bicyclic heterocycle of about
eight to ten ring atoms derived therefrom, particularly a
benz-derivative or one derived by fusing a propylene, trimethylene,
or tetramethylene diradical thereto.
[0016] The term ester linkage means --OC(.dbd.O)-- or
--C(.dbd.O)O--; the term thioester linkage means --SC(.dbd.O)-- or
--C(.dbd.O)S--; and the term amide linkage means --N(R)C(.dbd.O)--
or --C(.dbd.O)N(R)--, wherein each R is a suitable organic radical,
such as, for example, hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, aryl(C.sub.1-C.sub.6)alkyl, or
heteroaryl(C.sub.1-C.sub.6)alkyl. The term urethane or carbamate
linkage means --OC(.dbd.O)N(R)-- or --N(R)C(.dbd.O)O--, wherein
each R is a suitable organic radical, such as, for example,
hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, aryl(C.sub.1-C.sub.6)alkyl, or
heteroaryl(C.sub.1-C.sub.6)alkyl, and the term carbonate linkage
means --OC(.dbd.O)O--.
[0017] The term "amino acid," comprises the residues of the natural
amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl,
Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in
D or L form, as well as unnatural amino acids (e.g. phosphoserine,
phosphothreonine, phosphotyrosine, hydroxyproline,
gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, omithine, citruline, .alpha.-methyl-alanine,
para-benzoylphenylalanine, phenylglycine, propargylglycine,
sarcosine, and tert-butylglycine). The term also comprises natural
and unnatural amino acids bearing a conventional amino protecting
group (e.g. acetyl or benzyloxycarbonyl), as well as natural and
unnatural amino acids protected at the carboxy terminus (e.g. as a
(C.sub.1-C.sub.6)alkyl, phenyl or benzyl ester or amide; or as an
.alpha.-methylbenzyl amide). Other suitable amino and carboxy
protecting groups are known to those skilled in the art (See for
example, Greene, T. W.; Wutz, P. G. M. "Protecting Groups In
Organic Synthesis" second edition, 1991, New York, John Wiley &
sons, Inc., and references cited therein).
[0018] The term "host" includes animals and plants.
[0019] The term "peptide" describes a sequence of 2 to 35 amino
acids (e.g. as defined hereinabove) or peptidyl residues. The
sequence may be linear or cyclic. For example, a cyclic peptide can
be prepared or may result from the formation of disulfide bridges
between two cysteine residues in a sequence. Preferably a peptide
comprises 3 to 20, or 5 to 15 amino acids. Peptide derivatives can
be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371;
and 4,684,620, or as described in the Examples hereinbelow. Peptide
sequences specifically recited herein are written with the amino
terminus on the left and the carboxy terminus on the right.
Polymers of the Invention
[0020] The biocompatible, biodegradable polyanhydrides of the
invention are useful in a variety of applications where delivery of
a biologically active compound is desired. Examples of such
applications include, but are not limited to, medical, dental and
cosmetic uses.
[0021] The polymers of the invention may be prepared in accordance
with methods commonly employed in the field of synthetic polymers
to produce a variety of useful products with valuable physical and
chemical properties. The polymers can be readily processed into
pastes or solvent cast to yield films, coatings, microspheres and
fibers with different geometric shapes for design of various
medical implants, and may also be processed by compression molding
and extrusion.
[0022] Medical implant applications include the use of
polyanhydrides to form shaped articles such as vascular grafts and
stents, bone plates, sutures, implantable sensors, implantable drug
delivery devices, stents for tissue regeneration, and other
articles that decompose into non-toxic components within a known
time period.
[0023] Polymers of the present invention can also be incorporated
into oral formulations and into products such as skin moisturizers,
cleansers, pads, plasters, lotions, creams, gels, ointments,
solutions, shampoos, tanning products and lipsticks for topical
application.
[0024] Although the invention provides homopolymers that are
prepared from suitably functionalized biologically active
compounds, Applicant has discovered that the mechanical and
hydrolytic properties of polymers comprising one or more
biologically active compounds can be controlled by modifying the
linking group (R.sup.2) in the polymer backbone.
[0025] Preferably, the polymers of the invention comprise backbones
wherein biologically active compounds and linker groups (R.sup.2)
are bonded together through ester linkages, thioester linkages,
amide linkages, or a mixture thereof. Due to the presence of the
ester, thioester, and/or amide linkages, the polymers can be
hydrolyzed under physiological conditions to provide the
biologically active compounds. Thus, the polymers of the invention
can be particularly useful as a controlled release source for a
biologically active compound, or as a medium for the localized
delivery of a biologically active compound to a selected site. For
example, the polymers of the invention can be used for the
localized delivery of a therapeutic agent to a selected site within
the body of a human patient (i.e. within or near a tumor), where
the degradation of the polymer provides localized, controlled,
release of the therapeutic agent.
[0026] Biodegradable, biocompatible polyamydrides which serve as
linkers for low molecular weight drug molecules have now been
developed. Compositions comprising low molecular weight drugs
linked via polyanhydrides of the present invention are useful in a
variety of applications wherein delivery of the drugs in a
controlled fashion is desired. For purposes of the present
invention, by "low molecular weight drug" it is meant to include
any compound with one carboxylic acid group and at least one amine,
thiol, alcohol or phenol group within its structure, wherein the
compound has a demonstrated pharmacological activity and a
molecular weight of approximately 1000 daltons or less.
[0027] In one embodiment, polyanhydrides of the present invention
are prepared by the method described in Conix, Macromol. Synth., 2,
95-99 (1996). In this method, dicarboxylic acids are acetylated in
an excess of acetic anhydride at reflux temperatures followed by
melt condensation of the resulting carboxylic acid anhydride at
180.degree. C. for 2-3 hours. The resulting polymers are isolated
by precipitation into diethylether from methylene chloride. The
described process is essentially the conventional method for
polymerizing bisaromatic dicarboxylic acid anhydrides into aromatic
polyanhydrides.
[0028] Polyanhydrides of the present invention have average
molecular weights ranging between about 1500 daltons up to about
100,000 daltons, up to about 100,000 daltons, calculated by Gel
Permeation Chromatography (GPC) relative to narrow molecular weight
polystyrene standards. Preferred aromatic polyanhydrides have
average molecular weights of about 1500 daltons, up to about 50,000
daltons calculated by Gel Permeation Chromatography (GPC) relative
to narrow molecular weight polystyrene standards. Preferred
azo-polymers have average molecular weights of about 1500 daltons,
up to about 35,000 daltons.
Biologically Active Compounds
[0029] It has been found that the polyanhydride compounds of the
invention can serve as a polymer backbone for degradable polymeric
drug delivery systems for a multitude of low molecular weight
drugs. Drugs which can be linked into degradable copolymers via the
polyanhydrides have the following characteristics. The drugs have a
relatively low molecular weights of approximately 1,000 daltons or
less. The drug must contain within its molecular structure one
carboxylic acid group. In addition, the drug must contain at least
one carboxylic acid (--COOH), amine (--NHR), thiol (--SH), alcohol
(--OH) or phenol (--Ph--OH) group within its structure.
[0030] The term "biologically active compound" includes therapeutic
agents that provide a therapeutically desirable effect when
administered to an animal (e.g., a mammal, such as a human).
Therapeutic agents that can be incorporated into the polymers of
the invention include suitably functionalized analgesics,
anesthetics, anti-Parkinson's agents, anti-infectives, antiacne
agents, antibiotics, anticholinergics, anticoagulants,
anticonvulsants, antidiabetic agents, antidyskinetics, antifibrotic
agents, antifibrotics, antifungal agents, antiglaucoma agents,
anti-inflammatory agents, antineoplastics, antiosteoporotics,
antipagetics, antisporatics, antipyretics,
antiseptics/disinfectants, antithrombotics, bone resorption
inhibitors, calcium regulators, cardioprotective agents,
cardiovascular agents, central nervous system stimulants,
cholinesterase inhibitors, contraceptives, deodorants, dopamine
receptor agonists, erectile dysfunction agents, fertility agents,
gastrointestinal agents, gout agents, hormones, hypnotics,
immunomodulators, immunosuppressives, keratolytics, migraine
agents, motion sickness agents, muscle relaxants, nucleoside
analogs, obesity agents, ophthalmic agents, osteoporosis agents,
parasympatholytics, parasympathomimetics, prostaglandins,
psychotherapeutic agents, respiratory agents, sclerosing agents,
sedatives, skin and mucous membrane agents, smoking cessation
agents, sympatholytics, synthetic antibacterial agents, ultraviolet
screening agents, urinary tract agents, vaginal agents, and
vasodilators (see Physicians' Desk Reference, 55 ed., 2001, Medical
Economics Company, Inc., Montvale, N.J., pages 201-202).
[0031] In a preferred embodiment, suitable examples of low
molecular weight drugs with the required functional groups within
their structure can be found in almost all classes of drugs
including, but not limited to, analgesics, anesthetics, antiacne
agents, antibiotics, synthetic antibacterial agents,
anticholinergics, anticoagulants, antidyskinetics, antifibrotics,
antifungal agents, antiglaucoma agents, anti-inflammatory agents,
antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson's
agents, antisporatics, antipyretics, antiseptics/disinfectants,
antithrombotics, bone resorption inhibitors, calcium regulators,
keratolytics, sclerosing agents and ultraviolet screening
agents.
[0032] The biologically active compounds can also comprise other
functional groups (including hydroxy groups, mercapto groups, amine
groups, and carboxylic acids, as well as others) that can be used
to modify the properties of the polymer (e.g. for branching, for
cross linking, for appending other molecules (e.g. another
biologically active compound) to the polymer, for changing the
solubility of the polymer, or for effecting the biodistribution of
the polymer). Lists of therapeutic agents can be found, for
example, in: Physicians' Desk Reference, 55 ed., 2001, Medical
Economics Company, Inc., Montvale, N.J.; USPN Dictionary of USAN
and International Drug Names, 2000, The United States Pharmacopeial
Convention, Inc., Rockville, Md.; and The Merck Index, 12 ed.,
1996, Merck & Co., Inc., Whitehouse Station, N.J. One skilled
in the art can readily select therapeutic agents that possess the
necessary functional groups for incorporation into the polymers of
the invention from these lists.
[0033] Examples of anti-bacterial compounds suitable for use in the
present invention include, but are not limited to,
4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin,
ampicillin, apalcillin, apicycline, aspoxicillin, aztreonam,
bambermycin(s), biapenem, carbenicillin, carumonam, cefadroxil,
cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir,
cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefininox,
cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime,
cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide,
cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram,
ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin,
cephalosporin C, cephradine, ciprofloxacin, clinafloxacin,
cyclacillin, enoxacin, epicillin, flomoxef, grepafloxacin,
hetacillin, imipenem, lomefloxacin, lymecycline, meropenem,
moxalactam, mupirocin, nadifloxacin, norfloxacin, panipenem,
pazufloxacin, penicillin N, pipemidic acid, quinacillin, ritipenem,
salazosulfadimidine, sparfloxacin, succisulfone, sulfachrysoidine,
sulfaloxic acid, teicoplanin, temafloxacin, temocillin,
ticarcillin, tigemonam, tosufloxacin, trovafloxacin, vancomycin,
and the like.
[0034] Examples of anti-fungal compounds suitable for use in the
present invention include, but are not limited to amphotericin B,
azaserine, candicidin(s), lucensomycin, natanycin, nystatin, and
the like.
[0035] Examples of anti-neoplastic compounds suitable for use in
the present invention include, but are not limited to
6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A,
denopterin, edatrexate, eflornithine, melphalan, methotrexate,
mycophenolic acid, podophyllinic acid 2-ethylhydrazide,
pteropterin, streptonigrin, Tomudex.RTM.
(N-((5-(((1,4-Dihydro-2-methyl4-oxo-6-quinazolinyl)methyl)methylamino)-2--
thienyl)carbonyl)-L-glutamic acid), ubenimex, and the like.
[0036] Examples of anti-thrombotic compounds for use in the present
invention include, but are not limited to, argatroban, iloprost,
lamifiban, taprostene, tirofiban and the like.
[0037] Examples of immunosuppressive compounds suitable for use in
the present invention include, but are not limited to bucillamine,
mycophenolic acid, procodazole, romurtide, ubenimex and the
like.
[0038] Examples of NSAID compounds suitable for use in the present
invention include, but are not limited to 3-amino-4-hydroxybutyric
acid, aceclofenac, alminoprofen, bromfenac, bumadizon, caiprofen,
diclofenac, diflunisal, enfenamic acid, etodolac, fendosal,
flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid,
mesalamine, niflumic acid, olsalazine oxaceprol,
S-adenosylmethionine, salicylic acid, salsalate, sulfasalazine,
tolfenanic acid, and the like.
Linking Group "R.sup.2"
[0039] The nature of the linking group "R.sup.2" in a polymer of
the invention is not critical provided the polymer of the invention
possesses acceptable mechanical properties and release kinetics for
the selected therapeutic application. The linking group R.sup.2 is
typically a divalent organic radical having a molecular weight of
from about 25 daltons to about 400 daltons. More preferably,
R.sup.2 has a molecular weight of from about 40 daltons to about
200 daltons.
[0040] The linking group R.sup.2 typically has a length of from
about 5 angstroms to about 100 angstroms using standard bond
lengths and angles. More preferably, the linking group L has a
length of from about 10 angstroms to about 50 angstroms.
[0041] The linking group may be biologically inactive, or may
itself possess biological activity. The linking group can also
comprise other functional groups (including hydroxy groups,
mercapto groups, amine groups, carboxylic acids, as well as others)
that can be used to modify the properties of the polymer (e.g. for
branching, for cross linking, for appending other molecules (e.g.
another biologically active compound) to the polymer, for changing
the solubility of the polymer, or for effecting the biodistribution
of the polymer).
Specific and Preferred Values
[0042] Specific and preferred values listed herein for radicals,
substituents, groups, and ranges, are for illustration only; they
do not exclude other defined values or other values within defined
ranges for the radicals and substituents.
[0043] Specifically, (C.sub.1-C.sub.6)alkyl can be methyl, ethyl,
propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl,
or hexyl; (C.sub.3-C.sub.6)cycloalkyl can be cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl;
(C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkyl can be
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,
2-cyclopentylethyl, or 2-cyclohexylethyl; (C.sub.1-C.sub.6)alkoxy
can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy,
sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
(C.sub.1-C.sub.6)alkanoyl can be acetyl, propanoyl or butanoyl;
(C.sub.1-C.sub.6)alkoxycarbonyl can be methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl;
(C.sub.1-C.sub.6)alkylthio can be methylthio, ethylthio,
propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or
hexylthio; (C.sub.2-C.sub.6)alkanoyloxy can be acetoxy,
propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or
hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and
heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl,
isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl,
tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its
N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its
N-oxide).
[0044] A specific biologically active compound that can be
incorporated into the polymers of the invention is
3-amino-4-hydroxybutyric acid, 6-diazo-5-oxo-L-norleucine,
aceclofenac, acediasulfone, alminoprofen, amfenac, amoxicillin,
amphotericin B, ampicillin, apalcillin, apicycline, aspoxicillin,
azaserine, aztreonam, bambermycin(s), biapenem, bromfenac,
bucillamine, bumadizon, candicidin(s), carbenicillin, carprofen,
carumonam, carzinophillin A, cefadroxil, cefamandole, cefatrizine,
cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime,
cefetamet, cefixime, cefmenoxime, cefminox, cefodizime, cefonicid,
cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam,
cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil,
cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone,
cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine,
ciprofloxacin, clinafloxacin, cyclacillin, denopterin, diclofenac,
edatrexate, eflornithine, enfenamic acid, enoxacin, epicillin,
etodolac, flomoxef, flufenamic acid, grepafloxacin, hetacillin,
imipenem, lomefloxacin, lucensomycin, lymecycline, meclofenarnic
acid, mefenamic acid, melphalan, meropenem, methotrexate,
moxalactam, mupirocin, mycophenolic acid, mycophenolic acid,
nadifloxacin, natamycin, niflumic acid, norfloxacin, nystatin,
oxaceprol, panipenem, pazufloxacin, penicillin N, pipemidic acid,
podophyllinic acid 2-ethylhydrazide, procodazole, pteropterin,
quinacillin, ritipenem, romurtide, S-adenosylmethionine,
salazosulfadimidine, sparfloxacin, streptonigrin, succisulfone,
sulfachrysoidine, sulfaloxic acid, teicoplanin, temafloxacin,
temocillin, ticarcillin, tigemonam, tolfenarnic acid, Tomudex.RTM.
(N-((5-(((1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-
-thienyl)carbonyl)-L-glutamic acid), tosufloxacin, trovafloxacin,
ubenimex or vancomycin.
[0045] Another specific value for R.sup.2 is a divalent, branched
or unbranched, saturated or unsaturated, hydrocarbon chain, having
from 1 to 20 carbon atoms, wherein the chain is optionally
substituted on carbon with one or more (e.g. 1, 2, 3, or 4)
substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkanoyloxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkylthio, azido,
cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy,
heteroaryl, and heteroaryloxy.
[0046] Another specific value for R.sup.2 is an amino acid.
[0047] Another specific value for R.sup.2 is a peptide
[0048] Another specific value for R.sup.2 is a divalent, branched
or unbranched, saturated or unsaturated, hydrocarbon chain, having
from 1 to 20 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4)
of the carbon atoms is optionally replaced by (--O--) or
(--NR--).
[0049] A more specific value for R.sup.2 is a divalent, branched or
unbranched, saturated or unsaturated, hydrocarbon chain, having
from 3 to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4)
of the carbon atoms is optionally replaced by (--O--) or (--NR--),
and wherein the chain is optionally substituted on carbon with one
or more (e.g. 1, 2, 3, or 4) substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkanoyloxy,
(C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkylthio, azido,
cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy,
heteroaryl, and heteroaryloxy.
[0050] Another more specific value for R.sup.2 is a divalent,
branched or unbranched, saturated or unsaturated, hydrocarbon
chain, having from 3 to 15 carbon atoms, wherein one or more (e.g.
1, 2, 3, or 4) of the carbon atoms is optionally replaced by
(--O--) or (--NR--).
[0051] Another more specific value for R.sup.2 is a divalent,
branched or unbranched, saturated or unsaturated, hydrocarbon
chain, having from 3 to 15 carbon atoms.
[0052] Another more specific value for R.sup.2 is a divalent,
branched or unbranched, hydrocarbon chain, having from 3 to 15
carbon atoms.
[0053] A preferred value for R.sup.2 is a divalent, branched or
unbranched, hydrocarbon chain, having from 6 to 10 carbon
atoms.
[0054] A more preferred value for R.sup.2 is a divalent hydrocarbon
chain having 7, 8, or 9 carbon atoms.
[0055] A most preferred value for R.sup.2 is a divalent hydrocarbon
chain having 8 carbon atoms.
[0056] A specific polyanhydride linker of the present invention
comprises the structure of formula (I): ##STR1## wherein R.sup.1 is
selected from the group consisting of alkyls, cycloalkyls,
substituted alkyls, aromatics, substituted aromatics, lactams, and
lactones; X is selected from the group consisting of amides,
thioamides, esters and thioesters; and R.sup.2 is an alkyl
represented by --(CH.sub.2).sub.n-- wherein n is from 1 to 20.
[0057] A specific polyanhydride polymer of the present invention
includes biologically active compounds provided that the
biologically active compound is not an alpha-hydroxy carboxylic
acid.
[0058] A specific polyanhydride polymer of the present invention
includes biologically active compounds provided that the
biologically active compound is not an ortho-hydroxy aryl
carboxylic acid.
[0059] Such a polymer, wherein each R.sup.1 is a group that will
provide a different biologically active compound upon hydrolysis of
the polymer, are particularly useful for the administration of a
combination of two therapeutic agents to an animal.
[0060] A preferred group of polyanhydride compounds includes
polymers that are comprised of compounds containing at least one
free carboxylic acid group, and at least one alcohol group,
carboxylic acid or amine group available for reactions which can
self-polymerize or co-polymerize with carboxylic acid, alcohol or
amine groups or bis(acyl) chlorides.
Formulations
[0061] The polymers of the invention can be formulated as
pharmaceutical compositions and administered to a mammalian host,
such as a human patient in a variety of forms adapted to the chosen
route of administration, i.e., orally, rectally, or parenterally,
by intravenous, intramuscular, intraperitoneal, intraspinal,
intracranial, topical, ocular or subcutaneous routes. For some
routes of administration, the polymer can conveniently be
formulated as micronized particles.
[0062] Thus, the present compounds may be systemically
administered, e.g., orally, in combination with a pharmaceutically
acceptable vehicle such as an inert diluent or an assimilable
edible carrier. They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated
directly with the food of the patient's diet. For oral therapeutic
administration, the active compound may be combined with one or
more excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such compositions and preparations preferably contain
at least 0.1% of polymer by weight. The percentage of the
compositions and preparations may, of course, be varied and may
conveniently be between about 2 to about 80% of the weight and
preferably 2 to about 60% of a given unit dosage form. The amount
of polymer in such therapeutically useful compositions is such that
an effective dosage level will be obtained.
[0063] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0064] The polymer may also be administered intravenously,
intraspinal, intracranial, or intraperitoneally by infusion or
injection. Solutions of the polymer can be prepared a suitable
solvent such as an alcohol, optionally mixed with a nontoxic
surfactant. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, triacetin, and mixtures thereof and in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
[0065] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile solutions or dispersions or sterile
powders comprising the polymer containing the active ingredient
which are adapted for the extemporaneous preparation of sterile
injectable or infusible solutions or dispersions, optionally
encapsulated in liposomes. In all cases, the ultimate dosage form
should be sterile, fluid and stable under the conditions of
manufacture and storage. The liquid carrier or vehicle can be a
solvent or liquid dispersion medium comprising, for example,
ethanol, a polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycols, and the like), vegetable oils, nontoxic
glyceryl esters, and suitable mixtures thereof. The proper fluidity
can be maintained, for example, by the formation of liposomes, by
the maintenance of the required particle size in the case of
dispersions or by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0066] Sterile injectable solutions are prepared by incorporating
the polymer in the required amount in the appropriate solvent with
various of the other ingredients enumerated above, as required,
followed by filter sterilization. In the case of sterile powders
for the preparation of sterile injectable solutions, the preferred
methods of preparation are vacuum drying and the freeze drying
techniques, which yield a powder of the active ingredient plus any
additional desired ingredient present in the previously
sterile-filtered solutions.
[0067] For topical administration, the present polymers can be
applied in pure form. However, it will generally be desirable to
administer them as compositions or formulations, in combination
with a dermatologically acceptable carrier, which may be a solid or
a liquid.
[0068] Useful solid carriers include finely divided solids such as
talc, clay, microcrystalline cellulose, silica, alumina and the
like. Useful liquid carriers include, alcohols or glycols or
alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0069] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts and esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0070] Examples of useful dermatological compositions which can be
used to deliver the polymers of the invention to the skin are known
to the art; for example, see Jacquet et al. (U.S. Pat. No.
4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S.
Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Dosages
[0071] Useful dosages of the polymers can be determined by
comparing their in vitro activity, and in vivo activity of the
therapeutic agent in animal models. Methods for the extrapolation
of effective dosages in mice, and other animals, to humans are
known to the art; for example, see U.S. Pat. No. 4,938,949.
Additionally, useful dosages can be determined by measuring the
rate of hydrolysis for a given polymer under various physiological
conditions. The amount of a polymer required for use in treatment
will vary not only with the particular polymer selected but also
with the route of administration, the nature of the condition being
treated and the age and condition of the patient and will be
ultimately at the discretion of the attendant physician or
clinician.
[0072] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations.
Combination Therapies
[0073] The polymers of the invention are also useful for
administering a combination of therapeutic agents to an animal.
Such a combination therapy can be carried out in the following
ways: 1) a second therapeutic agent can be dispersed within the
polymer matrix of a polymer of the invention, and can be released
upon degradation of the polymer; 2) a second therapeutic agent can
be appended to a polymer of the invention (i.e. not in the backbone
of the polymer) with bonds that hydrolyze to release the second
therapeutic agent under physiological conditions; 3) the polymer of
the invention can incorporate two therapeutic agents into the
polymer backbone (e.g. a polymer comprising one or more units of
formula (I)) or 4) two polymers of the invention, each with a
different therapeutic agent can be administered together (or within
a short period of time).
[0074] Thus, the invention also provides a pharmaceutical
composition comprising a polymer of the invention and a second
therapeutic agent that is dispersed within the polymer matrix of a
polymer of the invention. The invention also provides a
pharmaceutical composition comprising a polymer of the invention
having a second therapeutic agent appended to the polymer (e.g.
with bonds that will hydrolyze to release the second therapeutic
agent under physiological conditions).
[0075] The polymers of the invention can also be administered in
combination with other therapeutic agents that are effective to
treat a given condition to provide a combination therapy. Thus, the
invention also provides a method for treating a disease in a mammal
comprising administering an effective amount of a combination of a
polymer of the invention and another therapeutic agent. The
invention also provides a pharmaceutical composition comprising a
polymer of the invention, another therapeutic agent, and a
pharmaceutically acceptable carrier.
PREPARATION OF POLYMERS OF THE INVENTION
[0076] Processes for preparing polyanhydride polymers of the
invention are provided as further embodiments of the invention and
are illustrated by the following procedures in which the meanings
of the generic radicals are as given above unless otherwise
qualified.
[0077] For example, a polymer of the invention can be prepared, as
illustrated in Scheme I, from a biologically active compound of
formula (Z.sub.1-R.sup.1-Z.sub.2) and a linker precursor of formula
Y.sub.1--R.sup.2--Y.sub.2, wherein one of Z.sub.1, and Z.sub.2 is a
carboxylic acid group and the other groups Y.sub.1, Y.sub.2,
Z.sub.1, and Z.sub.2 are independently selected from the values in
the table below. ##STR2## The biologically active compound and the
linker precursor can be polymerized using well known synthetic
techniques (e.g. by condensation) to provide a polymer of the
invention (I) wherein each X is independently an ester linkage, a
thioester linkage, or an amide linkage.
[0078] Depending on the reactive functional group (Z.sub.1, and
Z.sub.2) of the biologically active compound, a corresponding
functional group (Y.sub.1 or Y.sub.2) can be selected from the
following table, to provide an ester linkage, thioester linkage, or
amide linkage in the polymer backbone. TABLE-US-00001 Functional
Group On Biologically active Functional Group On compound Linker
Precursor Resulting Linkage In (Z.sub.1 or Z.sub.2) (Y.sub.1 or
Y.sub.2) Polymer --COOH --OH Ester --COOH --NHR Amide --COOH --SH
Thioester --OH --COOH Ester --SH --COOH Thioester --NHR --COOH
Amide
[0079] As will be clear to one skilled in the art, suitable
protecting groups can be used during the reaction illustrated in
Scheme I (and in the reactions illustrated in Schemes II-XV below).
For example, other functional groups present in the biologically
active compound or the linker precursor can be protected during
polymerization, and the protecting groups can subsequently be
removed to provide the polymer of the invention. Suitable
protecting groups and methods for their incorporation and removal
are well known in the art (see for example Greene, T. W.; Wutz, P.
G. M. "Protecting Groups In Organic Synthesis" second edition,
1991, New York, John Wiley & sons, Inc.).
[0080] Additionally, when a carboxylic acid is reacted with a
hydroxy group, a mercapto group, or an amine group to provide an
ester linkage, thioester linkage, or an amide linkage, the
carboxylic acid can be activated prior to the reaction, for
example, by formation of the corresponding acid chloride. Numerous
methods for activating carboxylic acids, and for preparing ester
linkages, thioester linkages, and amide linkages, are known in the
art (see for example Advanced Organic Chemistry: Reaction
Mechanisms and Structure, 4 ed., Jerry March, John Wiley &
Sons, pages 419-437 and 1281).
[0081] A polyanhydride/polyester of the invention can be formed
from a hydroxy/carboxylic acid containing compound of formula
(HOOC--R.sup.1--OH) and from a linker precursor of formula
HOOC--R.sup.2--COOH as illustrated in Scheme 2. ##STR3##
[0082] A polyanhydride/polyamide of the invention can be prepared
using a procedure similar to that illustrated in Scheme 2 by
replacing the biologically active hydroxy/carboxylic acid compound
in Scheme 2 with a suitable biologically active amine/carboxylic
acid compound.
[0083] A polyanhydride/polythioester of the invention can be
prepared using a procedure similar to that illustrated in Scheme 2
by replacing the biologically active hydroxy/carboxylic acid
compound in Scheme 2 with a suitable mercapto/carboxylic acid
compound.
[0084] Alternatively, a polyanhydride/polyester of the invention
can be formed from a dicarboxylic acid containing compound of
formula HOOC--R.sup.1--COOH and from a diol linker precursor of
formula (HO--R.sup.2--OH) as illustrated in Scheme 3. ##STR4##
[0085] A polyanhydride/polyamide of the invention can be prepared
using a procedure similar to that illustrated in Scheme 2 by
replacing the diol linker compound in Scheme 3 with a suitable
diamine compound.
[0086] A polyanhydride/polythioester of the invention can be
prepared using a procedure similar to that illustrated in Scheme 2
by replacing the diol linker compound in Scheme 3 with a suitable
dimercapto compound.
[0087] Other polymers of the invention can be formed using the
reactions described herein, using starting materials that have
suitable groups to prepare the desired polymer.
[0088] Polymeric drug delivery systems of the present invention can
be characterized by proton nuclear magnetic resonance (NMR)
spectroscopy, infrared (IR) spectroscopy, gel permeation
chromatography (GPC), high performance liquid chromatography
(HPLC), differential scanning calorimetry (DSC), and thermal
gravimetric analysis (TGA). For infrared spectroscopy, samples are
prepared by solvent casting on NaCl plates. .sup.1H and .sup.13C
NMR spectroscopy is obtained in solutions of CDCl.sub.3 or
DMSO-d.sub.6 with solvent as the internal reference.
[0089] GPC is performed to determine molecular weight and
polydispersity. In this method, samples are dissolved in
tetrahydrofuran and eluted through a mixed bed column (PE PL gel, 5
.mu.m mixed bed) at a flow rate of 0.5 mL/minute. It is preferred
that the samples (about 5 mg/mL) be dissolved into the
tetrahydrofuran and filtered using 0.5 .mu.m PTFE syringe filters
prior to column injection. Molecular weights are determined
relative to narrow molecular weight polystyrene standards
(Polysciences, Inc.).
[0090] Thermal analysis can also be performed using a system such
as the Perkin-Elmer system consisting of a TGA 7 thermal
gravimetric analyzer equipped with PE AD-4 autobalance and Pyris 1
DSC analyzer. In this system, Pyris software is used to carry out
data analysis on a DEC Venturis 5100 computer. For DSC, an average
sample weight of 5-10 mg is heated at 10.degree. C./minute at a 30
psi flow of N.sub.2. For TGA, an average sample weight of 10 mg is
heated at 20.degree. C./minute under a 8 psi flow of N.sub.2.
Sessile drop contact angle measurements are obtained with an NRL
Goniometer (Rame-hart) using distilled water. Solutions of polymer
in methylene chloride (10% wt/volume) are spun-coated onto glass
slips, at 5,000 rpm for 30 seconds.
[0091] Degradation and drug release profiles of the polymer drug
delivery systems of the present invention can also be determined
routinely. For these experiments, the polymers are processed into
either films, pellets, microspheres, nanospheres or fibers
(depending on their properties). After processing, the materials
are be characterized to determine if any physicochemical changes
have occurred during processing. Uniform processed, weighed, and
characterized samples are then degraded in acidic, neutral, and
basic phosphate buffer (conditions chosen to simulate physiological
range) in triplicate. Periodically the buffer is removed and
replaced with fresh media to simulate sink conditions. The spent
buffer is analyzed by TPLC to determine the cumulative release of
the drug. At defined time periods, samples are removed from the
buffer and superficially dried (blotted). They are then weighed to
determine the water uptake. At this point, the contact angle
(hydrated) is also measured to determine changes in hydrophobicity
during degradation. The samples are then thoroughly dried under
vacuum and weighed to determine their mass loss. Contact angles
(dry) are measured again to determine the hydrophobicity of the dry
material, and how it compares to that of the hydrated material. By
plotting cumulative release of the degradation products over time,
the degradation kinetics can be defined. Wet and dry polymer
weights over time indicate if the material is bulk or surface
eroding. If there is an increase in water uptake, it can be
determined that the polymer is bulk eroding, whereas if there is
little or no water uptake the material is considered
surface-eroding. By plotting the changes in dry weight versus time,
the mass lost by the polymer as it erodes can be determined. This
information will give additional insight into how the material is
degrading. Changes in molecular weight over time are also examined
to bolster the degradation results.
[0092] Polyanhydride compounds of the present invention can be
isolated by known methods commonly employed in the field of
synthetic polymers and used to produce a variety of drug delivery
products with valuable physical and chemical properties. Polymeric
drug delivery systems comprising the polyanhydride compounds of the
invention can be readily processed into pastes or solvent cast to
yield films, coatings, microspheres and fibers with different
geometric shapes for design of various medical implants, and may
also be processed by compression molding and extrusion. Medical
implant applications include the use of polyanhydrides to form
shaped articles such as vascular grafts and stents, bone plates,
sutures, implantable sensors, implantable drug delivery devices,
stents for tissue regeneration, and other articles that decompose
harmlessly while delivering a selected low molecular weight drug at
the site of implantation within a known time period. Drugs linked
via these polyanhydrides of the present invention can also be
incorporated into oral formulations and into products such as skin
moisturizers, cleansers, pads, plasters, lotions, creams, gels,
ointments, solutions, shampoos, tanning products and lipsticks for
topical application.
[0093] The quantity of polymeric drug to be administered to a host
which is effective for the selected use can be readily determined
by those of ordinary skill in the art without undue
experimentation. The quantity essentially corresponds
stoichiometrically to the amount of drug which is known to produce
an effective treatment for the selected use.
[0094] The present invention also relates to methods of using
compositions comprising these low molecular weight drugs linked via
the polyanhydrides in any application wherein delivery of the low
molecular weight drug is desired. Route of delivery is selected in
accordance with drug being administered and the condition being
treated. For example, compositions of the present invention
comprising a polyanhydride of Formula (I) linking a low molecular
weight drug such as, for example, amoxicillin or cephalexin can be
administered orally or topically to treat bacterial infections.
Similarly, compositions of the present invention comprising a
polyanhydride of Formula (I) linking a low molecular weight drug
such as carbidopa or levodopa can be administered orally to
patients suffering from Parkinson's disease to alleviate the
symptoms of this disease.
[0095] In one embodiment of the present invention, the
polyanhydride of Formula (I) is used to link two different low
molecular weight drugs into a single polymeric drug delivery
system. For example, the polyanhydride of Formula (I) can be used
to link a drug molecule of carbidopa with a drug molecule of
levodopa so that both drugs can be delivered simultaneously via a
single polymeric drug delivery system.
[0096] Another embodiment of the present invention includes a
method of linking low molecular weight drug molecules containing
within their structure one carboxylic acid group and at least one
amine, thiol, alcohol or phenol group into polymeric drug delivery
systems comprising; (a) protecting the carboxylic acid group of the
lowmolecular weight drug molecules; (b) adding to the low molecular
weight drug molecules a chlorinated polyanhydride linker of formula
(IV) ##STR5## wherein n is from 1 to 20, so that drug molecules
displace the chlorinegroups of the polyanhydride linker of Formula
(IV) and bind to the linker via their amine, thiol, alcohol or
phenol group; and (c) exposing the linked drug molecules to heat or
vacuum so that the protecting groups are removed. In a preferred
compound of formula (IV) n is from 6-8.
[0097] The linking of a drug in a anhydride polymer of the present
invention is shown in the following schemes. The carboxylic acid
group of the low molecular weight drug molecule is protected,
preferably via acetylation. The protected drug molecules are then
exposed to the linker of the linker of formula (IV), optionally in
an activated form, e.g., the chlorinated form and bind to the
linker (R.sup.2) via the amine, thiol, alcohol or phenol groups of
the drug molecules. The drug and linker are then exposed to heat
and/or vacuum to remove the protecting groups, thereby resulting in
a polymeric drug delivery system. The polymers of the invention
will have from about 10 to about 30 repeating units.
[0098] The linkage of low molecular weight drugs meeting the
structural requirements of a single carboxylic acid group and at
least one amine, thiol, alcohol or phenol group within its
structure are exemplified in the following Examples 1 and 2.
EXAMPLE 1
Synthesis of Amoxicillin Polymer
[0099] The linkage of amoxicillin in a polyanhydride of the present
invention is shown in the scheme 1. The carboxylic acid group of
the low molecular weight drug molecule is protected, preferably via
acetylation. The protected drug molecules are then exposed to a
chlorinated form of the linker of formula (IV), wherein n is 8. The
amine groups from the drug molecules displace the chlorine groups
of the diacyl halide Formula (IV) and bind to the linker(R.sup.2)
via the amine, groups of the drug molecules. The linked drug is
exposed to heat and/or vacuum to remove the protecting groups,
thereby resulting in a polymeric drug delivery system. ##STR6##
EXAMPLE 2
Synthesis of Cephalexin Polymer
[0100] A cephalexin polymer is prepared as depicted in scheme 2.
The carboxylic acid group of cephalexin is first protected, for
example with a benzylic group. The drug is then linked to sebacoyl
chloride (formula (IV) where n is 8). Following this linkage, the
protecting groups are removed to produce carboxylic acids which are
then acetylated to produce monomer. The monomer is polymerized as a
melt. ##STR7## ##STR8##
EXAMPLE 3
[0101] Other polymeric drug delivery systems can be prepared in
accordance with this method via the polyanhydride linker of Formula
(I) of the present invention include, but are certainly not limited
to, a carbidopa delivery system, a levodopa delivery system and an
amtenac delivery system. Homopolymers of the carbidopa and levodopa
drug delivery systems are depicted in Formulas (V) and (VI),
respectively ##STR9##
[0102] While these structures depict homopolymers, copolymers of
such drugs can also be prepared routinely based upon the teachings
provided herein. Further, polymeric drug delivery systems
comprising the polyanhydride of Formula (I) and other drugs meeting
the structural requirements, namely one carboxylic acid group, at
least one amine, thiol, alcohol or phenol group, and having a
molecular weight of approximately 1000 daltons or less can also be
routinely prepared via the disclosed methods.
ACTIVITY
[0103] The ability of a polymer of the invention to produce a given
therapeutic effect can be determined using in vitro and in vivo
pharmacological models which are well known to the art.
[0104] All publications, patents, and patent documents (including
the entire contents of U.S. Provisional Patent Application No.
60/220,998, filed 27 Jul. 2000) are incorporated by reference
herein, as though individually incorporated by reference. The
invention has been described with reference to various specific and
preferred embodiments and techniques. However, it should be
understood that many variations and modifications may be made while
remaining within the spirit and scope of the invention.
* * * * *